Complement factor B inhibitors

Abstract

The present disclosure provides complement factor B inhibitors having a structure essentially as shown in general formula (I), wherein each substituent in the formula is defined as described herein. The compounds provided herein have significant complement factor B inhibitory activity and can be used to prevent and / or treat diseases or conditions mediated by complement factor B inhibitors. [Formula 1] JPEG2026502915000164.jpg5846

Description

[Technical Field]

[0001] The present invention is in the field of biomedicine, and specifically relates to complement factor B inhibitors. [Background technology]

[0002] The complement system is a part of the host's innate immune system involved in lysing foreign cells, enhancing antigen phagocytosis, agglutinating antigen-carrying substances, and attracting macrophages and neutrophils. It is an important component of the body's innate immunity against infections by foreign pathogens, bacteria, and parasites, as well as a crucial component linking innate and adaptive immunity. Complement is composed of Ife plasma proteins, including soluble proteins, membrane-bound proteins, and complement receptors. It is produced primarily by membrane proteins expressed on the liver and cell surfaces and acts in plasma, tissues, or intracellularly. The complement system is a key regulator of inflammatory responses and tissue damage, and is composed of more than 20 serum proteins and cell surface proteins. The complement system contains intrinsic complement components and multiple regulatory proteins. Intrinsic complement components include C1–C9, with C3 being the most abundant. The complement system is activated via three main pathways: the classical pathway (CP), the lectin pathway (LP), and the alternative pathway (AP).

[0003] Under normal physiological conditions in healthy individuals, the AP pathway remains activated at a low level, allowing for easy monitoring of the invasion of foreign pathogens. Complement proteins are distributed on the surface of apoptotic cells, and complement activation is tightly regulated to eliminate only apoptotic cells without further activating other innate or adaptive immune responses. Upon infection with a foreign pathogen, the complement system is fully activated, triggering inflammatory, regulatory, or phagocytic responses to destroy the pathogen and ultimately activating the adaptive immune response. Both understimulation and overstimulation of complement are harmful to humans and are associated with increased susceptibility to infectious and non-infectious diseases. Complement dysfunction or overactivation is associated with certain autoimmune, inflammatory, and neurodegenerative diseases, as well as ischemia-reperfusion injury and cancer. For example, activation of the alternative pathway of the complement cascade contributes to the production of C3a and C5a (both potent allergenic toxins) and is also involved in many inflammatory diseases. Therefore, in some cases, suppressing complement pathway responses (including the alternative pathway) is expected.

[0004] Complement factor B (FB) is a key protein involved in AP activation, and inhibiting FB activity can prevent activation of the AP pathway without inhibiting the CP or LP pathways, thereby avoiding the increased risk of infection caused by inhibition of the complement system. Therefore, the search for novel and effective small molecule inhibitors of complement factor B is an important direction in current research into therapeutic drugs for various diseases caused by complement abnormalities. Summary of the Invention [Problem to be solved by the invention]

[0005] An object of the present invention is to provide a novel complement factor B inhibitor compound, an isomer thereof or a pharmaceutically acceptable salt thereof. [Means for solving the problem]

[0006] In an embodiment of the present invention, the present invention provides a compound represented by general formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of general formula (I) is as follows: [ka]

[0007] (where X is CH2, NH, S, O or [ka] is selected from Y and Z are each independently selected from CH or N; when X is CH2, Z is N; R 1 is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, or C3-C6 heterocycloalkyl, wherein said C1-C6 alkyl or C3-C6 cycloalkyl is optionally substituted with halogen, oxo, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, or C3-C6 halocycloalkyl; R 2 is hydrogen or R 1 and R 2 taken together with the atom to which they are attached form a C10-C15 heterocyclyl, said heterocyclyl being optionally substituted with halogen; R 3 is selected from C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted with deuterium or halogen.

[0008] In a preferred embodiment of the present invention, the compound represented by general formula (I), its isomer, or a pharmaceutically acceptable salt thereof is further represented by general formula (II-1), (II-2), or (II-3). [ka] (where X, Y, R 1 , R 3 is as defined above, P is selected from CH, NH, S or O; R 4 is selected from hydrogen, halogen, or C1-C3 alkyl; m is 0, 1, or 2.

[0009] In a preferred embodiment of the present invention, the compound represented by general formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof is further represented by general formula (II-1-1) or (II-1-2). [ka] (where X, Y, R 1 , R 3 is as defined above.)

[0010] In a preferred embodiment of the present invention, the compound represented by general formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof is further represented by general formula (II-2-1) or (II-2-2). [ka] (where X, Y, R 1 , R 3 is as defined above.)

[0011] In a further preferred embodiment of the present invention, Y is selected from CH or N, preferably CH.

[0012] In a preferred embodiment of the present invention, Y is selected from CH.

[0013] In a preferred embodiment of the present invention, Y is selected from N.

[0014] In a preferred embodiment of the present invention, the compound represented by general formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof is further represented by general formula (III-1) or (III-2). [ka] (where X, R 1 , R 3 is as defined above.)

[0015] In a preferred embodiment of the present invention, the compound represented by general formula (I), its isomer, or a pharmaceutically acceptable salt thereof is further represented by general formula (III-1-1), (III-1-2), (III-1-3), or (III-1-4). [ka] (where X, R 1 , R 3 is as defined above.)

[0016] In a preferred embodiment of the present invention, the compound represented by general formula (I), its isomer, or a pharmaceutically acceptable salt thereof is further represented by general formula (III-2-1), (III-2-2), (III-2-3), (III-2-4), (III-2-5), (III-2-6), (III-2-7), or (III-2-8). [ka] (where X, R 1 , R 3 is as defined above.)

[0017] In a further preferred embodiment of the invention, X is NH, S, O or [ka] is selected from.

[0018] In a further preferred embodiment of the present invention, X is selected from CH2, S or O, preferably S or O.

[0019] In a preferred embodiment of the invention, X is selected from CH2.

[0020] In a preferred embodiment of the present invention, X is selected from S.

[0021] In a preferred embodiment of the present invention, X is selected from O.

[0022] In a preferred embodiment of the invention, X is selected from NH.

[0023] In a preferred embodiment of the present invention, X is [ka] is selected from.

[0024] In a preferred embodiment of the invention, Z is selected from CH or N.

[0025] In a preferred embodiment of the present invention, Z is selected from N.

[0026] In a preferred embodiment of the invention, Z is selected from CH.

[0027] In a further preferred embodiment of the present invention, R 1 is selected from C1-C3 alkyl, C1-C3 alkoxy, C3-C4 cycloalkyl, or C3-C4 heterocycloalkyl, wherein said C1-C3 alkyl or C3-C4 cycloalkyl is optionally substituted with fluorine, chlorine, bromine, iodine, oxo, C1-C3 haloalkyl, C3-C4 cycloalkyl, C3-C4 heterocycloalkyl, or C3-C4 halocycloalkyl.

[0028] In one preferred embodiment of the present invention, R 1 is selected from C1-C3 alkyl, C1-C3 alkoxy, C3-C4 cycloalkyl, or C3-C4 heterocycloalkyl, wherein said C1-C3 alkyl or C3-C4 cycloalkyl is optionally substituted with 1, 2, or 3 substituents selected from fluorine, chlorine, bromine, iodine, oxoalkyl, C1-C3 haloalkyl, C3-C4 cycloalkyl, C3-C4 heterocycloalkyl, or C3-C4 halocycloalkyl.

[0029] In one preferred embodiment of the present invention, R 1 is selected from C1-C3 alkyl, said C1-C3 alkyl being optionally substituted with 1, 2 or 3 substituents selected from fluorine, chlorine, bromine, iodine.

[0030] In one preferred embodiment of the present invention, the C1-C3 fluoroalkyl is selected from fluoromethyl, difluoromethyl or trifluoromethyl, preferably trifluoromethyl.

[0031] In one preferred embodiment of the present invention, R 1 is selected from C3-C4 cycloalkyl, said C3-C4 cycloalkyl being optionally substituted with 1, 2 or 3 substituents selected from C1-C3 fluoroalkyl.

[0032] In a further preferred embodiment of the present invention, R 1 is selected from methyl, ethyl, propyl, ethoxy, cyclobutyl or oxetane, said ethyl, propyl or cyclobutyl being optionally substituted with fluorine, oxo, trifluoromethyl, cyclopropyl, fluorocyclopropyl or oxetane.

[0033] In a further preferred embodiment of the present invention, R 1is selected from methyl, ethyl, propyl, ethoxy, cyclobutyl or oxetane, wherein said ethyl, propyl or cyclobutyl is optionally substituted with 1, 2 or 3 substituents selected from fluorine, oxo, trifluoromethyl, cyclopropyl, fluorocyclopropyl or oxetane.

[0034] In a further preferred embodiment of the present invention, R 1 is selected from methyl, ethyl or propyl, said methyl, ethyl or propyl being optionally substituted with 1, 2 or 3 fluorines.

[0035] In a further preferred embodiment of the present invention, R 1 teeth, [ka] is selected from, preferably [ka] and more preferably selected from: [ka] is selected from.

[0036] In a further preferred embodiment of the present invention, R 1 teeth, [ka] is selected from.

[0037] In a further preferred embodiment of the present invention, R 3 is selected from C1-C3 alkyl or C3-C4 cycloalkyl, wherein said C1-C3 alkyl is optionally substituted with deuterium, fluorine, chlorine, bromine or iodine.

[0038] In a further preferred embodiment of the present invention, R3 is selected from C1-C3 alkyl or C3-C4 cycloalkyl, wherein said C1-C3 alkyl is optionally substituted with 1, 2 or 3 substituents selected from deuterium, fluorine, chlorine, bromine or iodine.

[0039] In a further preferred embodiment of the present invention, R 3 is selected from methyl or cyclopropyl, said methyl being optionally substituted with deuterium or fluorine.

[0040] In a further preferred embodiment of the present invention, R 3 is selected from methyl or cyclopropyl, said methyl being optionally substituted with 1, 2 or 3 substituents selected from deuterium or fluorine.

[0041] In a further preferred embodiment of the present invention, R 3 is methyl, -CD3, [ka] -CF3 or [ka] is selected from, preferably methyl, -CD3, -CF3 or [ka] and preferably methyl.

[0042] In a further preferred embodiment of the present invention, P is selected from CH2, NH, S or O, preferably O.

[0043] In a further preferred embodiment of the present invention, R 4 is selected from fluorine, chlorine, bromine or iodine, preferably fluorine.

[0044] In a further preferred embodiment of the present invention, R 4 is selected from hydrogen.

[0045] In a further preferred embodiment of the present invention, m is 0, 1 or 2, preferably 2.

[0046] In a further preferred embodiment of the present invention, the compound, its isomer, or a pharmaceutically acceptable salt thereof has the following structure: [ka] [ka] [ka]

[0047] The present invention provides the following compounds, isomers thereof, or pharmaceutically acceptable salts thereof: [ka]

[0048] In a further preferred embodiment of the present invention, the compound, its isomer, or a pharmaceutically acceptable salt thereof has the following structure: [ka] [ka] [ka] [ka] [ka] [ka]

[0049] The present invention provides the following compounds, their isomers or pharmaceutically acceptable salts thereof: [ka]

[0050] In a further preferred embodiment of the present invention, the compound, its isomer, or a pharmaceutically acceptable salt thereof has the following structure: [ka]

[0051] In a further preferred embodiment of the invention, the compound, its isomer or a pharmaceutically acceptable salt thereof has the following structure: [ka]

[0052] In a preferred embodiment of the invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 2.06 minutes, and the specific method is as follows: Chromatography column: Lux Cellulose-4 4.6 x 50 mm, 3 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol Gradient: 10% to 50% in 2.0 minutes; 50% in 1.0 minute hold Detection wavelength: 220 nm

[0053] In a preferred embodiment of the invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 2.34 minutes, as follows: Chromatography column: Lux Cellulose-4 4.6 x 50 mm, 3 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol Gradient: 10% to 50% in 2.0 minutes; 50% in 1.0 minute hold Detection wavelength: 220 nm

[0054] In one preferred embodiment, the compound [ka] The isomers were separated by chiral SFC with a retention time of 4.90 min. The specific method is as follows: Chromatography column: DAICEL CHIRALCEL (registered trademark) OZ 4250 x 20 mm, 10 μm Mobile phase A: Supercritical CO2, Mobile phase B: Methanol (+0.1% 7.0 mol / L ammonia methanol) Flow rate: 70mL / min Mobile phase ratio: A:B=75:25 Detection wavelength: 214 nm

[0055] In one preferred embodiment, the compound [ka] The isomers were separated by chiral SFC with a retention time of 6.20 min. The specific method is as follows: Chromatography column: DAICEL CHIRALCEL (registered trademark) OZ 4250 x 20 mm, 10 μm Mobile phase A: Supercritical CO2, Mobile phase B: Methanol (+0.1% 7.0 mol / L ammonia methanol) Mobile phase ratio: A:B=75:25 Detection wavelength: 214 nm

[0056] In one preferred embodiment, the compound [ka] The isomers were separated by chiral SFC with a retention time of 2.31 minutes, as follows: Chromatography column: CHIRALPAK IE-3 4.6 x 50 mm, 3 μm Mobile phase A: (n-hexane:dichloromethane=3:1) (0.1% diethylamine); Mobile phase B: isopropanol, A:B=80:20; Flow rate: 1.0mL / min Detection wavelength: 220 / 254 dual wavelength detection

[0057] In one preferred embodiment, the compound [ka] The isomers were separated by chiral SFC with a retention time of 3.57 minutes, as follows: Chromatography column: CHIRALPAK IE-3 4.6 x 50 mm, 3 μm Mobile phase A: (n-hexane:dichloromethane=3:1) (0.1% diethylamine); Mobile phase B: isopropanol, A:B=80:20 Flow rate: 1.0mL / min Detection wavelength: 220 / 254 dual wavelength detection

[0058] In a preferred embodiment of the invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 2.12 minutes, as follows: Chromatography column: DAICELCHIRALCEL® OZ 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:75:25 Flow rate: 70mL / min Detection wavelength: 214 nm

[0059] In a preferred embodiment of the invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 3.03 minutes, as follows: Chromatography column: DAICELCHIRALCEL® OZ 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:75:25 Flow rate: 70mL / min Detection wavelength: 214 nm

[0060] In one preferred embodiment, the compound [ka] The isomers were separated by chiral SFC with a retention time of 1.08 minutes, as follows: Chromatography column: DAICELCHIRALCEL® OZ 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:70:30 Flow rate: 100mL / min Detection wavelength: 214 nm

[0061] In one preferred embodiment, the compound [ka] The isomers were separated by chiral SFC with a retention time of 2.24 minutes, as follows: Chromatography column: DAICELCHIRALCEL® OZ 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:70:30 Flow rate: 100mL / min Detection wavelength: 214 nm

[0062] In a preferred embodiment of the invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 1.19 minutes, as follows: Chromatography column: DAICELCHIRALPAK® IC 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:75:25 Flow rate: 100mL / min Detection wavelength: 214 nm

[0063] In a preferred embodiment of the invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 1.95 min. The specific method is as follows: Chromatography column: DAICELCHIRALPAK® IC 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:75:25 Flow rate: 100mL / min Detection wavelength: 214 nm

[0064] In a preferred embodiment of the invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 1.29 minutes, as follows: Chromatography column: DAICELCHIRALPAK® IC 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:75:25 Flow rate: 100mL / min Detection wavelength: 214 nm

[0065] In a preferred embodiment of the invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 4.00 min. The specific method is as follows: Chromatography column: DAICELCHIRALPAK® IC 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:75:25 Flow rate: 100mL / min Detection wavelength: 214 nm

[0066] In a preferred embodiment of the invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 1.87 min as follows: Chromatography column: DAICEL CHIRALPAK (registered trademark) OZ 250 x 25 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:75:25 Flow rate: 100mL / min Detection wavelength: 214 nm

[0067] In a preferred embodiment of the invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 2.73 minutes, as follows: Chromatography column: DAICEL CHIRALPAK (registered trademark) OZ 250 x 25 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:75:25 Flow rate: 100mL / min Detection wavelength: 214 nm

[0068] In a preferred embodiment of the invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 1.06 minutes, as follows: Chromatography column: DAICELCHIRALPAK® IC 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:75:25 Flow rate: 100mL / min Detection wavelength: 214 nm

[0069] In a preferred embodiment of the invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 2.37 minutes, as follows: Chromatography column: DAICELCHIRALPAK® IC 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:75:25 Flow rate: 100mL / min Detection wavelength: 214 nm

[0070] In a preferred embodiment of the invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 1.25 min. The specific method is as follows: Chromatography column: DAICELCHIRALPAK® IC 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:75:25 Flow rate: 100mL / min Detection wavelength: 214 nm

[0071] In a preferred embodiment of the invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 2.00 min. The specific method is as follows: Chromatography column: DAICELCHIRALPAK® IC 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:75:25 Flow rate: 100mL / min Detection wavelength: 214 nm

[0072] In a preferred embodiment of the invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 0.91 min. The specific method is as follows: Chromatography column: DAICELCHIRALPAK® IC 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:75:25 Flow rate: 100mL / min Detection wavelength: 214 nm

[0073] In a preferred embodiment of the invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 2.35 minutes, as follows: Chromatography column: DAICELCHIRALPAK® IC 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:75:25 Flow rate: 100mL / min Detection wavelength: 214 nm

[0074] In a preferred embodiment of the invention, the compound [ka] The isomers were analyzed by chiral SFC, with a retention time of 3.20 minutes, and the specific method is as follows: Chromatography column: DAICELCHIRALCEL® OZ 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:70:30 Flow rate: 100mL / min Detection wavelength: 214 nm

[0075] In a preferred embodiment of the invention, the compound [ka] The isomer was analyzed by chiral SFC, and the retention time was 3.60 minutes. The specific method is as follows: Chromatography column: DAICELCHIRALCEL® OZ 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:70:30 Flow rate: 100mL / min Detection wavelength: 214 nm

[0076] In a preferred embodiment of the invention, the compound [ka] The isomer was analyzed by chiral SFC, and the retention time was 3.72 minutes. The specific method is as follows: Chromatography column: DAICELCHIRALCEL® OZ 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:70:30 Flow rate: 100mL / min Detection wavelength: 214 nm

[0077] In a preferred embodiment of the invention, the compound [ka] The isomer was analyzed by chiral SFC, and the retention time was 5.48 minutes. The specific method is as follows: Chromatography column: DAICELCHIRALCEL® OZ 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:70:30 Flow rate: 100mL / min Detection wavelength: 214 nm

[0078] In a preferred embodiment of the invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 0.88 min. The specific method is as follows: Chromatography column: DAICELCHIRALPAK® IC 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:75:25 Flow rate: 100mL / min Detection wavelength: 214 nm

[0079] In a preferred embodiment of the invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 1.39 min. The specific method is as follows: Chromatography column: DAICELCHIRALPAK® IC 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:75:25 Flow rate: 100mL / min Detection wavelength: 214 nm

[0080] In a preferred embodiment of the invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 5.45 minutes, as follows: Chromatography column: DAICELCHIRALPAK® IG 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:50:50 Flow rate: 100mL / min Detection wavelength: 214 nm

[0081] In a preferred embodiment of the invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 6.03 minutes, as follows: Chromatography column: DAICELCHIRALPAK® IG 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:50:50 Flow rate: 100mL / min Detection wavelength: 214 nm

[0082] In a preferred embodiment of the invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 5.33 minutes, as follows: Chromatography column: DAICELCHIRALPAK® IG 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:50:50 Flow rate: 100mL / min Detection wavelength: 214 nm

[0083] In a preferred embodiment of the invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 7.81 minutes, as follows: Chromatography column: DAICELCHIRALPAK® IG 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:50:50 Flow rate: 100mL / min Detection wavelength: 214 nm

[0084] In a preferred embodiment of the invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 5.14 minutes, as follows: Chromatography column: DAICELCHIRALPAK® IC 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:55:45 Flow rate: 70mL / min Detection wavelength: 214 nm

[0085] In a preferred embodiment of the invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 5.73 minutes, as follows: Chromatography column: DAICELCHIRALPAK® IC 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:55:45 Flow rate: 70mL / min Detection wavelength: 214 nm

[0086] In a preferred embodiment of the invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 5.20 min. The specific method is as follows: Chromatography column: DAICELCHIRALPAK® IC 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:55:45 Flow rate: 70mL / min Detection wavelength: 214 nm

[0087] In a preferred embodiment of the invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 6.30 min. The specific method is as follows: Chromatography column: DAICELCHIRALPAK® IC 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:55:45 Flow rate: 70mL / min Detection wavelength: 214 nm

[0088] In a preferred embodiment of the invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 4.70 min. The specific method is as follows: Chromatography column: DAICELCHIRALCEL® AD 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:70:30 Flow rate: 100mL / min Detection wavelength: 214 nm

[0089] Detection wavelength: 214 nm. In a preferred embodiment of the present invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 4.80 min. The specific method is as follows: Chromatography column: DAICELCHIRALCEL® AD 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:70:30 Flow rate: 100mL / min Detection wavelength: 214 nm

[0090] Detection wavelength: 214 nm. In a preferred embodiment of the present invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 3.43 minutes, as follows: Chromatography column: DAICELCHIRALCEL® AD 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:70:30 Flow rate: 100mL / min Detection wavelength: 214 nm

[0091] Detection wavelength: 214 nm. In a preferred embodiment of the present invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 3.59 minutes, as follows: Chromatography column: DAICELCHIRALCEL® AD 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:70:30 Flow rate: 100mL / min Detection wavelength: 214 nm

[0092] In a preferred embodiment of the invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 0.89 min. The specific method is as follows: Chromatography column: DAICELCHIRALCEL® AD 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:75:25 Flow rate: 120mL / min Detection wavelength: 214 nm

[0093] In a preferred embodiment of the invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 1.22 minutes, as follows: Chromatography column: DAICELCHIRALCEL® AD 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:75:25 Flow rate: 120mL / min Detection wavelength: 214 nm

[0094] Detection wavelength: 214 nm. In a preferred embodiment of the present invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 0.92 minutes, as follows: Chromatography column: DAICELCHIRALCEL® AD 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:75:25 Flow rate: 120mL / min Detection wavelength: 214 nm

[0095] Detection wavelength: 214 nm. In a preferred embodiment of the present invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 1.46 minutes, as follows: Chromatography column: DAICELCHIRALCEL® AD 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:75:25 Flow rate: 120mL / min Detection wavelength: 214 nm

[0096] In a preferred embodiment of the invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 1.34 minutes, as follows: Chromatography column: DAICELCHIRALCEL® AD 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:55:45 Flow rate: 70mL / min Detection wavelength: 214 nm

[0097] In a preferred embodiment of the invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 2.68 minutes, as follows: Chromatography column: DAICELCHIRALCEL® AD 250 x 20 mm, 10 μm Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol), A:B:55:45 Flow rate: 70mL / min Detection wavelength: 214 nm

[0098] In a preferred embodiment of the invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 5.47 minutes, as follows: Chromatography column: CHIRALPAK-IG 2 x 25 cm Mobile phase A: n-hexane (0.1% formic acid); Mobile phase B: ethanol:dichloromethane = 1:1, A:B: = 1:1 Flow rate: 20mL / min Detection wavelength: 220 / 254 nm

[0099] In a preferred embodiment of the invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 7.57 minutes, as follows: Chromatography column: CHIRALPAK-IG 2 x 25 cm Mobile phase A: n-hexane (0.1% formic acid); Mobile phase B: ethanol:dichloromethane = 1:1, A:B: = 1:1 Flow rate: 20mL / min Detection wavelength: 220 / 254 nm

[0100] In a preferred embodiment of the invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 10.6 minutes, as follows: Chromatography column: CHIRALPAK-IG 2 x 25 cm Mobile phase A: n-hexane (0.1% formic acid); Mobile phase B: ethanol:dichloromethane = 1:1, A:B = 1:1 Flow rate: 20mL / min Detection wavelength: 220 / 254 nm

[0101] In a preferred embodiment of the invention, the compound [ka] The isomers were separated by chiral SFC with a retention time of 15.2 minutes, as follows: Chromatography column: CHIRALPAK-IG 2 x 25 cm Mobile phase A: n-hexane (0.1% formic acid); Mobile phase B: ethanol:dichloromethane = 1:1, A:B = 1:1 Flow rate: 20mL / min Detection wavelength: 220 / 254 nm

[0102] It is an intermediate for preparing the above compound or its salt, and its structure is shown below. [ka]

[0103] In a preferred embodiment of the present invention, the intermediate [ka] The isomers were separated by chiral SFC with a retention time of 20.33 min. The specific method is as follows: Chromatography column: DAICELCHIRALPAK® IC 250 x 4.6 mm, 5 μm Mobile phase A: n-hexane, mobile phase B: ethanol, A:B:90:10 Flow rate: 1mL / min Detection wavelength: 254 nm

[0104] In a preferred embodiment of the present invention, the intermediate [ka] The isomers were separated by chiral SFC with a retention time of 16.51 minutes, as follows: Chromatography column: DAICELCHIRALPAK® IC 250 x 4.6 mm, 5 μm Mobile phase A: n-hexane, mobile phase B: ethanol, A:B:90:10 Flow rate: 1mL / min Detection wavelength: 254 nm

[0105] In a preferred embodiment of the present invention, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of any of the above-described compounds, their isomers, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers.

[0106] The pharmaceutical compositions according to the present invention can be administered by any applicable route or method, such as oral or parenteral (e.g., intravenous) administration. For oral administration, the pharmaceutical compositions of the present invention are generally provided in the form of tablets, capsules, or solutions. Tablets may contain the compound of the present invention, its isomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The carrier may include, but is not limited to, a diluent, a disintegrant, a binder, a lubricant, a coloring agent, or a preservative. Capsules include hard capsules and soft capsules.

[0107] For parenteral administration, the pharmaceutical compositions of the present invention can be administered by intravenous, intramuscular, or subcutaneous injection, and are usually provided as sterile aqueous solutions or suspensions, or lyophilized powders, adjusted to an appropriate pH and isotonicity.

[0108] In a preferred form of the invention, the invention also provides the use of any of the above compounds, their isomers, or pharmaceutically acceptable salts thereof in the preparation of a medicament for the prevention and / or treatment of a disease or condition mediated by complement factor B.

[0109] In a preferred form of the invention, the invention also provides a method for preventing and / or treating a disease or condition mediated by complement factor B, comprising administering to an individual in need thereof a compound of the invention, an isomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention.

