Complement factor b inhibitors

Abstract

The present application belongs to the field of biological medicine, and particularly relates to a complement factor B inhibitor, the structure of the complement factor B inhibitor is basically shown in general formula (I), wherein the definitions of the substituents are shown in the specification. The compound provided by the present application has significant complement factor B inhibitory activity, and can be used for preventing and / or treating diseases or disease states mediated by the complement factor B inhibitor.

Description

[0001] This application is a divisional application of the national invention patent application with application number CN2024800068129, which was filed on January 9, 2024, and is entitled "Complement Factor B Inhibitor". Technical Field

[0002] This invention belongs to the field of biomedicine, and specifically relates to a complement factor B inhibitor. Background Technology

[0003] The complement system is part of the host's innate immune system, involved in lysing exogenous cells, enhancing antigen phagocytosis, agglutinating antigen carriers, and attracting macrophages and neutrophils. It is a crucial component of the body's innate immune response against infections from exogenous pathogens, bacteria, and parasites, and also a vital link between innate and adaptive immunity. Complement is composed of plasma proteins, including soluble proteins, membrane-bound proteins, and complement receptors. It is primarily produced by membrane proteins expressed on the liver or cell surface and functions in plasma, tissues, or cells. The complement system is an important regulator of inflammatory responses and tissue damage, composed of more than 20 serum proteins and cell surface proteins. The complement system includes intrinsic complement components and various regulatory proteins. Intrinsic complement components include C1–C9, with C3 being the most abundant. The complement system is activated primarily through three pathways: the classical pathway (CP), the lectin pathway (LP), and the alternative pathway (AP).

[0004] In healthy individuals under normal physiological conditions, the complement pathway remains at a low level of activation to monitor for invasion by foreign pathogens. Complement proteins are distributed on the surface of apoptotic cells, and complement activation is tightly regulated, serving only to eliminate apoptotic cells without further activating other innate or adaptive immune responses. In the event of infection by foreign pathogens, the complement system is fully activated, producing inflammatory responses, opsonization, or phagocytosis, destroying pathogens and ultimately activating adaptive immune responses. Both ineffective and excessive complement stimulation can be harmful to the human body and are associated with increased susceptibility to infectious and non-infectious diseases. Complement dysfunction or overactivation has been linked to certain autoimmune, inflammatory, and neurodegenerative diseases, as well as ischemia-reperfusion injury and cancer. For example, activation of the alternative pathway in the complement cascade contributes to the production of C3a and C5a (both potent anaphylatoxins), which also play a role in many inflammatory diseases. Therefore, in some cases, it is desirable to reduce the response of complement pathways (including alternative complement pathways).

[0005] Complement factor B (FB) is a key protein involved in the activation of complement pathway (AP). Inhibiting FB activity can prevent AP pathway activation without interfering with the CP and LP pathways, thus avoiding the increased risk of infection due to complement system inhibition. Therefore, finding a novel and effective small molecule inhibitor of complement factor B is an important direction in current drug development research on diseases caused by complement abnormalities. Summary of the Invention

[0006] The purpose of this invention is to provide a novel complement factor B inhibitor compound, its isomer, or a pharmaceutically acceptable salt thereof.

[0007] In an embodiment of the present invention, the present invention provides a compound of general formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of general formula (I) is as follows:

[0008] in: X is selected from CH2, NH, S, O, or ; Y and Z are each independently selected from CH or N; And when X is CH2, Z is N; R 1 Selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl or C3-C6 heterocyclic groups, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally substituted with halogen, oxo, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 heterocyclic or C3-C6 halocycloalkyl; R 2 It is hydrogen, or R 1 and R 2 The atoms bonded to them form C10-15 heterocyclic groups, which are optionally substituted with halogens; R 3 It is selected from C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted with deuterium or halogen.

[0009] In a preferred embodiment of the invention, the compound represented by general formula (I), its isomers, or pharmaceutically acceptable salts thereof, is further represented as shown in general formulas (II-1), (II-2), or (II-3):

[0010] in: X, Y, R 1 R 3 As mentioned above; P is selected from CH2, NH, S, or O; R 4 Selected from hydrogen, halogens, or C1-C3 alkyl groups; m can be 0, 1, or 2.

[0011] In a preferred embodiment of the invention, the compound represented by general formula (I), its isomers, or pharmaceutically acceptable salts thereof, is further represented as shown in general formula (II-1-1) or (II-1-2):

[0012] in: X, Y, R 1 R 3 As defined above.

[0013] In a preferred embodiment of the invention, the compound represented by general formula (I), its isomers, or pharmaceutically acceptable salts thereof, is further represented as shown in general formula (II-2-1) or (II-2-2):

[0014] in: X, Y, R 1 R 3 As defined above. In a further preferred embodiment of the invention, Y is selected from CH or N; preferably CH.

[0015] In a preferred embodiment of the present invention, Y is selected from CH.

[0016] In a preferred embodiment of the present invention, Y is selected from N.

[0017] In a preferred embodiment of the invention, the compound represented by general formula (I), its isomers, or pharmaceutically acceptable salts thereof, is further represented as shown in general formula (III-1) or (III-2):

[0018] in: X, R 1 R 3 As defined above.

[0019] In a preferred embodiment of the invention, the compound represented by general formula (I), its isomers, or pharmaceutically acceptable salts thereof, is further represented as in general formulas (III-1-1), (III-1-2), (III-1-3), or (III-1-4):

[0020] in: X, R 1 R 3 As defined above.

[0021] In a preferred embodiment of the invention, the compound represented by general formula (I), its isomers, or pharmaceutically acceptable salts thereof, is further represented as in general formulas (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):

[0022] in: X, R 1 R 3 As defined above.

[0023] In a further preferred embodiment of the invention, X is selected from NH, S, O, or .

[0024] In a further preferred embodiment of the present invention, X is selected from CH2, S or O; preferably S or O.

[0025] In a preferred embodiment of the present invention, X is selected from CH2.

[0026] In a preferred embodiment of the present invention, X is selected from S.

[0027] In a preferred embodiment of the present invention, X is selected from O.

[0028] In a preferred embodiment of the present invention, X is selected from NH.

[0029] In a preferred embodiment of the present invention, X is selected from... .

[0030] In a preferred embodiment of the present invention, Z is selected from CH or N.

[0031] In a preferred embodiment of the present invention, Z is selected from N.

[0032] In a preferred embodiment of the present invention, Z is selected from CH.

[0033] In a further preferred embodiment of the invention, R 1It is selected from C1-C3 alkyl, C1-C3 alkoxy, C3-C4 cycloalkyl or C3-C4 heterocyclic groups, wherein the C1-C3 alkyl or C3-C4 cycloalkyl is optionally substituted with fluorine, chlorine, bromine, iodine, oxo, C1-C3 haloalkyl, C3-C4 cycloalkyl, C3-C4 heterocyclic or C3-C4 halocycloalkyl.

[0034] In a preferred embodiment of the present invention, R 1 The group is selected from C1-C3 alkyl, C1-C3 alkoxy, C3-C4 cycloalkyl or C3-C4 heterocyclic groups, wherein the C1-C3 alkyl or C3-C4 cycloalkyl is optionally substituted by 1, 2 or 3 substituents selected from fluorine, chlorine, bromine, iodine, oxo, C1-C3 haloalkyl, C3-C4 cycloalkyl, C3-C4 heterocyclic or C3-C4 halocycloalkyl.

[0035] In a preferred embodiment of the present invention, R 1 The alkyl group is selected from C1-C3 alkyl groups, which are optionally substituted by one, two or three substituents selected from fluorine, chlorine, bromine or iodine.

[0036] In a preferred embodiment of the present invention, the C1-C3 fluoroalkyl group is selected from fluoromethyl, difluoromethyl or trifluoromethyl, preferably trifluoromethyl.

[0037] In a preferred embodiment of the present invention, R 1 The components are selected from C3-C4 cycloalkyl groups, wherein the C3-C4 cycloalkyl groups are optionally substituted by one, two or three substituents selected from C1-C3 fluoroalkyl groups.

[0038] In a further preferred embodiment of the invention, R 1 The molecule is selected from methyl, ethyl, propyl, ethoxy, cyclobutyl, or oxetane, wherein the ethyl, propyl, or cyclobutyl group is optionally substituted with fluorine, oxo, trifluoromethyl, cyclopropyl, fluorocyclopropyl, or oxetane.

[0039] In a further preferred embodiment of the invention, R 1 The ethyl, propyl, ethoxy, cyclobutyl, or oxetane are selected from methyl, ethyl, propyl, cyclobutyl, or oxetane, wherein the ethyl, propyl, or cyclobutyl group is optionally substituted by one, two, or three substituents selected from fluorine, oxo, trifluoromethyl, cyclopropyl, fluorocyclopropyl, or oxetane.

[0040] In a further preferred embodiment of the invention, R 1 Selected from methyl, ethyl, or propyl, wherein the methyl, ethyl, or propyl group is optionally substituted with 1, 2, or 3 fluorine atoms. In a further preferred embodiment of the invention, R 1 Selected from , , , , , , , , , , , or Preferred , , or More preferably , or .

[0041] In a further preferred embodiment of the invention, R 1 Selected from .

[0042] In a further preferred embodiment of the invention, R 3 It is selected from C1-C3 alkyl or C3-C4 cycloalkyl, wherein the C1-C3 alkyl is optionally substituted with deuterium, fluorine, chlorine, bromine or iodine.

[0043] In a further preferred embodiment of the invention, R 3 The radical is selected from C1-C3 alkyl or C3-C4 cycloalkyl, wherein the C1-C3 alkyl group is optionally substituted with one, two, or three substituents selected from deuterium, fluorine, chlorine, bromine, or iodine. In a further preferred embodiment of the invention, R 3 Selected from methyl or cyclopropyl, wherein the methyl group is optionally substituted with deuterium or fluorine.

[0044] In a further preferred embodiment of the invention, R 3 The group is selected from methyl or cyclopropyl, wherein the methyl group is optionally substituted by one, two or three substituents selected from deuterium or fluorine.

[0045] In a further preferred embodiment of the invention, R 3 Selected from methyl, -CD3, -CF3 or Preferred methyl, -CD3, -CF3 or ; Methyl group is preferred.

[0046] In a further preferred embodiment of the present invention, P is selected from CH2, NH, S or O; preferably O.

[0047] In a further preferred embodiment of the invention, R 4 Selected from fluorine, chlorine, bromine or iodine; fluorine is preferred.

[0048] In a further preferred embodiment of the invention, R 4 Selected from hydrogen.

[0049] In a further preferred embodiment of the present invention, m is 0, 1 or 2; preferably 2.

[0050] In a further preferred embodiment of the invention, the compound, its isomers, or pharmaceutically acceptable salts thereof have the following structure: or .

[0051] This invention provides the following compounds, their isomers, or pharmaceutically acceptable salts thereof: .

[0052] In a further preferred embodiment of the invention, the compound, its isomers, or pharmaceutically acceptable salts thereof have the following structure: or .

[0053] This invention provides the following compounds, their isomers, or pharmaceutically acceptable salts thereof: or .

[0054] In a further preferred embodiment of the invention, the compound, its isomers, or pharmaceutically acceptable salts thereof have the following structure: or .

[0055] In a further preferred embodiment of the invention, the compound, its isomers, or pharmaceutically acceptable salts thereof have the following structure: or .

[0056] In a preferred embodiment of the present invention, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 2.06 min. The specific separation method is as follows: Column: Lux Cellulose-4 4.6*50 mm, 3 μm; Mobile phase A: supercritical CO2; Mobile phase B: methanol; Gradient: 10% ~ 50% flow for 2.0 minutes, 50% hold for 1.0 minute; Detection wavelength: 220nm.

[0057] In a preferred embodiment of the present invention, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 2.34 min. The specific separation method is as follows: Column: Lux Cellulose-4 4.6*50 mm, 3 μm; Mobile phase A: supercritical CO2; Mobile phase B: methanol; Gradient: 10% ~ 50% flow for 2.0 minutes, 50% hold for 1.0 minute; Detection wavelength: 220nm.

[0058] In a preferred embodiment, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 4.90 min. The specific separation method is as follows: 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: 214nm.

[0059] In a preferred embodiment, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 6.20 min. The specific separation method is as follows: 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); Mobile phase ratio: A:B = 75:25; Detection wavelength: 214nm.

[0060] In a preferred embodiment, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 2.31 min. The specific separation method is as follows: 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; Flow rate: 1.0 mL / min; Detection wavelength: 220 / 254 dual-wavelength detection.

[0061] In a preferred embodiment, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 3.57 min. The specific separation method is as follows: 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; Flow rate: 1.0 mL / min; Detection wavelength: 220 / 254 dual-wavelength detection.

[0062] In a preferred embodiment of the present invention, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 2.12 min. The specific separation method is as follows: Column: DAICELCHIRALCEL® OZ 250*20 mm, 10μm; 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: 214nm.

[0063] In a preferred embodiment of the present invention, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 3.03 min. The specific separation method is as follows: Column: DAICELCHIRALCEL® OZ 250*20 mm, 10μm; 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: 214nm.