[0110] In a preferred embodiment of the invention, the disease or condition mediated by complement factor B is one or more selected from ophthalmic diseases, autoimmune diseases (including arthritis), diseases related to the renal system, respiratory diseases, and cardiovascular diseases.

[0111] In a preferred embodiment of the invention, the complement factor B-mediated disease or condition is arthritis.

[0112] Related Definitions As used herein, unless otherwise indicated, the terms "comprise," "include," "have," and "contain," including their grammatical equivalents, should generally be understood to be open-ended and non-limiting, e.g., not excluding other unrecited elements or steps.

[0113] As used in the specification and claims, the following terms have the following meanings unless otherwise specified.

[0114] The "compounds" of the present invention may be asymmetric, e.g., have one or more chiral centers. Unless otherwise specified, the "compounds" of the present invention may be any one isomer or a mixture of two or more isomers. The "compounds" of the present invention include isomers (e.g., stereoisomers), enantiomers, diastereomers, racemates, or mixtures of two or more isomers of the compound.

[0115] The term "isomer" refers to compounds that have the same molecular formula but a different arrangement or configuration of atoms. "Enantiomers" refer to a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. Where appropriate, this term is used to refer to a racemic mixture. The use of "rel" indicates that the orientation of the diastereomer is known, but the absolute stereochemistry is not. For example, as used herein, the designation "rel-3S,4S" indicates that the relative stereochemistry at the 3- and 4-positions is 3S, 4S or 3R, 4R, and for the purposes of the present invention, the ordering of the positions in the alicyclic ring is as follows: [ka] Absolute stereochemistry is not measured, but optical rotation and / or chiral chromatographic conditions indicate which isomers are present. "Diastereomers" are stereoisomers that contain at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. If a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be described as either R or S. Separate compounds of unknown absolute configuration can be designated as (+) or (-) by the direction of rotated plane polarized light (right-handed or left-handed) at the sodium D-line wavelength or by their retention time when separated by chiral chromatography. Some compounds described herein contain one or more asymmetric centers or axes and may give rise to enantiomers, diastereomers, and other stereoisomers that are either defined in terms of absolute stereochemistry as (R)- or (S)- or designated by a (+) or (-) symbol. The present invention encompasses all such possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or can be separated by conventional techniques. When a compound contains a double bond, the substituent may be in the E- or Z-configuration. When a compound contains a disubstituted cyclic hydrocarbon, the cyclic hydrocarbon substituent may have a cis- or trans-configuration. Thus, the compounds of the present invention include, but are not limited to, cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof. Compounds of the present invention containing asymmetric carbon atoms can be obtained by isolation in optically pure form or as a mixture of two or more isomers. Optically pure forms can be separated from a mixture of two or more isomers or synthesized using chiral starting materials or chiral reagents.

[0116] The "compounds" of the present invention also include tautomers. Tautomers result from the swapping of a single bond with an adjacent double bond, accompanied by the migration of one proton. The term "tautomer" or "tautomeric form" means that at room temperature, isomers of different functional groups are in dynamic equilibrium and can be rapidly converted into each other.

[0117] Those skilled in the art can separate the isomeric mixtures obtained according to the present invention into individual isomers using known methods. Diastereomers can be separated, for example, by partitioning between multiphase solvent mixtures, recrystallization, and / or chromatographic separation, for example, silica gel chromatography, or medium-pressure liquid chromatography, for example, using a reverse-phase column. Racemates can be separated, for example, by forming salts with optically pure salt-forming agents and separating the resulting diastereomeric mixtures (for example, using stepwise crystallization), or by chromatography on optically activated column materials. Intermediates and final products can be worked up and / or purified according to standard methods, for example, using chromatography, partitioning, (re)crystallization, etc. At all stages of the reaction, the formed isomeric mixtures can be separated into individual isomers, for example, diastereomers or enantiomers, or any desired isomeric mixture, for example, a racemic or diastereomeric mixture.

[0118] Absolute stereochemistry and / or optical rotation are provided in the embodiments of the present invention, where appropriate. The present invention relates to all stereochemical forms of the compounds provided herein. In some cases, compounds contain two or more chiral centers. The relative stereochemistry of these compounds is identified by NMR studies and / or X-ray diffraction. In these cases, compounds are identified using the prefix "rel" followed by the R / S nomenclature. Obviously, when "rel" is used, R / S only provides relative stereochemical information (e.g., trans or cis) and does not indicate absolute stereochemistry. In some cases, the relative stereochemistry of a diastereomeric pair is not determined, so when only one isomer is isolated and / or available, enantiomers are labeled / differentiated based on their retention time under specified HPLC conditions. While identical samples typically have the same retention time, there may be operational errors. When samples obtained by corresponding methods are examined by a person skilled in the art using the same equipment and detection method, the retention time error is usually within ±0.2 minutes, preferably within ±0.1 minutes. When different persons skilled in the art use different devices, retention time errors outside the range may occur accidentally, such as retention time errors within ±0.5 minutes, ±0.3 minutes, or ±0.2 minutes, so retention time errors within ±0.5 minutes, ±0.3 minutes, ±0.2 minutes, or ±0.1 minutes can be interpreted as being within the protection scope of the present invention.

[0119] If each diastereomer is identified as a racemate, but the relative stereochemistry has not been determined, and only one isomer is isolated and / or available, the compound is designated with the symbol "(±)" and the name "diastereomer-1" or "diastereomer-2."

[0120] In the present invention, [ka] and [ka] is used to denote the absolute configuration of a stereocenter. [ka] of [ka] means a chemical bond connection. [ka] If there is an unspecified linkage position, the linkage site is [ka] indicates that the atom is limited to any atom on the monocyclic ring where

[0121] The compounds of the present invention may be structurally confirmed by conventional methods known to those skilled in the art, and where the invention relates to the absolute configuration of a compound, that absolute configuration may be confirmed by conventional techniques in the art, for example, single crystal X-ray diffraction (SARD).

[0122] The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes the occurrence of the event or circumstance and the non-occurrence of the event or circumstance.

[0123] The term "halogen" means fluorine, chlorine, bromine, and iodine.

[0124] The term "substituted" means that any one or more (e.g., 1, 2, 3, or 4, etc.) hydrogen atoms on the specified group are replaced with substituents, which may be the same or different, provided that the valence states of the specified group are normal and the substituted compound is stable. For example, "substituted with halogen" means that any one or more (e.g., 1, 2, 3, or 4, etc.) hydrogen atoms on the specified group are replaced with the same or different halogens, provided that the valence states of the specified group are normal and the substituted compound is stable.

[0125] Numerical ranges herein refer to individual integers within the given range. For example, "C1-C6" means that the group may have 1, 2, 3, 4, 5, or 6 carbon atoms, and "C1-C3" means that the group may have 1, 2, or 3 carbon atoms.

[0126] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain or branched saturated hydrocarbon groups, wherein the hydrocarbon group has the indicated number of carbon atoms. For example, the term "C1-C6 alkyl" includes C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, n-hexyl, 2-hexyl, 3-hexyl, and the like.

[0127] The term "haloalkyl" means that one or more hydrogen atoms in an alkyl are replaced with a halogen atom (fluorine, chlorine, bromine, iodine); for example, the term "C1-C6 haloalkyl" means a haloalkyl containing 1 to 6 carbon atoms, examples of which include, but are not limited to, trifluoromethyl and trifluoroethyl.

[0128] The term "cycloalkyl" means a monocyclic saturated hydrocarbon system containing no heteroatoms or double bonds. Examples of the term "C3-C6 cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0129] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent. The term "C3-C6 heterocyclyl" refers to a ring containing 3 to 6 carbon atoms and one or more heteroatoms selected from nitrogen, oxygen, or sulfur, preferably one to three heteroatoms. The term "C10-15 heterocyclyl" refers to a ring containing 10 to 15 carbon atoms and one or more heteroatoms selected from nitrogen, oxygen, or sulfur, preferably one to three heteroatoms, preferably 11 or 12 carbon atoms and one or two heteroatoms selected from oxygen or nitrogen.

[0130] The term "pharmaceutically acceptable" means that a carrier, vehicle, excipient, diluent, and / or formed salt is generally chemically or physically compatible with the other ingredients that make up the pharmaceutical dosage form and physiologically compatible with the recipient.

[0131] The term "pharmaceutically acceptable carrier" refers to a carrier that does not significantly irritate the body and does not impair the biological activity and properties of the active compound. This includes, but is not limited to, any diluent, disintegrant, binder, flow aid, wetting agent, etc. that are commonly used in the art for human or animal use.

[0132] The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness of the free acid and free base of a particular compound without causing adverse biological effects. Examples include acid (including organic and inorganic acid) addition salts or base addition salts (including organic and inorganic bases), as well as zwitterionic salts and quaternary ammonium salts, such as alkylammonium salts. The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid or basic groups by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or free base forms of these compounds with the stoichiometrically appropriate base or acid in water, an organic solvent, or a mixture of both.

[0133] The term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a drug or agent to produce a desired effect while remaining non-toxic. The exact amount administered will vary depending on a variety of factors, including subject-dependent variables (e.g., age, immune system health, etc.), the disease or disorder, and the treatment being administered.

[0134] The term "pharmaceutical composition" means a composition comprising a compound described in the present disclosure or a pharmaceutically acceptable salt thereof, and, depending on the method of administration and the nature of the dosage form, at least one pharmaceutically acceptable ingredient selected from the following, including, but not limited to, carriers, diluents, adjuvants, excipients, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, dispersing agents, temperature-sensitive materials, temperature regulators, adhesives, stabilizers, suspending aids, and the like.

[0135] The drugs or pharmaceutical compositions of the present disclosure can be administered orally, topically, parenterally, or mucosally (e.g., sublingually, by inhalation, or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers. Often, it is desirable to use the oral route. The active agent can be administered orally in the form of capsules, tablets, etc.

[0136] The drug or pharmaceutical composition of the present disclosure can be administered parenterally, i.e., intravenously (iv), intracerebroventricularly (icv), subcutaneously (sc), intraperitoneally (ip), intramuscularly (im), subcutaneously (sd), or intradermally (id), for example, by direct injection via rapid concentrated infusion or continuous infusion. Injectable formulations can be provided in unit dosage form, e.g., in ampoules or multidose containers, with an added preservative. The composition can take the form of an excipient, such as a suspension, solution, or emulsion in an oily or aqueous carrier, and can contain formulation agents such as antisettling agents, stabilizers, and / or dispersants. Alternatively, the active ingredient can be reconstituted in powder form in a suitable carrier (e.g., sterile, nonpyrogenic water) before use.

[0137] Drug or pharmaceutical compositions of the disclosure may also be formulated for rectal administration such as suppositories or retention enemas (e.g., containing conventional suppository bases such as cocoa butter or other glycerides).

[0138] The term "treatment" includes suppressing, alleviating, preventing, or eliminating one or more symptoms or side effects associated with the disease, condition, or disorder being treated.

[0139] Abbreviations used in the claims and specification have the following meanings: M: mol / L DMSO: dimethyl sulfoxide DMSO-d6: Deuterated dimethyl sulfoxide DEA: Diethylamine DCM: dichloromethane IPA: Isopropyl alcohol FA: Formic acid 1H NMR: Nuclear Magnetic Resonance Hydrogen Spectroscopy HPLC: High-performance liquid chromatography LCMS: Liquid Chromatography Mass Spectrometry M: mole MEOH: Methanol m / z: mass-to-charge ratio SFC: Supercritical Fluid Chromatography V / V: Volume / Volume [Brief explanation of the drawings]

[0140] [Figure 1] 1 is a graph showing arthritis scores of Example 13a-2 in an experiment on collagen antibody-induced mouse arthritis in Experimental Example 4. [Figure 2] 1 is a graph showing the change in thickness of the plantar pad of Example 13a-2 in the collagen antibody-induced mouse arthritis experiment of Experimental Example 4. [Figure 3] 1 is a graph of AUC changes in the CAIA mouse model efficacy study of Experimental Example 5. [Figure 4] 1 shows the crystal structure of the compound 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid in Experimental Example 6. [Figure 5] 1 shows the crystal structure of the compound of Experimental Example 7, 4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid. [Figure 6] 1 shows the crystal structure of the compound (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester of Experimental Example 8. DETAILED DESCRIPTION OF THE INVENTION

[0141] The methods for preparing the compounds of the present invention are described in more detail below, but these specific preparation methods are not intended to limit the scope of the present invention in any way. Furthermore, reaction conditions such as reactants, solvents, bases, amounts of compounds used, reaction temperature, reaction time, etc. are not limited to the following examples.

[0142] Furthermore, the compounds of the present invention can be easily produced by any combination of various synthetic methods described herein or known to those skilled in the art, and such combinations can be easily carried out by those skilled in the art.

[0143] Unless otherwise specified, all materials and equipment used in specific embodiments of the present invention are known products and are commercially available.

[0144] Example 1: (S)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-propylpiperazin-2-yl)benzoic acid and (R)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-propylpiperazin-2-yl)benzoic acid [ka] a) Preparation of methyl 4-(pyrazin-2-yl)benzoate (4-(Methoxycarbonyl)phenyl)boronic acid (2 g), 1,4-dioxane (100 mL), and water (20 mL) were added to a two-necked flask (250 mL), and sodium carbonate (3.53 g) and tetrakis(triphenylphosphine palladium) (1.28 g) were added. The mixture was protected by nitrogen substitution, and 2-chloropyrazine (1.91 g) was added. The mixture was stirred at 100°C for 4.5 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to give sand, and the mixture was purified by column chromatography (mobile phase: dichloromethane / methanol = 10 / 1 (V / V)) to give 2.04 g of the title compound.

[0145] b) Preparation of methyl (±) 4-(piperazin-2-yl)benzoate Methyl 4-(pyrazin-2-yl)benzoate (1 g) was dissolved in a mixed solvent of acetic acid / methanol (28 ml / 14 mL), palladium acetate (105 mg) and palladium / carbon (350 mg) were added, the mixture was purged with hydrogen, stirred at room temperature overnight, filtered through diatomaceous earth, and the filtrate was evaporated to give 0.9 g of the title compound.

[0146] c) Preparation of (±)3-(4-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester Methyl (±)4-(piperazin-2-yl)benzoate (480 mg) was added to a 50 mL two-necked flask, dichloromethane (30 mL) and triethylamine (661.54 mg) were added, and the mixture was protected by nitrogen substitution. Di-tert-butyl dicarbonate (475.59 mg) was added and stirred at room temperature for 1 hour. After quenching with water, the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give sand. The mixture was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 300 mg of the title compound.

[0147] d) Preparation of (±)4-((4-(tert-butoxycarbonyl)-2-(4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester 4-Formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (270.9 mg) was added to a 50 mL two-necked flask, 1,2-dichloroethane (10 mL) was added, and (±)3-(4-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (300 mg) was added. The mixture was protected by nitrogen substitution, cooled to 0 ° C in an ice bath, sodium triacetoxyborohydride (396.9 mg) was added, stirred at room temperature overnight, quenched by adding water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give sand. The mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to give the title compound (380 mg).

[0148] e) Preparation of (±)5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (±)4-((4-(tert-butoxycarbonyl)-2-(4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (150 mg) was added to a 25 mL two-necked flask, and methanol (5 mL) and 4 M hydrogen chloride in 1,4-dioxane solution (5 mL) were added. The mixture was protected by nitrogen substitution, stirred at room temperature for 2 hours, and concentrated under reduced pressure to give 120 mg of the title compound.

[0149] f) Preparation of (±)5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-propylpiperazin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (±) 5-Methoxy-4-((2-(4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (70 mg) was added to a 15 mL sealed tube, and acetonitrile (8 mL), 1-bromopropane (52 mg), and triethylamine (86.1 mg) were added. The mixture was stirred at 50°C overnight, and then the reaction mixture was concentrated under reduced pressure to give sand. The mixture was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 40 mg of the title compound.

[0150] g) Preparation of (±)4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-propylpiperazin-2-yl)benzoic acid (±) 5-Methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-propylpiperazin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (40 mg) was dissolved in a mixed solvent of dichloromethane / methanol (2 mL / 2 mL), and 1 N aqueous lithium hydroxide solution (1 mL) was added. After stirring at 70°C for 1 hour, the reaction solution was directly rotary evaporated, water was added to dissolve the residue, the pH was adjusted to neutral with dilute hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give sand. The resulting mixture was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to obtain 9 mg of the title compound.

[0151] 1 HNMR(400MHz,DMSO-d6)δ10.82(s,1H),7.96(s,2H),7.62(s,2H),7.25(t,J=2.7Hz ,1H),6.65(s,1H),6.44(s,1H),3.70(s,3H),3.56(d,J=11.9Hz,2H),3.25-3.13(m, 2H),2.70(t,J=9.2Hz,2H),2.41(s,3H),2.18(dd,J=18.8,11.5Hz,2H),1.98(d,J=7 .5Hz,2H),1.87(t,J=10.9Hz,1H),1.37(dt,J=12.0,6.1Hz,2H),0.85-0.80(m,3H). LCMS m / z=422.2[M+1] +

[0152] The enantiomers of (±)4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-propylpiperazin-2-yl)benzoic acid were separated by chiral SFC to give 1-1, tr = 2.06 min, and 1-2, tr = 2.34 min. (The specific separation method was as follows: Chromatography column: Lux Cellulose-4 4.6 × 50 mm, 3 μm; Mobile phase A: supercritical CO2; Mobile phase B: methanol gradient: 10% to 50% over 2.0 min; 50% hold: 1.0 min; Detection wavelength: 220 nm).

[0153] 1-1,t r =2.06 minutes 1 HNMR(400MHz,DMSO-d6)δ10.82(s,1H),7.97(d,J=8.3Hz,2H),7.69(d,J=6.7Hz,2H),7.25( t,J=2.7Hz,1H),6.66(s,1H),6.53-6.35(m,1H),3.71(s,3H),3.56(d,J=11.8Hz,1H),3.38( s,1H),3.23(d,J=11.8Hz,1H),2.71(t,J=10.0Hz,2H),2.63(d,J=11.4Hz,1H),2.42(s,3H), 2.26-2.10(m,3H),1.93(dt,J=21.0,10.9Hz,2H),1.47-1.30(m,2H),0.82(t,J=7.3Hz,3H).

[0154] 1-2,t r =2.34 minutes 1 HNMR(400MHz,DMSO-d6)δ10.82(s,1H),7.97(d,J=8.3Hz,2H),7.69(d,J=6.7Hz,2H),7.25(s ,1H),6.66(s,1H),6.52-6.35(m,1H),3.71(s,3H),3.56(d,J=11.8Hz,1H),3.39(d,J=10.4H z,1H),3.23(d,J=11.8Hz,1H),2.71(t,J=10.2Hz,2H),2.63(d,J=11.4Hz,1H),2.42(s,3H), 2.28-2.09(m,3H),1.93(dt,J=21.2,11.1Hz,2H),1.46-1.29(m,2H),0.82(t,J=7.3Hz,3H).

[0155] Example 2: (±) 4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-propionylpiperazin-2-yl)benzoic acid [ka] This was prepared by referring to the preparation method of Example 1, except that 1-bromopropane in step f) was replaced with propionyl chloride.

[0156] 1 HNMR(400MHz,DMSO-d6)δ12.94(s,1H),10.85(s,1H),8.01(d,J=6.4Hz,2H),7. 73(dd,J=16.2,7.7Hz,2H),7.27(s,1H),6.67(s,1H),6.42(d,J=8.7Hz,1H),4.2 6(s,1H),3.72(s,3H),3.57(s,2H),3.23(d,J=11.9Hz,2H),3.04-2.92(m,1H),2 .67-2.61(m,2H),2.43(s,3H),2.26(s,1H),1.99(s,2H),0.98(t,J=7.4Hz,3H). LCMS m / z=436.2[M+1] +

[0157] Example 3: (±)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(oxetan-3-yl)piperazin-2-yl)benzoic acid [ka]

[0158] a) Preparation of (±) 5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(oxetan-3-yl)piperazin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester A solution of (±)5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (70 mg) in 1,2-dichloroethane (8 mL) was added to a 25 mL two-necked flask, followed by the addition of sodium triacetoxyborohydride (120.2 mg). The mixture was cooled to 0°C in an ice bath and protected by nitrogen substitution. Oxetan-3-one (20.44 mg) was added and stirred overnight. The reaction mixture was then concentrated under reduced pressure to give sand, which was then purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 50 mg of the title compound.

[0159] b) Preparation of (±)4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(oxetan-3-yl)piperazin-2-yl)benzoic acid (±) 5-Methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(oxetan-3-yl)piperazin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (50 mg) was dissolved in a mixed solvent of tetrahydrofuran / methanol (2 mL / 2 mL), and 1N aqueous lithium hydroxide solution (1 mL) was added. The mixture was stirred at 70°C for 3 hours. The reaction solution was then rotary evaporated and dissolved in water. The pH was adjusted to neutral with dilute hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give sand. The resulting mixture was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 22 mg of the title compound.

[0160] 1 HNMR(400MHz,DMSO-d6)δ10.83(s,1H),7.97(d,J=8.0Hz,2H),7.68(d,J=6.1Hz ,2H),7.25(s,1H),6.66(s,1H),6.43(s,1H),4.51-4.43(m,2H),4.40(t,J=5.8 Hz,2H),3.71(s,3H),3.58(d,J=11.8Hz,2H),3.24(d,J=11.8Hz,2H),2.67(s,1 H),2.66-2.55(m,2H),2.42(s,3H),2.24(t,J=10.6Hz,1H),1.92-1.81(m,2H). LCMS m / z=436.2[M+1] + .

[0161] Example 4: (±) 4-(4-(cyclopropylmethyl)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperazin-2-yl)benzoic acid [ka] This was prepared by referring to the preparation method of Example 1, except that 1-bromopropane in step f) was replaced with (bromomethyl)cyclopropane.

[0162] 1 HNMR(400MHz,DMSO-d6)δ10.82(s,1H),7.97(d,J=8.2Hz,2H),7.69(s,2H),7.26(s,1H),6.66(s,1 H),6.45(s,1H),3.71(s,3H),3.56(d,J=11.8Hz,1H),3.23(d,J=11.7Hz,1H),2.84(dd,J=19.7,10 .8Hz,2H),2.64(d,J=11.5Hz,1H),2.42(s,3H),2.23(t,J=10.7Hz,1H),2.14(d,J=6.4Hz,2H),1.9 9(dt,J=22.0,11.1Hz,2H),1.24(s,1H),0.78(s,1H),0.40(d,J=7.8Hz,2H),0.04(d,J=7.8Hz,2H). LCMS m / z=434.3[M+1] + .

[0163] Example 5: (±) 4-(4-((2,2-difluorocyclopropyl)methyl)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperazin-2-yl)benzoic acid [ka] This was prepared by referring to the preparation method of Example 1, but replacing 1-bromopropane with 2-(bromomethyl)-1,1-difluorocyclopropane in step f).

[0164] 1HNMR(400MHz,DMSO-d6)δ12.87(s,1H),10.84(s,1H),7.98(d,J=7.7Hz,2H),7.71(s,2H),7.2 6(t,J=2.5Hz,1H),6.66(s,1H),6.45(d,J=2.0Hz,1H),3.72(s,3H),3.57(d,J=11.1Hz,1H),3. 41(s,1H),3.24(d,J=11.8Hz,2H),2.78(d,J=15.2Hz,2H),2.66(d,J=11.2Hz,1H),2.43(s,3H) ,2.37-2.15(m,2H),2.15-1.93(m,2H),1.79(d,J=6.3Hz,1H),1.60-1.46(m,1H),1.12(s,1H). LCMS m / z=470.3[M+1] + .

[0165] Example 6: (S)-4-(4-(2,2-difluoroethyl)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperazin-2-yl)benzoic acid and (R)-4-(4-(2,2-difluoroethyl)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperazin-2-yl)benzoic acid [ka] This was prepared by referring to the preparation method of Example 1, except that 1-bromopropane in step f) was replaced with 1,1-difluoro-2-iodoethane.

[0166] 1HNMR(400MHz,DMSO-d6)δ10.83(s,1H),7.97(d,J=8.2Hz,2H),7.68(d,J=6.5Hz,2 H),7.25(t,J=2.7Hz,1H),6.66(s,1H),6.47-6.40(m,1H),6.26-5.96(m,1H),3.7 1(s,3H),3.65-3.48(m,1H),3.41(d,J=10.6Hz,1H),3.22(d,J=11.9Hz,1H),2.78 (dd,J=21.1,10.5Hz,2H),2.69-2.57(m,3H),2.42(s,3H),2.26(d,J=10.9Hz,3H). LCMS m / z=444.2[M+1] + .

[0167] The enantiomers of (±)4-(4-(2,2-difluoroethyl)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperazin-2-yl)benzoic acid were separated by chiral SFC, and 6-1,t r =4.90 minutes and 6-2,t r = 6.20 min (Separation method: Chromatography column: DAICELCHIRALCEL® OZ 4250 × 20 mm, 10 μm; Mobile phase A: Supercritical CO2; Mobile phase B: Methanol (+ 0.1% 7.0 mol / L ammonia methanol); Flow rate: 70 mL / min; Mobile phase ratio: A:B = 75:25; Detection wavelength: 214 nm).

[0168] 6-1,t r =4.90 minutes 1 HNMR(400MHz,DMSO-d6)δ10.82(s,1H),7.96(d,J=8.0Hz,2H),7.65(s,2H) ,7.25(t,J=2.7Hz,1H),6.66(s,1H),6.43(s,1H),6.31-5.91(m,1H),3.71( s,3H),3.57(d,J=12.0Hz,1H),3.40(s,1H),3.22(d,J=11.8Hz,1H),2.78(d d,J=21.5,10.3Hz,2H),2.72-2.58(m,3H),2.42(s,3H),2.30-2.17(m,3H). LCMS m / z=444.2[M+1] + .

[0169] 6-2,t r =6.20 minutes 1 HNMR(400MHz,DMSO-d6)δ12.90(s,1H),10.83(s,1H),7.99(d,J=8.4Hz,2H),7.70(d,J= 7.1Hz,2H),7.26(t,J=2.7Hz,1H),6.66(s,1H),6.44(dd,J=2.8,2.0Hz,1H),6.11(tt,J= 55.7,4.3Hz,1H),3.71(s,3H),3.57(d,J=11.8Hz,1H),3.42(d,J=8.2Hz,1H),3.24(d,J= 11.8Hz,1H),2.82(d,J=10.8Hz,1H),2.79-2.59(m,4H),2.42(s,3H),2.31-2.14(m,3H). LCMS m / z=444.2[M+1] + .

[0170] Example 7: (±) 4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(oxetan-2-ylmethyl)piperazin-2-yl)benzoic acid [ka] This was prepared by following the procedure of Example 1, except that 1-bromopropane in step f) was replaced with 2-iodomethyloxetane.

[0171] 1HNMR(400MHz,DMSO)δ8.01(d,J=8.2Hz,2H),7.68(d,J=7.8Hz,2H),7.29(s,1H),6 .68(s,1H),6.47(s,1H),5.00(s,1H),4.64(d,J=5.0Hz,1H),4.56-4.46(m,2H),4. 34(s,1H),3.78(s,3H),3.62-3.52(m,2H),3.29(d,J=8.4Hz,2H),2.86(d,J=11.9H z,2H),2.73(s,1H),2.66(d,J=4.4Hz,3H),2.39(s,2H),2.13(s,1H),1.30(s,1H). LCMS m / z=450[M+1] + .

[0172] Example 8: (±) 4-(4-((1-fluorocyclopropyl)methyl)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperazin-2-yl)benzoic acid [ka] a) Preparation of (1-fluorocyclopropyl)methanol 1-Fluorocyclopropane-1-carboxylic acid (520 mg) was dissolved in tetrahydrofuran (20 mL), and the solution was protected by nitrogen substitution. Lithium aluminum hydride (209 mg) was added at 0°C and the mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding ice water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (420 mg).

[0173] b) Preparation of (1-fluorocyclopropyl)methyl-4-methylbenzenesulfonate (1-Fluorocyclopropyl)methanol (420 mg) was dissolved in dichloromethane (20 mL), and p-toluenesulfonyl chloride (209 mg) and triethylamine (209 mg) were added sequentially. After stirring at room temperature overnight, the reaction mixture was concentrated under reduced pressure to give sand, which was then purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 20 / 1 (V / V)) to give the title compound (230 mg).

[0174] c) Preparation of (±)4-((4-((1-fluorocyclopropyl)methyl)-2-(4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester 5-Methoxy-4-((2-(4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (50 mg) and (1-fluorocyclopropyl)methyl-4-methylbenzenesulfonate (230 mg, 0.9 mmol) were added to a sealed tube, followed by the addition of N,N-dimethylformamide (10 mL) and sodium hydrogen carbonate (20 mg). The mixture was stirred at 70°C overnight, and then the reaction mixture was concentrated under reduced pressure to give sand. The mixture was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 12 mg of the title compound.

[0175] d) Preparation of (±)4-(4-((1-fluorocyclopropylmethyl)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperazin-2-yl)benzoic acid (±) 4-((4-((1-fluorocyclopropyl)methyl)-2-(4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (12 mg) was dissolved in a mixed solution of anhydrous tetrahydrofuran (3 mL) and methanol (3 mL), and 1N aqueous lithium hydroxide solution (0.5 mL) was added. The mixture was heated to 70 ° C. and reacted for 3 hours. Water was added to dissolve the mixture, and the pH was adjusted to neutral with dilute hydrochloric acid. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give sand. The mixture was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 3.45 mg of the title compound.

[0176] 1 HNMR(400MHz,DMSO-d6)δ7.97(d,J=7.6Hz,2H),7.64(s,2H),7.32(d,J=3.1H z,1H),6.64(s,1H),6.44(s,1H),4.72(d,J=20.5Hz,2H),3.73(s,3H),3.52(d ,J=10.7Hz,2H),3.25-3.12(m,2H),2.80(s,1H),2.66(s,3H),2.33(s,1H),2 .12-1.91(m,2H),1.46(s,1H),1.04(d,J=19.0Hz,2H),0.87(d,J=7.0Hz,2H). LCMS m / z=452.2[M+1] + .

[0177] Example 9: (R)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(3,3,3-trifluoropropyl)perazin-2-yl)benzoic acid and (S)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(3,3,3-trifluoropropyl)piperazin-2-yl)benzoic acid [ka] Prepared by referring to the preparation method of Example 8, but replacing (1-fluorocyclopropyl)methyl-4-methylbenzenesulfonate with 3,3,3-trifluoropropyl-4-methylbenzenesulfonate in step c).

[0178] 1 HNMR(400MHz,DMSO-d6)δ12.87(s,1H),10.83(s,1H),7.98(d,J=8.1Hz,2H),7.71(s, 2H),7.28(s,1H),6.66(s,1H),6.44(s,1H),3.71(s,3H),3.57(d,J=11.8Hz,1H),3.4 9-3.39(m,2H),3.23(d,J=11.8Hz,2H),2.77(dd,J=19.2,10.5Hz,2H),2.69-2.59(m, 1H),2.46(d,J=10.1Hz,1H),2.42(s,3H),2.21(t,J=10.9Hz,1H),2.10-1.91(m,3H). LCMS m / z=476.2[M+1] + .

[0179] The enantiomers of (±)4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(3,3,3-trifluoropropyl)piperazin-2-yl)benzoic acid were separated by chiral HPLC and 9-1,t r =2.31 minutes and 9-2,t r = 3.57 min (Separation method: Chromatography column: CHIRALPAK IE-3 4.6 × 50 mm, 3 μm; Mobile phase A: (n-hexane: dichloromethane = 3:1) (0.1% diethylamine); Mobile phase B: isopropanol; A:B = 80:20; Detection wavelength: 220 / 254 dual wavelength detection; Flow rate: 1.0 mL / min).

[0180] 9-1,t r =2.31 minutes 1HNMR(400MHz,DMSO-d6)δ10.82(s,1H),7.94(d,J=8.3Hz,2H),7.62(d,J=6.6Hz,2H),7. 25(t,J=2.7Hz,1H),6.66(s,1H),6.43(s,1H),3.71(s,3H),3.57(d,J=11.8Hz,2H),3.22 (d,J=11.8Hz,2H),2.84(q,J=7.2Hz,2H),2.76(dd,J=17.2,11.2Hz,2H),2.63(d,J=11. 5Hz,1H),2.45(d,J=9.8Hz,1H),2.42(s,3H),2.20(t,J=10.5Hz,1H),2.10-1.92(m,2H).

[0181] 9-2,t r =3.57 minutes 1 HNMR(400MHz,DMSO-d6)δ10.82(s,1H),7.94(d,J=8.3Hz,2H),7.61(d,J=6.3Hz,2H),7.25( t,J=2.7Hz,1H),6.66(s,1H),6.47-6.38(m,1H),3.71(s,3H),3.57(d,J=11.8Hz,2H),3.21 (d,J=11.8Hz,2H),2.82(dd,J=14.5,7.2Hz,2H),2.77-2.69(m,2H),2.63(d,J=11.5Hz,1H) ,2.45(d,J=9.7Hz,1H),2.42(s,3H),2.19(t,J=10.4Hz,1H),2.01(dt,J=20.7,10.2Hz,2H).

[0182] Example 10: (S)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(3-(trifluoromethyl)cyclobutyl))perazin-2-yl)benzoic acid and (R)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(3-(trifluoromethyl)cyclobutyl)piperazin-2-yl)benzoic acid [ka] Prepared according to the preparation method of Example 3, but replacing xetan-3-one with 3-(trifluoromethyl)cyclobutan-1-one in step a).

[0183] 1 HNMR(400MHz,DMSO-d6)δ10.83(s,1H),7.98(d,J=8.1Hz,2H),7.68(d,J=7.3Hz,2H) ,7.26(s,1H),6.66(s,1H),6.44(s,1H),3.71(s,3H),3.57(d,J=11.9Hz,1H),3.43(d ,J=8.7Hz,2H),3.24(d,J=12.0Hz,3H),3.20-3.07(m,3H),2.79(t,J=11.7Hz,2H),2 .62(d,J=11.1Hz,1H),2.46-2.37(m,4H),2.35(d,J=11.6Hz,1H),2.28-2.19(m,1H). LCMS m / z=502.2[M+1] + .

[0184] The enantiomers of (±)4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(3-(trifluoromethyl)cyclobutyl))piperazin-2-yl)benzoic acid were separated by chiral SFC, and 10-1,t r = 2.12 minutes and 10-2,t r = 3.03 min (Separation method: Chromatography column: DAICELCHIRALCEL® OZ 250 × 20 mm, 10 μm; Mobile phase A: Supercritical CO2; Mobile phase B: Methanol (+ 0.1% 7.0 mol / L ammonia methanol); A:B: 75:25; Flow rate: 70 mL / min; Detection wavelength: 214 nm).

[0185] 10-1,t r =2.12 minutes 1HNMR(400MHz,DMSO-d6)δ10.82(s,1H),7.96(d,J=8.2Hz,2H),7.67(s,2H),7.2 5(s,1H),6.65(s,1H),6.43(s,1H),3.70(s,3H),3.57(d,J=11.7Hz,2H),3.23( d,J=11.7Hz,2H),2.84-2.74(m,1H),2.65(d,J=13.1Hz,3H),2.42(s,3H),2.18 (dd,J=18.3,9.4Hz,3H),2.03-1.93(m,1H),1.83(dd,J=19.4,8.6Hz,3H).LCMS m / z=502.2[M+1] + .

[0186] 10-2,t r =3.03 minutes 1 HNMR(400MHz,DMSO-d6)δ10.82(s,1H),7.95(d,J=8.0Hz,2H),7.65(s,2H),7. 25(s,1H),6.65(s,1H),6.43(s,1H),3.70(s,3H),3.57(d,J=11.8Hz,2H),3.22 (d,J=11.9Hz,2H),2.83(d,J=9.1Hz,1H),2.65(d,J=12.1Hz,3H),2.42(s,3H) ,2.18(d,J=26.6Hz,3H),2.03-1.93(m,1H),1.83(dd,J=19.6,9.5Hz,3H).LCMS m / z=502.2[M+1] + .

[0187] Example 11: (S)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(2,2,3-trifluoroethyl)perazin-2-yl)benzoic acid and (R)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-((2,2,3-trifluoroethyl)piperazin-2-yl)benzoic acid [ka] Prepared by referring to the preparation method of Example 8, but replacing (1-fluorocyclopropyl)methyl-4-methylbenzenesulfonate with 2,2,2-trifluoroethyl trifluoromethanesulfonate in step c).

[0188] 1 HNMR(400MHz,DMSO-d6)δ10.83(s,1H),7.96(d,J=8.4Hz,2H),7.66(d,J=7.5Hz,2 H),7.26(t,J=2.7Hz,1H),6.66(s,1H),6.44(dd,J=2.8,2.0Hz,1H),3.71(s,3H),3 .57(d,J=11.8Hz,1H),3.47-3.40(m,1H),3.22(s,1H),3.19-3.07(m,2H),2.79(t, J=12.1Hz,2H),2.67(d,J=11.5Hz,1H),2.46-2.31(m,5H),2.23(t,J=10.7Hz,1H). LCMS m / z=462.2[M+1] + .

[0189] The enantiomers of (±)4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(2,2,3-trifluoroethyl)piperazin-2-yl)benzoic acid were separated by chiral SFC, and 11-1,t r =1.08 min and 11-2,t r = 2.24 min. (Separation method: Chromatography column: DAICELCHIRALPAK® IG 250 × 20 mm, 10 μm; Mobile phase A: Supercritical CO2; Mobile phase B: MEOH (+ 0.1% 7.0 mol / L ammonia methanol); A:B: 70:30; Flow rate: 100 mL / min; Detection wavelength: 214 nm)

[0190] 11-1,t r =1.08 minutes LCMS m / z=462.2[M+1] + . 1HNMR(400MHz,DMSO-d6)δ10.83(s,1H),7.98(d,J=8.4Hz,2H),7.68(d,J=7.5Hz,2H) ,7.26(t,J=2.7Hz,1H),6.66(s,1H),6.44(dd,J=2.8,2.0Hz,1H),3.71(s,3H),3.57 (d,J=11.8Hz,1H),3.47-3.40(m,1H),3.26-3.20(m,1H),3.19-3.07(m,2H),2.79(t ,J=12.1Hz,2H),2.62(d,J=11.5Hz,1H),2.46-2.31(m,5H),2.23(t,J=10.7Hz,1H).

[0191] 11-2,t r =2.24 minutes 1 HNMR(400MHz,DMSO-d6)δ10.83(s,1H),7.98(d,J=8.4Hz,2H),7.69(d,J=7.3Hz,2H ),7.26(t,J=2.7Hz,1H),6.66(s,1H),6.47-6.37(m,1H),3.71(s,3H),3.57(d,J=1 1.8Hz,1H),3.46-3.40(m,1H),3.24(d,J=11.9Hz,1H),3.19-3.08(m,2H),2.79(t, J=11.8Hz,2H),2.62(d,J=11.4Hz,1H),2.46-2.31(m,5H),2.23(t,J=10.5Hz,1H). LCMS m / z=462.2[M+1] + .

[0192] Example 12: (±) 4-(4-(3,3-difluorocyclobutyl)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperazin-2-yl)benzoic acid [ka] This was prepared according to the preparation method of Example 3, except that xetan-3-one in step a) was replaced with 3,3-difluorocyclobutan-1-one.

[0193] 1 HNMR(400MHz,DMSO-d6)δ10.82(s,1H),7.97(d,J=7.8Hz,2H),7.69(s,2H),7.19(s,1H),6.66(s,1H),6.43(s,1H),3.71(s,3H),3.58(d,J=12.4 Hz,1H),3.35(s,1H),3.23(d,J=11.9Hz,1H),2.67(s,3H),2.61(s,1H), 2.42(s,2H),2.33(s,1H),2.21(s,2H),2.07-1.94(m,2H),1.45(s,3H). LCMS m / z=470.2[M+1] + .

[0194] Example 13: 4-((3S,4S)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid, 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid, 4-((3S,4R)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid and 4-((3R,4S)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid [ka] a) Preparation of (±)3-(4-(methoxycarbonyl)phenyl)-4-oxopiperidine-1-carboxylic acid tert-butyl ester 3-Bromo-4-oxopiperidine-1-carboxylic acid tert-butyl ester (50 g), (4-(methoxycarbonyl)phenyl)boronic acid (48.52 g), nickel(II) trifluoromethanesulfonate (3.21 g), 1,10-phenanthroline (1.62 g), potassium carbonate (49.62 g), and 1,4-dioxane (500 mL) were added to a reaction flask, and the flask was protected with nitrogen and stirred at 80° C. for 16 hours. The reaction mixture was diluted with water (500 mL), extracted with ethyl acetate (3×500 mL), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give sand. The resulting mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate=5 / 1 (V / V)) to give the title compound (32 g).

[0195] b) Preparation of (±)-rel-(3S,4R)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester and (±)-rel-(3S,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (±)3-(4-(Methoxycarbonyl)phenyl)-4-oxopiperidine-1-carboxylic acid tert-butyl ester (30 g) was added to a reaction flask, methanol (300 mL) was added, and the mixture was protected by nitrogen substitution. Sodium borohydride (10.21 g) was added batchwise at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction was quenched by adding water (500 mL) under ice bath, extracted with ethyl acetate (3×500 mL), and the layers were separated. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to sand. The mixture was purified by column chromatography (mobile phase: petroleum ether-ethyl acetate=3 / 1 (V / V)) according to the corresponding elution gradient to give 8.9 g and 21.3 g of the title compounds, respectively.

[0196] (±)-rel-(3S,4R)-4-Hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester 1HNMR(400MHz,DMSO-d6)δ7.88(d,J=8.4Hz,2H),7.43(d,J=8.4Hz,2H),4.75(d,J=4.2Hz,1H),3.99(d,J=7.8Hz,1H),3.84(s ,3H),3.77(d,J=12.4Hz,2H),3.49(d,J=14.2Hz,1H),3.16(s,1H),2.83(d,J=11.2Hz,1H),1.71-1.64(m,2H),1.39(s,9H).

[0197] (±)-rel-(3S,4S)-4-Hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester 1 HNMR(400MHz,DMSO-d6)δ7.90(d,J=8.3Hz,2H),7.42(d,J=8.3Hz,2H),4.71(d,J=6.0Hz,1H),4.03(q,J=7.1Hz,1H),3.97 (d,J=11.8Hz,1H),3.85(s,3H),3.83-3.72(m,2H),2.89(s,2H),1.99(s,1H),1.89(dd,J=12.4,3.8Hz,1H),1.40(s,9H).

[0198] Example 13a: 4-((3S,4S)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid and 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid a) Preparation of (±)-rel-(3S,4S)-4-((1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester 4-Hydroxy-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (10.06 g), (±)-rel-(3S,4R)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (8.4 g), triphenylphosphine (23.82 g), and anhydrous tetrahydrofuran (200 mL) were added to a three-necked flask and protected with nitrogen. Diisopropyl azodicarboxylate (18.33 g) was added dropwise at 0 ° C., and the reaction system was warmed to room temperature and reacted for 16 hours. The reaction mixture was diluted with water (500 mL), extracted with ethyl acetate (3 × 200 mL), separated, and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give sand. The title compound (22 g) was obtained by column chromatography (mobile phase: petroleum ether ethyl acetate = 5 / 1 (V / V)).

[0199] b) Preparation of (±)-rel-(3S,4S)-5-methoxy-4-((3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (±)-rel-(3S,4S)-4-((1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (10 g) was dissolved in 4 M hydrochloric acid 1,4-dioxane (70 mL), stirred at room temperature for 4 hours, and then concentrated under reduced pressure to give 16 g of the residue, i.e., the title compound. LCMS m / z=495.4[M+1] + .

[0200] c) Preparation of (±)-rel-(3S,4S)-4-((1-(2,2-difluoroethyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (±)-rel-(3S,4S)-5-methoxy-4-((3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (8 g) and N,N-diisopropylethylamine (8.4 mL) were added to a reaction flask, tetrahydrofuran (80 mL) was added, and then 2,2-difluoroethyl trifluoromethanesulfonate (10.4 g) was added. The mixture was protected by nitrogen substitution and stirred at 70°C for 2 hours. The reaction mixture was diluted with water (500 mL), extracted with ethyl acetate (3 x 200 mL), separated, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give sand. The mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to give the title compound (12.4 g).

[0201] d) Preparation of 4-((3S,4S)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid and 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid (±)-rel-(3S,4S)-4-((1-(2,2-difluoroethyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (6.2 g) was added to a reaction flask, methanol (120 mL), lithium hydroxide (7.8 g), and water (40 mL) were added, and the mixture was protected by nitrogen substitution and stirred at 70 ° C. for 16 hours. Dilute hydrochloric acid (3 M) was added to adjust the reaction solution to pH = 6, diluted with water (100 mL), extracted with ethyl acetate (3 × 500 mL), separated, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (mobile phase: dichloromethane-methanol 5 / 1 (V / V)) to obtain 7.6 g of the title compound enantiomer. LCMS m / z=445[M+1] + .

[0202] The (±)-rel-(3S,4S)-4-(1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid enantiomers were separated by chiral SFC to give 4-((3S,4S)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid (13a-1,t r = 1.19 min) and 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid (13a-2,t r =1.95 min), and the absolute stereochemical configuration of 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid was confirmed by X-ray single crystal diffraction in Experimental Example 6 (separation method: chromatography column: DAICELCHIRALPAK (registered trademark) IC 250 × 20 mm, 10 μm; mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B:75:25; flow rate: 100 mL / min; detection wavelength: 214 nm).

[0203] 4-((3S,4S)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid 1 HNMR(400MHz,DMSO-d6)δ10.83(s,1H),7.90(d,J=8.2Hz,2H),7.56(d,J=8 .1Hz,2H),7.20-7.13(m,1H),6.62(s,1H),6.30-5.96(m,2H),4.48-4.38(m ,1H),3.60(s,3H),3.29(s,1H),3.12(s,1H),2.93(dd,J=23.7,11.6Hz,2H ),2.78(t,J=15.5Hz,2H),2.34(d,J=8.9Hz,3H),2.28(s,1H),1.70(s,2H). LCMS m / z=445.1[M+1] + .

[0204] 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid 1 HNMR(400MHz,DMSO-d6)δ10.83(s,1H),7.88(d,J=8.1Hz,2H),7.51(d,J=8.1Hz,2H),7.16(t,J=2.7Hz,1H),6.62(s,1H),6.29-5.97(m,2H),4.51 -4.39(m,1H),3.60(s,3H),3.38(d,J=3.5Hz,1H),3.09(s,1H),2.95-2.8 7(m,2H),2.75(d,J=15.6Hz,2H),2.36(s,3H),2.26(s,1H),1.69(s,2H). LCMS m / z=445.1[M+1] + .

[0205] Example 13b: 4-((3S,4R)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid and 4-((3R,4S)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid Prepared by reference to the preparation of Example 13a, except that in step a) (±)-rel-(3S,4R)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester was replaced with (±)-rel-(3S,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester.

[0206] The (±)-rel-(3S,4R)-4-(1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid enantiomers were separated by chiral SFC, and 13b-1,t r =1.29 min, 13b-2,t r = 4.00 min (Separation method: Chromatography column: DAICELCHIRALPAK® IC 250 × 20 mm, 10 μm; Mobile phase A: Supercritical CO2; Mobile phase B: Methanol (+ 0.1% 7.0 mol / L ammonia methanol); A:B: 75:25; Flow rate: 100 mL / min; Detection wavelength: 214 nm).

[0207] 13b-1,t r =1.29 minutes 1 HNMR(400MHz,DMSO-d6)δ10.83(s,1H),7.89(d,J=8.3Hz,2H),7.57(d,J=8.4Hz,2H),7.09(t,J=2.7Hz,1H),6.61(s,1H),6.38-5.99(m,1H), 5.73(s,1H),4.65(s,1H),3.55(s,3H),3.18(dd,J=22.7,10.9Hz,2H),2.88(dd,J=17.7,12.0Hz,4H),2.67(s,1H),2.34(s,3H),1.66(s,2H). LCMS m / z=445.1[M+1] + .

[0208] 13b-2,t r =4.00 minutes 1HNMR(400MHz,DMSO-d6)δ13.09-12.27(m,1H),10.83(s,1H),7.90(d,J=8.3H z,2H),7.58(d,J=8.3Hz,2H),7.09(t,J=2.8Hz,1H),6.61(s,1H),6.37-6.02 (m,1H),5.77-5.71(m,1H),4.66(s,1H),3.55(s,3H),3.21(dd,J=24.5,13.9 Hz,2H),2.96-2.83(m,4H),2.66(d,J=10.6Hz,1H),2.34(s,3H),1.66(s,2H). LCMS m / z=445.1[M+1] + .

[0209] Example 14: 4-((3S,4S)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid, 4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid carboxylic acid, 4-((3S,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid and 4-((3R,4S)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid [ka]

[0210] Example 14a: 4-((3S,4S)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid and 4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid a) Preparation of (±)-rel-(3S,4S)-5-methoxy-4-((3-(4-(methoxycarbonyl)phenyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0111] Referring to Example 13, (±)-rel-(3S,4S)-4-((3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester was prepared by adding (±)-rel-(3S,4S)-4-((3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (6.3 g), N,N-diisopropylethylamine ( A solution of 6.6 mL of tetrahydrofuran (80 mL) was added to a reaction flask, followed by the addition of 2,2,2-trifluoroethyl trifluoromethanesulfonate (8.9 g). The mixture was protected by nitrogen substitution and stirred at 70°C for 2.2 hours. The reaction mixture was diluted with water (500 mL), extracted with ethyl acetate (3 x 200 mL), and the layers were separated. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give sand. The mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to give 5 g of the title compound. LCMS m / z=577.1[M+H] + .

[0211] b) Preparation of 4-((3S,4S)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid and 4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid (±)-rel-(3S,4S)-5-methoxy-4-((3-(4-(methoxycarbonyl)phenyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (5 g) was added to a reaction flask, methanol (120 mL), lithium hydroxide (6.25 g), and water (100 mL) were added, and the mixture was protected by nitrogen substitution and stirred at 70°C for 16 hours. Dilute hydrochloric acid (3 M) was added to adjust the reaction solution to pH = 6, diluted with water (100 mL), extracted with ethyl acetate (3 x 500 mL), separated, the organic phases combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (mobile phase: dichloromethane-methanol 5 / 1 (V / V)) to give 1.7 g of the title compound enantiomer.

[0212] (±)-rel-(3S,4S)-4-(4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid enantiomers were separated by chiral SFC to give 4-((3S,4S)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid (14a-1,t r = 1.87 min) and 4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid (14a-2,t r =2.73 min), and the absolute stereochemical configuration of 4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid was confirmed by X-ray single crystal diffraction in Experimental Example 7 (separation method: chromatography column: DAICELCHIRALCEL (registered trademark) OZ 250 × 25 mm, 10 μm; mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 75:25; flow rate: 100 mL / min; detection wavelength: 214 nm).

[0213] 14a-1,t r =1.87 points 1 HNMR(400MHz,DMSO-d6)δ10.84(s,1H),7.89(d,J=8.2Hz,2H),7.55(d,J=8.2Hz,2H) ,7.17(t,J=2.8Hz,1H),6.63(s,1H),6.21-6.16(m,1H),4.47(dd,J=16.1,7.7Hz,1H) ,3.60(s,3H),3.24(d,J=3.5Hz,2H),3.16-3.08(m,1H),2.94(t,J=12.7Hz,2H),2.67 (t,J=11.2Hz,1H),2.47-2.41(m,1H),2.34(d,J=11.4Hz,3H),1.70(d,J=3.6Hz,2H). LCMS m / z = 463.1 [M+H] + .

[0214] 14a-2,t r =2.73 points 1 HNMR(400MHz,DMSO-d6)δ10.81(s,1H),7.86(d,J=8.2Hz,2H),7.51(d,J=8.2Hz,2H ),7.14(t,J=2.8Hz,1H),6.59(s,1H),6.15(dd,J=3.0,2.0Hz,1H),4.44(dd,J=16. 1,7.8Hz,1H),3.57(s,3H),3.20(d,J=3.6Hz,2H),3.12-3.05(m,1H),2.89(d,J=13 .0Hz,2H),2.64(t,J=11.3Hz,1H),2.42(s,1H),2.32(s,3H),1.67(d,J=3.5Hz,2H). LCMS m / z = 463.1 [M+H] + .

[0215] Example 14b: (±)-rel-(3S,4R)-4-(4-((5-メトキシ-7-メチル-1H-インドール-4-イル)オキシ)-1-(2,2,2-トリフルオロエチル)ピペリジン-3-イル)benzoic acid Prepared by reference to the preparation method of Example 14a, except that in step a) (±)-rel-(3S,4S)-4-((1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester was replaced with (±)-rel-(3S,4R)-4-((1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester.