[0064] In a preferred embodiment, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 1.08 min. The specific separation method is as follows: Column: DAICELCHIRALCEL® OZ 250*20 mm, 10μm; 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: 214nm.

[0065] In a preferred embodiment, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 2.24 min. The specific separation method is as follows: Column: DAICELCHIRALCEL® OZ 250*20 mm, 10μm; 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: 214nm.

[0066] In a preferred embodiment of the present invention, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 1.19 min. The specific separation method is as follows: 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: 214nm.

[0067] In a preferred embodiment of the present invention, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 1.95 min. The specific separation method is as follows: 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: 214nm.

[0068] In a preferred embodiment of the present invention, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 1.29 min. The specific separation method is as follows: 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: 214nm.

[0069] In a preferred embodiment of the present invention, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 4.00 min. The specific separation method is as follows: 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: 214nm.

[0070] In a preferred embodiment of the present invention, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 1.87 min. The specific separation method is as follows: Column: DAICELCHIRALPAK® 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: 214nm.

[0071] In a preferred embodiment of the present invention, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 2.73 min. The specific separation method is as follows: Column: DAICELCHIRALPAK® 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: 214nm.

[0072] In a preferred embodiment of the present invention, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 1.06 min. The specific separation method is as follows: 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: 214nm.

[0073] In a preferred embodiment of the present invention, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 2.37 min. The specific separation method is as follows: 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: 214nm.

[0074] In a preferred embodiment of the present invention, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 1.25 min. The specific separation method is as follows: 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: 214nm.

[0075] In a preferred embodiment of the present invention, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 2.00 min. The specific separation method is as follows: 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: 214nm.

[0076] In a preferred embodiment of the present invention, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 0.91 min. The specific separation method is as follows: 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: 214nm.

[0077] In a preferred embodiment of the present invention, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 2.35 min. The specific separation method is as follows: 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: 214nm.

[0078] In a preferred embodiment of the present invention, the compound " The isomer of "" was analyzed by chiral SFC, and the retention time was 3.20 min. The specific analytical method is as follows: 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: 70:30; Flow rate: 100 mL / min; Detection wavelength: 214nm.

[0079] In a preferred embodiment of the present invention, the compound " The isomer of "" was analyzed by chiral SFC, and the retention time was 3.60 min. The specific analytical method is as follows: 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: 70:30; Flow rate: 100 mL / min; Detection wavelength: 214nm.

[0080] In a preferred embodiment of the present invention, the compound " The isomer of "" was analyzed by chiral SFC, and the retention time was 3.72 min. The specific analytical method is as follows: 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: 70:30; Flow rate: 100 mL / min; Detection wavelength: 214nm.

[0081] In a preferred embodiment of the present invention, the compound " The isomer of "" was analyzed by chiral SFC, and the retention time was 5.48 min. The specific analytical method is as follows: 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: 70:30; Flow rate: 100 mL / min; Detection wavelength: 214nm.

[0082] In a preferred embodiment of the present invention, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 0.88 min. The specific separation method is as follows: 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: 214nm.

[0083] In a preferred embodiment of the present invention, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 1.39 min. The specific separation method is as follows: 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: 214nm.

[0084] In a preferred embodiment of the present invention, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 5.45 min. The specific separation method is as follows: Column: DAICELCHIRALPAK®IG 250*20 mm, 10μm; 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: 214nm.

[0085] In a preferred embodiment of the present invention, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 6.03 min. The specific separation method is as follows: Column: DAICELCHIRALPAK®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: 214nm.

[0086] In a preferred embodiment of the present invention, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 5.33 min. The specific separation method is as follows: Column: DAICELCHIRALPAK® 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: 214nm.

[0087] In a preferred embodiment of the present invention, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 7.81 min. The specific separation method is as follows: Column: DAICELCHIRALPAK®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: 214nm.

[0088] In a preferred embodiment of the present invention, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 5.14 min. The specific separation method is as follows: 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: 55:45; Flow rate: 70 mL / min; Detection wavelength: 214nm.

[0089] In a preferred embodiment of the present invention, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 5.73 min. The specific separation method is as follows: 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: 55:45; Flow rate: 70 mL / min; Detection wavelength: 214nm.

[0090] In a preferred embodiment of the present invention, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 5.20 min. The specific separation method is as follows: 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: 55:45; Flow rate: 70 mL / min; Detection wavelength: 214nm.

[0091] In a preferred embodiment of the present invention, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 6.30 min. The specific separation method is as follows: 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: 55:45; Flow rate: 70 mL / min; Detection wavelength: 214nm.

[0092] In a preferred embodiment of the present invention, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 4.70 min. The specific separation method is as follows: 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: 70:30; Flow rate: 100 mL / min; Detection wavelength: 214nm.

[0093] Detection wavelength: 214 nm. In a preferred embodiment of the present invention, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 4.80 min. The specific separation method is as follows: 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: 70:30; Flow rate: 100 mL / min; Detection wavelength: 214nm.

[0094] Detection wavelength: 214nm. In a preferred embodiment of the present invention, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 3.43 min. The specific separation method is as follows: 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: 70:30; Flow rate: 100 mL / min; Detection wavelength: 214nm.

[0095] Detection wavelength: 214nm. In a preferred embodiment of the present invention, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 3.59 min. The specific separation method is as follows: 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: 70:30; Flow rate: 100 mL / min; Detection wavelength: 214nm.

[0096] In a preferred embodiment of the present invention, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 0.89 min. The specific separation method is as follows: 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: 214nm.

[0097] In a preferred embodiment of the present invention, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 1.22 min. The specific separation method is as follows: 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: 214nm.

[0098] Detection wavelength: 214 nm. In a preferred embodiment of the present invention, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 0.92 min. The specific separation method is as follows: 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: 214nm.

[0099] Detection wavelength: 214 nm. In a preferred embodiment of the present invention, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 1.46 min. The specific separation method is as follows: 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: 214nm.

[0100] In a preferred embodiment of the present invention, the compound " The isomer of "" was separated by chiral SFC, with a retention time of 1.34 min. The specific separation method is as follows: 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: 214nm.

[0101] In a preferred embodiment of the present invention, compound " The isomer of "" was separated by chiral SFC, with a retention time of 2.68 min. The specific separation method is as follows: 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: 214nm.

[0102] In a preferred embodiment of the present invention, compound " The isomer of "" was separated by chiral SFC, with a retention time of 5.47 min. The specific separation method is as follows: Column: CHIRALPAK-IG 2*25cm; Mobile phase A: n-hexane (0.1% formic acid); Mobile phase B: Ethanol: Dichloromethane = 1:1; A:B: = 1:1; Flow rate: 20 mL / min; Detection wavelength: 220 / 254nm.

[0103] In a preferred embodiment of the present invention, compound " The isomer of "" was separated by chiral SFC, with a retention time of 7.57 min. The specific separation method is as follows: Column: CHIRALPAK-IG 2*25cm; Mobile phase A: n-hexane (0.1% formic acid); Mobile phase B: Ethanol: Dichloromethane = 1:1; A:B: = 1:1; Flow rate: 20 mL / min; Detection wavelength: 220 / 254nm.

[0104] In a preferred embodiment of the present invention, compound " The isomer of "" was separated by chiral SFC, with a retention time of 10.6 min. The specific separation method is as follows: Column: CHIRALPAK-IG 2*25cm; Mobile phase A: n-hexane (0.1% formic acid); Mobile phase B: Ethanol: Dichloromethane = 1:1; A:B: = 1:1; Flow rate: 20 mL / min; Detection wavelength: 220 / 254nm.

[0105] In a preferred embodiment of the present invention, compound " The isomer of "" was separated by chiral SFC, with a retention time of 15.2 min. The specific separation method is as follows: Column: CHIRALPAK-IG 2*25cm; Mobile phase A: n-hexane (0.1% formic acid); Mobile phase B: Ethanol: Dichloromethane = 1:1; A:B: = 1:1; Flow rate: 20 mL / min; Detection wavelength: 220 / 254nm.

[0106] An intermediate for preparing the above-mentioned compound or its salt, having the following structure: .

[0107] In a preferred embodiment of the present invention, the intermediate " The isomer of "" was separated by chiral SFC, with a retention time of 20.33 min. The specific separation method is as follows: Chromatographic column: DAICELCHIRALPAK® IC 250*4.6mm, 5 μm; Mobile phase A: n-hexane; Mobile phase B: ethanol; A:B: 90:10; Flow rate: 1 mL / min; Detection wavelength: 254nm.

[0108] In a preferred embodiment of the present invention, the intermediate " The isomer of "" was separated by chiral SFC, with a retention time of 16.51 min. The specific separation method is as follows: Chromatographic column: DAICELCHIRALPAK® IC 250*4.6mm, 5 μm; Mobile phase A: n-hexane; Mobile phase B: ethanol; A:B: 90:10; Flow rate: 1 mL / min; Detection wavelength: 254nm.

[0109] In a preferred embodiment of the invention, the 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.

[0110] The pharmaceutical compositions of this invention can be administered via any suitable route or method, such as oral or parenteral (e.g., intravenous). For oral administration, the pharmaceutical compositions of this invention are generally provided in the form of tablets, capsules, or solutions. Tablets may contain the compounds of this invention, their isomers, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier. The carrier includes, but is not limited to, diluents, disintegrants, binders, lubricants, colorants, or preservatives. Capsules include hard capsules and soft capsules.

[0111] For parenteral administration, the pharmaceutical compositions of the present invention can be administered via intravenous, intramuscular, or subcutaneous injection. They are typically provided as sterile aqueous solutions, suspensions, or lyophilized powders, adjusted to a suitable pH and isotonicity.

[0112] In a preferred embodiment of the invention, the invention also provides the use of any of the foregoing compounds, their isomers or pharmaceutically acceptable salts thereof in the preparation of medicaments for the prevention and / or treatment of complement factor B-mediated diseases or disease states.

[0113] In a preferred embodiment of the invention, the invention also provides a method for preventing and / or treating complement factor B-mediated diseases or disease states, comprising administering to an individual in need a compound of the invention, an isomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0114] In a preferred embodiment of the present invention, the disease or disease state mediated by complement factor B is selected from one or more of ophthalmic diseases, autoimmune diseases (including arthritis), kidney-related diseases, respiratory diseases, and cardiovascular diseases.

[0115] In a preferred embodiment of the present invention, the complement factor B-mediated disease or disease state is arthritis.

[0116] Related definitions As used herein and unless otherwise stated, the terms “comprising,” “including,” “having,” “containing,” and their grammatical equivalents, including their grammatical equivalents, should generally be understood as open-ended and non-restrictive, e.g., not excluding other unlisted elements or steps.

[0117] Unless otherwise specified, the following terms used in the specification and claims shall have the following meanings: The "compound" of this invention may be asymmetric, for example, having one or more chiral centers. Unless otherwise stated, the "compound" of this invention may be any one isomer or a mixture of two or more isomers. The "compound" of this invention includes isomers (such as stereoisomers), enantiomers, diastereomers, racemates, or mixtures of two or more isomers of the compound.

[0118] The term "isomer" refers to different compounds having the same molecular formula but different atomic arrangements and configurations. "Enantiomers" are 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 racemic mixtures. The use of "rel" indicates that the diastereomeric orientation is known, but the absolute stereochemistry is not. For example, the name "rel-3S,4S" as used herein indicates that the relative stereochemistry at positions 3 and 4 is 3S,4S or 3R,4R, in which case the order of the aliphatic ring positions is as follows: Absolute stereochemistry is not determined, but optical rotation and / or chiral chromatographic conditions will indicate which isomer is present. A “diastereomer” is a stereoisomer having at least two asymmetric atoms, but not being mirror images of each other. Absolute stereochemistry is defined according to the Cahn-Lngold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry on each chiral carbon can be described as R or S. Compounds whose absolute configuration is unknown after separation can be designated as (+) or (-) based on the direction of their rotational plane-polarized light at the sodium D line wavelength (dextrorotatory- or levorotatory-) or their retention time during chiral chromatographic separation. Some compounds described herein contain one or more asymmetric centers or axes, thus producing enantiomers, diastereomers, and other stereoisomers that can be defined absolutely stereochemically as (R)- or (S)- or indicated by (+) or (-) symbols. This invention includes 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 resolved using conventional techniques. If the compound contains a double bond, the substituent can be of E or Z configuration. If the compound contains a disubstituted cyclic hydrocarbon group, the cyclic hydrocarbon substituent can have a cis- or trans- configuration. That is, 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, racemic mixtures thereof, and other mixtures. The compounds of the present invention containing asymmetric carbon atoms can be isolated in optically active pure form or in the form of a mixture of two or more isomers. The optically active pure form can be resolved from a mixture of two or more isomers or synthesized using chiral starting materials or chiral reagents.

[0119] The "compounds" of this invention also include tautomer forms. A tautomer form arises from the exchange of a single bond with an adjacent double bond, accompanied by the migration of a proton. The terms "tautomer" or "tautomer form" refer to isomers of different functional groups in dynamic equilibrium at room temperature, capable of rapidly interconverting into each other.

[0120] Those skilled in the art can separate the isomer mixtures obtainable according to the invention into individual isomers in known ways; diastereomers can be separated, for example, by partitioning between multiphase solvent mixtures, recrystallization and / or chromatographic separation, such as silica gel chromatography, or by medium-pressure liquid chromatography, for example, using a reversed-phase column; racemic mixtures can be separated, for example, by forming a salt with an optically pure salting agent and separating (e.g., by fractional crystallization) the diastereomer mixtures thus obtained, or by chromatographic treatment on an optically active column material. Intermediates and final products can be post-treated and / or purified according to standard methods, such as chromatography, partitioning, (re)crystallization, etc. At all reaction stages, the resulting isomer mixtures can be separated into individual isomers, such as diastereomers or enantiomers, or into any desired mixture of isomers, such as racemic mixtures or diastereomer mixtures.

[0121] Absolute stereochemistry and / or optical rotation are provided as appropriate for embodiments of the invention. This invention focuses on all stereochemical forms of the compounds provided herein. In some cases, the 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, the compounds are identified using the prefix "rel" followed by R / S nomenclature. Clearly, if "rel" is used, the R / S only provides relative stereochemical information (e.g., trans or cis), not absolute stereochemistry. In some cases, the relative stereochemistry of diastereomer pairs has not been determined; therefore, when only one isomer is isolated and / or available, enantiomers are identified / distinguished based on retention times under the given HPLC conditions. Identical samples typically have the same retention time, but there may be some operational errors. When samples obtained by a person skilled in the art using appropriate methods are tested using the same instruments and detection methods, the retention time error is usually within ±0.2 min, preferably within ±0.1 min. Different technicians using different instruments may occasionally produce a few retention time errors that exceed this range, such as errors within ±0.5 min, ±0.3 min, or ±0.2 min. These should all be considered as belonging to the same substance. Therefore, retention time errors within ±0.5 min, ±0.3 min, ±0.2 min, or ±0.1 min can all be interpreted as being within the scope of protection of this invention.

[0122] In cases where each isomer is identified as racemic but its relative stereochemistry has not been determined, the compound is named with the symbol “(±)” and the name “diastere-1” or “diastere-2” if only one isomer is isolated and / or available.

[0123] In this invention, " "and" "Represents the absolute configuration of the center of a solid." “ in "" refers to the junction of chemical bonds. When a "" appears in a bicyclic or polycyclic ring... "And if the connection location is uncertain, it means that the connection point is limited to " "Any atom on the single ring, as long as the valence allows."

[0124] The structures of the compounds of this invention can be confirmed using conventional methods well known to those skilled in the art. If the invention relates to the absolute configuration of a compound, the absolute configuration can be confirmed using conventional techniques in the art, such as single-crystal X-ray diffraction (SARD).

[0125] The term “optional” or “optionally” means that the event or situation described below may or may not occur, including both the occurrence and non-occurrence of the event or situation.

[0126] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0127] The term "substituted" refers to the substitution of one or more hydrogen atoms (e.g., 1, 2, 3, or 4) on a specific group by a substituent, which may be the same or different, as long as the valence state of the specific group is normal and the resulting compound is stable. For example, "halogen substituted" means that one or more hydrogen atoms (e.g., 1, 2, 3, or 4) on a specific group are substituted by the same or different halogens, as long as the valence state of the specific group is normal and the resulting compound is stable.

[0128] The numerical ranges mentioned in this article refer to the integers within a given range. For example, "C1-C6" means that the group can have 1, 2, 3, 4, 5, or 6 carbon atoms; "C1-C3" means that the group can have 1, 2, or 3 carbon atoms.

[0129] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain or branched saturated hydrocarbon groups having 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 of which 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, etc.

[0130] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen atoms (fluorine, chlorine, bromine, iodine). For example, the term "C1-C6 haloalkyl" refers to a haloalkyl group containing 1 to 6 carbon atoms, including, but not limited to, trifluoromethyl and trifluoroethyl.

[0131] The term "cycloalkyl" refers to a monocyclic saturated hydrocarbon system without heteroatoms or double bonds. Examples of the term "C3-C6 cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0132] The term "heterocyclic group" refers to a substituent in a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon. The term "C3-C6 membered heterocyclic group" contains 3 to 6 carbon atoms as ring atoms, and further includes one or more heteroatoms selected from nitrogen, oxygen, or sulfur as ring atoms, preferably containing 1 to 3 heteroatoms; the term "C10-15 heterocyclic group" contains 10 to 15 carbon atoms as ring atoms, and further includes one or more heteroatoms selected from nitrogen, oxygen, or sulfur as ring atoms, preferably containing 1 to 3 heteroatoms, more preferably including 11 or 12 carbon atoms as ring atoms, and further including 1 or 2 heteroatoms selected from oxygen or nitrogen as ring atoms.

[0133] The term "pharmaceutically acceptable" means that a carrier, delivery substance, excipient, diluent, and / or the salt formed therefrom is generally chemically or physically compatible with other components constituting a drug dosage form and physiologically compatible with receptors.

[0134] The term "pharmaceutically acceptable carrier" refers to carriers that do not cause significant irritation to the body and do not impair the biological activity and properties of the active compound. This includes, but is not limited to, any diluents, disintegrants, binders, glidants, and wetting agents commonly used in the art for human or animal use.

[0135] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological potency of the free acid or base of a particular compound without any adverse biological effects. Examples include acid (including organic and inorganic acids) 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 an acid radical or base using conventional chemical methods. Generally, such salts are prepared by reacting these compounds, in their free acid or base form, with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of both.

[0136] The term "effective dose" or "therapeutic effective dose" refers to a sufficient amount of a drug or agent that is non-toxic but achieves the desired effect. The precise dosage will vary depending on a variety of factors, such as variables dependent on the subject (e.g., age, immune system health, etc.), the disease or illness, and the treatment administered.

[0137] The term "pharmaceutical composition" means a composition comprising the compounds described in this disclosure or their pharmaceutically acceptable salts, and at least one pharmaceutically acceptable ingredient selected from the following, depending on the manner of administration and the nature of the dosage form: carriers, diluents, adjuvants, excipients, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, dispersants, thermosensitive materials, temperature regulators, adhesives, stabilizers, suspending agents, etc.

[0138] The pharmaceutical products or pharmaceutical compositions disclosed herein can be administered orally, topically, parenterally, or via mucosal routes (e.g., sublingually, by inhalation, or rectally) in dosage units comprising a conventional, non-toxic, pharmaceutically acceptable carrier. Oral administration is generally preferred. The active agent can be administered orally in capsule, tablet, or other similar forms.

[0139] The pharmaceutical products or pharmaceutical compositions disclosed herein can be delivered parenterally, i.e., administered intravenously (IV), intraventricularly (ICV), subcutaneously (SC), intraperitoneally (IP), intramuscularly (IM), subcutaneously (SD), or intradermally (ID), by direct injection, such as rapid concentration or continuous infusion. Formulations for injection may be presented in unit dosage forms, such as in ampoules or multi-dose containers with added preservatives. The compositions may be in the form of excipients, suspensions, solutions, or emulsions in oil or aqueous carriers, and may contain formulation agents such as anti-settling agents, stabilizers, and / or dispersants. Alternatively, the active ingredient may be reconstituted in powder form with a suitable carrier (e.g., sterile, pyrogen-free water) prior to use.

[0140] The pharmaceutical or pharmaceutical composition disclosed herein may also be formulated for rectal administration, for example as a suppository or retention enema (e.g., containing a conventional suppository base such as cocoa butter or other glycerides).

[0141] 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.

[0142] The abbreviations used in the claims and description 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 1 1H NMR: Proton NMR spectrum HPLC: High Performance Liquid Chromatography LCMS: Liquid Chromatography-Mass Spectrometry M: Moore MEOH: Methanol m / z: Mass-to-charge ratio SFC: Supercritical Fluid Chromatography V / V: Volume / Volume Attached Figure Description

[0143] Figure 1 This is the arthritis score map of Example 13a-2 in the collagen antibody-induced mouse arthritis experiment in Experiment 4; Figure 2 This is a graph showing the change in footpad thickness in Example 13a-2 of the collagen antibody-induced arthritis experiment in mice in Experiment 4; Figure 3 This is the AUC change spectrum of the CAIA mouse model in Experiment Example 5 for drug efficacy study; Figure 4 The crystal structure of 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 is shown. Figure 5 The crystal structure of compound 4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid in Experimental Example 7 is shown. Figure 6 The crystal structure of compound (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester in Experimental Example 8 is shown. Detailed Implementation

[0144] The preparation methods of the compounds of the present invention are described in more detail below, but these specific preparation methods do not constitute any limitation on the scope of the present invention. Furthermore, reaction conditions such as reactants, solvents, bases, amounts of compounds used, reaction temperatures, and reaction times are not limited to the examples below.

[0145] The compounds of the present invention can also be conveniently prepared by combining various synthetic methods described in this specification or known in the art, such combinations being readily performed by those skilled in the art.

[0146] Unless otherwise specified, the raw materials and equipment used in the specific embodiments of the present invention are all known products and can be obtained by purchasing commercially available products.

[0147] 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

[0148] a) Preparation of methyl 4-(pyrazin-2-yl)benzoate (4-(methoxycarbonyl)phenyl)boronic acid (2g), 1,4-dioxane (100mL), and water (20mL) were added to a 250mL two-necked flask. Sodium carbonate (3.53g) and tetra(triphenylphosphine palladium) (1.28g) were then added. Under nitrogen purging protection, 2-chloropyrazine (1.91g) was added. The mixture was stirred at 100°C for 4.5 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain slag. The slag was purified by column chromatography (mobile phase: dichloromethane / methanol = 10 / 1 (V / V)) to obtain 2.04g of the title compound.

[0149] b) Preparation of (±) methyl 4-(piperazin-2-yl)benzoate 1 g of methyl 4-(pyrazin-2-yl)benzoate was dissolved in a mixed solvent of acetic acid / methanol (28 ml / 14 mL), 105 mg of palladium acetate and 350 mg of palladium / carbon were added, hydrogen was purged, the mixture was stirred overnight at room temperature, filtered through diatomaceous earth, and the filtrate was evaporated to dryness to give 0.9 g of the title compound.

[0150] c) Preparation of (±) 3-(4-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (±) 4-(piperazin-2-yl)benzoate methyl ester (480 mg) was added to a 50 mL two-necked flask, followed by dichloromethane (30 mL) and triethylamine (661.54 mg). Under nitrogen purging protection, di-tert-butyl dicarbonate (475.59 mg) was added. The mixture was stirred at room temperature for 1 hour, quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to prepare slurry, and purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to obtain 300 mg of the title compound.

[0151] d) Preparation of tert-butyl 4-((4-(tert-butoxycarbonyl)-2-(4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid 270.9 mg of 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester was added to a 50 mL two-necked flask, followed by 10 mL of 1,2-dichloroethane, and then (±) 3-(4-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (300 mg). The mixture was purged with nitrogen and cooled to 0 °C in an ice bath. 396.9 mg of sodium triacetoxyborohydride was added. The mixture was stirred overnight at room temperature, quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to give 380 mg of the title compound.

[0152] e) Preparation of tert-butyl 5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid 150 mg of 4-((4-(tert-butyloxycarbonyl)-2-(4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester was added to a 25 mL two-necked flask, followed by 5 mL of methanol and 5 mL of 4M 1,4-dioxane hydrogen chloride solution. The mixture was then purged with nitrogen and stirred at room temperature for 2 h. The solution was concentrated under reduced pressure to obtain 120 mg of the title compound.

[0153] 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, followed by acetonitrile (8 mL), 1-bromopropane (52 mg), and triethylamine (86.1 mg). The mixture was stirred overnight at 50 °C. The reaction solution was concentrated under reduced pressure to obtain sand, which was then purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 40 mg of the title compound.

[0154] Preparation of g) (±)4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-propylpiperazin-2-yl)benzoic acid 40 mg of 5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-propylpiperazin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester was dissolved in a mixed solvent of dichloromethane / methanol (2 mL / 2 mL), and 1 mL of 1N lithium hydroxide aqueous solution was added. The mixture was stirred at 70 °C for 1 hour. The reaction solution was directly evaporated to dryness, dissolved in water, and the pH was adjusted to neutral with dilute hydrochloric acid. The solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to prepare slurry. The slurry was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 9 mg of the title compound.