[0216] (±)-rel-(3S,4R)-4-(4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid was separated by chiral SFC, and 14b-1,t r =1.06 min, 14b-2,t r = 2.37 min (Separation method: Chromatography column: DAICELCHIRALPAK® IC 250 × 20 mm, 10 μm; Mobile phase A: Supercritical CO2; Mobile phase B: Methanol (+ 0.1% 7.0 mol / L ammonia methanol); A:B: 75:25; Flow rate: 100 mL / min; Detection wavelength: 214 nm).

[0217] 14b-1,t r =1.06 minutes 1 HNMR(400MHz,DMSO-d6)δ10.83(s,1H),7.89(d,J=8.3Hz,2H),7.56(d,J=8.3Hz ,2H),7.09(t,J=2.8Hz,1H),6.61(s,1H),5.71(dd,J=3.0,2.0Hz,1H),4.65(d, J=2.5Hz,1H),3.55(s,3H),3.42-3.36(m,2H),3.30-3.25(m,2H),3.14-3.07(m ,1H),2.89(d,J=7.6Hz,1H),2.68(d,J=10.9Hz,1H),2.34(s,3H),1.65(s,2H). LCMS m / z=463.1[M+H]+ .

[0218] 14b-2,t r =2.37 minutes 1 HNMR(400MHz,DMSO-d6)δ10.84(s,1H),7.90(d,J=8.3Hz,2H),7.58(d,J=8.3Hz,2H ),7.09(t,J=2.7Hz,1H),6.61(s,1H),5.72(dd,J=2.9,2.0Hz,1H),4.66(d,J=2.4H z,1H),3.55(s,3H),3.44-3.36(m,2H),3.29(d,J=5.9Hz,2H),3.12(td,J=10.6,5. 6Hz,1H),2.89(d,J=7.8Hz,1H),2.69(d,J=11.1Hz,1H),2.34(s,3H),1.66(s,2H). LCMS m / z=463.1[M+H] + .

[0219] Example 15: 4-((3S,4S)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid, 4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid aromatic acid, 4-((3S,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid and 4-((3R,4S)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid [ka]

[0220] Example 15a: (±)-rel-(3S,4S)-4-(4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid Prepared by reference to the preparation of Example 13a, but replacing 2,2-difluoroethyl trifluoromethanesulfonate with 3,3,3-trifluoropropyl trifluoromethanesulfonate in step c).

[0221] (±)-rel-(3S,4S)-4-(4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid was separated by chiral SFC, and 15a-1,t r =1.25 min, 15a-2,t r = 2.00 min (Separation method: Chromatography column: DAICELCHIRALPAK® IC 250 × 20 mm, 10 μm; Mobile phase A: Supercritical CO2; Mobile phase B: Methanol (+ 0.1% 7.0 mol / L ammonia methanol); A:B: 75:25; Flow rate: 100 mL / min; Detection wavelength: 214 nm).

[0222] 15a-1,t r =1.25 minutes 1 HNMR(400MHz,DMSO-d6)δ10.83(s,1H),7.91(d,J=8.1Hz,2H),7.58(d,J=8.1Hz,2H),7.17(t ,J=2.4Hz,1H),6.63(s,1H),6.17(s,1H),4.46(td,J=9.5,4.8Hz,1H),3.60(s,3H),3.12(td ,J=10.2,3.6Hz,1H),2.89(dd,J=24.1,10.3Hz,2H),2.57(dd,J=9.6,6.7Hz,2H),2.49(d,J= 13.4Hz,2H),2.36(s,3H),2.30(d,J=11.0Hz,1H),2.07(t,J=10.1Hz,1H),1.79-1.64(m,2H). LCMS m / z=475.0[M−H] + .

[0223] 15a-2,t r =2.00 minutes 1 HNMR(400MHz,DMSO-d6)δ10.83(s,1H),7.91(d,J=8.1Hz,2H),7.58(d,J=8.2Hz,2H),7. 17(t,J=2.6Hz,1H),6.63(s,1H),6.17(s,1H),4.46(td,J=9.5,4.8Hz,1H),3.60(s,3H) ,3.12(td,J=10.2,3.7Hz,1H),2.93-2.83(m,2H),2.62-2.53(m,2H),2.52-2.45(m,2H) ,2.36(s,3H),2.31(t,J=11.1Hz,1H),2.05(dt,J=15.0,7.5Hz,1H),1.80-1.62(m,2H). LCMS m / z=475.0[M−H] + .

[0224] Example 15b: (±)-rel-(3S,4R)-4-(4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid Prepared by reference to the preparation of Example 13b, but replacing 2,2-difluoroethyl trifluoromethanesulfonate with 2,2,2-trifluoropropyl trifluoromethanesulfonate in step c).

[0225] (±)-rel-(3S,4R)-4-(-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid was separated by chiral SFC, and 15b-1,t r =0.91 min, 15b-2,t r= 2.35 minutes were obtained (separation method: chromatography column: DAICEL CHIRALPAK (registered trademark) IC 250×20 mm, 10 μm; mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 75:25; flow rate: 100 mL / min; detection wavelength: 214 nm).

[0226] 15b-1,t r = 0.91 minutes 1 HNMR (400 MHz, DMSO-d6) δ 12.88 - 12.26 (m, 1H), 10.83 (s, 1H), 7.90 (d, J = 8.3 Hz, 2H), 7.60 (d, J = 8.3 Hz, 2H), 7.10 (t, J = 2.7 Hz, 1H), 6.61 (s, 1H), 5.76 (s, 1H), 4.67 (d, J = 2.5 Hz, 1H), 3.54 (s, 3H), 3.29 (s, 1H), 3.24 (s, 1H), 3.00 (t, J = 10.8 Hz, 1H), 2.84 (d, J = 9.4 Hz, 1H), 2.73 - 2.54 (m, 5H), 2.33 (dd, J = 5.6, 1.0 Hz, 3H), 1.67 (t, J = 14.4 Hz, 2H).

[0227] 15b-2,t r = 2.35 minutes 1 HNMR (400 MHz, DMSO-d6) δ 12.66 - 11.86 (m, 1H), 10.83 (s, 1H), 7.90 (d, J = 7.9 Hz, 2H), 7.60 (d, J = 8.3 Hz, 2H), 7.10 (t, J = 2.7 Hz, 1H), 6.61 (s, 1H), 5.76 (s, 1H), 4.67 (s, 1H), 3.55 (s, 3H), 3.29 (s, 1H), 3.28 - 3.21 (m, 1H), 3.00 (s, 1H), 2.85 (s, 1H), 2.6 (dd, J = 24.2, 22.4 Hz, 5H), 2.37 - 2.32 (m, 3H), 1.68 (s, 2H).

[0228] Example 16: 4-((3S,4S)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)thio)piperidin-3-yl)benzoic acid, 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)thio)piperidin-3-yl)benzoic acid, 4-((3S,4R)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)thio)piperidin-3-yl)benzoic acid and 4-((3R,4S)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)thio)piperidin-3-yl)benzoic acid [ka] a) Preparation of 1-bromo-2-methoxy-4-methyl-5-nitrobenzene 1-Bromo-2-fluoro-4-methyl-5-nitrobenzene (100 g) was dissolved in methanol (1 L), and sodium methoxide (25.6 g) was added. The mixture was protected by nitrogen substitution and stirred at 30°C for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give 73 g of the title compound.

[0229] b) Preparation of 4-bromo-5-methoxy-7-methyl-1H-indole 1-Bromo-2-methoxy-4-methyl-5-nitrobenzene (73 g) was added to a 2 L three-necked flask, tetrahydrofuran (730 mL) was added, the flask was protected with nitrogen, and the temperature was lowered to -40 ° C. A solution of vinylmagnesium bromide in tetrahydrofuran (1750 mL, 1.3 M) was slowly added dropwise, and the reaction mixture was stirred at -40 ° C. for 3 hours. The reaction mixture was quenched with an aqueous ammonium chloride solution (200 mL), extracted with ethyl acetate (3 × 200 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give sand. The mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 20 / 1 (V / V)) to obtain 8.5 g of the title compound.

[0230] c) Preparation of 4-bromo-5-methoxy-7-methyl-1-toluenesulfonyl-1H-indole 4-Bromo-5-methoxy-7-methyl-1H-indole (8.5 g) was added to a reaction flask, followed by the addition of potassium hydroxide (6.0 g) and N,N-dimethylformamide (100 mL). The mixture was cooled to 0°C, p-toluenesulfonyl chloride (10.1 g) was added, the mixture was warmed to room temperature and stirred for 16 hours, the reaction was quenched with water (50 mL), extracted with ethyl acetate (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give sand. The mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to obtain 8.1 g of the title compound.

[0231] d) Preparation of S-(5-methoxy-7-methyl-1-toluenesulfonyl-1H-indol-4-yl)ethanesulfonic acid ester S-(5-Methoxy-7-methyl-1-tolyl-1H-indol-4-yl)ethanesulfonic acid ester (8 g), potassium thioacetate (2.55 g), tris(dibenzylidene-BASEacetone)dipalladium (9.29 g), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (17.6 g), N,N-diisopropylethylamine (7.87 g), 1,4-dioxane (120 mL) were added to a reaction flask and heated in a microwave at 140 °C for 2 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (300 mL), separated, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to sand, and purified by column chromatography (mobile phase: petroleum ether ethyl acetate = 5 / 1 (V / V)) to obtain 2.6 g of the title compound.

[0232] e) Preparation of 5-methoxy-7-methyl-1-methylbenzenesulfonyl-1H-indole-4-thiol S-(5-Methoxy-7-methyl-1-tolyl-1H-indol-4-yl)ethanesulfonic acid ester (300 mg) was dissolved in a tetrahydrofuran / methanol (1.5 mL / 3.0 mL) mixed solution, 1 N lithium hydroxide (1 mL) was added, and the mixture was protected by nitrogen substitution. The mixture was stirred at room temperature for 1 hour, and the reaction solution was diluted with 1 N dilute hydrochloric acid (10 mL) and water (30 mL), extracted with ethyl acetate (60 mL), and the layers were separated. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 260 mg of the title compound. LCMS m / z=348[M+1] + .

[0233] f) Preparation of (±) tert-butyl-3-(4-(methoxycarbonyl)phenyl)-4-(2-toluenesulfonylhydrazone)piperidine-1-carboxylic acid ester (±)3-(4-(Methoxycarbonyl)phenyl)-4-oxopiperidine-1-carboxylic acid tert-butyl ester (2.194 g) and 4-toluenesulfonyl hydrazide (1.838 g) were added to the reaction flask, and the mixture was protected with nitrogen by purging with methanol (35 mL). The mixture was stirred at room temperature for 16 hours, concentrated under reduced pressure, and the evaporated residue was purified on a reverse-phase column (WelFlash C18-I, Regular C18 20-40 μm, 330 g; Mobile phase A: 10 mmol formic acid / HO, B: MeCN; Flow rate: 150 mL / min; Isocratic elution: 77.5% MeCN) to give 0.9 g of the title compound.

[0234] g) Preparation of (±)4-((5-methoxy-7-methyl-1-tolyl-1H-indol-4-yl)thio)-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester 5-Methoxy-7-methyl-1-toluenesulfonyl-1H-indole-4-thiol (260 mg), cesium carbonate (856 mg), 1,4-dioxane (10 mL), (±)tert-butyl-3-(4-(methoxycarbonyl)phenyl)-4-(2-toluenesulfonylhydrazonyl)piperidine-1-carboxylate (590 mg) were added to a reaction flask and stirred at 110° C. for 1 hour under nitrogen protection. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL×3). The layers were separated, and the combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give sand. The mixture was purified by column chromatography (mobile phase: petroleum ether, ethyl acetate=5 / 1 (V / V)) to give the title compound (470 mg).

[0235] h) Preparation of (±) methyl 4-(4-((5-methoxy-7-methyl-1-tolyl-1H-indol-4-yl)thio)piperidin-3-yl)benzoate (±)4-((5-Methoxy-7-methyl-1-tolyl-1H-indol-4-yl)thio)-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (470 mg) was dissolved in 4 M 1,4-dioxane hydrochloride (5.0 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (220 mg).

[0236] i) Preparation of (±) methyl 4-(1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1-tolyl-1H-indol-4-yl)thio)piperidin-3-yl)benzoate (±) Methyl 4-(4-((5-methoxy-7-methyl-1-tolyl-1H-indol-4-yl)thio)piperidin-3-yl)benzoate (200 mg), N,N-diisopropylethylamine (226 mg), anhydrous tetrahydrofuran (10 mL), and 2,2-difluoroethyl trifluoromethanesulfonate (227 mg) were stirred at 70°C for 2 hours under nitrogen protection, and the reaction mixture was concentrated under reduced pressure to give sand. The mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to give 190 mg of a diastereomeric mixture.

[0237] (±) methyl 4-(1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1-tolyl-1H-indol-4-yl)thio)piperidin-3-yl)benzoate was separated by chiral SFC, and peak -1,t r = 2.24 min, 64 mg; Peak-2, t r = 2.65 min, 61 mg; Peak-3, t r = 2.55 min, 60 mg; Peak -4, t r = 3.38 min, yield 80 mg (separation method: column chromatography: DAICELCHIRALCEL® OZ 250 × 20 mm, 10 μm; mobile phase A: supercritical CO2; mobile phase B: methanol (+ 0.1% 7.0 mol / L ammonia methanol); A:B: 70:30; flow rate: 100 mL / min; detection wavelength: 214 nm).

[0238] Peak-1,t r =2.24 minutes 1 HNMR(400MHz,CDCl3)δ7.86(d,J=8.4Hz,2H),7.64(d,J=3.8Hz,1H),7.48(d,J=8 .4Hz,2H),7.25-7.16(m,4H),6.66(d,J=3.8Hz,1H),6.50(s,1H),5.98-5.70(m,1 H),3.91(s,3H),3.81(s,3H),3.34-3.29(m,1H),2.97-2.92(m,3H),2.72(td,J=1 5.0,4.4Hz,2H),2.51(s,3H),2.34(s,3H),2.32-2.22(m,2H),1.85-1.74(m,2H).

[0239] Peak-2,t r =2.65 minutes 11H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.2 Hz, 2H), 7.64 (d, J = 3.8 Hz, 1H), 7.48 (d, J = 8.2 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H), 7.19 (d, J = 8.2 Hz, 2H), 6.66 (d, J = 3.8 Hz, 1H), 6.50 (s, 1H), 6.01 - 5.66 (m, 1H), 3.91 (s, 3H), 3.81 (s, 3H), 3.31 (dt, J = 11.0, 5.6 Hz, 1H), 2.97 - 2.92 (m, 3H), 2.72 (td, J = 15.0, 4.4 Hz, 2H), 2.51 (s, 3H), 2.34 (s, 3H), 2.32 - 2.20 (m, 2H), 1.85 - 1.74 (m, 2H).

[0240] Peak - 3, t r = 2.55 minutes 1 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 3.8 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 7.19 (d, J = 8.2 Hz, 2H), 6.49 (d, J = 3.8 Hz, 2H), 5.90 (tt, J = 55.8, 4.4 Hz, 1H), 3.92 (s, 3H), 3.78 - 3.68 (m, 4H), 3.39 - 3.31 (m, 1H), 3.11 (t, J = 10.6 Hz, 1H), 2.99 - 2.81 (m, 4H), 2.67 - 2.64 (m, 1H), 2.50 (s, 3H), 2.35 (s, 3H), 1.96 - 1.90 (m, 1H), 1.78 - 1.74 (m, 1H).

[0241] Peak - 4, t r = 3.38 minutes 1HNMR(400MHz,CDCl3)δ7.89(d,J=8.4Hz,2H),7.60(d,J=3.8Hz,1H),7.46(d,J=8.4Hz,2H), 7.33(d,J=8.2Hz,2H),7.19(d,J=8.2Hz,2H),6.49(d,J=3.8Hz,2H),5.90(tt,J=55.8,4.4Hz ,1H),3.92(s,3H),3.78-3.69(m,4H),3.40-3.31(m,1H),3.12(t,J=10.6Hz,1H),2.99-2.82 (m,4H),2.67-2.64(m,1H),2.50(s,3H),2.35(s,3H),1.96-1.90(m,1H),1.78-1.74(m,1H).

[0242] j) Preparation of 4-((3S,4S)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)thio)piperidin-3-yl)benzoic acid, 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)thio)piperidin-3-yl)benzoic acid, 4-((3S,4R)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)thio)piperidin-3-yl)benzoic acid and 4-((3R,4S)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)thio)piperidin-3-yl)benzoic acid Referring to the method of step d) of Example 13a, the four title compounds can be obtained separately, and chiral HPLC analysis shows peak times 16-1,t r =3.20 minutes, 16-2,t r =3.60 min, 16-3,t r =3.72 min, 16-4,t r =5.48 minutes.

[0243] 16-1, t r =3.20 minutes 1HNMR(400MHz, DMSO-d6) δ 11.00 (s, 1H), 7.86 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.29 (t, J = 2.8 Hz, 1H), 6.71 (s, 1H), 6.32 - 6.29 (m, 1H), 6.08 (dd, J = 57.9, 53.6 Hz, 1H), 3.75 (s, 3H), 2.85 (dd, J = 27.0, 11.8 Hz, 4H), 2.75 - 2.62 (m, 2H), 2.44 (s, 3H), 2.30 (dd, J = 19.8, 8.3 Hz, 1H), 2.15 (t, J = 11.6 Hz, 1H), 1.67 - 1.47 (m, 2H).

[0244] 16 - 2, t r = 3.60 minutes 1 HNMR(400MHz, DMSO-d6) δ 11.01 (s, 1H), 7.86 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.30 (t, J = 2.8 Hz, 1H), 6.71 (s, 1H), 6.32 - 6.29 (m, 1H), 6.23 - 5.91 (m, 1H), 3.76 (s, 3H), 2.92 - 2.78 (m, 4H), 2.74 - 2.63 (m, 2H), 2.45 (s, 3H), 2.30 (dd, J = 20.7, 9.9 Hz, 1H), 2.14 (t, J = 10.7 Hz, 1H), 1.57 (dd, J = 35.0, 9.4 Hz, 2H).

[0245] 16 - 3, t r = 3.72 minutes 1 HNMR(400MHz, DMSO-d6) δ 10.98 (s, 1H), 7.85 (dd, J = 14.8, 8.2 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 7.26 (t, J = 2.8 Hz, 1H), 6.67 (s, 1H), 6.34 - 5.95 (m, 2H), 3.74 (d, J = 3.9 Hz, 1H), 3.69 (s, 3H), 3.03 (t, J = 10.8 Hz, 2H), 2.92 (d, J = 8.7 Hz, 2H), 2.86 - 2.77 (m, 2H), 2.54 (d, J = 12.8 Hz, 1H), 2.41 (d, J = 8.5 Hz, 3H), 1.77 (d, J = 6.6 Hz, 1H), 1.48 (d, J = 11.0 Hz, 1H).

[0246] 16-4, t r =5.48 minutes 1 HNMR(400MHz,DMSO-d6)δ10.98(s,1H),7.84(dd,J=14.4,8.3Hz,2H),7.42(d,J=8.0H z,2H),7.26(t,J=2.8Hz,1H),6.67(s,1H),6.34-5.99(m,2H),3.74(d,J=3.8Hz,1H),3 .70(s,3H),3.03(t,J=10.7Hz,2H),2.93(t,J=10.0Hz,2H),2.87-2.76(m,2H),2.54(d ,J=11.2Hz,1H),2.41(d,J=9.8Hz,3H),1.77(d,J=8.3Hz,1H),1.48(d,J=10.5Hz,1H).

[0247] Example 17: 4-((3S,4S)-4-((5-(methoxy-d3)-7-methyl-1H-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid and 4-((3R,4R)-4-((5-(methoxy-d3)-7-methyl-1H-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid [ka] a) Preparation of 5-hydroxy-7-methyl-1H-indole-4-carbaldehyde 4-Formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (5.0 g) and dichloromethane (120 mL) were added to a two-necked flask, and the flask was protected by nitrogen substitution. Aluminum trichloride (23.04 g) was added batchwise in an ice bath, and the mixture was stirred for 10 minutes and then stirred at 40°C overnight. The reaction was quenched by adding 3N dilute aqueous hydrochloric acid, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give sand, and the mixture was purified by column chromatography (mobile phase: petroleum ether / dichloromethane = 3 / 7 (V / V)) to give 1.4 g of the title compound.

[0248] b) Preparation of 4-formyl-5-hydroxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester 5-Hydroxy-7-methyl-1H-indole-4-carbaldehyde (1.4 g), dichloromethane (40 mL), di-tert-butyl dicarbonate (5.23 g), and 4-dimethylaminopyridine (390 mg) were added to a reaction flask, and the flask was protected with nitrogen and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give sand, and the resulting mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 6 / 1 (V / V)) to give 2.03 g of the title compound.

[0249] c) Preparation of 4-formyl-5-(methoxy-d3)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester 4-Formyl-5-hydroxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (0.4 g), N,N-dimethylformamide (20 mL), potassium carbonate (602.4 mg), and deuterated iodomethane (631.8 mg) were stirred at room temperature overnight, extracted with ethyl acetate and water, and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give sand, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 9 / 1 (V / V)) to give 375 mg of the title compound.

[0250] d) Preparation of 4-hydroxy-5-(methoxy-d3)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester 4-Formyl-5-(methoxy-d3)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (350 mg), tetrahydrofuran (10 mL) and methanol (25 mL) were added to a reaction flask, and hydrogen peroxide (1.75 mL) was added dropwise under an ice-water bath, followed by concentrated sulfuric acid (0.2 mL). The reaction was allowed to proceed for 2.5 hours under an ice-water bath. The reaction was quenched by slowly adding saturated aqueous sodium sulfite solution under an ice-water bath, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give sand. The resulting mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 9 / 1 (V / V)) to give the title compound (310 mg).

[0251] Example 17a: (R)-4-(-4-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(3,3,3-trifluoropropyl)perazin-3-yl)benzoic acid and (S)-4-(-4-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(3,3,3-trifluoropropyl)piperazin-3-yl)benzoic acid Prepared by referring to the preparation method of Example 13a, except that in step a) 4-hydroxy-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester was replaced with 4-hydroxy-5-(methoxy-d3)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester, and in step c) 2,2-difluoroethyl trifluoromethanesulfonate was replaced with 3,3,3-trifluoropropyl trifluoromethanesulfonate.

[0252] 1HNMR(400MHz,DMSO-d6)δ12.80(s,1H),10.83(s,1H),7.91(d,J=8.2Hz,2H),7.58(d,J=8.3Hz,2 H),7.17(t,J=2.7Hz,1H),6.62(s,1H),6.16(d,J=2.0Hz,1H),4.45(td,J=9.5,4.8Hz,1H),3.11 (td,J=10.3,3.8Hz,1H),2.89(dd,J=22.7,10.0Hz,2H),2.56(dd,J=10.1,6.7Hz,2H),2.48-2.3 8(m,2H),2.36(s,3H),2.34-2.25(m,1H),2.07(t,J=10.4Hz,1H),1.68(dd,J=27.4,6.2Hz,2H). LCMS m / z=480.3[M+1] + .

[0253] (±)-rel-(3S,4S)-4-(-4-((5-(methoxy-d3)-7-methyl-1H-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid was separated by chiral SFC and 17a-1,t r =0.88 min, 17a-2,t r = 1.39 min (Separation method: Chromatography column: DAICELCHIRALPAK® IC 250 × 20 mm, 10 μm; Mobile phase A: Supercritical CO2; Mobile phase B: Methanol (+ 0.1% 7.0 mol / L ammonia methanol); A:B: 75:25; Flow rate: 100 mL / min; Detection wavelength: 214 nm).

[0254] 17a-1,t r =0.88 minutes 1HNMR(400MHz,DMSO-d6)δ12.98-12.11(m,1H),10.83(s,1H),7.90(d,J=8.1Hz ,2H),7.59(d,J=8.3Hz,2H),7.16(t,J=2.6Hz,1H),6.62(s,1H),6.15(s,1H),4 .45(d,J=4.9Hz,1H),3.29(s,1H),3.11(s,1H),2.89(dd,J=23.0,10.2Hz,2H) ,2.53(d,J=4.7Hz,4H),2.35(d,J=7.1Hz,3H),2.12-2.00(m,1H),1.72(s,2H).

[0255] 17a-2,t r =1.39 minutes 1 HNMR(400MHz,DMSO-d6)δ12.80(s,1H),10.83(s,1H),7.91(d,J=8.0Hz,2H),7.59 (d,J=8.0Hz,2H),7.17(t,J=2.6Hz,1H),6.62(s,1H),6.15(s,1H),4.45(d,J=4.9 Hz,1H),3.10(s,1H),2.91(dd,J=23.0,10.2Hz,2H),2.69-2.66(m,1H),2.55(d,J =4.7Hz,3H),2.36(d,J=7.1Hz,3H),2.34-2.31(m,1H),2.07(m,1H),1.72(s,2H).

[0256] Example 18: (±)-rel-(3S,4S)-4-((7-methyl-5-(trifluoromethoxy)-1H-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid [ka] This was prepared by following the procedure of Example 17, except that 4-hydroxy-5-(methoxy-d3)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester was replaced with 4-hydroxy-7-methyl-5-(trifluoromethoxy)-1H-indole-1-carboxylic acid tert-butyl ester.

[0257] 1 HNMR(400MHz,DMSO-d6)δ10.80(s,1H),7.88(d,J=8.2Hz,2H),7.51(d,J=8.2 Hz,2H),7.14(s,1H),6.60(s,1H),6.08(s,1H),4.42(td,J=10.3,4.1Hz,1H) ,3.22-3.10(m,2H),2.34(s,3H),1.95(d,J=11.2Hz,1H),1.77(dt,J=21.8,1 3.9Hz,3H),1.63-1.48(m,1H),1.37(t,J=13.3Hz,1H),1.18(t,J=7.0Hz,3H). LCMS m / z=530.1[M+1] + .