[0155] 1 HNMR (400 MHz, DMSO -d6 ) δ 10.82 (s, 1H), 7.96 (s, 2H), 7.62 (s, 2H),7.25 (t, J = 2.7 Hz, 1H), 6.65 (s, 1H), 6.44 (s, 1H), 3.70 (s, 3H), 3.56 (d, J =11.9 Hz, 2H), 3.25 – 3.13 (m, 2H), 2.70 (t, J = 9.2 Hz, 2H), 2.41 (s, 3H), 2.18(dd, J = 18.8, 11.5 Hz, 2H), 1.98 (d, J = 7.5 Hz, 2H), 1.87 (t, J = 10.9 Hz, 1H), 1.37 (dt, J = 12.0, 6.1 Hz, 2H), 0.85 – 0.80 (m, 3H). LCMS m / z = 422.2 [M+1] + Resolution of the enantiomers of (±)4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-propylpiperazin-2-yl)benzoic acid by chiral SFC yielded 1-1,t r =2.06min and 1-2,t r = 2.34 min. (Specific separation method is as follows: Column: Lux Cellulose-4 4.6*50 mm, 3 μm; Mobile phase A: supercritical CO2; Mobile phase B: methanol; Gradient: 10% to 50% flow for 2.0 min, 50% hold for 1.0 min; Detection wavelength: 220 nm) 1-1,tr =2.06min 1 HNMR (400 MHz, DMSO -d6 ) δ 10.82 (s, 1H), 7.97 (d, J = 8.3 Hz, 2H), 7.69 (d, J = 6.7 Hz, 2H), 7.25 (t, J = 2.7 Hz, 1H), 6.66 (s, 1H), 6.53 – 6.35(m, 1H), 3.71 (s, 3H), 3.56 (d, J = 11.8 Hz, 1H), 3.38 (s, 1H), 3.23 (d, J =11.8 Hz, 1H), 2.71 (t, J = 10.0 Hz, 2H), 2.63 (d, J = 11.4 Hz, 1H), 2.42 (s,3H), 2.26 – 2.10 (m, 3H), 1.93 (dt, J = 21.0, 10.9 Hz, 2H), 1.47 – 1.30 (m,2H), 0.82 (t, J = 7.3 Hz, 3H). 1-2,t r =2.34min 1 HNMR (400 MHz, DMSO -d6 ) δ 10.82 (s, 1H), 7.97 (d, J = 8.3 Hz, 2H), 7.69 (d, J = 6.7 Hz, 2H), 7.25 (s, 1H), 6.66 (s, 1H), 6.52 – 6.35 (m, 1H), 3.71 (s, 3H), 3.56 (d, J = 11.8 Hz, 1H), 3.39 (d, J = 10.4 Hz, 1H), 3.23 (d,J = 11.8 Hz, 1H), 2.71 (t, J = 10.2 Hz, 2H), 2.63 (d, J = 11.4 Hz, 1H), 2.42(s, 3H), 2.28 – 2.09 (m, 3H), 1.93 (dt, J = 21.2, 11.1 Hz, 2H), 1.46 – 1.29(m, 2H), 0.82 (t, J = 7.3 Hz, 3H). Example 2: (±)4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-propionylpiperazin-2-yl)benzoic acid

[0156] Prepared according to the preparation method of Example 1, except that 1-bromopropane in step f) is replaced with propionyl chloride.

[0157] 1 HNMR (400 MHz, DMSO -d6 ) δ 12.94 (s, 1H), 10.85 (s, 1H), 8.01 (d, J =6.4 Hz, 2H), 7.73 (dd, J = 16.2, 7.7 Hz, 2H), 7.27 (s, 1H), 6.67 (s, 1H),6.42 (d, J = 8.7 Hz, 1H), 4.26 (s, 1H), 3.72 (s, 3H), 3.57 (s, 2H), 3.23 (d,J = 11.9 Hz, 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 = 7.4 Hz, 3H). LCMS m / z = 436.2 [M+1] + Example 3: (±)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(oxecyclobutane-3-yl)piperazin-2-yl)benzoic acid

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

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

[0160] 1 HNMR (400 MHz, DMSO -d6 ) δ 10.83 (s, 1H), 7.97 (d, J = 8.0 Hz, 2H), 7.68 (d, J = 6.1 Hz, 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 = 11.8 Hz, 2H), 3.24(d, J = 11.8 Hz, 2H), 2.67 (s, 1H), 2.66 – 2.55 (m, 2H), 2.42 (s, 3H), 2.24 (t, J = 10.6 Hz, 1H), 1.92 – 1.81 (m, 2H). LCMS m / z = 436.2 [M+1] + . Example 4: (±)4-(4-(cyclopropylmethyl)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperazin-2-yl)benzoic acid

[0161] Prepared according to the preparation method of Example 1, except that 1-bromopropane in step f) is replaced with (bromomethyl)cyclopropane.

[0162] 1HNMR (400 MHz, DMSO -d6 ) δ 10.82 (s, 1H), 7.97 (d, J = 8.2 Hz, 2H),7.69 (s, 2H), 7.26 (s, 1H), 6.66 (s, 1H), 6.45 (s, 1H), 3.71 (s, 3H), 3.56(d, J = 11.8 Hz, 1H), 3.23 (d, J = 11.7 Hz, 1H), 2.84 (dd, J = 19.7, 10.8 Hz, 2H), 2.64 (d, J = 11.5 Hz, 1H), 2.42 (s, 3H), 2.23 (t, J = 10.7 Hz, 1H), 2.14 (d, J =6.4 Hz, 2H), 1.99 (dt, J = 22.0, 11.1 Hz, 2H), 1.24 (s, 1H), 0.78 (s, 1H), 0.40(d, J = 7.8 Hz, 2H), 0.04 (d, J = 7.8 Hz, 2H). LCMS m / z = 434.3 [M+1] + . Example 5: (±)4-(4-((2,2-difluorocyclopropyl)methyl)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperazin-2-yl)benzoic acid

[0163] Prepared according to the preparation method of Example 1, except that 1-bromopropane in step f) is replaced with 2-(bromomethyl)-1,1-difluorocyclopropane.

[0164] 1 HNMR (400 MHz, DMSO -d6) δ 12.87 (s, 1H), 10.84 (s, 1H), 7.98 (d, J =7.7 Hz, 2H), 7.71 (s, 2H), 7.26 (t, J = 2.5 Hz, 1H), 6.66 (s, 1H), 6.45 (d, J= 2.0 Hz, 1H), 3.72 (s, 3H), 3.57 (d, J = 11.1 Hz, 1H), 3.41 (s, 1H), 3.24(d, J = 11.8 Hz, 2H), 2.78 (d, J = 15.2 Hz, 2H), 2.66 (d, J = 11.2 Hz, 1H),2.43 (s, 3H), 2.37 - 2.15 (m, 2H), 2.15 - 1.93 (m, 2H), 1.79 (d, J = 6.3 Hz,1H), 1.60 - 1.46 (m, 1H), 1.12 (s, 1H). LCMS m / z = 470.3 [M+1] + . 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

[0165] Prepared according to the preparation method of Example 1, except that 1-bromopropane in step f) is replaced with 1,1-difluoro-2-iodoethane.

[0166] 1 HNMR (400 MHz, DMSO -d6) δ 10.83 (s, 1H), 7.97 (d, J = 8.2 Hz, 2H), 7.68 (d, J = 6.5 Hz, 2H), 7.25 (t, J = 2.7 Hz, 1H), 6.66 (s, 1H), 6.47 – 6.40(m, 1H), 6.26 – 5.96 (m, 1H), 3.71 (s, 3H), 3.65 – 3.48 (m, 1H), 3.41 (d, J= 10.6 Hz, 1H), 3.22 (d, J = 11.9 Hz, 1H), 2.78 (dd, J = 21.1, 10.5 Hz, 2H),2.69 – 2.57 (m, 3H), 2.42 (s, 3H), 2.26 (d, J = 10.9 Hz, 3H). LCMS m / z = 444.2 [M+1] + . Resolution of the enantiomers of (±)4-(4-(2,2-difluoroethyl)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperazin-2-yl)benzoic acid by chiral SFC yielded 6-1,t r =4.90min and 6-2,t r = 6.20 min. (Separation method: 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) 6-1,t r =4.90min 1 HNMR (400 MHz, DMSO -d6) δ 10.82 (s, 1H), 7.96 (d, J = 8.0 Hz, 2H), 7.65 (s, 2H), 7.25 (t, J = 2.7 Hz, 1H), 6.66 (s, 1H), 6.43 (s, 1H), 6.31 –5.91 (m, 1H), 3.71 (s, 3H), 3.57 (d, J = 12.0 Hz, 1H), 3.40 (s, 1H), 3.22 (d,J = 11.8 Hz, 1H), 2.78 (dd, J = 21.5, 10.3 Hz, 2H), 2.72 – 2.58 (m, 3H), 2.42(s, 3H), 2.30 – 2.17 (m, 3H). LCMS m / z = 444.2 [M+1] + . 6-2,t r =6.20min 1 HNMR (400 MHz, DMSO-d6) δ12.90 (s, 1H), 10.83 (s, 1H), 7.99 (d, J =8.4 Hz, 2H), 7.70 (d, J = 7.1 Hz, 2H), 7.26 (t, J = 2.7 Hz, 1H), 6.66 (s,1H), 6.44 (dd, J = 2.8, 2.0 Hz, 1H), 6.11 (tt, J = 55.7, 4.3 Hz, 1H), 3.71(s, 3H), 3.57 (d, J = 11.8 Hz, 1H), 3.42 (d, J = 8.2 Hz, 1H), 3.24 (d, J =11.8 Hz, 1H), 2.82 (d, J = 10.8 Hz, 1H), 2.79 – 2.59 (m, 4H), 2.42 (s, 3H), 2.31 – 2.14 (m, 3H). LCMS m / z = 444.2 [M+1] + . Example 7: (±)4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(oxetane-2-ylmethyl)piperazin-2-yl)benzoic acid

[0167] Prepared according to the preparation method of Example 1, except that 1-bromopropane in step f) is replaced with 2-iodomethyloxetane.

[0168] 1 HNMR (400 MHz, DMSO) δ 8.01 (d, J = 8.2 Hz, 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 =5.0 Hz, 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 = 8.4 Hz, 2H), 2.86 (d, J = 11.9 Hz, 2H), 2.73 (s, 1H), 2.66(d, J = 4.4 Hz, 3H), 2.39 (s, 2H), 2.13 (s, 1H), 1.30 (s, 1H). LCMS m / z = 450 [M+1] + . Example 8: (±)4-(4-((1-fluorocyclopropyl)methyl)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperazin-2-yl)benzoic acid

[0169] a) Preparation of (1-fluorocyclopropyl)methanol 1-Fluorocyclopropane-1-carboxylic acid (520 mg) was dissolved in tetrahydrofuran (20 mL) under nitrogen purging protection. 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 with 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 420 mg of the title compound.

[0170] 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. The mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure to prepare sand, and purified by column chromatography (mobile phase: petroleum ether ethyl acetate = 20 / 1 (V / V)) to obtain 230 mg of the title compound.

[0171] c) Preparation of tert-butyl 4-((4-((1-fluorocyclopropyl)methyl)-2-(4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid 50 mg of 5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester and (1-fluorocyclopropyl)methyl-4-methylbenzenesulfonate (230 mg, 0.9 mmol) were added to a sealed tube, followed by 10 mL of N,N-dimethylformamide and 20 mg of sodium hydroxide. The mixture was stirred overnight at 70 °C. The reaction solution was cooled to room temperature and concentrated under reduced pressure to prepare sand. The sand was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 12 mg of the title compound.

[0172] d) Preparation of (±)4-(4-((1-fluorocyclopropyl)methyl)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperazin-2-yl)benzoic acid 12 mg of tert-butyl 4-((4-((1-fluorocyclopropyl)methyl)-2-(4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid was dissolved in a mixture of anhydrous tetrahydrofuran (3 mL) and methanol (3 mL), and 0.5 mL of 1N lithium hydroxide aqueous solution was added. The mixture was heated to 70 °C and reacted for 3 h. After dissolving in water, 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 prepare slurry. The slurry was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 3.45 mg of the title compound.

[0173] 1 HNMR (400 MHz, DMSO -d6 ) δ 7.97 (d, J = 7.6 Hz, 2H), 7.64 (s, 2H), 7.32(d, J = 3.1 Hz, 1H), 6.64 (s, 1H), 6.44 (s, 1H), 4.72 (d, J = 20.5 Hz, 2H), 3.73(s, 3H), 3.52 (d, J= 10.7 Hz, 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 = 19.0 Hz, 2H), 0.87 (d, J = 7.0 Hz, 2H). LCMS m / z = 452.2 [M+1] + . Example 9: (R)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(3,3,3-trifluoropropyl)piperazin-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

[0174] Prepared according to the preparation method of Example 8, except that (1-fluorocyclopropyl)methyl-4-methylbenzenesulfonate in step c) can be replaced with 3,3,3-trifluoropropyl-4-methylbenzenesulfonate.

[0175] 1 HNMR (400 MHz, DMSO- d 6) δ 12.87 (s, 1H), 10.83 (s, 1H), 7.98 (d, J =8.1 Hz, 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 = 11.8 Hz, 1H), 3.49 – 3.39 (m, 2H), 3.23 (d, J = 11.8 Hz, 2H), 2.77 (dd, J = 19.2, 10.5 Hz, 2H), 2.69 – 2.59 (m, 1H), 2.46 (d, J = 10.1 Hz, 1H),2.42 (s, 3H), 2.21 (t, J = 10.9 Hz, 1H), 2.10 – 1.91 (m, 3H). LCMS m / z = 476.2 [M+1]+ . 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 resolved by chiral HPLC to give 9-1,t r =2.31min and 9-2,t r = 3.57 min. (Separation method: 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) 9-1, tr=2.31min 1 HNMR (400 MHz, DMSO- d6 ) δ10.82 (s, 1H), 7.94 (d, J = 8.3 Hz, 2H), 7.62(d, J = 6.6 Hz, 2H), 7.25 (t, J = 2.7 Hz, 1H), 6.66 (s, 1H), 6.43 (s, 1H), 3.71(s, 3H), 3.57 (d, J = 11.8 Hz, 2H), 3.22 (d, J = 11.8 Hz, 2H), 2.84 (q, J = 7.2 Hz, 2H), 2.76 (dd, J = 17.2, 11.2 Hz, 2H), 2.63 (d, J = 11.5 Hz, 1H), 2.45 (d, J = 9.8Hz, 1H), 2.42 (s, 3H), 2.20 (t, J = 10.5 Hz, 1H), 2.10 – 1.92 (m, 2H). 9-2,t r =3.57min 1 HNMR (400 MHz, DMSO- d6 ) δ10.82 (s, 1H), 7.94 (d, J = 8.3 Hz, 2H), 7.61(d, J= 6.3 Hz, 2H), 7.25 (t, J = 2.7 Hz, 1H), 6.66 (s, 1H), 6.47 – 6.38 (m, 1H), 3.71 (s, 3H), 3.57 (d, J = 11.8 Hz, 2H), 3.21 (d, J = 11.8 Hz, 2H), 2.82 (dd, J =14.5, 7.2 Hz, 2H), 2.77 – 2.69 (m, 2H), 2.63 (d, J = 11.5 Hz, 1H), 2.45 (d, J =9.7 Hz, 1H), 2.42 (s, 3H), 2.19 (t, J = 10.4 Hz, 1H), 2.01 (dt, J = 20.7, 10.2Hz, 2H). Example 10: (S)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(3-(trifluoromethyl)cyclobutyl)piperazin-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

[0176] Prepared according to the preparation method of Example 3, except that the oxetane-3-one in step a) is replaced with 3-(trifluoromethyl)cyclobutane-1-one.

[0177] 1 HNMR (400 MHz, DMSO- d6) δ 10.83 (s, 1H), 7.98 (d, J = 8.1 Hz, 2H), 7.68 (d, J = 7.3 Hz, 2H), 7.26 (s, 1H), 6.66 (s, 1H), 6.44 (s, 1H), 3.71 (s,3H), 3.57 (d, J = 11.9 Hz, 1H), 3.43 (d, J = 8.7 Hz, 2H), 3.24 (d, J = 12.0Hz, 3H), 3.20 – 3.07 (m,3H), 2.79 (t, J = 11.7 Hz, 2H), 2.62 (d, J = 11.1 Hz,1H), 2.46 – 2.37 (m, 4H), 2.35 (d, J = 11.6 Hz, 1H), 2.28 – 2.19 (m, 1H). LCMS m / z = 502.2 [M+1] + . Resolution of the enantiomer of (±)4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(3-(trifluoromethyl)cyclobutyl)piperazin-2-yl)benzoic acid by chiral SFC yielded 10⁻¹,t r =2.12min and 10-2,t r = 3.03 min. (Separation method: 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) 10-1,t r =2.12min 1 HNMR (400 MHz, DMSO- d6) δ 10.82 (s, 1H), 7.96 (d, J = 8.2 Hz, 2H), 7.67 (s, 2H), 7.25 (s, 1H), 6.65 (s, 1H), 6.43 (s, 1H), 3.70 (s, 3H), 3.57(d, J = 11.7 Hz, 2H), 3.23 (d, J = 11.7 Hz, 2H), 2.84 – 2.74 (m, 1H), 2.65 (d, J = 13.1 Hz, 3H), 2.42 (s, 3H), 2.18 (dd, J = 18.3, 9.4 Hz, 3H), 2.03 –1.93 (m, 1H), 1.83 (dd, J = 19.4, 8.6 Hz, 3H). LCMS m / z= 502.2 [M+1] + . 10-2,t r =3.03min 1 HNMR (400 MHz, DMSO- d6 ) δ 10.82 (s, 1H), 7.95 (d, J = 8.0 Hz, 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 = 11.8 Hz, 2H), 3.22 (d, J = 11.9 Hz, 2H), 2.83 (d, J = 9.1 Hz, 1H), 2.65 (d, J = 12.1 Hz, 3H), 2.42 (s, 3H), 2.18 (d, J = 26.6 Hz, 3H), 2.03 –1.93 (m, 1H), 1.83 (dd, J = 19.6, 9.5 Hz, 3H). LCMS m / z= 502.2 [M+1] + . Example 11: (S)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(2,2,2-trifluoroethyl)piperazin-2-yl)benzoic acid and (R)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(2,2,2-trifluoroethyl)piperazin-2-yl)benzoic acid.

[0178]

[0179] Prepared according to the preparation method of Example 8, except that (1-fluorocyclopropyl)methyl-4-methylbenzenesulfonate in step c) can be replaced with 2,2,2-trifluoroethyltrifluoromethanesulfonate.

[0180] 1 HNMR (400 MHz, DMSO- d 6) δ 10.83 (s, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 7.5 Hz, 2H), 7.26 (t, J = 2.7 Hz, 1H), 6.66 (s, 1H), 6.44 (dd, J= 2.8, 2.0 Hz, 1H), 3.71 (s, 3H), 3.57 (d, J = 11.8 Hz, 1H), 3.47 – 3.40 (m,1H), 3.22 (s, 1H), 3.19 – 3.07 (m, 2H), 2.79 (t, J = 12.1 Hz, 2H), 2.67 (d, J= 11.5 Hz, 1H), 2.46 – 2.31 (m, 5H), 2.23 (t, J = 10.7 Hz, 1H). LCMS m / z = 462.2 [M+1] + . Resolution of the enantiomer of (±)4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(2,2,2-trifluoroethyl)piperazin-2-yl)benzoic acid by chiral SFC yielded 11-1,t r =1.08min and 11-2,t r = 2.24 min. (Separation method: 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) 11-1,t r =1.08min LCMS m / z = 462.2[M+1] + . 1 HNMR (400 MHz, DMSO -d6) δ 10.83 (s, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 7.5 Hz, 2H), 7.26 (t, J = 2.7 Hz, 1H), 6.66 (s, 1H), 6.44 (dd, J= 2.8, 2.0 Hz, 1H), 3.71 (s, 3H), 3.57 (d, J = 11.8 Hz, 1H), 3.47 – 3.40 (m,1H), 3.26 – 3.20 (m, 1H), 3.19 – 3.07 (m, 2H), 2.79 (t, J = 12.1 Hz, 2H),2.62 (d, J = 11.5 Hz, 1H), 2.46 – 2.31 (m, 5H), 2.23 (t, J = 10.7 Hz, 1H). 11-2,t r =2.24min 1 HNMR (400 MHz, DMSO -d6 ) δ 10.83 (s, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 7.3 Hz, 2H), 7.26 (t, J = 2.7 Hz, 1H), 6.66 (s, 1H), 6.47 – 6.37 (m,1H), 3.71 (s, 3H), 3.57 (d, J = 11.8 Hz, 1H), 3.46 – 3.40 (m, 1H), 3.24 (d, J =11.9 Hz, 1H), 3.19 – 3.08 (m, 2H), 2.79 (t, J = 11.8 Hz, 2H), 2.62 (d, J = 11.4Hz, 1H), 2.46 – 2.31 (m, 5H), 2.23 (t, J = 10.5 Hz, 1H). LCMS m / z = 462.2 [M+1] + . Example 12: (±)4-(4-(3,3-difluorocyclobutyl)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperazin-2-yl)benzoic acid

[0181] Prepared according to the preparation method of Example 3, except that the oxetane-3-one in step a) is replaced with 3,3-difluorocyclobutane-1-one.

[0182] 1 HNMR (400 MHz, DMSO- d 6) δ 10.82 (s, 1H), 7.97 (d, J = 7.8 Hz, 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 = 11.9 Hz, 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] + . Example 13: 4-((3S,4S)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indole-4-yl)oxy)piperidin-3-yl)benzoic acid and 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indole-4-yl)oxy)piperidin-3-yl)benzoic acid and 4-((3S,4R)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indole-4-yl)oxy)piperidin-3-yl)benzoic acid

[0183] a) Preparation of (±)3-(4-(methoxycarbonyl)phenyl)-4-oxopiperidin-1-carboxylic acid tert-butyl ester 50 g of tert-butyl 3-bromo-4-oxopiperidin-1-carboxylate, 48.52 g of (4-(methoxycarbonyl)phenyl)boronic acid, 3.21 g of nickel(II) trifluoromethanesulfonate, 1.62 g of 1,10-phenanthroline, 49.62 g of potassium carbonate, and 500 mL of 1,4-dioxane were added to a reaction flask. Under nitrogen purging protection, the mixture was stirred at 80 °C for 16 h. The reaction solution was diluted with 500 mL of water, extracted with ethyl acetate (3 × 500 mL), separated, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to prepare slurry. The slurry was purified by column chromatography (mobile phase: petroleum ether ethyl acetate = 5 / 1 (V / V)) to obtain 32 g of the title compound.

[0184] 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 30 g of (±)3-(4-(methoxycarbonyl)phenyl)-4-oxopiperidin-1-carboxylic acid tert-butyl ester was added to a reaction flask, followed by 300 mL of methanol. Under nitrogen protection, sodium borohydride (10.21 g) was added in portions at 0 °C. The mixture was stirred at room temperature for 1 hour. The reaction was quenched by adding water (500 mL) in an ice bath. The mixture was extracted with ethyl acetate (3 × 500 mL), separated, and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to prepare slurry. The slurry was purified by column chromatography (mobile phase: petroleum ether ethyl acetate = 3 / 1 (V / V)). The title compounds were obtained in 8.9 g and 21.3 g respectively according to the corresponding elution gradient.

[0185] (±)-rel-(3S,4R)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester 1 HNMR (400 MHz, DMSO- d 6 ) δ 7.88 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 4.75 (d, J = 4.2 Hz, 1H), 3.99 (d, J = 7.8 Hz, 1H), 3.84 (s, 3H), 3.77 (d, J =12.4 Hz, 2H), 3.49 (d, J = 14.2 Hz, 1H), 3.16 (s, 1H), 2.83 (d, J= 11.2 Hz, 1H), 1.71 – 1.64 (m, 2H), 1.39 (s, 9H). (±)-rel-(3S,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester 1 HNMR (400 MHz, DMSO- d 6 ) δ 7.90 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 8.3 Hz, 2H), 4.71 (d, J = 6.0 Hz, 1H), 4.03 (q, J = 7.1 Hz, 1H), 3.97 (d, J = 11.8 Hz, 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, 3.8 Hz, 1H), 1.40 (s, 9H). 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 10.06 g of 4-hydroxy-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester, (±)-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. Under nitrogen purging protection, diisopropyl azodicarbonate (18.33 g) was added dropwise at 0 °C. The reaction system was heated to room temperature and reacted for 16 hours. The reaction was diluted with water (500 mL), extracted with ethyl acetate (3 × 200 mL), separated, and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to prepare slurry. The slurry was purified by column chromatography (mobile phase: petroleum ether ethyl acetate = 5 / 1 (V / V)) to give 22 g of the title compound.

[0186] 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 10 g 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 was dissolved in 70 mL of 4 M hydrochloric acid and stirred at room temperature for 4 hours. The residue, namely the title compound, was concentrated under reduced pressure to obtain 16 g.

[0187] LCMS m / z = 495.4[M+1] + . 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, followed by tetrahydrofuran (80 mL) and then 2,2-difluoroethyltrifluoromethanesulfonate (10.4 g). The mixture was purged with nitrogen and stirred at 70 °C for 2 hours. The reaction solution was diluted with water (500 mL) and extracted with ethyl acetate (3 × 200 mL). The organic phases were separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to prepare slurry. The slurry was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to give 12.4 g of the title compound.

[0188] 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 6.2 g 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 was added to a reaction flask, along with methanol (120 mL), lithium hydroxide (7.8 g), and water (40 mL). The mixture was purged with nitrogen and stirred at 70 °C for 16 hours. The pH of the reaction solution was adjusted to 6 with dilute hydrochloric acid (3 M). The solution was diluted with water (100 mL) and extracted with ethyl acetate (3 × 500 mL). The organic phases were separated and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain slurry. The slurry was purified by column chromatography (mobile phase: dichloromethane / methanol 5 / 1 (V / V)) to obtain 7.6 g of the enantiomer of the title compound.