[0258] Example 19: 4-(1R,2R,5S)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)thio)cyclohexyl)benzoic acid, 4-(1S,2R,5R)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)thio)cyclohexyl)benzoic acid, 4-(1R,2S,5S)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)thio)cyclohexyl)benzoic acid, 4-(1S,2S,5R)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)thio)cyclohexyl)benzoic acid benzoic acid, 4-(1R,2S,5R)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)thio)cyclohexyl)benzoic acid, 4-(1S,2R,5S)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)thio)cyclohexyl)benzoic acid, 4-(1R,2R,5R)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)thio)cyclohexyl)benzoic acid and 4-(1S,2S,5S)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)thio)cyclohexyl)benzoic acid [ka] a) Preparation of 8-ethoxy-1,4-dioxaspiro[4.5]decane 1,4-Dioxaspiro[4.5]decan-8-ol (50 g) was dissolved in tetrahydrofuran (500 mL), and the mixture was protected by nitrogen substitution. Sodium hydride (15 g) was added at 0°C and stirred for 2 hours. Ethyl iodide (98.4 g) was added at 0°C and stirred at room temperature for 16 hours. The reaction was quenched with an aqueous ammonium chloride solution, extracted with ethyl acetate (100 mL), and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 65 g of the title compound.

[0259] (b) Preparation of 4-ethoxycyclohexan-1-one 8-Ethoxy-1,4-dioxaspiro[4.5]decane (65 g), dilute hydrochloric acid (3 M, 234 mL), and tetrahydrofuran (273 mL) were added to a reaction flask and stirred at 90°C for 2 hours. The reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (3 x 100 mL), and the layers were separated. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 40 g of the title compound.

[0260] c) (±)-4-(5-ethoxy-2-oxocyclohexyl)benzoic acid ethyl ester (diastereomeric mixture) 4-Ethoxycyclohexan-1-one (25 g), ethyl 4-iodobenzoate (48.5 g), tris(dibenzylidene-BASE acetone)dipalladium (16 g), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (20 g), cesium carbonate (115 g) and anhydrous 1,4-dioxane (500 mL) were added to a reaction flask, and the flask was protected with nitrogen and stirred at 100 ° C. for 16 hours. The reaction mixture was cooled and filtered. The filtrate was diluted with water (150 mL) and extracted with ethyl acetate (3 × 150 mL). The layers were separated, and the combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give sand. The mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to give 14.2 g of the title compound.

[0261] d) (±)-(5-ethoxy-2-(2-toluenesulfonylhydrazono)cyclohexyl)benzoate ethyl (±)-Ethyl 4-(5-ethoxy-2-oxocyclohexyl)benzoate (6.2 g), 4-toluenesulfonylhydrazide (4.772 g), and toluene (60 mL) were added to the reaction flask, and the reaction was stirred at 50 °C for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the evaporated residue was diluted with water (80 mL), extracted with ethyl acetate (100 mL), and the layers were separated. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to sand. The mixture was purified by column chromatography (mobile phase: petroleum ether-ethyl acetate = 5 / 1 (V / V)) using a reversed-phase column (WelFlash C18-I, Regular C18 20-40 μm, 120 g; mobile phase A: 10 mmOL). NH4HCO3 / H2O, B: MeCN; flow rate: 80 mL / min gradient: 60% MeCN) and following the corresponding elution order, the title compound (±)-4-(5-ethoxy-2-(2-toluenesulfonylhydrazone)cyclohexyl)ethyl benzoate (diastereomer-1, peak-1 t r =1.9 min) and (±)-4-(5-ethoxy-2-(2-toluenesulfonylhydrazone)cyclohexyl)ethyl benzoate (diastereomer-2, peak-2 t r = 2.0 min).

[0262] Peak 1: (±)-4-(5-ethoxy-2-(2-toluenesulfonylhydrazone)cyclohexyl)benzoate ethyl (diastereomer 1) 1 HNMR(400MHz,DMSO-d6)δ10.06(s,1H),7.85(d,J=8.2Hz,2H),7.19-7.13(m, 6H),4.36(q,J=7.2Hz,2H),3.68-2.61(m,2H),3.46(q,J=7.0Hz,2H),2.86-2 .77(m,1H),2.36(s,3H),2.19(d,J=11.6Hz,1H),2.10(d,J=11.2Hz,1H),2.0 1-1.92(m,1H),1.73-1.64(m,1H),1.39-1.29(m,4H),1.07(t,J=7.0Hz,3H).

[0263] Peak-2: Ethyl (±)-4-(5-ethoxy-2-(2-toluenesulfonylhydrazone)cyclohexyl)benzoate (diastereomer-2) 1 HNMR(400MHz,DMSO-d6)δ10.09(s,1H),7.84(d,J=8.3Hz,2H),7.27(d,J=8.3Hz,2H),7.16(dd,J= 14.9,8.2Hz,4H),4.35(q,J=7.1Hz,2H),3.77(dd,J=11.1,4.9Hz,1H),3.70(s,1H),3.51-3.43(m ,2H),2.48(d,J=4.7Hz,1H),2.38(s,4H),2.26-2.16(m,1H),2.14-2.06(m,1H),2.04-1.97(m,1H ),1.90(dd,J=13.6,3.8Hz,1H),1.73-1.61(m,1H),1.36(t,J=7.1Hz,3H),1.14(t,J=7.0Hz,3H).

[0264] Example 19a: 4-(1R,2R,5S)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)thio)cyclohexyl)benzoic acid, 4-(1S,2R,5R)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)thio)cyclohexyl)benzoic acid, 4-(1R,2S,5S)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)thio)cyclohexyl)benzoic acid and 4-(1S,2S,5R)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)thio)cyclohexyl)benzoic acid a) Preparation of (±)-4-(5-ethoxy-2-((5-methoxy-7-methyl-1-tolyl-1H-indol-4-yl)thio)cyclohexyl)benzoate 5-Methoxy-7-methyl-1-tolyl-1H-indole-4-thiol (650 mg), (±)-4-(5-ethoxy-2-(2-toluenesulfonylhydrazono)cyclohexyl)ethyl benzoate (diastereomer-1, peak-1 t r(=1.9 min) (1.286 g), 1,4-dioxane (30 mL), and cesium carbonate (2.134 g) were added to a reaction flask, the flask was protected by nitrogen substitution, and the mixture was stirred at 110°C for 1 hour. The reaction mixture was diluted with water (50 mL), extracted three times with ethyl acetate (150 mL), and the layers were separated. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give sand. The resulting mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to give 300 mg of the title compound.

[0265] b) Preparation of 4-(1R,2R,5S)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)thio)cyclohexyl)benzoic acid, 4-(1S,2R,5R)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)thio)cyclohexyl)benzoic acid, 4-(1R,2S,5S)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)thio)cyclohexyl)benzoic acid and 4-(1S,2S,5R)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)thio)cyclohexyl)benzoic acid Ethyl (±)-4-(5-ethoxy-2-((5-methoxy-7-methyl-1-tolyl-1H-indol-4-yl)thio)cyclohexyl)benzoate (300 mg) and LiOH (1.17 g) were added to a mixed solution of methanol / water (15 mL / 6 mL), and the reaction mixture was stirred at 70°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the evaporated residue was diluted with water and adjusted to neutral pH with 1N diluted hydrochloric acid. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to sand. The mixture was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 160 mg of the title isomer mixture. LCMS m / z=438.1[M-1] + .

[0266] The isomeric mixture was separated by chiral SFC to give 19a-1,t r =5.45 minutes, 19a-2,t r =6.03 minutes, 19a-3,tr = 5.33 minutes, 19a-4,t r = 7.81 minutes were obtained (separation method: chromatography column: DAICEL CHIRALPAK (registered trademark) IG 250×20 mm, 10 μm; mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 50:50; flow rate: 100 mL / min; detection wavelength: 214 nm).

[0267] 19a-1,t r = 5.45 minutes 1 HNMR (400 MHz, DMSO-d6) 10.98 (s, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 7.28 (t, J = 2.8 Hz, 1H), 6.69 (s, 1H), 6.29 - 6.23 (m, 1H), 3.74 (s, 3H), 3.34 - 3.33 (m, 3H), 3.32 - 3.30 (m, 2H), 2.78 - 2.67 (m, 1H), 2.44 (s, 3H), 2.05 (d, J = 13.5 Hz, 1H), 1.87 (d, J = 11.8 Hz, 1H), 1.70 (dd, J = 13.6, 3.5 Hz, 1H), 1.38 (dd, J = 23.5, 12.3 Hz, 2H), 1.03 (t, J = 7.0 Hz, 3H). LCMS m / z = 438.1 [M-1] + .

[0268] 19a-2,t r = 6.03 minutes 1HNMR(400MHz, DMSO-d6) δ 10.98 (s, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 7.28 (t, J = 2.8 Hz, 1H), 6.69 (s, 1H), 6.29 - 6.23 (m, 1H), 3.74 (s, 3H), 3.34 - 3.33 (m, 3H), 3.32 - 3.30 (m, 2H), 2.79 - 2.66 (m, 1H), 2.43 (s, 3H), 2.05 (d, J = 10.4 Hz, 1H), 1.87 (d, J = 11.9 Hz, 1H), 1.70 (dd, J = 13.2, 3.2 Hz, 1H), 1.38 (dd, J = 23.5, 12.1 Hz, 2H), 1.03 (t, J = 7.0 Hz, 3H). LCMS m / z = 438.1 [M - 1] + 。

[0269] 19a - 3, t r = 6.03 minutes 1 HNMR(400MHz, DMSO-d6) δ 10.95 (s, 1H), 7.90 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 7.24 (t, J = 2.8 Hz, 1H), 6.65 (s, 1H), 6.11 - 6.04 (m, 1H), 3.71 - 3.68 (m, 1H), 3.66 (s, 3H), 3.55 - 3.48 (m, 3H), 3.24 - 3.16 (m, 1H), 2.41 (s, 3H), 2.08 - 1.88 (m, 3H), 1.71 - 1.47 (m, 3H), 1.13 (t, J = 7.0 Hz, 3H). LCMS m / z = 438.1 [M - 1] + 。

[0270] '19a - 4, t r = 7.81 minutes 1HNMR(400MHz,DMSO-d6)δ10.96(s,1H),7.82(d,J=8.1Hz,2H),7.26-7.22( m,2H),7.21(s,1H),6.66(s,1H),6.11-6.08(m,1H),3.70(s,1H),3.67(s, 3H),3.51(tdd,J=9.3,7.0,2.3Hz,3H),3.14(d,J=12.8Hz,1H),2.42(s,3H ),2.08-1.91(m,3H),1.55(dd,J=42.6,29.5Hz,3H),1.13(t,J=7.0Hz,3H). LCMS m / z=438.1[M-1] + .

[0271] Example 19b: 4-(1R,2S,5R)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)thio)cyclohexyl)benzoic acid, 4-(1S,2R,5S)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)thio)cyclohexyl)benzoic acid, 4-(1R,2R,5R)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)thio)cyclohexyl)benzoic acid and 4-(1S,2S,5S)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)thio)cyclohexyl)benzoic acid Prepared by reference to the preparation of Example 19a, except that in step a) (±)-ethyl 4-(5-ethoxy-2-(2-toluenesulfonylhydrazone)cyclohexyl)benzoate (diastereomer-1) was replaced with (±)-ethyl 4-(5-ethoxy-2-(2-toluenesulfonylhydrazone)cyclohexyl)benzoate (diastereomer-2).

[0272] The isomeric mixture was separated by chiral SFC to give 19b-1,t r =5.14 minutes, 19b-2,t r =5.73 minutes, 19b-3,t r =5.20 minutes, 19b-4,t r= 6.30 minutes were obtained (separation method: chromatography column: DAICEL CHIRALPAK (registered trademark) IC 250×20 mm, 10 μm; mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B = 55:45; flow rate: 70 mL / min; detection wavelength: 214 nm).

[0273] 19b-1,t r = 5.14 minutes 1 HNMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 7.88 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 7.28 (t, J = 2.8 Hz, 1H), 6.69 (s, 1H), 6.28 (dd, J = 2.8, 2.0 Hz, 1H), 3.75 (S, 3H), 3.56 (s, 1H), 3.47 - 3.40 (m, 2H), 3.19 - 3.12 (m, 1H), 2.93 (td, J = 12.0, 3.4 Hz, 1H), 2.43 (s, 3H), 1.90 (d, J = 11.4 Hz, 1H), 1.75 (d, J = 13.8 Hz, 1H), 1.63 (dd, J = 23.8, 11.8 Hz, 2H), 1.44 - 1.40 (m, 1H), 1.33 - 1.24 (m, 1H), 1.14 (t, J = 7.0 Hz, 3H).

[0274] 19b-2,t r = 5.73 minutes 1 HNMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 7.27 (t, J = 2.8 Hz, 1H), 6.69 (s, 1H), 6.32 - 6.24 (m, 1H), 3.73 (s, 3H), 3.46 - 3.36 (m, 4H), 2.91 (td, J = 11.8, 3.4 Hz, 1H), 2.42 (s, 3H), 1.89 (d, J = 11.4 Hz, 1H), 1.73 (d, J = 13.8 Hz, 1H), 1.63 (t, J = 12.2 Hz, 2H), 1.44 - 1.37 (m, 1H), 1.33 - 1.26 (m, 1H), 1.13 (t, J = 7.0 Hz, 3H).

[0275] 19b-3,tr = 5:20 1 HNMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.24 (t, J = 2.8 Hz, 1H), 6.65 (s, 1H), 6.08 (dd, J = 2.8, 2.0 Hz, 1H), 3.80 - 3.76 (m, 2H), 3.66 (s, 3H), 3.51 - 3.47 (m, 1H), 3.44 - 3.28 (m, 2H), 2.42 (s, 3H), 2.25 - 2.10 (m, 2H), 1.97 - 1.82 (m, 2H), 1.56 (d, J = 13.4 Hz, 1H), 1.33 - 1.25 (m, 1H), 1.09 (t, J = 7.0 Hz, 3H).

[0276] 19b - 4, t r = 6:30 1 HNMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 7.90 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.2 Hz, 2H), 7.24 (t, J = 2.7 Hz, 1H), 6.65 (s, 1H), 6.15 - 6.03 (m, 1H), 3.79 (s, 2H), 3.66 (s, 3H), 3.47 (s, 1H), 3.40 (d, J = 7.0 Hz, 2H), 2.41 (s, 3H), 2.28 - 2.09 (m, 2H), 1.97 - 1.81 (m, 2H), 1.55 (d, J = 13.4 Hz, 1H), 1.33 - 1.25 (m, 1H), 1.09 (t, J = 7.0 Hz, 3H).

[0277] Example 20: 4-((1R,2S,5R)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid, 4-((1S,2S,5S)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid, 4-((1R,2R,5R)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid, 4-((1S,2R,5S)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid aromatic acid, 4-((1R,2R,5S)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid, 4-((1S,2R,5R)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid, 4-((1R,2S,5S)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid and 4-((1S,2S,5R)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid [ka] a) (±)-4-(5-ethoxy-2-oxocyclohexyl) ethyl benzoate (diastereomeric mixture) The title compound, (±) ethyl 4-(5-ethoxy-2-oxocyclohexyl)benzoate, was obtained by referring to the preparation method of step c) of Example 19, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate=5 / 1 (V / V)) in the corresponding elution order to obtain ethyl (±)-4-(5-ethoxy-2-oxocyclohexyl)benzoate (diastereomer-1, peak-1 tr=3.8 min) and ethyl (±)-4-(5-ethoxy-2-oxocyclohexyl)benzoate (diastereomer-2, peak-2 tr=3.5 min).

[0278] (±)-4-(5-ethoxy-2-oxocyclohexyl)ethyl benzoate (diastereomer-1, peak-1 t r =3.8 minutes) 1 HNMR(400MHz,DMSO-d6)δ7.88(d,J=8.1Hz,2H),7.30(t,J=8.2Hz,2H),4.34-4. 27(m,2H),4.05(dd,J=12.8,5.7Hz,1H),3.83(s,1H),3.54(dd,J=12.9,5.9Hz,2 H),2.77-2.65(m,1H),2.32-2.23(m,2H),2.18(dd,J=13.9,4.6Hz,2H),1.94(td ,J=13.3,6.6Hz,1H),1.32(dd,J=12.2,5.1Hz,3H),1.19(dt,J=7.1,5.6Hz,3H).

[0279] (±)-4-(5-ethoxy-2-oxocyclohexyl) ethyl benzoate (diastereomer-1, peak-2) r =3.5 minutes) 1 HNMR(400MHz,DMSO-d6)δ7.88(d,J=8.1Hz,2H),7.30(t,J=8.2Hz,2H),4.34-4. 27(m,2H),4.05(dd,J=12.8,5.7Hz,2H),3.83(s,2H),3.54(dd,J=12.9,5.9Hz,1 H),2.77-2.65(m,1H),2.32-2.23(m,2H),2.18(dd,J=13.9,4.6Hz,1H),1.94(td ,J=13.3,6.6Hz,1H),1.32(dd,J=12.2,5.1Hz,3H),1.19(dt,J=7.1,5.6Hz,3H).

[0280] Example 20a: 4-((1R,2S,5R)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid, 4-((1S,2S,5S)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid, 4-((1R,2R,5R)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid and 4-((1S,2R,5S)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid a) Preparation of ethyl (±)-4-(5-ethoxy-2-hydroxycyclohexyl)benzoate (±)-4-(5-ethoxy-2-oxocyclohexyl)ethyl benzoate (diastereomer-1, peak-1 t r (=3.8 min) (15 g) was added to a three-necked flask, and under nitrogen protection, tetrahydrofuran (300 mL) was added. The reaction system was cooled to -78 °C, and 1 M tri-sec-butyllithium borohydride (103 mL) was slowly added dropwise. The reaction mixture was allowed to react at -78 °C for 1 hour. The reaction mixture was poured into a saturated aqueous ammonium chloride solution with ice, extracted with ethyl acetate (3 × 200 mL), separated, and the organic phases were combined. The organic phase was washed with saturated brine (3 × 200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give sand. The resulting mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 8 / 1 (V / V)) to give 14 g of the title compound.

[0281] b) Preparation of (±)-4-((4-ethoxy-2-(4-(ethoxycarbonyl)phenyl)cyclohexyl)oxy)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester Ethyl (±)-4-(5-ethoxy-2-hydroxycyclohexyl)benzoate (7.88 g), 4-hydroxy-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (7.42 g), triphenylphosphine (14.14 g), and anhydrous tetrahydrofuran (400 mL) were added to a three-necked flask and protected with nitrogen. Diisopropyl azodicarboxylate (10.9 g) was added dropwise at 0 ° C. The reaction system was warmed to room temperature and reacted for 16 hours. The reaction mixture was diluted with water (500 mL), extracted with ethyl acetate (3 × 200 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give sand. The mixture was purified by column chromatography (mobile phase: petroleum ether ethyl acetate = 20 / 1 (V / V)) to obtain 4.2 g of the title compound.

[0282] c) Preparation of 4-((1R,2S,5R)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid, 4-((1S,2S,5S)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid, 4-((1R,2R,5R)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid and 4-((1S,2R,5S)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid Hydrolysis was carried out in accordance with the hydrolysis method of Example 17 to obtain a mixture of isomers. LCMS m / z=424.2[M+1] + .

[0283] The isomeric mixture was separated by chiral SFC to give 20a-1,t r =4.70min, 20a-2,t r =4.80min, 20a-3,t r =3.43 minutes, 20a-4,t r= 3.59 minutes were obtained (separation method: chromatography column: DAICEL CHIRALCEL® AD 250×20 mm, 10 μm; mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 70:30; flow rate: 100 mL / min; detection wavelength: 214 nm).

[0284] 20a-1,t r = 4.70 minutes 1 HNMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 7.90 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 8.2 Hz, 2H), 7.05 (t, J = 2.6 Hz, 1H), 6.60 (s, 1H), 5.60 (s, 1H), 4.64 (s, 1H), 3.84 (s, 1H), 3.55 (s, 3H), 3.45 (q, J = 6.9 Hz, 2H), 3.34 (s, 1H), 2.46 (d, J = 13.7 Hz, 1H), 2.33 (s, 3H), 2.13 (t, J = 13.0 Hz, 1H), 1.88 (d, J = 12.4 Hz, 1H), 1.66 (dd, J = 25.0, 13.2 Hz, 2H), 1.54 (d, J = 12.7 Hz, 1H), 1.14 (t, J = 7.0 Hz, 3H). LCMS m / z = 424.2 [M+1] + .

[0285] 20a-2,t r = 4.80 minutes 1 HNMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 7.90 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H), 7.05 (t, J = 2.6 Hz, 1H), 6.60 (s, 1H), 5.60 (s, 1H), 4.64 (s, 1H), 3.84 (s, 1H), 3.55 (s, 3H), 3.45 (q, J = 7.0 Hz, 2H), 3.35 (s, 1H), 2.46 (d, J = 13.7 Hz, 1H), 2.33 (s, 3H), 2.13 (t, J = 13.6 Hz, 1H), 1.88 (d, J = 12.7 Hz, 1H), 1.65 (dd, J = 24.9, 13.8 Hz, 2H), 1.53 (d, J = 11.8 Hz, 1H), 1.14 (t, J = 7.0 Hz, 3H). LCMS m / z = 424.2 [M+1] + .

[0286] 20a-3,t r = 3.43 minutes 1 HNMR(400 MHz, DMSO-d6) δ 12.64 (s, 1H), 10.79 (s, 1H), 7.89 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.2 Hz, 2H), 7.14 (t, J = 2.6 Hz, 1H), 6.60 (s, 1H), 6.08 (d, J = 2.2 Hz, 1H), 4.43 (td, J = 10.3, 4.0 Hz, 1H), 3.57 (s, 1H), 3.56 (s, 3H), 3.44 (q, J = 7.0 Hz, 2H), 3.22 - 3.14 (m, 1H), 2.34 (s, 3H), 1.95 (d, J = 11.1 Hz, 1H), 1.77 (dt, J = 21.9, 14.3 Hz, 3H), 1.60 - 1.50 (m, 1H), 1.37 (t, J = 13.3 Hz, 1H), 1.18 (t, J = 7.0 Hz, 3H). LCMS m / z = 424.2 [M+1] + .

[0287] 20a-4,t r = 3.59 minutes 1 HNMR(400 MHz, DMSO-d6) δ 13.29 -​​​​​Example 20b: 4-(((1R,2R,5S)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid, 4-((1S,2R,5R)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid, 4-((1R,2S,5S)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid and 4-((1S,2S,5R)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid See Example 20a to obtain a mixture of isomers.

[0289] The isomeric mixture was separated by chiral SFC to give 20b-1,t r =0.89min, 20b-2,t r =1.22 min, 20b-3,t r =0.92 min, Peak 20b-4,t r = 1.46 min (Separation method: Chromatography column: DAICELCHIRALCEL® AD 250 × 20 mm, 10 μm; Mobile phase A: Supercritical CO2; Mobile phase B: Methanol (+ 0.1% 7.0 mol / l ammonia methanol); A:B: 75:25; Flow rate: 120 mL / min; Detection wavelength: 214 nm).

[0290] 20b-1,t r =0.89 minutes 1 HNMR(400MHz,DMSO-d6)δ10.80(s,1H),7.89(d,J=8.2Hz,2H),7.54(d,J=8.2Hz,2H) ,7.05(t,J=2.8Hz,1H),6.60(s,1H),5.59(d,J=2.1Hz,1H),4.64(s,1H),3.84(s,1H) ),3.55(s,3H),3.45(dd,J=14.0,7.0Hz,3H),2.33(s,3H),2.14(s,1H),1.88(d,J=1 3.1Hz,1H),1.65(d,J=10.6Hz,2H),1.55(s,1H),1.24(s,1H),1.14(t,J=7.0Hz,3H). LCMS m / z = 424.1 [M+1] + .

[0291] 20b-2,t r = 1.22 minutes 1 HNMR(400 MHz, DMSO-d6) δ 10.80 (s, 1H), 7.91 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 8.3 Hz, 2H), 7.06 (t, J = 2.8 Hz, 1H), 6.61 (s, 1H), 5.61 - 5.59 (m, 1H), 4.65 (s, 1H), 3.85 (s, 1H), 3.55 (s, 3H), 3.46 (dd, J = 14.0, 7.0 Hz, 3H), 2.34 (s, 3H), 2.15 (s, 1H), 1.89 (d, J = 11.7 Hz, 1H), 1.66 (d, J = 11.3 Hz, 2H), 1.56 (s, 1H), 1.24 (s, 1H), 1.15 (t, J = 7.0 Hz, 3H).

[0292] 20b-3,t r = 0.92 minutes 1 HNMR(400 MHz, DMSO-d6) δ 12.69 (s, 1H), 10.81 (s, 1H), 7.90 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 8.3 Hz, 2H), 7.07 (t, J = 2.7 Hz, 1H), 6.60 (s, 1H), 5.62 (dd, J = 2.9, 2.0 Hz, 1H), 4.58 (s, 1H), 3.56 (dd, J = 7.0, 2.3 Hz, 1H), 3.53 (s, 3H), 3.50 (dd, J = 7.0, 2.3 Hz, 1H), 3.47 - 3.41 (m, 1H), 3.06 (d, J = 13.2 Hz, 1H), 2.33 (s, 3H), 2.21 (dd, J = 24.3, 11.6 Hz, 1H), 2.01 (d, J = 11.6 Hz, 1H), 1.94 - 1.83 (m, 1H), 1.77 (d, J = 13.9 Hz, 2H), 1.43 (t, J = 13.2 Hz, 1H), 1.14 (t, J = 7.0 Hz, 3H). LCMS m / z = 424.1 [M+1] + . <​​​=1.46 minutes 1 HNMR(400MHz,DMSO-d6)δ10.77(s,1H),7.87(d,J=8.3Hz,2H),7.52(d,J=8.3Hz,2H),7.03(t,J=2.7Hz,1H),6.5 6(s,1H),5.59(dd,J=2.8,2.0Hz,1H),4.55(s,1H),3.53(dd,J=7.0,2.3Hz,1H),3.50(s,3H),3.47(dd,J=7.0,2 .3Hz,1H),3.44-3.37(m,1H),3.03(d,J=13.0Hz,1H),2.30(s,3H),2.18(dd,J=24.2,11.8Hz,1H),1.98(d,J=11 .6Hz,1H),1.84(dd,J=19.4,8.1Hz,1H),1.72(t,J=13.6Hz,2H),1.39(t,J=13.0Hz,1H),1.10(t,J=7.0Hz,3H). LCMS m / z=424.1[M+1] + .

[0294] Example 21: 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)sulfonyl)piperidin-2-yl)benzoic acid and 4-((2R,4R)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)sulfonyl)piperidin-2-yl)benzoic acid [ka] a) Preparation of 5-methoxy-7-methyl-1-tolyl-1H-indole-4-sulfonyl chloride S-(5-Methoxy-7-methyl-1-tolyl-1H-indol-4-yl)ethanesulfonate (100 mg) and acetonitrile / water (2.5 mL / 0.5 mL) were added to a reaction flask, and under ice-water bath, N-chlorosuccinimide (103.0 mg) was added, and 2 M dilute hydrochloric acid (5 drops) was slowly added, and the mixture was stirred for 3.5 hours. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to sand. The mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 4 / 1 (V / V)) to give the title compound (88 mg).