[0189] LCMS m / z = 445[M+1] + . Enantiomers 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 resolved by chiral SFC to yield 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 =1.19min) 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), 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 Experiment 6. (Separation method: 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) 4-((3S,4S)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid 1 HNMR (400 MHz, DMSO- d 6 ) δ 10.83 (s, 1H), 7.90 (d, J = 8.2 Hz, 2H), 7.56(d, J = 8.1 Hz, 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, 11.6 Hz, 2H), 2.78 (t, J = 15.5 Hz, 2H), 2.34 (d, J = 8.9 Hz, 3H), 2.28 (s,1H), 1.70 (s, 2H). LCMS m / z = 445.1[M+1] + . 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid 1 HNMR (400 MHz, DMSO -d6 ) δ 10.83 (s, 1H), 7.88 (d, J = 8.1 Hz, 2H), 7.51 (d, J = 8.1 Hz, 2H), 7.16 (t, J = 2.7 Hz, 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 = 3.5 Hz, 1H), 3.09 (s, 1H), 2.95 – 2.87 (m, 2H), 2.75 (d, J= 15.6 Hz, 2H), 2.36 (s, 3H), 2.26 (s, 1H), 1.69 (s, 2H). LCMS m / z = 445.1[M+1] + . 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 according to the preparation method of Example 13a, except that (±)-rel-(3S,4R)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester in step a) is replaced with (±)-rel-(3S,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester.

[0190] Resolution of the enantiomers of (±)-rel-(3S,4R)-4-(1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid by chiral SFC yielded 13b-1,t r =1.29min and 13b-2,t r = 4.00 min (Separation method: 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) 13b-1,t r =1.29min 1 HNMR (400 MHz, DMSO -d6 ) δ 10.83 (s, 1H), 7.89 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.09 (t, J = 2.7 Hz, 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, 10.9 Hz,2H), 2.88 (dd, J = 17.7, 12.0 Hz, 4H), 2.67 (s, 1H), 2.34 (s, 3H), 1.66 (s, 2H). LCMS m / z = 445.1[M+1] + . 13b-2,t r =4.00min 1 HNMR (400 MHz, DMSO -d6 ) δ 13.09 – 12.27 (m, 1H), 10.83 (s, 1H), 7.90(d, J = 8.3 Hz, 2H), 7.58 (d, J = 8.3 Hz, 2H), 7.09 (t, J = 2.8 Hz, 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] + . 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 and 4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl) Benzoic acid and 4-((3S,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid

[0191] 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 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. (±)-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 (6.6 mL) were added to a reaction flask, followed by tetrahydrofuran (80 mL), and then 2,2,2-trifluoroethyltrifluoromethanesulfonate (8.9 g). The mixture was purged with nitrogen and stirred at 70°C for 2 hours. The reaction solution was diluted with water (500 mL) and diluted with ethyl acetate (3 × 200 mL). Extracted by extraction (mL), separated, combined organic phases, dried with anhydrous sodium sulfate, filtered, concentrated the filtrate under reduced pressure to prepare sand, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to obtain 5g of the title compound.

[0192] LCMS m / z = 577.1 [M+H] + . 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 5 g 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 was added to a reaction flask, along with methanol (120 mL), lithium hydroxide (6.25 g), and water (100 mL). The mixture was purged with nitrogen and stirred at 70 °C for 16 hours. The pH of the reaction solution was adjusted to 6 with dilute hydrochloric acid (3 M). The solution was diluted with water (100 mL) and extracted with ethyl acetate (3 × 500 mL). The organic phases were separated and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to prepare slurry. The slurry was purified by column chromatography (mobile phase: dichloromethane / methanol 5 / 1 (V / V)) to obtain 1.7 g of the enantiomer of the title compound.

[0193] Enantiomeric resorption of (±)-rel-(3S,4S)-4-(4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid by chiral SFC yielded 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 =1.87min) 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), 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 Experiment 7. (Separation method: Column: DAICELCHIRALCEL® 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) 14a-1,t r =1.87min 1 HNMR (400 MHz, DMSO -d6 ) δ 10.84 (s, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.55 (d, J = 8.2 Hz, 2H), 7.17 (t, J= 2.8 Hz, 1H), 6.63 (s, 1H), 6.21 – 6.16 (m,1H), 4.47 (dd, J = 16.1, 7.7 Hz, 1H), 3.60 (s, 3H), 3.24 (d, J = 3.5 Hz, 2H),3.16 – 3.08 (m, 1H), 2.94 (t, J = 12.7 Hz, 2H), 2.67 (t, J = 11.2 Hz, 1H), 2.47 –2.41 (m, 1H), 2.34 (d, J = 11.4 Hz, 3H), 1.70 (d, J = 3.6 Hz, 2H). LCMS m / z=463.1[M+H] + . 14a-2 ,t r =2.73min 1 HNMR (400 MHz, DMSO -d6 ) δ 10.81 (s, 1H), 7.86 (d, J = 8.2 Hz, 2H),7.51 (d, J = 8.2 Hz, 2H), 7.14 (t, J = 2.8 Hz, 1H), 6.59 (s, 1H), 6.15 (dd, J =3.0, 2.0 Hz, 1H), 4.44 (dd, J = 16.1, 7.8 Hz, 1H), 3.57 (s, 3H), 3.20 (d, J = 3.6Hz, 2H), 3.12 – 3.05 (m, 1H), 2.89 (d, J = 13.0 Hz, 2H), 2.64 (t, J = 11.3 Hz,1H), 2.42 (s, 1H), 2.32 (s, 3H), 1.67 (d, J = 3.5 Hz, 2H). LCMS m / z=463.1[M+H] + . Example 14b (±)-rel-(3S,4R)-4-(4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid Prepared according to the preparation method of Example 14a, except that (±)-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 in step a) is 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.

[0194] 14b-1,t was obtained by chiral SFC resolution of (±)-rel-(3S,4R)-4-(4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid. r =1.06min and 14b -2,t r = 2.37 min (Separation method: 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) 14b-1,t r =1.06min 1 HNMR (400 MHz, DMSO -d6 ) δ 10.83 (s, 1H), 7.89 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 8.3 Hz, 2H), 7.09 (t, J = 2.8 Hz, 1H), 6.61 (s, 1H), 5.71 (dd, J =3.0, 2.0 Hz, 1H), 4.65 (d, J = 2.5 Hz, 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= 7.6 Hz, 1H), 2.68 (d, J =10.9 Hz, 1H), 2.34 (s, 3H), 1.65 (s, 2H). LCMS m / z = 463.1 [M+H] + . 14b-2,t r =2.37min 1 HNMR (400 MHz, DMSO -d6 ) δ 10.84 (s, 1H), 7.90 (d, J = 8.3 Hz, 2H), 7.58 (d, J = 8.3 Hz, 2H), 7.09 (t, J = 2.7 Hz, 1H), 6.61 (s, 1H), 5.72 (dd, J =2.9, 2.0 Hz, 1H), 4.66 (d, J = 2.4 Hz, 1H), 3.55 (s, 3H), 3.44 – 3.36 (m, 2H), 3.29 (d, J = 5.9 Hz, 2H), 3.12 (td, J = 10.6, 5.6 Hz, 1H), 2.89 (d, J = 7.8 Hz, 1H), 2.69 (d, J = 11.1 Hz, 1H), 2.34 (s, 3H), 1.66 (s, 2H). LCMS m / z = 463.1 [M+H] + . 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 and 4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl) Benzoic acid and 4-((3S,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid

[0195] 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 according to the preparation method of Example 13a, except that 2,2-difluoroethyl trifluoromethanesulfonate in step c) is replaced with 3,3,3-trifluoropropyl trifluoromethanesulfonate.

[0196] 15a-1,t was obtained by chiral SFC resolution of (±)-rel-(3S,4S)4-(4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid. r =1.25min and 15a-2,t r = 2.00 min (Separation method: 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) 15a-1,t r =1.25min 1 HNMR (400 MHz, DMSO -d6 ) δ 10.83 (s, 1H), 7.91 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), 7.17 (t, J = 2.4 Hz, 1H), 6.63 (s, 1H), 6.17 (s, 1H), 4.46 (td, J = 9.5, 4.8 Hz, 1H), 3.60 (s, 3H), 3.12 (td, J = 10.2, 3.6 Hz, 1H), 2.89 (dd, J = 24.1, 10.3 Hz, 2H), 2.57 (dd, J = 9.6, 6.7 Hz, 2H), 2.49 (d, J = 13.4Hz, 2H), 2.36 (s, 3H), 2.30 (d, J= 11.0 Hz, 1H), 2.07 (t, J = 10.1 Hz, 1H), 1.79– 1.64 (m, 2H). LCMS m / z = 475.0 [MH] + . 15a-2,t r =2.00min 1 HNMR (400 MHz, DMSO -d6 ) δ 10.83 (s, 1H), 7.91 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 8.2 Hz, 2H), 7.17 (t, J = 2.6 Hz, 1H), 6.63 (s, 1H), 6.17 (s, 1H), 4.46 (td, J = 9.5, 4.8 Hz, 1H), 3.60 (s, 3H), 3.12 (td, J = 10.2, 3.7 Hz, 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 = 11.1 Hz, 1H), 2.05 (dt, J = 15.0, 7.5 Hz, 1H), 1.80 – 1.62 (m, 2H). LCMS m / z = 475.0 [MH] + . 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 according to the preparation method of Example 13b, except that 2,2-difluoroethyl trifluoromethanesulfonate in step c) can be replaced with 2,2,2-trifluoropropyl trifluoromethanesulfonate.

[0197] 15b-1,t was obtained by chiral SFC resolution of (±)-rel-(3S,4R)-4-(4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid. r=0.91min and 15b-2,t r = 2.35 min (Separation method: 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) 15b-1,t r =0.91min 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). 15b-2, tr=2.35min 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), 2.64 (dd, J = 24.2, 22.4 Hz, 5H), 2.37 – 2.32(m, 3H), 1.68 (s, 2H). Example 16: 4-((3S,4S)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)thio)piperidin-3-yl)benzoic acid and 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)thio)piperidin-3-yl)benzoic acid and 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

[0198] a) Preparation of 1-bromo-2-methoxy-4-methyl-5-nitrobenzene 100 g of 1-bromo-2-fluoro-4-methyl-5-nitrobenzene was dissolved in 1 L of methanol, and 25.6 g of sodium methoxide was added. Under nitrogen purging protection, the mixture was 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.

[0199] b) Preparation of 4-bromo-5-methoxy-7-methyl-1H-indole 73 g of 1-bromo-2-methoxy-4-methyl-5-nitrobenzene was added to a 2 L three-necked flask, followed by 730 mL of tetrahydrofuran. Under nitrogen protection, the mixture was cooled to -40 °C, and 1750 mL of vinyl magnesium bromide tetrahydrofuran solution (1.3 M) was slowly added dropwise. The reaction mixture was stirred at -40 °C for 3 hours. The reaction was quenched with 200 mL of ammonium chloride aqueous solution and extracted with ethyl acetate (3 x 200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to prepare slurry. The slurry was purified by column chromatography (mobile phase: petroleum ether ethyl acetate = 20 / 1 (V / V)) to obtain 8.5 g of the title compound.

[0200] 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 potassium hydroxide (6.0 g) and N,N-dimethylformamide (100 mL). The mixture was cooled to 0 °C, and p-toluenesulfonyl chloride (10.1 g) was added. The mixture was then heated 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 prepare slurry. The slurry was purified by column chromatography (mobile phase: petroleum ether ethyl acetate = 5 / 1 (V / V)) to obtain 8.1 g of the title compound.

[0201] d) Preparation of S-(5-methoxy-7-methyl-1-toluenesulfonyl-1H-indole-4-yl)ethanesulfonate A solution of S-(5-methoxy-7-methyl-1-tolyl-1H-indol-4-yl) ethanesulfonate (8 g), potassium thioacetate (2.55 g), tris(dibenzyl-BASE-acetone) dipalladium (9.29 g), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (17.6 g), N,N-diisopropylethylamine (7.87 g), and 1,4-dioxane (120 mL) was added to a reaction flask. The mixture was heated in a microwave oven at 140 °C for 2 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (300 mL), separated, dried over anhydrous sodium sulfate on the organic phase, filtered, concentrated under reduced pressure to obtain sinter, and purified by column chromatography (mobile phase: petroleum ether ethyl acetate = 5 / 1 (V / V)) to give 2.6 g of the title compound.

[0202] e) Preparation of 5-methoxy-7-methyl-1-toluenesulfonyl-1H-indole-4-thiol S-(5-methoxy-7-methyl-1-tolyl-1H-indol-4-yl) ethanesulfonate (300 mg) was dissolved in a mixed solution of tetrahydrofuran / methanol (1.5 mL / 3.0 mL), 1N lithium hydroxide (1 mL) was added, and the mixture was stirred at room temperature for 1 hour under nitrogen purging protection. The reaction solution was diluted with 1N dilute hydrochloric acid (10 mL) and water (30 mL), extracted with ethyl acetate (60 mL), separated, dried over anhydrous sodium sulfate on the organic phase, filtered, and concentrated under reduced pressure to give 260 mg of the title compound.

[0203] LCMS m / z = 348 [M+1] + . f) Preparation of (±) tert-butyl-3-(4-(methoxycarbonyl)phenyl)-4-(2-toluenesulfonylhydrazone)piperidine-1-carboxylate 2.194 g of tert-butyl 3-(4-(methoxycarbonyl)phenyl)-4-oxopiperidin-1-carboxylate and 1.838 g of 4-methylbenzenesulfonylhydrazine were added to a reaction flask, followed by 35 mL of methanol. The mixture was then purged with nitrogen and stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure and evaporated to dryness. The residue was purified by passing it through a reversed-phase column (WelFlash C18-I, Regular C18 20-40 μm, 330 g; mobile phase A: 10 mmol / L formic acid / H2O, B: MeCN; flow rate: 150 mL / min; isocratic elution: 77.5% MeCN) to obtain 0.9 g of the title compound.