[0295] b) Preparation of methyl (±)-rel-(2S,4S)-4-(4-ethoxy-1-((5-methoxy-7-methyl-1-tolyl-1H-indol-4-yl)sulfonyl)piperidin-2-yl)benzoate Methyl (±)-rel-(2S,4S)-4-(4-ethoxypiperidin-2-yl)benzoate (69.5 mg), triethylamine (80.1 mg), methylene chloride (5 mL) and 5-methoxy-7-methyl-1-tolyl-1H-indole-4-sulfonyl chloride (164 mg) were added to the reaction flask and stirred for 16 hours. The reaction was diluted with water (40 mL), extracted with dichloromethane (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to sand and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 2 / 1 (V / V)) to give 179 mg of the title compound.

[0296] c) Preparation of 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)sulfonyl)piperidin-2-yl)benzoic acid and 4-((2R,4R)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)sulfonyl)piperidin-2-yl)benzoic acid The enantiomers were obtained by hydrolysis according to the hydrolysis method of Example 17. LCMS m / z=473.1[M+1] + .

[0297] Enantiomeric isomers were separated by chiral SFC, and 21-1,t r =1.34 min and 21-2,t r = 2.68 min (Separation method: Chromatography column: DAICELCHIRALCEL® AD 250 × 20 mm, 10 μm; Mobile phase A: Supercritical CO2; Mobile phase B: Methanol (+ 0.1% 7.0 mol / L ammonia methanol); A:B: 55:45; Flow rate: 70 mL / min; Detection wavelength: 214 nm).

[0298] 21-1,t r =1.34 minutes 1 HNMR(400MHz,DMSO-d6)δ11.39(s,1H),7.92(d,J=8.4Hz,2H),7.55-7.42(m, 3H),6.94(s,1H),6.91(dd,J=3.0,2.0Hz,1H),5.39(s,1H),3.90(s,3H),3.8 4-3.81(m,1H),3.30(s,2H),3.06(s,1H),2.95-2.89(m,1H),2.55(s,3H),2. 05-1.93(m,1H),1.68(d,J=9.8Hz,1H),1.47-1.42(m,2H),0.99-0.96(m,3H).

[0299] 21-2,t r =2.68 minutes 1 HNMR(400MHz,DMSO-d6)δ11.39(s,1H),7.92(d,J=8.4Hz,2H),7.54-7.42(m ,3H),6.94(s,1H),6.93-6.88(m,1H),5.39(s,1H),3.90(s,3H),3.83(d,J=1 2.4Hz,1H),3.30(s,2H),3.06(s,1H),2.95-2.89(m,1H),2.55(s,3H),2.02 -1.97(m,1H),1.68(d,J=11.0Hz,1H),1.51-1.38(m,2H),0.99-0.96(m,3H).

[0300] Example 22: (±)(Z)-1 1-((5-Methoxy-7-methyl-1H-indol-4-yl)methyl)-3-oxa-1(2,4)-piperazine-2(1,2)-benzocyclohexanon-8-ene-2 4 -carboxylic acid [ka] a) Preparation of methyl 3-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate Methyl 4-bromo-3-hydroxybenzoate (10 g), bis(pinacolato)diboron (12.09 g), and potassium acetate (10.62 g) were added to a two-necked flask, and 1,4-dioxane (150 mL) was added. The mixture was protected by nitrogen substitution, and 1,1-bis(diphenylphosphino)ferrocene palladium dichloride dichloromethane complex (3.53 g) was added. The mixture was stirred at 90°C for 4 hours, cooled to room temperature, quenched by adding water, and extracted three times with ethyl acetate (100 mL x 3). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give sand. The mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to obtain the title compound (7.7 g). LCMS m / z=279.1[M+H] + .

[0301] b) Preparation of methyl 3-hydroxy-4-(pyrazin-2-yl)benzoate Methyl 3-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (7.5 g), 2-bromopyrazine (6.43 g), and sodium carbonate (8.57 g) were added to a two-necked flask, and a mixed solvent of 1,4-dioxane / water (150 mL / 30 mL) was added. The mixture was then purged with nitrogen and protected. Palladium tetrakis(triphenylphosphine) (2.49 g) was added, and the mixture was stirred at 100°C for 4 hours. The mixture was quenched by adding water and extracted three times with ethyl acetate (100 mL x 3). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give sand. The resulting mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to give the title compound (3.7 g). LCMS m / z=231.2[M+H] + .

[0302] c) Preparation of methyl (±) 3-hydroxy-4-(piperazin-2-yl)benzoate Methyl 3-hydroxy-4-(pyrazin-2-yl)benzoate (3.7 g) was dissolved in methanol (200 mL), and palladium acetate (361 mg), acetic acid (19.3 g), and palladium on carbon (1.3 g, 10%) were added. The atmosphere was replaced with hydrogen, and the mixture was stirred at room temperature overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 3 g of the title compound. LCMS m / z=237.1[M+H] + .

[0303] d) Preparation of (±)3-(2-hydroxy-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester Methyl (±)3-hydroxy-4-(piperazin-2-yl)benzoate (2.8 g) was dissolved in dichloromethane (100 mL), triethylamine (1.8 g) was added, and the mixture was protected by nitrogen substitution. A solution of di-tert-butyl dicarbonate (1.55 g) in dichloromethane (10 mL) was added dropwise and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give sand, and purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 2.5 g of the title compound. LCMS m / z=337.4[M+H] + .

[0304] e) Preparation of (±)3-(2-((tert-butyldimethylsilyl)oxy)-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (±) 3-(2-hydroxy-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (2.3 g) was dissolved in N,N-dimethylformamide (50 mL), imidazole (931 mg) was added, and the mixture was protected by nitrogen substitution and cooled to 0 °C in an ice-water bath. tert-Butyldimethylchlorosilane (2.06 g) and 4-dimethylaminopyridine (84 mg) were added, and the mixture was stirred at room temperature overnight. The mixture was quenched by adding water and extracted three times with ethyl acetate (50 mL × 3). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to sand, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 20 / 1 (V / V)) to obtain 2.2 g of the title compound. LCMS m / z=451.7[M+H] + .

[0305] f) Preparation of (±)4-((4-(tert-butoxycarbonyl)-2-(2-((tert-butyldimethylsilyl)oxy)-4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester 4-(hydroxymethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (1.32 g) was dissolved in dichloromethane (30 mL), protected by nitrogen substitution, cooled to 0°C in an ice-water bath, dibromotriphenylphosphorane (2.07 g) was added in batches, stirred at 0°C for 1.5 hours, and then (±)3-(2-((tert-butyldimethylsilyl)oxy)-4-(methoxycarbonyl)phenyl)piperazine-1- Carboxylic acid tert-butyl ester (1.7 g) and N,N-diisopropylethylamine (1.46 g) were added and stirred at 0°C for 1.5 hours. The reaction was quenched with water and extracted three times with dichloromethane (30 mL x 3). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to sand, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to give 2.5 g of the title compound. LCMS m / z=725.0[M+H] + .

[0306] g) Preparation of (±)4-((4-(tert-butoxycarbonyl)-2-(2-hydroxy-4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (±) 4-((4-(tert-butoxycarbonyl)-2-(2-((tert-butyldimethylsilyl)oxy)-4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (2.4 g) was dissolved in tetrahydrofuran (50 mL), substituted with nitrogen, protected, and tetrabutylammonium fluoride in tetrahydrofuran (5.6 mL, 1 mol / L) was added, stirred at room temperature for 1 hour, quenched the reaction by adding water, extracted three times with ethyl acetate (30 mL × 3), the organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to sand, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to give the title compound 2 g. LCMS m / z=610.7[M+H] + .

[0307] h) Preparation of (±) 4-((4-(tert-butoxycarbonyl)-2-(2-(hex-5-en-1-oxy)-4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (±) 4-((4-(tert-butoxycarbonyl)-2-(2-hydroxy-4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (2 g) was dissolved in N,N-dimethylformamide (30 mL), potassium carbonate (1.36 g) was added, and the mixture was protected by nitrogen substitution. 6-Bromohexan-1-ene (1.07 g) was then added and stirred at room temperature overnight. Water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (30 mL × 3). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to sand, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to give the title compound 2 g. LCMS m / z=692.9[M+H] + .

[0308] i) Preparation of (±) 4-((2-(2-(hex-5-en-1-oxy)-4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (±) 4-((4-(tert-butoxycarbonyl)-2-(2-(hex-5-en-1-oxy)-4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (2 g) was dissolved in methanol (50 mL), and a solution of hydrochloric acid in 1,4-dioxane (11 mL, 4 M) was added. The mixture was stirred at room temperature for 2 hours, and the reaction mixture was concentrated under reduced pressure to give 1.8 g of the title compound. LCMS m / z=592.7[M+H] + .

[0309] j) Preparation of (±) 4-(4-allyl-2-(2-(hex-5-en-1-oxy)-4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (±) 4-((2-(2-(hex-5-en-1-oxy)-4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (1.6 g, 2.7 mmol), 3-bromoprop-1-ene (0.98 g) were dissolved in acetonitrile (40 mL), triethylamine (1.64 g) was added, and the mixture was protected by nitrogen substitution and stirred at room temperature overnight. The reaction was quenched by adding water, and extracted three times with ethyl acetate (30 mL × 3). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to sand, and purified by column chromatography (mobile phase: dichloromethane / methanol = 50 / 1 (V / V)) to give the title compound (1.2 g). LCMS m / z=632.8[M+H] + .

[0310] k) (±) methyl(Z)-1 1 -((1-(tert-butoxycarbonyl)-5-methoxy-7-methyl-1H-indol-4-yl)methyl)-3-oxa-1(2,4)-piperazine-2(1,2)-benzocyclohexanon-8-ene-2 4 -Preparation of carboxylic acid esters (±) 4-(4-Allyl-2-(2-(hex-5-en-1-oxy)-4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (200 mg) was dissolved in toluene (200 mL), Grubbs 1st (130 mg) was added, and the mixture was protected by nitrogen substitution and stirred at 80°C for 18 hours. The reaction mixture was concentrated under reduced pressure to give sand, and purified by column chromatography (mobile phase: dichloromethane / methanol = 10 / 1 (V / V)) to give 175 mg of the title compound.

[0311] l)(±)(Z)-1 1 -((5-Methoxy-7-methyl-1H-indol-4-yl)methyl)-3-oxa-1(2,4)-piperazine-2(1,2)-benzocyclohexanon-8-ene-2 4 Preparation of carboxylic acids (±) Methyl(Z)-1 1 -((1-(tert-butoxycarbonyl)-5-methoxy-7-methyl-1H-indol-4-yl)methyl)-3-oxa-1(2,4)-piperazine-2(1,2)-benzocyclohexanon-8-ene-2 4 The carboxylic acid ester (175 mg) was dissolved in methanol / tetrahydrofuran (10 mL / 10 mL), and an aqueous solution of lithium hydroxide (10 mL, 2N) was added. The mixture was stirred at 70°C for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure, diluted with water, and adjusted to pH 7 with dilute hydrochloric acid. The mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and evaporated to dryness. The filtrate was concentrated under reduced pressure to sand, and purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to obtain 5 mg of the title compound.

[0312] 1HNMR(400MHz,DMSO-d6)δ10.84(s,1H),7.99(d,J=7.9Hz,1H),7.62(d,J=8.0Hz,1H),7.44(s,1H),7.28(s,1 H),6.76-6.64(m,1H),6.62(s,1H),5.45(t,J=10.5Hz,1H),5.29(s,1H),4.25(s,1H),4.16(d,J=9.3Hz,1H) ,3.95(t,J=10.9Hz,2H),3.77(d,J=11.9Hz,1H),3.74(s,3H),2.90(d,J=11.5Hz,2H),2.75(d,J=11.3Hz,1H ),2.68(d,J=17.4Hz,2H),2.43(s,3H),2.33(d,J=11.7Hz,2H),1.91(s,2H),1.66(s,1H),1.30-1.08(m,4H). LCMS m / z=490.6[M+1] + .

[0313] Example 23: (1 3 R,1 4 R,Z)-1 4 -((5-Methoxy-7-methyl-1H-indol-4-yl)oxy)-3-oxa-1(3,1)-piperidin-2(1,2)-benzocyclohexanon-8-ene-2 4 -carboxylic acid [ka] a) Preparation of methyl 3-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate Methyl 4-bromo-3-hydroxybenzoate (25 g), bis(pinacolato)diboron (30.23 g), and potassium acetate (26.55 g) were added to a 500 mL three-neck flask, followed by the addition of 1,4-dioxane (350 mL), purging with nitrogen, protecting the flask, and adding [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (4.42 g). The mixture was heated to 90 °C and stirred for 4 hours. Water (300 mL) was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (200 mL × 3). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give sand. The resulting mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to obtain the title compound (30 g). LCMS m / z=279.1[M+H] + .

[0314] b) Preparation of 5-(2-hydroxy-4-(methoxycarbonyl)phenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester Methyl 3-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (19 g), 5-bromo-4-oxo-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (12.58 g), and potassium carbonate (18.88 g) were added to a three-necked flask, followed by the addition of 1,4-dioxane / water (300 mL / 100 mL). The mixture was substituted with nitrogen to obtain a protected tetrakis(trifluoromethyl)benzoate. The reaction mixture was heated to 60°C and stirred for 4 hours. Water (300 mL) was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (200 mL x 3). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give sand. The resulting mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to give 7.5 g of the title compound. LCMS m / z=348.4[M+H] + .

[0315] c) Preparation of (3R,4S)-4-hydroxy-3-(2-hydroxy-4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester Add formic anhydride (30 mL) dropwise to triethylamine (43 mL) at 0°C to form a solution and set it aside (control the temperature at 5-10°C), add 5-(2-hydroxy-4-(methoxycarbonyl)phenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (7.5 g) and RuCl(p-cymene)[(S,S)-Ts-DPEN] (1.36 g) to the reaction flask, then add the prepared solution of formic anhydride and triethylamine to the reaction flask, replace with nitrogen, and slowly warm to room temperature. The temperature was raised and stirred overnight. The reaction system was cooled to 0-5°C in an ice-water bath, triethylamine (5 mL) was slowly added to adjust the pH to weakly alkaline, the temperature was controlled at about 10°C, water (200 mL) was added to quench the reaction, the mixture was extracted with ethyl acetate (150 mL × 3), washed with saturated brine (200 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give sand. The mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 20 / 3 (V / V)) to give 2 g of the title compound. LCMS m / z=352.4[M+H] + .

[0316] d) Preparation of (3R,4S)-3-(2-(hex-5-en-1-yloxy)-4-(methoxycarbonyl)phenyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (3R,4S)-4-Hydroxy-3-(2-hydroxy-4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (1.9 g), 6-bromohex-1-ene (1.59 g), and potassium carbonate (2.24 g) were added to a three-necked flask, followed by the addition of N,N-dimethylformamide (40 mL), purging with nitrogen, and stirring overnight at room temperature. The mixture was quenched with water (100 mL), extracted with ethyl acetate (100 mL × 3), and the combined organic phases were washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give sand. The resulting mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 20 / 3 (V / V)) to give the title compound (1.55 g). LCMS m / z=434.5[M+H] + .

[0317] e) Preparation of 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(2-(hex-5-en-1-yloxy)-4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (3R,4S)-3-(2-(hex-5-en-1-yloxy)-4-(methoxycarbonyl)phenyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (1.55 g, 3.58 mmol), 4-hydroxy-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (1.5 g), and triphenylphosphine (1.13 g) were added to a three-necked flask, and the flask was protected by nitrogen substitution. Anhydrous tetrahydrofuran (40 mL) was added, and the resulting mixture was then decanted. Diisopropyl azodicarboxylate (868 mg) was added dropwise at 0°C, the temperature of the reaction system was slowly raised to room temperature, and the mixture was stirred overnight. Water (100 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to sand. The mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 20 / 1 (V / V)) to give 550 mg of the title compound. LCMS m / z=693.9[M+H] + .

[0318] f) Preparation of 4-(((3R,4R)-3-(2-(hex-5-en-1-yloxy)-4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(2-(hex-5-en-1-yloxy)-4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (530 mg) was added to 1,4-dioxane (3 mL), 1,4-dioxane hydrochloric acid solution (3 mL, 4 M) was added, and the mixture was protected with nitrogen and stirred at room temperature for 2 hours. The mixture was neutralized with saturated aqueous sodium bicarbonate solution (30 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and evaporated to dryness to give 440 mg of the title compound. LCMS m / z=593.7[M+H] + .

[0319] g) Preparation of 4-(((3R,4R)-1-allyl-3-(2-(hex-5-en-1-yloxy)-4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester 4-(((3R,4R)-3-(2-(hex-5-en-1-yloxy)-4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (430 mg) was dissolved in acetonitrile (10 mL), triethylamine (440 mg), 3-bromoprop-1-enyl (264 mg) were added, and the reaction was stirred at 50 ° C. overnight. The mixture was quenched with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with saturated brine (50 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to sand, and purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to obtain the title compound 350 mg. LCMS m / z=633.8[M+H] + .

[0320] h) Methyl (1 3 R,1 4 R,Z)-1 4 -((1-(tert-butoxycarbonyl)-5-methoxy-7-methyl-1H-indol-4-yl)oxy)-3-oxa-1(3,1)-piperidin-2(1,2)-benzocyclohexanon-8-ene-2 4 -Preparation of carboxylic acid esters 4-(((3R,4R)-1-Allyl-3-(2-(hex-5-en-1-yloxy)-4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (350 mg) was added to dichloromethane (350 mL), Grubbs 1st (228 mg) was added, and the mixture was protected by nitrogen substitution and stirred at 40°C for 18 hours. The reaction solution was concentrated under reduced pressure to give sand, and purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 130 mg of the title compound. LCMS m / z=605.7[M+H] + .

[0321] i)(1 3 R,14 R,Z)-1 4 -((5-Methoxy-7-methyl-1H-indol-4-yl)oxy)-3-oxa-1(3,1)-piperidin-2(1,2)-benzocyclohexanon-8-ene-2 4 Preparation of carboxylic acids Methyl (1 3 R,1 4 R,Z)-1 4 -((1-(tert-butoxycarbonyl)-5-methoxy-7-methyl-1H-indol-4-yl)oxy)-3-oxa-1(3,1)-piperidin-2(1,2)-benzocyclohexanon-8-ene-2 4 The carboxylic acid ester (35 mg) was dissolved in a mixed solution of tetrahydrofuran / methanol (3 mL / 3 mL), and an aqueous lithium hydroxide solution (3 mL, 2N) was added. The mixture was stirred at 70°C for 2 hours, concentrated to dryness under reduced pressure, and diluted aqueous hydrochloric acid was added to adjust the pH to neutral. The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to sand. The resulting mixture was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 6.1 mg of the title compound.

[0322] 1 HNMR(400MHz,DMSO-d6)δ10.87(d,J=9.4Hz,1H),7.90(dd,J=30.1,7.7Hz,1H),7.57(t, J=7.3Hz,1H),7.40(dd,J=20.6,12.0Hz,2H),7.24-7.17(m,1H),6.71(d,J=16.0Hz,1H) ,5.43(s,1H),4.93(d,J=34.3Hz,1H),4.09(s,1H),3.79(t,J=15.9Hz,3H),2.39(d,J=5 .7Hz,3H),2.23-2.15(m,1H),2.03-1.96(m,2H),1.30(s,3H),1.26(s,5H),1.23(s,6H). LCMS m / z=491.6[M+H] + .

[0323] Example 24: (13 R,1 4 R)-1 4 -((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-3-oxa-(3,1)-piperidine-2(1,2)-benzocyclohexane-2 4 -carboxylic acid [ka] a) Methyl (1 3 R,1 4 R)-1 4 -((1-(tert-butoxycarbonyl)-5-methoxy-7-methyl-1H-indol-4-yl)oxy)-3-oxa-1(3,1)-piperidine-2(1,2)-benzocyclohexane-2 4 Preparation of carboxylic acid esters Methyl (1 3 R,1 4 R,Z)-1 4 -((1-(tert-butoxycarbonyl)-5-methoxy-7-methyl-1H-indol-4-yl)oxy)-3-oxa-1(3,1)-piperidin-2(1,2)-benzocyclohexanon-8-ene-2 4 The carboxylic acid ester (60 mg) was dissolved in methanol (5 mL) and added to a three-necked flask. Palladium / carbon (35 mg, 10%) was added, the mixture was purged with hydrogen, and the mixture was stirred at room temperature overnight. The mixture was then filtered through diatomaceous earth, and the filtrate was evaporated to dryness under reduced pressure to give 45 mg of the title compound. LCMS m / z=607.4[M+H] + .

[0324] b)(1 3 R,1 4 R)-1 4 -((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-3-oxa-1(3,1)-piperidine-2(1,2)-benzocyclohexane-2 4 Preparation of carboxylic acids Methyl (1 3 R,1 4 R)-1 4-((1-(tert-butoxycarbonyl)-5-methoxy-7-methyl-1H-indol-4-yl)oxy)-3-oxa-1(3,1)-piperidine-2(1,2)-benzocyclohexane-2 4 The carboxylic acid ester (50 mg) was dissolved in a mixed solution of tetrahydrofuran / methanol (3 mL / 3 mL), and an aqueous solution of lithium hydroxide (3 mL, 2N) was added. The mixture was stirred at 70°C for 2 hours, concentrated to dryness under reduced pressure, and diluted aqueous hydrochloric acid was added to adjust the pH to neutral. The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to sand. The resulting mixture was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 5.1 mg of the title compound.

[0325] 1 HNMR(400MHz,DMSO-d6)δ10.86(s,1H),7.85(d,J=7.5Hz,1H),7.54(d,J=7.9Hz,1H),7.45( s,1H),7.20(s,1H),6.74(s,1H),6.38(s,1H),4.84(d,J=7.9Hz,1H),4.21(s,1H),3.83(s,3 H),3.25(d,J=10.5Hz,3H),2.71(d,J=9.7Hz,2H),2.40(s,3H),2.10(d,J=11.2Hz,1H),1.98 (s,2H),1.83(s,1H),1.70(s,3H),1.55(s,2H),1.40(s,2H),1.30(dd,J=26.9,17.4Hz,4H). LCMS m / z=493.3[M+H] + .

[0326] Example 25: 4-((3S,4S)-4-((5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid and 4-((3R,4R)-4-((5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid [ka]

[0327] a) Preparation of 5-(difluoromethoxy)-4-formyl-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester 4-Formyl-5-hydroxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (1.5 g) was dissolved in dichloromethane (25 mL), added to a two-necked flask, and protected by nitrogen substitution. The temperature was lowered to 0 ° C. in an ice-water bath, and an aqueous potassium hydroxide solution (12.23 g) was added dropwise, stirred for 5 minutes, and a solution of difluorobromomethyltrimethylsilane (3.32 g) in dichloromethane (5 mL) was added dropwise. The reaction was allowed to proceed at 0 ° C. for 2 hours. Water (50 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give sand, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to obtain the title compound (670 mg). LCMS m / z=326[M+H] + .

[0328] b) Preparation of 5-(difluoromethoxy)-4-hydroxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester 5-(Difluoromethoxy)-4-formyl-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (670 mg) was dissolved in dichloromethane (20 mL), added to a 100 mL two-necked flask, and protected by nitrogen substitution. m-Chloroperoxybenzoic acid (3.55 g) was added at 0°C and reacted at room temperature for 3 hours. The reaction was quenched by adding aqueous sodium hydrogen sulfite solution, and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to sand, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 4 / 1 (V / V)) to obtain 170 mg of the title compound. LCMS m / z=314.2[M+H] + .

[0329] c) Preparation of (±)-rel-(3S,4S)-4-((1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester 5-(Difluoromethoxy)-4-hydroxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (120 mg), (±)-rel-(3S,4R)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (193 mg), and triphenylphosphine (201 mg) were added to a 25 mL two-neck flask, substituted with nitrogen, and protected with anhydrous tetrahydrofuran (10 mL). The mixture was added with diisopropyl azodicarboxylate (155 mg) dropwise at 0°C, slowly warmed to room temperature, stirred overnight, quenched by adding water (20 mL), extracted with dichloromethane (20 mL × 3), the organic phases were combined, washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to sand, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 4 / 1 (V / V)) to give 137 mg of the title compound. LCMS m / z=631.3[M+H] + .

[0330] d) Preparation of (±)-rel-(3S,4S)-5-(difluoromethoxy)-4-((3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (±)-rel-(3S,4S)-4-((1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (137 mg) was dissolved in methanol (15 mL), and a solution of hydrogen chloride in 1,4-dioxane (10 mL, 4 M) was added. The mixture was protected by nitrogen substitution and stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure to give 150 mg of the title compound. LCMS m / z=531[M+H] + .

[0331] e) Preparation of (±)-rel-(3S,4S)-5-(difluoromethoxy)-4-((3-(4-(methoxycarbonyl)phenyl)-1-(3,3,3-trifluoropropyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (±)-rel-(3S,4S)-5-(difluoromethoxy)-4-((3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (150 mg) was dissolved in tetrahydrofuran (10 mL), 3,3,3-trifluoropropyl trifluoromethanesulfonate (195.6 mg) was added, N,N-diisopropylethylamine (137 mg) was added, the mixture was stirred at 70 ° C. overnight, water (20 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to sand, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 4 / 1 (V / V)) to give the title compound 140 mg. LCMS m / z=627[M+H] + .

[0332] f) Preparation of 4-((3S,4S)-4-((5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid and 4-((3R,4R)-4-((5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid (±)-rel-(3S,4S)-5-(difluoromethoxy)-4-((3-(4-(methoxycarbonyl)phenyl)-1-(3,3,3-trifluoropropyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (140 mg) was dissolved in tetrahydrofuran / methanol (10 mL / 10 mL), and an aqueous solution of lithium hydroxide (5 mL, 2N) was added. The mixture was stirred at 70 ° C. for 2 hours, concentrated to dryness under reduced pressure, and diluted aqueous hydrochloric acid was added to adjust the pH to neutral. The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to sand. The mixture was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to obtain 130 mg of the enantiomer of the title compound.