[0204] Preparation of g) (±)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), and (±)-tert-butyl-3-(4-(methoxycarbonyl)phenyl)-4-(2-toluenesulfonylhydrazone)piperidine-1-carboxylate (590 mg) were added to a reaction flask. Under nitrogen protection, the mixture was stirred at 110 °C for 1 hour. The reaction was diluted with water (30 mL), extracted with ethyl acetate (30 mL x 3), separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain slurry. The slurry was purified by column chromatography (mobile phase: petroleum ether ethyl acetate = 5 / 1 (V / V)) to give 470 mg of the title compound.

[0205] Preparation of methyl benzoate (h) (±)4-(4-((5-methoxy-7-methyl-1-tolyl-1H-indol-4-yl)thio)piperidin-3-yl)benzoate 470 mg of tert-butyl piperidine-1-carboxylate (±) was dissolved in 5.0 mL of 4 M 1,4-dioxane hydrochloride solution and stirred at room temperature for 1 hour. The reaction solution was then concentrated under reduced pressure to give 220 mg of the title compound.

[0206] 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 benzoate (±)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-difluoroethyltrifluoromethanesulfonate (227 mg) were stirred at 70 °C for 2 hours under nitrogen purging protection. The reaction solution was concentrated under reduced pressure to prepare sand, and purified by column chromatography (mobile phase: petroleum ether ethyl acetate = 5 / 1 (V / V)) to obtain 190 mg of diastereomer mixture.

[0207] The peak -1,t was obtained by chiral SFC resolution of methyl 4-(1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1-tolyl-1H-indol-4-yl)thio)piperidin-3-yl)benzoate. r =2.24min, 64mg; peak -2,t r =2.65min, 61mg; peak -3,t r =2.55min, 60mg; peak -4,t r = 3.38 min, 80 mg (Separation method: 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:70:30; Flow rate: 100 mL / min; Detection wavelength: 214 nm) peak-1,t r =2.24min 1 HNMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 3.8Hz, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.25 – 7.16 (m, 4H), 6.66 (d, J = 3.8 Hz,1H), 6.50 (s, 1H), 5.98 – 5.70 (m, 1H), 3.91 (s, 3H), 3.81 (s, 3H), 3.34 –3.29 (m, 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 – 2.22 (m, 2H), 1.85 – 1.74 (m, 2H). peak-2,t r=2.65min 1 HNMR (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). Peak-3, t r =2.55min 1 HNMR (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). Peak-4,t r =3.38min 1 HNMR (400 MHz, CDCl3) δ 7.89 (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 –3.69 (m, 4H), 3.40– 3.31 (m, 1H), 3.12 (t, J = 10.6 Hz, 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). 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 and 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)thio)piperidin-3-yl)benzoic acid and 4-((3S,4R)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)thio)piperidin-3-yl)benzoic acid Following step d) of Example 13a, the four title compounds were obtained, with chiral HPLC analysis showing peak elution times of 16-1 t.r =3.20min,16-2,t r =3.60min,16-3,t r =3.72min,16-4,t r =5.48min。

[0208] 16-1,t r =3.20min 1 HNMR (400 MHz, 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). 16-2,t r =3.60min 1 HNMR (400 MHz, 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). 16-3,t r =3.72min 1 HNMR (400 MHz, 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). 16-4,t r =5.48min 1 HNMR (400 MHz, DMSO -d6 ) δ 10.98 (s, 1H), 7.84 (dd, J = 14.4, 8.3 Hz,2H), 7.42 (d, J = 8.0 Hz, 2H), 7.26 (t, J = 2.8 Hz, 1H), 6.67 (s, 1H), 6.34 –5.99 (m, 2H), 3.74 (d, J = 3.8 Hz, 1H), 3.70 (s, 3H), 3.03 (t, J= 10.7 Hz, 2H), 2.93 (t, J = 10.0 Hz, 2H), 2.87 – 2.76 (m, 2H), 2.54 (d, J = 11.2 Hz, 1H), 2.41(d, J = 9.8 Hz, 3H), 1.77 (d, J = 8.3 Hz, 1H), 1.48 (d, J = 10.5 Hz, 1H). 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

[0209] a) Preparation of 5-hydroxy-7-methyl-1H-indole-4-carboxaldehyde 5.0 g of 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester and 120 mL of dichloromethane were added to a two-necked flask. Under nitrogen purging protection, 23.04 g of aluminum trichloride was added in portions under ice bath conditions, and the mixture was stirred for 10 minutes. The mixture was stirred overnight at 40 °C. After the reaction cooled to room temperature, it was slowly poured into ice water, and the reaction was quenched by adding 3N dilute hydrochloric acid aqueous solution. The mixture was extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to prepare slurry. The slurry was purified by column chromatography (mobile phase: petroleum ether / dichloromethane = 3 / 7 (V / V)) to give 1.4 g of the title compound.

[0210] b) Preparation of tert-butyl 4-formyl-5-hydroxy-7-methyl-1H-indole-1-carboxylic acid 1.4 g of 5-hydroxy-7-methyl-1H-indole-4-carboxaldehyde, 40 mL of dichloromethane, 5.23 g of ditert-butyl dicarbonate, and 390 mg of 4-dimethylaminopyridine were added to a reaction flask. The mixture was purged under nitrogen protection and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure to obtain sintered sand, which was then purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 6 / 1 (V / V)) to give 2.03 g of the title compound.

[0211] c) 4-Formyl-5-(methoxy- d3 Preparation of 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 overnight at room temperature. Ethyl acetate and water were added, followed by extraction and separation. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to prepare slurry. The slurry was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 9 / 1 (V / V)) to give 375 mg of the title compound.

[0212] d) 4-Hydroxy-5-(methoxy- d3 Preparation of 7-methyl-1H-indole-1-carboxylic acid tert-butyl ester 4-formyl-5-(methoxy- d3 350 mg of 7-methyl-1H-indole-1-carboxylic acid tert-butyl ester, 10 mL of tetrahydrofuran, and 25 mL of methanol were added to a reaction flask. Hydrogen peroxide (1.75 mL) was added dropwise under an ice-water bath, followed by concentrated sulfuric acid (0.2 mL). The reaction was carried out under an ice-water bath for 2.5 hours. The reaction was quenched by slowly adding saturated sodium sulfite solution under an ice-water bath. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to prepare slag. The slag was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 9 / 1 (V / V)) to obtain 310 mg of the title compound.

[0213] Example 17a: 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 Prepared according to the preparation method of Example 13a, except that 4-hydroxy-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester in step a) is replaced with 4-hydroxy-5-(methoxy- d3 7-Methyl-1H-indole-1-carboxylic acid tert-butyl ester can be used. Alternatively, 2,2-difluoroethyl trifluoromethanesulfonate in step c) can be replaced with 3,3,3-trifluoropropyl trifluoromethanesulfonate.

[0214] 1 HNMR (400 MHz, DMSO -d6) δ 12.80 (s, 1H), 10.83 (s, 1H), 7.91 (d, J =8.2 Hz, 2H), 7.58 (d, J = 8.3 Hz, 2H), 7.17 (t, J = 2.7 Hz, 1H), 6.62 (s,1H), 6.16 (d, J = 2.0 Hz, 1H), 4.45 (td, J = 9.5, 4.8 Hz, 1H), 3.11 (td, J =10.3, 3.8 Hz, 1H), 2.89 (dd, J = 22.7, 10.0 Hz, 2H), 2.56 (dd, J = 10.1, 6.7Hz, 2H), 2.48 – 2.38 (m, 2H), 2.36 (s, 3H), 2.34 – 2.25 (m, 1H), 2.07 (t, J =10.4 Hz, 1H), 1.68 (dd, J = 27.4, 6.2 Hz, 2H). LCMS m / z = 480.3 [M+1] + . 17a-1,t was obtained by chiral SFC resolution of (±)-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. r =0.88min and 17a-2,t r = 1.39 min (Separation method: 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) 17a-1,t r =0.88min 1 HNMR (400 MHz, DMSO -d6) δ 12.98 – 12.11 (m, 1H), 10.83 (s, 1H), 7.90(d, J = 8.1 Hz, 2H), 7.59 (d, J = 8.3 Hz, 2H), 7.16 (t, J = 2.6 Hz, 1H), 6.62(s, 1H), 6.15 (s, 1H), 4.45 (d, J = 4.9 Hz, 1H), 3.29 (s, 1H), 3.11 (s, 1H), 2.89 (dd, J = 23.0, 10.2 Hz, 2H), 2.53 (d, J = 4.7 Hz, 4H), 2.35 (d, J = 7.1Hz, 3H), 2.12 – 2.00 (m, 1H), 1.72 (s, 2H). 17a-2,t r =1.39min 1 HNMR (400 MHz, DMSO -d6 ) δ 12.80 (s, 1H), 10.83 (s, 1H), 7.91 (d, J =8.0 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H), 7.17 (t, J = 2.6 Hz, 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, 10.2 Hz, 2H), 2.69 – 2.66 (m, 1H), 2.55 (d, J = 4.7 Hz, 3H), 2.36 (d, J= 7.1 Hz, 3H), 2.34 – 2.31 (m, 1H), 2.07 (m, 1H), 1.72 (s, 2H). 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

[0215] Prepared according to the preparation method of Example 17, 4-hydroxy-5-(methoxy- d3 4-hydroxy-7-methyl-5-(trifluoromethoxy)-1H-indole-1-carboxylic acid tert-butyl ester can be replaced with 4-hydroxy-7-methyl-5-(trifluoromethoxy)-1H-indole-1-carboxylic acid tert-butyl ester.

[0216] 1 HNMR (400 MHz, DMSO -d6 ) δ 10.80 (s, 1H), 7.88 (d, J = 8.2 Hz, 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, 4.1 Hz, 1H), 3.22 – 3.10 (m, 2H), 2.34 (s, 3H), 1.95 (d, J = 11.2Hz, 1H), 1.77 (dt, J = 21.8, 13.9 Hz, 3H), 1.63 – 1.48 (m, 1H), 1.37 (t, J =13.3 Hz, 1H), 1.18 (t, J = 7.0 Hz, 3H). LCMS m / z = 530.1 [M+1] + . Example 19: 4-(1R,2R,5R)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)thio)cyclohexyl)benzoic acid and 4-(1S,2R,5R)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)thio)cyclohexyl)benzoic acid and 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 and 4-(1R,2S,5R)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indole-4-yl)thio)cyclohexyl)benzoic acid and 4-(1S,2R,5S)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indole-4-yl)thio)cyclohexyl)benzoic acid and 4-(1S,2S,5S)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indole-4-yl)thio)cyclohexyl)benzoic acid

[0217] a) Preparation of 8-ethoxy-1,4-dioxaspiro[4.5]decane 1,4-dioxaspiro[4.5]dec-8-ol (50 g) was dissolved in tetrahydrofuran (500 mL). Under nitrogen purging protection, sodium hydrogen (15 g) was added at 0 °C and stirred for 2 hours. Iodoethane (98.4 g) was added at 0 °C and stirred at room temperature for 16 hours. The reaction was quenched with ammonium chloride aqueous solution, extracted with ethyl acetate (100 mL), separated, dried over anhydrous sodium sulfate on the organic phase, filtered, and the filtrate was concentrated under reduced pressure to give 65 g of the title compound.

[0218] b) Preparation of 4-ethoxycyclohexane-1-one 65 g of 8-ethoxy-1,4-dioxaspiro[4.5]decane, 234 mL of dilute hydrochloric acid (3 M), and 273 mL of tetrahydrofuran were added to a reaction flask and stirred at 90 °C for 2 hours. The reaction solution was diluted with 50 mL of water and extracted with ethyl acetate (3 × 100 mL). The layers were separated, and the organic layers were dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to obtain 40 g of the title compound.

[0219] c) (±)-4-(5-ethoxy-2-oxocyclohexyl)ethyl benzoate (diastereomeric mixture) 25 g of 4-ethoxycyclohexane-1-one, 48.5 g of ethyl 4-iodobenzoate, 16 g of tris(dibenzylene-BASEacetone)dipalladium, 20 g of 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene), 115 g of cesium carbonate, and 500 mL of anhydrous 1,4-dioxane were added to a reaction flask. Under nitrogen purging protection, the mixture was stirred at 100 °C for 16 hours. The reaction solution was cooled, filtered, and the filtrate was diluted with 150 mL of water and extracted with ethyl acetate (3 × 150 mL). The layers were separated, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain slag. The slag was purified by column chromatography (mobile phase: petroleum ether ethyl acetate = 5 / 1 (V / V)) to give 14.2 g of the title compound.