[0333] 1 HNMR(400MHz,DMSO-d6)δ11.16(s,1H),7.89(d,J=8.2Hz,2H),7.57(d,J=8.2Hz,2H),7.28( t,J=2.7Hz,1H),6.94-6.54(m,2H),6.21(s,1H),4.59-4.47(m,1H),3.56(t,J=6.1Hz,1H),3 .19-3.07(m,1H),2.91(dd,J=21.7,10.3Hz,2H),2.56(d,J=6.9Hz,2H),2.36(s,3H),2.12( t,J=10.6Hz,1H),1.77(d,J=8.8Hz,1H),1.69(d,J=9.1Hz,1H),1.43(dd,J=7.8,5.5Hz,2H). LCMS m / z=513.2[M+1] + .

[0334] The enantiomeric isomers of (±)-rel-(3S,4S)-4-(1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid were separated by chiral SFC, and 25-1,t r =1.69 min, 25-2,t r = 2.40 min (Separation method: Chromatography column: DAICELCHIRALPAK® IC 250 × 20 mm, 10 μm; Mobile phase A: Supercritical CO2; Mobile phase B: Methanol (+ 0.1% 7.0 mol / L ammonia methanol); A:B: 75:25; Flow rate: 100 mL / min; Detection wavelength: 214 nm).

[0335] 25-1,t r =1.69 minutes 1 HNMR(400MHz,DMSO-d6)δ11.18(s,1H),7.89(d,J=8.2Hz,2H),7.57(d,J=8.2Hz,2H),7.28(t,J=2.7H z,1H),6.72(dd,J=89.3,62.3Hz,2H),6.27-6.14(m,1H),4.53(td,J=9.6,4.3Hz,1H),3.55(dd,J=17. 3,11.2Hz,1H),3.12(td,J=10.0,3.7Hz,1H),2.91(dd,J=23.0,11.6Hz,2H),2.56(dd,J=15.0,8.3Hz ,2H),2.42-2.31(m,3H),2.11(dd,J=20.1,8.8Hz,1H),1.73(q,J=10.7Hz,2H),1.51(d,J=2.7Hz,2H).

[0336] 25-2,t r =2.40 minutes. 1HNMR(400MHz,DMSO)δ11.19(s,1H),7.89(d,J=8.3Hz,2H),7.57(d,J=8.3Hz,2H),7.28(t,J=2.8 Hz,1H),6.72(dd,J=89.4,62.1Hz,2H),6.21(dd,J=3.0,2.0Hz,1H),4.53(td,J=9.8,4.5Hz,1H) ,3.56(t,J=6.1Hz,1H),3.12(td,J=10.4,3.9Hz,1H),2.91(dd,J=23.0,11.4Hz,2H),2.64-2.53 (m,2H),2.41-2.33(m,3H),2.11(dd,J=19.4,9.1Hz,1H),1.82-1.63(m,2H),1.49-1.36(m,2H).

[0337] Example 26: Preparation of 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5-(methoxy-d3)-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid [ka] a) Preparation of 5-hydroxy-7-methyl-1H-indole-4-carbaldehyde In an ice-water bath, 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (5.0 g) was added to a 250 mL two-neck flask, followed by addition of dichloromethane (130 mL), and the mixture was protected by nitrogen substitution. Boron tribromide (21.66 g) was added dropwise, and the mixture was slowly warmed to room temperature and reacted overnight. The reaction solution was poured into ice water, suction filtered, the filter cake was washed with methylene chloride, the filtrate was washed with saturated sodium bicarbonate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to sand, and purified by column chromatography (mobile phase: petroleum ether / dichloromethane=3 / 2 (V / V)) to obtain 1.2 g of the title compound. LCMS m / z=176.1[M+H] + .

[0338] b) Preparation of 5-(difluoromethoxy)-4-hydroxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester 5-Hydroxy-7-methyl-1H-indole-4-carbaldehyde (1.2 g) was added to dichloromethane (40 mL), followed by the addition of di-tert-butyl dicarbonate (4.48 g) and 4-dimethylaminopyridine (334 mg). The mixture was protected by nitrogen substitution and stirred at room temperature overnight. The reaction mixture was concentrated to dryness under reduced pressure, methanol (30 mL) and potassium carbonate (10 g) were added, and the mixture was stirred at room temperature for 1 hour. The pH was adjusted to weak acidity with dilute hydrochloric acid, and then water and ethyl acetate were added for extraction and separation. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to sand, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 85 / 15 (V / V)) to obtain 1.56 g of the title compound. LCMS m / z=276.1[M+H] + .

[0339] c) Preparation of 4-formyl-5-(methoxy-d3)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester 5-(Difluoromethoxy)-4-hydroxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (1.4 g), N,N-dimethylformamide (20 mL), deuterated iodomethane (2.21 g) and potassium carbonate (2.11 g) were added to a reaction flask and reacted at room temperature overnight. After that, water (30 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give sand. The resulting mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 85 / 15 (V / V)) to give 873 mg of the title compound. LCMS m / z=293.2[M+H]+.

[0340] d) Preparation of 4-hydroxy-5-(methoxy-d3)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester 4-Formyl-5-(methoxy-d3)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (800 mg), tetrahydrofuran (5 mL), and methanol (15 mL) were added to a reaction flask, the temperature was lowered in an ice-water bath, hydrogen peroxide (5 mL) and sulfuric acid (0.5 mL) were added dropwise successively, and the mixture was stirred in an ice-water bath for another 2.5 hours. The reaction was quenched by slowly adding saturated aqueous sodium sulfite solution, and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give sand. The mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 90 / 10 (V / V)) to give 723 mg of the title compound as an enantiomer.

[0341] e) Preparation of 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-(methoxy-d3)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester The enantiomeric isomers of (±)-rel-(3S,4R)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester were separated on a chiral column, and (3S,4R)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (t r = 20.33 min) and (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (t r =16.51 min), and the absolute stereochemical configuration of (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester was confirmed by X-ray single crystal diffraction in Experimental Example 8 (separation method: chromatography column: DAICELCHIRALPAK (registered trademark) IC 250 × 4.6 mm, 5 μm; mobile phase A: n-hexane; mobile phase B: ethanol; A:B: 90:10; flow rate: 1 mL / min; detection wavelength: 254 nm).

[0342] (3S,4R)-4-Hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester 1 HNMR(400MHz,DMSO-d6)δ7.88(d,J=8.3Hz,2H),7.42(d,J=8.3Hz,2H),4.75(d,J=4.2Hz,1H),4.00(d,J=14.8Hz,1H),3.84( s,3H),3.77(d,J=11.7Hz,2H),3.34(s,1H),3.16(s,1H),2.82(d,J=11.1Hz,1H),1.69(dd,J=19.9,3.0Hz,2H),1.39(s,9H).

[0343] (3R,4S)-4-Hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester 1 HNMR(400MHz,DMSO-d6)δ7.88(d,J=8.3Hz,2H),7.42(d,J=8.3Hz,2H),4.75(d,J=4.1Hz,1H),4.00(d,J=14.8Hz,1H),3.82( d,J=15.6Hz,3H),3.76(d,J=11.9Hz,2H),3.37(s,1H),3.16(s,1H),2.82(d,J=11.1Hz,1H),1.81-1.59(m,2H),1.39(s,9H).

[0344] 4-Hydroxy-5-(methoxy-d3)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (200 mg), (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (250.8 mg), and triphenylphosphine (187.7 mg) were added to a 50 mL three-neck flask, and the flask was protected by nitrogen substitution. Anhydrous tetrahydrofuran (20 mL) was added, and diisopropyl ether was added. Pyrazolidinyl azodicarboxylate (144.7 mg) was added dropwise in an ice-water bath, the reaction system was slowly warmed to room temperature, and stirred overnight. Water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give sand. The mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 90 / 10 (V / V)) to give 171 mg of the title compound.

[0345] f) Preparation of 5-(methoxy-d3)-4-(((3R,4R)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-(methoxy-d3)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (171 mg) was dissolved in 1,4-dioxane (2 mL), 1,4-dioxane hydrochloric acid solution (1 mL, 4 M) was added, and the mixture was protected by nitrogen substitution and stirred at room temperature for 3.5 hours. A saturated aqueous solution of sodium bicarbonate (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 141 mg of the title compound. LCMS m / z=498.3[M+H] + .

[0346] g) Preparation of 4-(((3R,4R)-1-(2,2-difluoroethyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-(methoxy-d3)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester 5-(Methoxy-d3)-4-(((3R,4R)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (75 mg) was added to a 50 mL reaction flask, tetrahydrofuran (5 mL) and N,N-diisopropylethylamine (78.8 mg) were added, and the mixture was protected by nitrogen substitution. 2,2-Difluoroethyl trifluoromethanesulfonate (97 mg) was added, and the mixture was stirred at 50°C overnight. The reaction solution was concentrated under reduced pressure, evaporated to dryness, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 90 / 10 (V / V)) to give the title compound (61 mg).

[0347] h) Preparation of 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5-(methoxy-d3)-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid 4-(((3R,4R)-1-(2,2-difluoroethyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-(methoxy-d3)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (60 mg) was dissolved in tetrahydrofuran / methanol (2 mL / 2 mL), and an aqueous solution of lithium hydroxide (1 mL, 2N) was added. The mixture was stirred at 70 ° C. for 3.5 hours, concentrated to dryness under reduced pressure, and diluted aqueous hydrochloric acid was added to adjust the pH to neutral. Extraction was performed with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to sand. The resulting mixture was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to obtain 25.2 mg of the title compound.

[0348] 1HNMR(400MHz,DMSO-d6)δ12.80(s,1H),10.83(s,1H),7.91(d,J=8.2Hz,2H),7.58(d ,J=8.2Hz,2H),7.17(s,1H),6.62(s,1H),6.17(s,1H),6.33-5.96(m,1H),4.45(dd,J =15.1,9.0Hz,1H),3.13(td,J=10.2,3.8Hz,1H),2.93(dd,J=23.5,11.9Hz,2H),2.7 8(t,J=15.5Hz,2H),2.36(s,3H),2.32-2.18(m,1H),2.08-1.91(m,1H),1.70(s,2H). LCMS m / z=448.2 [M+H]+.

[0349] Example 27: 4-((3R,4R)-4-((5-(methoxy-d3)-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid [ka] Prepared according to the preparation method of Example 26, but replacing 2,2-difluoroethyl trifluoromethanesulfonate with 2,2,2-trifluoroethyl trifluoromethanesulfonate in step g).

[0350] 1 HNMR(400MHz,DMSO-d6)δ12.76(s,1H),10.84(s,1H),7.91(d,J=7.9Hz,2H),7.58(d,J=7.9Hz,2H),7.17(s,1H),6.62(s,1H),6.18(s,1H),4 .49-4.45(m,1H),3.26(d,J=10.1Hz,3H),3.15(d,J=10.0Hz,1H),2.95(t,J=13.0Hz,2H),2.68(t,J=11.1Hz,1H),2.36(s,3H),1.71(s,2H). LCMS m / z=466.2[M+H] + .

[0351] Example 28: 4-((3R,4R)-4-((5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid [ka] a) Preparation of 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester 5-(Difluoromethoxy)-4-hydroxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (80 mg), (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (172 mg), and triphenylphosphine (134 mg) were added to a 25 mL three-necked flask, and the flask was protected with nitrogen. Anhydrous tetrahydrofuran (10 mL) was added, and diisopropyl azodicarboxylate (104 mg) was added dropwise in an ice-water bath. The reaction system was slowly warmed to room temperature and stirred overnight. Water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give sand. The title compound (80 mg) was obtained by column chromatography (mobile phase: petroleum ether / ethyl acetate = 90 / 10 (V / V)). LCMS m / z=631.3[M+H] + .

[0352] b) Preparation of 5-(difluoromethoxy)-4-(((3R,4R)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (80 mg) was dissolved in 1,4-dioxane (5 mL), 1,4-dioxane hydrochloric acid solution (5 mL, 4 M) was added, and the mixture was protected by nitrogen substitution and stirred at room temperature for 3.5 hours. A saturated aqueous sodium bicarbonate solution (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 65 mg of the title compound. LCMS m / z=531[M+H] + .

[0353] c) Preparation of 5-(difluoromethoxy)-4-(((3R,4R)-3-(4-(methoxycarbonyl)phenyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester 5-(Difluoromethoxy)-4-(((3R,4R)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (37 mg) was added to a 50 mL reaction flask, tetrahydrofuran (5 mL) and N,N-diisopropylethylamine (36 mg) were added, and the mixture was protected by nitrogen substitution. 2,2,2-trifluoroethyl trifluoromethanesulfonate (49 mg) was added, and the mixture was stirred at 50°C for 2 hours. The reaction solution was concentrated under reduced pressure, evaporated to dryness, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 90 / 10 (V / V)) to obtain 28 mg of the title compound.

[0354] d) 4-((3R,4R)-4-((5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid 5-(Difluoromethoxy)-4-((3R,4R)-3-(4-(methoxycarbonyl)phenyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (28 mg) was dissolved in tetrahydrofuran / methanol (5 mL / 5 mL), and an aqueous solution of lithium hydroxide (5 mL, 2N) was added. The mixture was stirred at 70 ° C. for 2 hours, concentrated to dryness under reduced pressure, and diluted aqueous hydrochloric acid was added to adjust the pH to neutral. The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to sand. The resulting mixture was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give the title compound (12 mg).

[0355] 1 HNMR(400MHz,DMSO-d6)δ12.83(s,1H),11.17(s,1H),7.89(d,J=8.3Hz,2H),7.57(d ,J=8.3Hz,2H),7.29(t,J=2.8Hz,1H),6.94-6.56(t,1H),6.67(s,1H),6.28-6.21(m, 1H),4.56(td,J=9.5,4.8Hz,1H),3.24(d,J=10.2Hz,1H),3.19-3.11(m,1H),2.96(t, J=12.7Hz,2H),2.74(t,J=11.4Hz,1H),2.36(s,3H),1.80-1.66(m,2H),1.23(s,2H). LCMS m / z=499[M+H] + .

[0356] Example 29: 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid [ka] Prepared by following the procedure of Example 26, but replacing 2,2,2-trifluoroethyl trifluoromethanesulfonate with 2,2-difluoroethyl trifluoromethanesulfonate in step g).

[0357] 1 HNMR(400MHz,DMSO-d6)δ12.77(s,1H),11.17(s,1H),7.89(d,J=8.3Hz,2H),7.57(d,J=8.3Hz,2H),7.2 8(t,J=2.8Hz,1H),6.94-6.56(t,1H),6.67(s,1H),6.29-6.01(tt,J=4.2Hz,1H),6.22(dd,J=2.9,2.0Hz ,1H),4.53(td,J=9.7,5.0Hz,1H),3.14(td,J=10.4,3.9Hz,1H),2.94(dd,J=20.9,10.8Hz,2H),2.79(td ,J=15.9,3.0Hz,2H),2.56(t,J=11.3Hz,1H),2.36(s,3H),1.74(d,J=3.7Hz,1H),1.25(d,J=9.2Hz,2H). LCMS m / z=481[M+H] + .

[0358] Example 30: 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((7-methyl-5-(trifluoromethoxy)-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid [ka] a) Preparation of 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester 4-Hydroxy-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (1.49 g), (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (1.2 g), and triphenylphosphine (1.13 g) were added to a 100 mL three-neck flask, and the flask was protected by nitrogen substitution. Anhydrous tetrahydrofuran (40 mL) was added, and the mixture was stirred in an ice-water bath with diisopropyl ether. The reaction mixture was slowly warmed to room temperature and stirred overnight. Water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give sand. The resulting mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 85 / 15 (V / V)) to give 1.1 g of the title compound.

[0359] b) Preparation of methyl 4-((3R,4R)-4-((5-hydroxy-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoate 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (1.1 g) was added to a reaction flask, and the mixture was protected by nitrogen substitution. Dichloromethane (20 mL) was added, and boron tribromide (187.7 mg) was added dropwise in an ice-water bath. The reaction system was slowly warmed to room temperature and the reaction was continued for approximately 6 hours. Triethylamine was added dropwise in an ice-water bath to make the mixture weakly basic, and the reaction solution was concentrated under reduced pressure to dryness to obtain 0.8 g of the title compound. LCMS m / z=381.2[M+H] + .

[0360] c) Preparation of 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-hydroxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester 5-Hydroxy-7-methyl-1H-indole-4-carbaldehyde (0.8 g) was added to dichloromethane (40 mL), followed by the addition of di-tert-butyldicarboxylic acid ester (2.0 g) and 4-dimethylaminopyridine (102 mg). The mixture was protected by nitrogen substitution and stirred at room temperature overnight. Water and ethyl acetate were added for extraction and separation, followed by drying over anhydrous sodium sulfate, filtration, and concentration under reduced pressure to sand. The mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 85 / 15 (V / V)) to give 447 mg of the title compound.

[0361] d) 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-5-(trifluoromethoxy)-1H-indole-1-carboxylic acid tert-butyl ester 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-hydroxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (447 mg), 2,8-difluoro-5-(trifluoromethyl)-5H-dibenzo[B,D]thiophen-5-ium trifluoromethanesulfonate (405 mg), potassium carbonate (159.6 mg) were added to a reaction flask, followed by the addition of N,N-dimethylformamide (20 mL). The mixture was stirred at room temperature overnight, and the reaction was quenched by adding water (20 mL). The mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give sand. The mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 90 / 10 (V / V)) to give 158 mg of the title compound.

[0362] e) 4-(((3R,4R)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-5-(trifluoromethoxy)-1H-indole-1-carboxylic acid tert-butyl ester 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-5-(trifluoromethoxy)-1H-indole-1-carboxylic acid tert-butyl ester (158 mg) was dissolved in 1,4-dioxane (5 mL), 1,4-dioxane hydrochloric acid solution (5 mL, 4 M) was added, and the mixture was protected by nitrogen substitution and stirred at room temperature for 3.5 hours. A saturated aqueous solution of sodium bicarbonate (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 105 mg of the title compound.

[0363] f) Preparation of 4-(((3R,4R)-1-(2,2-difluoroethyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-5-(trifluoromethoxy)-1H-indole-1-carboxylic acid tert-butyl ester 4-(((3R,4R)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-5-(trifluoromethoxy)-1H-indole-1-carboxylic acid tert-butyl ester (65 mg) was added to a 50 mL reaction flask, tetrahydrofuran (5 mL) and N,N-diisopropylethylamine (61 mg) were added, and the mixture was protected by nitrogen substitution. 2,2-difluoroethyl trifluoromethanesulfonate (75.8 mg) was added, and the mixture was stirred at 50°C overnight. The reaction mixture was concentrated under reduced pressure, evaporated to dryness, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 80 / 20 (V / V)) to give the title compound (49 mg).

[0364] g) 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((7-methyl-5-(trifluoromethoxy)-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid 4-(((3R,4R)-1-(2,2-difluoroethyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-5-(trifluoromethoxy)-1H-indole-1-carboxylic acid tert-butyl ester (49 mg) was dissolved in tetrahydrofuran / methanol (5 mL / 5 mL), and an aqueous solution of lithium hydroxide (5 mL, 2N) was added. The mixture was stirred at 70 ° C. for 3.5 hours, concentrated to dryness under reduced pressure, and diluted aqueous hydrochloric acid was added to adjust the pH to neutral. Extraction was performed with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to sand. The resulting mixture was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give the title compound (18.3 mg).

[0365] 1 HNMR(400MHz,DMSO-d6)δ12.92(s,1H),10.93(s,1H),8.00(d,J=8.4Hz,2H),7.67(d,J= 8.4Hz,2H),7.25(t,J=2.8Hz,1H),6.72(s,1H),6.44-6.02(m,2H),4.45(dd,J=16.1,9. 5Hz,1H),3.23(td,J=10.7,4.2Hz,1H),3.03(dd,J=21.3,10.7Hz,2H),2.85(dd,J=33.4 ,21.7Hz,2H),2.43(d,J=17.8Hz,3H),2.39(d,J=14.4Hz,1H),1.80(s,2H),1.33(s,1H). LCMS m / z=499.2[M+H] + .

[0366] Example 31: 4-((3R,4R)-4-((7-methyl-5-(trifluoromethoxy)-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid [ka] Prepared by referring to the preparation method of Example 30, except that in step f) 2,2-difluoroethyl trifluoromethanesulfonate was replaced with 2,2,2-trifluoroethyl trifluoromethanesulfonate.

[0367] 1 HNMR(400MHz,DMSO-d6)δ12.90(s,1H),10.93(s,1H),8.00(d,J=8.1Hz,2H ),7.68(d,J=8.1Hz,2H),7.27(s,1H),6.72(s,1H),6.28(s,1H),4.58(d,J= 7.4Hz,1H),3.36(d,J=9.2Hz,3H),3.24(dd,J=9.5,6.8Hz,1H),3.05(t,J=1 2.4Hz, 2H), 2.78 (t, J=11.1Hz, 1H), 2.45 (s, 3H), 1.81 (s, 1H), 1.33 (s, 1H). LCMS m / z=517.2[M+H] + .

[0368] Example 32: 4-((2R,5S)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-1-yl)benzoic acid, 4-((2S,5R)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-1-yl)benzoic acid, 4-((2S,5S)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-1-yl)benzoic acid and 4-((2R,5R)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-1-yl)benzoic acid [ka] a) Preparation of methyl 5-ethoxypyridine-2-carboxylate Methyl 5-hydroxypyridine-2-carboxylate (49 g), ethyl iodide (54.90 g), and potassium carbonate (66 g) were added to a reaction flask, followed by the addition of N,N-dimethylformamide (490 mL), protection by nitrogen substitution, and stirring at room temperature overnight. The reaction was quenched with water and extracted with ethyl acetate (5 x 100 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 54 g of the title compound. LCMS m / z=182[M+H] + .

[0369] b) Preparation of (5-ethoxypyridin-2-yl)methanol Methyl 5-ethoxypyridine-2-carboxylate (54 g), sodium borohydride (33.82 g), calcium chloride (46.6 g) were added to a reaction flask, followed by the addition of ethanol (540 mL) and stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give a residue, to which water was added and extracted with ethyl acetate (3 x 100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 36.9 g of the title compound. LCMS m / z=154[M+H] + .

[0370] c) Preparation of 1-benzyl-5-ethoxy-2-(hydroxymethyl)pyridine-1-ammonium bromide (5-Ethoxypyridin-2-yl)methanol (34.4 g), benzyl bromide (57.61 g) were added to a reaction flask, acetonitrile (344 mL) was added, and the mixture was stirred at 90°C overnight. The mixture was cooled to room temperature, and the precipitated solid was collected by filtration and washed with ethyl acetate (3 x 20 mL) to give 64 g of the title compound. LCMS m / z=244[M+H] + .

[0371] d) Preparation of (1-benzyl-5-ethoxy-3,6-dihydro-2H-pyridin-2-yl)methanol 1-Benzyl-5-ethoxy-2-(hydroxymethyl)pyridine-1-ammonium bromide (40 g) was added to a reaction flask, and a mixed solution of methanol / tetrahydrofuran (200 mL / 200 mL) was added. The mixture was cooled to -60°C, sodium borohydride (11.6 g) was added, the mixture was slowly warmed to room temperature and stirred for 2 hours, water (200 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine (200 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give sand. The mixture was purified by column chromatography (mobile phase: dichloromethane / methanol = 10 / 1 (V / V)) to obtain 29 g of the title compound. LCMS m / z=248[M+H] + .

[0372] e) Preparation of 1-benzyl-5-ethoxy-2-((methoxymethoxy)methyl)-1,2,3,6-tetrahydropyridine (1-benzyl-5-ethoxy-3,6-dihydro-2H-pyridin-2-yl)methanol (28 g) was added to the reaction flask, followed by the addition of tetrahydrofuran (311 mL). Sodium hydride (13.58 g) was added under an ice bath and stirred at 0°C for 30 minutes. Bromo(methoxy)methane (16.98 g) was then added dropwise, and the reaction was slowly warmed to room temperature and stirred for 2 hours. Water / ice (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give sand. The mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 (V / V)) to give the title compound (29 g). LCMS m / z=292[M+H] + .

[0373] f) Preparation of 5-ethoxy-2-((methoxymethoxy)methyl)piperidine 1-Benzyl-5-ethoxy-2-((methoxymethoxy)methyl)-1,2,3,6-tetrahydropyridine (29 g) and palladium / carbon (2.86 g) were added to a reaction flask, followed by addition of methanol (193 mL), replacement with hydrogen, stirring at room temperature for 3 hours, filtration, washing the filter cake with methanol (3 × 5 mL), and concentration of the filtrate to dryness under reduced pressure to give 16.2 g of the title compound. LCMS m / z=204[M+H] + .

[0374] g) Preparation of methyl 4-(5-ethoxy-2-((methoxymethoxy)methyl)piperidin-1-yl)benzoate 5-Ethoxy-2-((methoxymethoxy)methyl)piperidine (5 g), methyl 4-bromobenzoate (4.23), tris(dibenzylidene-BASEacetone)dipalladium (2.55 g), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (4.59 g), and cesium carbonate (24.04 g) were added to a reaction flask, and then toluene (50 mL) was added. The mixture was protected by nitrogen substitution and stirred at 100°C for 24 hours. The reaction solution was concentrated under reduced pressure to give sand, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 (V / V)) to obtain 5.6 g of the title compound. LCMS m / z=338[M+H] + .

[0375] h) Preparation of methyl 4-(5-ethoxy-2-(hydroxymethyl)piperidin-1-yl)benzoate Methyl 4-(5-ethoxy-2-((methoxymethoxy)methyl)piperidin-1-yl)benzoate (5 g) was dissolved in methanol (20 mL), and a solution of hydrogen chloride in 1,4-dioxane (4 M, 20.0 mL) was added. The mixture was stirred at room temperature for 2 hours, and the reaction mixture was concentrated to dryness under reduced pressure to give the title compound (3 g). LCMS m / z=294 [M+H] + .

[0376] i) Preparation of methyl 4-(5-ethoxy-2-formylpiperidin-1-yl)benzoate Methyl 4-(5-ethoxy-2-(hydroxymethyl)piperidin-1-yl)benzoate (4 g) and Dess-Martin oxidant (8.67 g) were added to a reaction flask, followed by the addition of dichloromethane (40.0 mL). The mixture was stirred at room temperature for 2 hours, filtered, and the filter cake was washed with dichloromethane (3 × 10 mL). The filtrate was concentrated under reduced pressure to give sand, which was then purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to give the title compound (3 g). LCMS m / z=292[M+H] + .

[0377] j) Preparation of methyl (Z)-4-(5-ethoxy-2-((2-toluenesulfonylhydrazino)methyl)piperidin-1-yl)benzoate Methyl 4-(5-ethoxy-2-formylpiperidin-1-yl)benzoate (2 g) and p-toluenesulfonylhydrazine (1.4 g) were dissolved in methanol (20 mL) and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give sand, which was then purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 (V / V)) to give 2.2 g of the title compound. LCMS m / z=460[M+H] + .

[0378] k) Preparation of (E)-4-((5-ethoxy-1-(4-(methoxycarbonyl)phenyl)piperidin-2-ylidene)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (Z)-4-(5-ethoxy-2-((2-toluenesulfonylhydrazino)methyl)piperidin-1-yl)benzoic acid methyl ester (600 mg), 4-bromo-5-methoxy-7-methylindole-1-carboxylic acid tert-butyl ester (666.2 mg), tris-(dibenzylidene-BASE acetone)dipalladium (135.1 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropyl Pyrbiphenyl (62.2 mg) and lithium tert-butoxide (313.5 mg) were added to a reaction flask, followed by the addition of 1,4-dioxane (10 mL). The mixture was stirred at 100°C under nitrogen protection for 3 hours, water was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (30 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to give 900 mg of the title compound. LCMS m / z=535[M+H] + .

[0379] l) Preparation of 4-((5-ethoxy-1-(4-(methoxycarbonyl)phenyl)piperidin-2-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (E)-4-((5-ethoxy-1-(4-(methoxycarbonyl)phenyl)piperidin-2-ylidene)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (900 mg), sodium cyanoborohydride (126.9 mg), acetic acid (1.35 mL), and methanol (13.5 mL) were added to a reaction flask, stirred at room temperature for 20 hours, concentrated under reduced pressure to give sand, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 (V / V)) to give the title compound (80 mg). LCMS m / z=537[M+H] + .

[0380] m) Preparation of 4-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-1-yl)benzoic acid 4-((5-Ethoxy-1-(4-(methoxycarbonyl)phenyl)piperidin-2-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (80 mg) was added to a reaction flask, followed by the addition of aqueous lithium hydroxide (1.8 mL, 2N) and tetrahydrofuran (1 mL) and stirring at 70°C for 30 hours. The residue was acidified to pH 4 with concentrated sulfuric acid, and the precipitated solid was collected by filtration. The filter cake was washed with water (3 x 5 mL) to give 32 mg of the title compound.

[0381] The isomeric mixture was separated by chiral SFC to give 32a-1,t r =5.47 minutes, 32a-2,t r =7.57 minutes, 32a-3,t r =10.6 minutes, 32a-4,t r = 15.2 min (separation method: chromatography column: CHIRALPAK-IG 2 × 25 cm; mobile phase A: n-hexane (0.1% formic acid); mobile phase B: ethanol: dichloromethane = 1:1A:B = 1:1; flow rate: 20 mL / min; detection wavelength: 220 / 254 nm).

[0382] 32a-1,t r =5.47 minutes 1 HNMR(400MHz,DMSO-d6)δ10.86(s,1H),7.82-7.73(m,2H),7.30(t,J=2.8Hz,1H),7.03(d,J=8.8Hz,2H), 6.71(s,1H),6.44(dd,J=3.1,1.9Hz,1H),4.30(s,1H),3.88(d,J=13.9Hz,1H),3.82(s,3H),3.67(s,1H) ,3.49-3.41(m,2H),3.21(t,J=11.8Hz,2H),2.75(dd,J=12.7,4.1Hz,1H),2.46-2.39(m,3H),2.08(dd,J =14.7,11.4Hz,1H),1.66(q,J=15.2,14.4Hz,2H),1.15(d,J=8.2Hz,1H),1.05(t,J=7.0Hz,3H).Lack of active hydrogen

[0383] 32a-2,t r= 7.57 points 1 HNMR(400MHz, DMSO-d6) δ 12.04(s, 1H), 10.86(s, 1H), 7.77(d, J = 8.9Hz, 2H), 7.30(t, J = 2.8Hz, 1H), 7.03(d, J = 8.8Hz, 2H), 6.71(s, 1H), 6.49 - 6.40(m, 1H), 4.30(s, 1H), 3.88(d, J = 14.3Hz, 1H), 3.82(s, 3H), 3.67(s, 1H), 3.45(dt, J = 7.0, 3.3Hz, 2H), 3.19(d, J = 11.8Hz, 2H), 2.75(dd, J = 12.8, 4.0Hz, 1H), 2.43(s, 3H), 2.08(t, J = 13.3Hz, 1H), 1.73 - 1.59(m, 2H), 1.15(d, J = 13.0Hz, 1H), 1.05(t, J = 7.0Hz, 3H).

[0384] 32a - 3, t r = 10.6 points 1 HNMR(400MHz, DMSO-d6) δ 12.12(s, 1H), 10.87(s, 1H), 7.79(d, J = 8.6Hz, 2H), 7.30(t, J = 2.9Hz, 1H), 7.05(d, J = 8.8Hz, 2H), 6.70(s,​​​​​​​HNMR(400MHz,DMSO-d6)δ12.15(s,1H),10.87(s,1H),7.84-7.72(m,2H),7.30(t,J=2.8Hz,1H),7.05(d,J=9.1 Hz,2H),6.70(s,1H),6.37(dd,J=3.2,1.9Hz,1H),4.29(d,J=9.3Hz,1H),3.88(dd,J=12.4,4.8Hz,1H),3.80(s, 3H),3.60(qd,J=6.9,4.8Hz,2H),3.18(d,J=11.7Hz,2H),2.93(t,J=11.4Hz,1H),2.71(dd,J=12.7,4.1Hz,1H), 2.43(s,3H),1.87(d,J=9.5Hz,1H),1.76(p,J=11.6,10.7Hz,1H),1.43(d,J=5.6Hz,2H),1.16(t,J=7.0Hz,3H).

[0386] Example 33: 5-(4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)phenyl)-1,3,4-oxadiazol-2(3H)-one [ka] a) Preparation of 4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoylhydrazine 4- ((3R,4R)-4- ((5-methoxy-7-methyl-1H-indol-4-yl) oxy) -1- (2,2,2-trifluoroethyl) piperidin-3-yl) benzoic acid (50 mg) was added to a reaction flask, followed by the addition of tetrahydrofuran (5 mL), N,N'-carbonyldiimidazole (26.3 mg), and stirred at 50 ° C. for 2 hours. Further, hydrazine hydrochloride (14.8 mg) and 1,8-diazobispiro [5.4.0] undec-7-ene (41.2 mg) were added sequentially, and the mixture was reacted overnight at 50 ° C., cooled, water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain 25 mg of the title compound. LCMS m / z=477.2[M+H] + .

[0387] b) Preparation of 5-(4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)phenyl)-1,3,4-oxadiazol-2(3H)-one 4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoylhydrazine (25 mg) was added to a reaction flask, followed by the addition of acetonitrile (10 mL), N,N'-carbonyldiimidazole (12.8 mg), and 1,8-diazobispiro[5.4.0]undec-7-ene (32 mg). The mixture was heated to 50°C and reacted overnight. The reaction solution was concentrated under reduced pressure to give sand, and purified by column chromatography (mobile phase: dichloromethane / methanol = 90 / 10 (V / V)) to obtain 14.4 mg of the title compound.

[0388] 1HNMR(400MHz,DMSO-d6)δ12.43(s,1H),10.83(s,1H),7.76(d,J=8.2Hz,2H),7.63 (d,J=8.2Hz,2H),7.17(s,1H),6.63(s,1H),6.20(s,1H),4.47(dd,J=15.4,8.5Hz, 1H),3.61(s,3H),3.23(d,J=10.0Hz,2H),3.14(td,J=10.1,3.6Hz,1H),3.02-2.8 7(m,2H),2.69(t,J=11.2Hz,1H),2.44(s,1H),2.36(s,3H),1.71(d,J=3.4Hz,2H). LCMS m / z=503.2[M+H] + .

[0389] Experimental Example 1: Human complement factor B TR-FRET assay The inhibitory activity of the compounds against complement factor B was tested in a competitive binding experiment using the small molecule inhibitor (+) or (-)-2-((1E,3E,5E)-5-(1-(6-((2-(3-(4-((R)-3-amino-3-phenylpropanoyl)-1-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazin-2-yl)phenoxy)ethyl)amino)-6-oxohexyl)-3,3-dimethyl-5-sulfoindolin-2-ylidene)penta-1,3-dien-1-yl)-1-ethyl-3,3-dimethyl-5-sulfo-3H-indol-1-ium (CN2480050471.1 prepared with reference to Biological Example 2) as a probe. Complement factor B (ComplementTech, A135) was purified using EZ-Link TM After incubation with Sulfo-NHS-LC-LC-biotin (Thermo, 21338) at a ratio of 1:20 on ice for 2 hours, the reaction was stopped by adding 1 M Tris (pH 7.5). TMBiotin-labeled complement factor B was obtained by purifying twice using a desalting spin column (Thermo, 89890). In the experiment, biotin-labeled complement factor B at a final concentration of 25 nM was incubated with different concentrations of compounds in buffer (PBS containing 10 mM MgCl2 and 0.05% Chaps) for 30 minutes at 4°C. Cy5 fluorescently labeled probe and europium chelate-labeled streptavidin (PerkinElmer, AD0060) were added at final concentrations of 75 nM and 0.225 nM, respectively, and the reaction was allowed to proceed at 4°C for 2 hours. After the reaction was completed, time-dependent fluorescence energy transfer (TR-FRET) data were read using a microplate reader (Tecan, SPARK; excitation wavelengths: 337 nm, 615 nm, and 665 nm), and the IC was calculated. 50 was determined, and the test results are shown in Table 1 below.

[0390] Control LNP023: CN2480050471.1 was synthesized with reference to Example 26, and its structure is as follows: [ka] [Table 1]

[0391] Experimental Example 2: Serum alternative pathway complement deposition experiment The Wieslab® Complement System Alternative Pathway Kit (WIESLAB® Complement System Alternative Pathway AP330 RUO) was used to detect the inhibitory activity of compounds against the alternative complement pathway in human serum. Human serum was diluted 18-fold with the kit's diluent, and 130 μL of the diluted serum was added to a 96-well plate. The corresponding concentrations of test compounds were then added using a compound titration system (Tecan, D300e). Test compounds were tested in a single-well assay with a starting concentration of 10 μM, 3-fold dilutions, and six concentration points. DMSO was uniformly adjusted to 0.1% in all drug-added wells. 0.1% DMSO and 130 μL of diluted serum were added to positive control wells, and 0.1% DMSO and 130 μL of diluent were added to negative control wells. The wells were pre-incubated at room temperature for 15 minutes. The incubated mixture was transferred to a 96-well plate (100 μL per well) and incubated at 37°C for 60 minutes. The wells were then discarded, and 300 μL of the kit's wash buffer was added to each well. After washing three times, 100 μL of the kit's coupling antibody conjugate was added to each well and incubated at room temperature for 30 minutes. The wells were then cleared of the liquid, and 300 μL of the kit's wash buffer was added to each well. After washing three times, 100 μL of substrate solution was added to each well and incubated at room temperature for 30 minutes. Detection was performed using a microplate reader (Tecan, SPARK), and the absorbance at 405 nm was read. The experimental data are shown in Table 2 below. [Table 2]

[0392] Experimental Example 3: Pharmacokinetic study in mice Experimental objective: To investigate the plasma pharmacokinetics of compounds of the present invention after a single intravenous injection and oral administration in male ICR (CD-1) mice. Experimental animals: male ICR (CD-1) mice weighing 32-35 g; supplier: Vital River Laboratory Animal Technology Co., Ltd.

[0393] Experimental procedure: Injection (IV): Oral administration (PO): Dose is 10 mg / kg (Vehicle: Water (0.5% methylcellulose (w / v) and 0.5% Tween 80 (v / v))).

[0394] Sample collection: At each time point, 40 μL of blood was collected from the experimental animals via the orbit and placed in an anticoagulant tube containing EDTA-K2. The whole blood sample was centrifuged at 1500 g for 10 minutes to separate the plasma, and the upper layer of the plasma sample was collected and placed in a sample tube for LC-MS / MS analysis.

[0395] Data analysis: WinNonlin TM Plasma concentrations were processed using a non-arterial model in pharmacokinetic software Version 6.3 (Pharsight, Mountain View, CA), and the pharmacokinetic parameters Cl, T were calculated using the linear-logarithmic trapezoidal method. 1 / 2 , C max and AUC 0-24 were calculated and the results are shown in the table below. [Table 3]

[0396] Experimental Example 4: Collagen antibody-induced murine arthritis model Experimental Objective: To investigate the pharmacodynamic effects of the compounds of the present invention on collagen antibody- and lipopolysaccharide-induced arthritis (CAIA) in BALB / c mice. Experimental Animals: BALB / c mice, male, 6-8 weeks, 18-20 g; Supplier: Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0397] Testing Procedure: 1. Induction of the murine CAIA model: On day 0, all mice were injected with 0.15 mL of Arthrogen-CIA 5-clone mixed type II collagen antibody (10 mg / mL, Chondrex) via the tail vein. On day 3, mice were injected with 0.2 mL of LPS (Escherichia coli 0111:B4 lipopolysaccharide, 0.5 mg / mL, Chondrex).

[0398] 2. Administration: [Table 4]

[0399] Data were analyzed using one-way ANOVA / Dunnett's method in Graphpad Prism and repeated measures ANOVA / Bonferroni method in SPSS. P<0.05 was considered significant.

[0400] Arthritis score: The development of arthritis in the limbs of animals in each group was observed three times weekly from the day of modeling until the end of the experiment. The severity of the lesions (redness and swelling) was scored on a scale of 0 to 4. The scoring criteria were as follows: 0: no signs of erythema or swelling; 1: erythema or slight swelling of the midfoot (ankle); 2: erythema and slight swelling from the ankle to the midfoot; 3: erythema and moderate swelling from the ankle joint to the metatarsal joint; 4: erythema and severe swelling from the toes or fingers to the ankle or wrist joint.

[0401] Joint swelling: The thickness of the left and right footpads of the animals was measured three times a week from the day of modeling until the end of the experiment using a spiral micrometer (Mitutoyo, 0-25 mm, minimum 0.001 mm).

[0402] Experimental Results: The experimental data are shown in Tables 5 and 6 and Figures 1 and 2. [Table 5] [Table 6]

[0403] Experimental conclusion: According to the scoring results, all of the compounds of the present invention can significantly improve the severity of arthritis lesions and reduce joint swelling in model animals compared with the model group, and their effects are superior to those of LNP023.

[0404] Experimental Example 5: Pharmacodynamic study of test substances in CAIA model mice Experimental Objective: To evaluate the pharmacodynamic effects of test substances on collagen antibody and lipopolysaccharide-induced arthritis (CAIA) in BALB / c mice.

[0405] Experimental animal: BALB / c mouse, male, 6~8 weeks, 18~20g; Supplier: Shanghai Jihui Experimental Animal Feeding Co., Ltd.

[0406] Testing Procedure: 1. Induction of the murine CAIA model: On day 0, all mice were injected with 0.15 mL of Arthrogen-CIA 5-clone mixed type II collagen antibody (10 mg / mL, Chondrex) via the tail vein. On day 3, mice were injected with 0.2 mL of LPS (Escherichia coli 0111:B4 lipopolysaccharide, 0.5 mg / mL, Chondrex).

[0407] 2. Administration: [Table 7]

[0408] Experimental data are expressed as mean ± SEM. Data were analyzed using one-way ANOVA / Dunnett's method in Graphpad Prism and repeated measures ANOVA / Bonferroni method in SPSS. P < 0.05 was considered significant.

[0409] Arthritis score: The development of arthritis in the limbs of animals in each group was observed three times weekly from the day of modeling until the end of the experiment. The severity of the lesions (redness and swelling) was scored on a scale of 0 to 4. The scoring criteria were as follows: 0: no signs of erythema or swelling; 1: erythema or slight swelling of the midfoot (ankle); 2: erythema and slight swelling from the ankle joint to the midfoot; 3: erythema and moderate swelling from the joint to the metatarsal joint; 4: erythema and severe swelling from the toes or fingers to the ankle or wrist joint.

[0410] AUC Scoring: After the experiment was completed, the mean arthritis scores for each group and the scores for each time point were calculated and analyzed using GraphPad Prism 8.4.3 software. The area under the curve (AUC) was selected for XY analysis to determine the arthritis AUC score for each group. A higher AUC indicates a more severe arthritis. The results of the AUC experiment are shown in Table 8 and Figure 3. [Table 8]

[0411] Experimental conclusion: According to the scoring results, the compounds of the present invention significantly improved the severity of arthritis lesions in model animals compared with the model group, and showed a significantly lower scoring AUC than LNP023.

[0412] Experimental Example 6: X-ray single crystal diffraction experiment Preparation method: Compound 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid (13a-2,t r 5 mg of the solution (=1.95 min) was placed in a glass vial, dissolved in 0.6 ml of a mixed solvent of acetone and water (2:1, v / v), filtered into another clean vial, sealed with a sealing film, punctured with a syringe needle, and left at room temperature for 3 days to allow evaporation, yielding a rod-shaped single crystal sample.

[0413] Diffraction data were integrated and reduced using the SAINT program, and empirical absorption corrections were applied to the data using the SADABS program. The single crystal structure was solved using direct methods using SHELXT2014, followed by structural refinement using least-squares methods. Hydrogen atom refinement was performed using isotropic calculations, and hydrogen atoms on CH were determined by computational hydrogen addition, followed by refinement using a riding model. Figure 4 and Table 9 below show the single crystal data for Example 13a-2, 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid monohydrate. The Flack constant is 0.10(9), and C11 and C15 are in the R configuration. [Table 9]

[0414] Experimental Example 7: X-ray single crystal diffraction experiment Preparation method: Compound 4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid (14a-2,t r A saturated solution of acetonitrile (1 mL) at high temperature (approximately 60°C) was prepared in a 3 mL glass flask. The above clear solution was drawn up into a 2 mL syringe while still hot and filtered through a hydrophilic PTFE needle filter (13 mm × 0.45 μm). The filtrate was transferred to another clean 3 mL glass flask, then transferred to room temperature and left to stand for 1 day, yielding a transparent single crystal.

[0415] Diffraction data were integrated and reduced using the SAINT program, and empirical absorption corrections were applied to the data using the SADABS program. The single crystal structure was solved using direct methods using SHELXT2014, followed by structural refinement using least-squares fitting. Hydrogen atom refinement was performed using isotropic calculations, and hydrogen atoms on CH were determined by computational hydrogen addition, followed by refinement using a riding model. The Flack constant was 0.09(10), and the chirality of C11 and C17 was R-configuration. Figure 5 and Table 10 below show the single crystal results for Example 14a-2, 4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid in acetonitrile solvate. [Table 10]

[0416] Experimental Example 8: X-ray single crystal diffraction experiment Preparation method: Compound (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (t r A saturated solution of 1 ml of ethanol / water (1:2, v / v) was prepared at a high temperature (approximately 50°C) and then transferred to room temperature and left for 1 day to obtain a transparent single crystal.

[0417] The diffraction data were integrated and reduced using the SAINT program, and empirical absorption corrections were applied to the data using the SADABS program. The single crystal structure was solved using direct methods using SHELXT2014, and further refined using the least-squares method. The hydrogen atom refinement process was obtained by isotropic calculations. The hydrogen atoms on N and O were obtained using the residual electron density, and the hydrogen atoms on CH were determined by computational hydrogen addition, and refinement was performed using the riding model. The Flack constant was 0.08(7), with C10 in the R configuration and C14 in the S configuration. Figure 6 and the following Table 11 show the intermediate compound (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (t) obtained by separating step e) of Example 26. r =16.51 min) dihydrate single crystal. [Table 11]

[0418] The foregoing description of specific exemplary embodiments of the present invention has been presented for purposes of explanation and illustration. It is not intended that these descriptions be construed as limiting the invention to the precise forms disclosed, and it is apparent that many modifications and variations are possible in light of the above teachings. The purpose of selecting and describing the exemplary examples is to explain certain principles of the present invention and their practical application, so that those skilled in the art can realize and utilize various different exemplary embodiments of the present invention, as well as various alternatives and modifications. It is intended that the scope of the present invention be limited by the claims and their equivalents.

Claims

1. A compound represented by formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 (where X is CH ２ , NH, S, O or 【Chemistry 2】 is selected from Y and Z are each independently selected from CH or N; X is CH ２ then Z is N; R １ is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, or C3-C6 heterocycloalkyl, wherein said C1-C6 alkyl or C3-C6 cycloalkyl is optionally substituted with halogen, oxo, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, or C3-C6 halocycloalkyl; R ２ is hydrogen or R １ and R ２ together with the atom to which they are attached form a C10-C15 heterocyclyl, said heterocyclyl being optionally substituted with halogen; R ３ is selected from C1-C6 alkyl or C3-C6 cycloalkyl, wherein said C1-C6 alkyl is optionally substituted with deuterium or halogen.

2. The compound according to claim 1, its isomer or a pharmaceutically acceptable salt thereof, wherein the compound is represented by general formula (II-1), (II-2) or (II-3): 【Transformation 3】 (where X, Y, R １ , R ３ is as defined in claim 1, P is CH ２ , NH, S or O; R ４ is selected from hydrogen, halogen, or C1-C3 alkyl; m is 0, 1 or 2.

3. The compound according to claim 1, its isomer or a pharmaceutically acceptable salt thereof, wherein the compound is represented by general formula (II-1-1) or (II-1-2): 【Chemistry 4】 (where X, Y, R １ , R ３ is as defined in claim 1.

4. The compound according to claim 1, its isomer, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by general formula (II-2-1) or (II-2-2): 【Transformation 5】 (where X, Y, R １ , R ３ is as defined in claim 1.

5. The compound according to claim 1, an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by general formula (III-1) or (III-2): 【Transformation 6】 (where X, R １ , R ３ is as defined in claim 1, Preferably, the compound, its isomer, or a pharmaceutically acceptable salt thereof is represented by general formula (III-1-1), (III-1-2), (III-1-3), or (III-1-4): 【Transformation 7】 where X, R １ , R ３ is as defined in claim 1.

6. The compound according to claim 1, its isomer, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the general formula (III-2-1), (III-2-2), (III-2-3), (III-2-4), (III-2-5), (III-2-6), (III-2-7) or (III-2-8). 【Transformation 8】 (where X, R １ , R ３ is as defined in claim 1.

7. X is CN ２ , S or O, preferably S or O; Y is selected from CH or N, preferably CH; Z is selected from CH or N, preferably N; R １ is selected from C1-C3 alkyl, C1-C3 alkoxy, C3-C4 cycloalkyl, or C3-C4 heterocycloalkyl, wherein said C1-C3 alkyl or C3-C4 cycloalkyl is optionally substituted with fluorine, chlorine, bromine, iodine, oxo, C1-C3 haloalkyl, C3-C4 cycloalkyl, C3-C4 heterocycloalkyl, or C3-C4 halocycloalkyl; Preferably, R １ is selected from methyl, ethyl, propyl, ethoxy, cyclobutyl or oxetane, said ethyl, propyl or cyclobutyl being optionally substituted with fluorine, oxo, trifluoromethyl, cyclopropyl, fluorocyclopropyl or oxetane, more preferably R １ teeth, 【Chemistry 9】 is selected from, preferably 【Chemistry 10】 and more preferably 【Chemistry 11】 and more preferably, R １ teeth 【Chemistry 12】 is selected from R ３ is selected from C1-C3 alkyl or C3-C4 cycloalkyl, said C1-C3 alkyl being optionally substituted with deuterium, fluorine, chlorine, bromine or iodine, preferably R ３ is selected from methyl or cyclopropyl, said methyl being optionally substituted with deuterium or fluorine, more preferably R ３ is methyl, -CD ３ , 【Chemistry 13】 -CF ３ or 【Chemistry 14】 and more preferably selected from methyl; P is CH ２ , NH, S or O, preferably O; R ４ is selected from fluorine, chlorine, bromine or iodine, preferably fluorine; m is 0, 1 or 2, preferably 2; The compound according to any one of claims 1 to 6, an isomer thereof, or a pharmaceutically acceptable salt thereof.

8. X is NH, S, O or 【Chemistry 15】 is selected from Y is selected from CH or N, preferably CH; Z is selected from CH or N, preferably N; R １ is selected from C1-C3 alkyl, C1-C3 alkoxy, C3-C4 cycloalkyl, or C3-C4 heterocycloalkyl, wherein said C1-C3 alkyl or C3-C4 cycloalkyl is optionally substituted with fluorine, chlorine, bromine, iodine, oxo, C1-C3 haloalkyl, C3-C4 cycloalkyl, C3-C4 heterocycloalkyl, or C3-C4 halocycloalkyl; Preferably, R １ is selected from methyl, ethyl, propyl, ethoxy, cyclobutyl or oxetane, said ethyl, propyl or cyclobutyl being optionally substituted with fluorine, oxo, trifluoromethyl, cyclopropyl, fluorocyclopropyl or oxetane, more preferably R １ teeth 【Chemistry 16】 is selected from, preferably 【Chemistry 17】 and more preferably [Chemistry 18] and more preferably, R １ teeth 【Chemistry 19】 is selected from R ３ is selected from C1-C3 alkyl or C3-C4 cycloalkyl, said C1-C3 alkyl being optionally substituted with deuterium, fluorine, chlorine, bromine or iodine, preferably R ３ is selected from methyl or cyclopropyl, said methyl being optionally substituted with deuterium or fluorine, more preferably R ３ is methyl, -CD ３ , 【Chemistry 20】 , -CF ３ or 【Chemistry 21】 and more preferably selected from methyl; P is CH ２ , NH, S or O, preferably O; R ４ is selected from fluorine, chlorine, bromine or iodine, preferably fluorine; m is 0, 1 or 2, preferably 2; The compound according to any one of claims 1 to 6, an isomer thereof, or a pharmaceutically acceptable salt thereof.

9. The following compound, its isomer or a pharmaceutically acceptable salt thereof, said compound having the following structure: 【Chemistry 22】 【Chemistry 23】

10. The following compound, its isomer or a pharmaceutically acceptable salt thereof, said compound having the following structure: 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】

11. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 10, its isomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

12. Use of a compound according to any one of claims 1 to 10, an isomer thereof or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition according to claim 11 in the preparation of a medicament for the prevention and / or treatment of a disease or condition mediated by complement factor B.

13. 13. The use according to claim 12, wherein the disease or condition mediated by complement factor B is one or more selected from ophthalmological diseases, autoimmune diseases, diseases related to the renal system, respiratory diseases, cardiovascular diseases, preferably arthritis.

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