[0220] d) (±)-(5-ethoxy-2-(2-toluenesulfonylhydrazone)cyclohexyl)ethyl benzoate Ethyl (±)-4-(5-ethoxy-2-oxocyclohexyl)benzoate (6.2 g), 4-methylbenzenesulfonyl hydrazine (4.772 g), and toluene (60 mL) were added to a reaction flask. The reaction mixture was stirred at 50 °C for 1.5 h. The reaction solution was concentrated under reduced pressure, the residue was evaporated to dryness, diluted with water (80 mL), extracted with ethyl acetate (100 mL), separated, and the combined organic layers were dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain slurry. The slurry was purified by column chromatography (mobile phase: petroleum ether ethyl acetate = 5 / 1 (V / V)) and 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). The title compound (±) was obtained according to the corresponding elution order. -4-(5-ethoxy-2-(2-toluenesulfonylhydrazone)cyclohexyl)ethyl benzoate (diastere-1, peak -1 tr=1.9 min) and (±)-4-(5-ethoxy-2-(2-toluenesulfonylhydrazone)cyclohexyl)ethyl benzoate (diastere-2, peak -2 tr=2.0 min) Peak 1: (±)-4-(5-ethoxy-2-(2-toluenesulfonylhydrazone)cyclohexyl)ethyl benzoate (diastere-1) 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.06 (s, 1H), 7.85 (d, J = 8.2 Hz, 2H),7.19 – 7.13 (m, 6H), 4.36 (q, J = 7.2 Hz, 2H), 3.68 – 2.61 (m, 2H), 3.46 (q, J =7.0 Hz, 2H), 2.86 – 2.77 (m, 1H), 2.36 (s, 3H), 2.19 (d, J = 11.6 Hz, 1H), 2.10(d, J = 11.2 Hz, 1H), 2.01 – 1.92 (m, 1H), 1.73 – 1.64 (m, 1H), 1.39 – 1.29 (m,4H), 1.07 (t, J = 7.0 Hz, 3H). Peak-2: (±)-4-(5-ethoxy-2-(2-toluenesulfonylhydrazone)cyclohexyl)ethyl benzoate (diastere-2) 1 HNMR (400 MHz, DMSO- d 6 ) δ 10.09 (s, 1H), 7.84 (d, J = 8.3 Hz, 2H), 7.27(d, J = 8.3 Hz, 2H), 7.16 (dd, J = 14.9, 8.2 Hz, 4H), 4.35 (q, J = 7.1 Hz, 2H), 3.77 (dd, J = 11.1, 4.9 Hz, 1H), 3.70 (s, 1H), 3.51 – 3.43 (m, 2H), 2.48 (d, J =4.7 Hz, 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, 3.8 Hz, 1H), 1.73 – 1.61 (m, 1H), 1.36 (t, J =7.1 Hz, 3H), 1.14 (t, J = 7.0 Hz, 3H). Example 19a: 4-(1R,2R,5S)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indole-4-yl)thio)cyclohexyl)benzoic acid and 4-(1S,2R,5R)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indole-4-yl)thio)cyclohexyl)benzoic acid and 4-(1R,2S,5S)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indole-4-yl)thio)cyclohexyl)benzoic acid a) Preparation of ethyl (±)-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-toluenesulfonylhydrazone)cyclohexyl)benzoate (diastere-1, peak-1 tr=1.9 min) (1.286 g), 1,4-dioxane (30 mL), and cesium carbonate (2.134 g) were added to a reaction flask. Under nitrogen purging protection, the mixture was stirred at 110 °C for 1 hour. The reaction solution was diluted with water (50 mL) and extracted three times with ethyl acetate (150 mL). The organic phases were separated, washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain sintered precipitate. The sintered precipitate was purified by column chromatography (mobile phase: petroleum ether ethyl acetate = 10 / 1 (V / V)) to give 300 mg of the title compound.

[0221] b) Preparation of 4-(1R,2R,5R)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)thio)cyclohexyl)benzoic acid and 4-(1S,2R,5R)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)thio)cyclohexyl)benzoic acid and 4-(1R,2S,5S)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)thio)cyclohexyl)benzoic acid Ethyl benzoate (±)-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 methanol / water mixture (15 mL / 6 mL). The reaction was stirred at 70 °C for 16 hours. The reaction was concentrated under reduced pressure, the residue was evaporated to dryness, diluted with water, and the pH was adjusted to neutral with 1N dilute hydrochloric acid. The residue was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to prepare slurry. The slurry was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to obtain 160 mg of the title isomer mixture.

[0222] LCMS m / z = 438.1 [M-1] + 。

[0223] The isomer mixture was resolved by chiral SFC to obtain 19a-1,t r =5.45min and 19a-2,t r =6.03min, 19a-3,t r =5.33min and 19a-4,t r= 7.81 min (Separation method: Column: DAICELCHIRALPAK® 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) 19a-1,t r =5.45min 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] + . 19a-2,t r =6.03min 1 HNMR (400 MHz, DMSO -d6 ) δ10.98 (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] + . 19a-3,t r =5.33min 1 HNMR (400 MHz, 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 = 7.0Hz, 3H). LCMS m / z= 438.1[M-1] + . 19a-4,tr=7.81min 1 HNMR (400 MHz, DMSO -d6 ) δ 10.96 (s, 1H), 7.82 (d, J= 8.1 Hz, 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, 2.3 Hz, 3H), 3.14 (d, J = 12.8Hz, 1H), 2.42 (s, 3H), 2.08 – 1.91 (m, 3H), 1.55 (dd, J = 42.6, 29.5 Hz, 3H), 1.13 (t, J = 7.0 Hz, 3H). LCMS m / z = 438.1 [M-1] + . Example 19b: 4-(1R,2S,5R)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indole-4-yl)thio)cyclohexyl)benzoic acid and 4-(1S,2R,5S)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indole-4-yl)thio)cyclohexyl)benzoic acid and 4-(1R,2R,5R)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indole-4-yl)thio)cyclohexyl)benzoic acid Prepared according to the preparation method of Example 19a, except that (±)-4-(5-ethoxy-2-(2-toluenesulfonylhydrazone)cyclohexyl)ethyl benzoate (diastere-1) in step a) is replaced with (±)-4-(5-ethoxy-2-(2-toluenesulfonylhydrazone)cyclohexyl)ethyl benzoate (diastere-2).

[0224] The isomer mixture was resolved by chiral SFC to obtain 19b-1,t r =5.14min and 19b-2,t r =5.73min, 19b-3,t r =5.20min and 19b-4,t r= 6.30 min (Separation method: 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: 55:45; Flow rate: 70 mL / min; Detection wavelength: 214 nm) 19b-1,t r =5.14min 1 HNMR (400 MHz, DMSO- d 6 ) 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, 2.0Hz, 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). 19b-2,t r =5.73min 1 HNMR (400 MHz, DMSO- d 6 ) 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). 19b-3 ,t r =5.20min 1 HNMR (400 MHz, DMSO- d 6 ) 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, 2.0Hz, 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). 19b-4 ,t r =6.30min 1 HNMR (400 MHz, DMSO- d 6 ) 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). Example 20: 4-((1R,2S,5R)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indole-4-yl)oxy)cyclohexyl)benzoic acid and 4-((1S,2S,5S)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indole-4-yl)oxy)cyclohexyl)benzoic acid and 4-((1R,2R,5R)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indole-4-yl)oxy)cyclohexyl)benzoic acid and 4-((1S,2R,5S)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indole-4-yl)oxy)cyclohexyl) Benzoic acid and 4-((1R,2R,5S)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indole-4-yl)oxy)cyclohexyl)benzoic acid and 4-((1S,2R,5R)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indole-4-yl)oxy)cyclohexyl)benzoic acid and 4-((1R,2S,5S)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indole-4-yl)oxy)cyclohexyl)benzoic acid

[0225] a) (±)-4-(5-ethoxy-2-oxocyclohexyl)ethyl benzoate (diastereomeric mixture) Following the preparation method in step c of Example 19, ethyl (±)-4-(5-ethoxy-2-oxocyclohexyl)benzoate was obtained. Purification was performed by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)). Following the appropriate elution sequence, ethyl (±)-4-(5-ethoxy-2-oxocyclohexyl)benzoate (diastereomer-1, peak-1 t) was obtained. r =3.8min) and (±)-4-(5-ethoxy-2-oxocyclohexyl)ethyl benzoate (diastere-2, peak-2 t) r =3.5min) (±)-4-(5-ethoxy-2-oxocyclohexyl)ethyl benzoate (diastere-1, peak-1 t) r =3.8min) 1 HNMR (400 MHz, DMSO -d6 ) δ 7.88 (d, J = 8.1 Hz, 2H), 7.30 (t, J = 8.2 Hz,2H), 4.34 – 4.27 (m, 2H), 4.05 (dd, J = 12.8, 5.7 Hz, 1H), 3.83 (s, 1H), 3.54(dd, J = 12.9, 5.9 Hz, 2H), 2.77 – 2.65 (m, 1H), 2.32 – 2.23 (m, 2H), 2.18 (dd, J = 13.9, 4.6 Hz, 2H), 1.94 (td, J = 13.3, 6.6 Hz, 1H), 1.32 (dd, J = 12.2, 5.1Hz, 3H), 1.19 (dt, J = 7.1, 5.6 Hz, 3H). (±)-4-(5-ethoxy-2-oxocyclohexyl)ethyl benzoate (diastere-2, peak-2 t) r =3.5min) 1 HNMR (400 MHz, DMSO -d6 ) δ 7.88 (d, J = 8.1 Hz, 2H), 7.30 (t, J = 8.2 Hz,2H), 4.34 – 4.27 (m, 2H), 4.05 (dd, J= 12.8, 5.7 Hz, 2H), 3.83 (s, 2H), 3.54(dd, J = 12.9, 5.9 Hz, 1H), 2.77 – 2.65 (m, 1H), 2.32 – 2.23 (m, 2H), 2.18 (dd, J = 13.9, 4.6 Hz, 1H), 1.94 (td, J = 13.3, 6.6 Hz, 1H), 1.32 (dd, J = 12.2, 5.1Hz, 3H), 1.19 (dt, J = 7.1, 5.6 Hz, 3H). Example 20a; 4-((1R,2S,5R)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indole-4-yl)oxy)cyclohexyl)benzoic acid and 4-((1S,2S,5S)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indole-4-yl)oxy)cyclohexyl)benzoic acid and 4-((1R,2R,5R)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indole-4-yl)oxy)cyclohexyl)benzoic acid a) Preparation of (±)-4-(5-ethoxy-2-hydroxycyclohexyl)benzoate ethyl ester Ethyl (±)-4-(5-ethoxy-2-oxocyclohexyl)benzoate (diastere-1, peak-1 t) r =3.8 min) (15 g) was added to a three-necked flask. Under nitrogen protection, tetrahydrofuran (300 mL) was added. The reaction system was cooled to -78 °C, and 1 M trisec-butylborohydride (103 mL) was slowly added dropwise. The reaction was carried out at -78 °C for 1 hour. The reaction solution was poured into a saturated ammonium chloride ice-water solution and extracted with ethyl acetate (3*200 mL). The organic phases were separated and combined, washed with saturated saline solution (3*200 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by sand column chromatography (mobile phase: petroleum ether / ethyl acetate = 8 / 1 (V / V)) to give 14 g of the title compound.

[0226] 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), tert-butyl 4-hydroxy-5-methoxy-7-methyl-1H-indole-1-carboxylic acid (7.42 g), triphenylphosphine (14.14 g), and anhydrous tetrahydrofuran (400 mL) were added to a three-necked flask. Under nitrogen purging protection, diisopropyl azodicarbonate (10.9 g) was added dropwise at 0 °C. The reaction system was heated to room temperature and reacted for 16 hours. The reaction was diluted with water (500 mL), extracted with ethyl acetate (3 × 200 mL), separated, and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to prepare slurry. The slurry was purified by column chromatography (mobile phase: petroleum ether ethyl acetate = 20 / 1 (V / V)) to give 4.2 g of the title compound.

[0227] c) Preparation of 4-((1R,2S,5R)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indole-4-yl)oxy)cyclohexyl)benzoic acid and 4-((1S,2S,5S)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indole-4-yl)oxy)cyclohexyl)benzoic acid and 4-((1R,2R,5R)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indole-4-yl)oxy)cyclohexyl)benzoic acid The isomer mixture was obtained by hydrolysis in accordance with the method described in Example 17.

[0228] LCMS m / z = 424.2[M+1] + . The isomer mixture was resolved by chiral SFC to obtain 20a-1,t r =4.70min and 20a-2,t r =4.80min, 20a-3,t r =3.43min and 20a-4,t r = 3.59 min (Separation method: 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: 70:30; Flow rate: 100 mL / min; Detection wavelength: 214 nm) 20a-1,t r =4.70min 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] + . 20a-2 ,t r =4.80min 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] + . 20a-3 ,t r =3.43min 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] + . 20a-4 ,t r =3.59min 1 HNMR (400 MHz, DMSO -d6 ) δ 13.29 – 11.95 (m, 1H), 10.80 (s, 1H), 7.90(d, J= 8.2 Hz, 2H), 7.55 (d, J = 8.2 Hz, 2H), 7.14 (t, J = 2.7 Hz, 1H), 6.60 (s,1H), 6.12 – 6.04 (m, 1H), 4.43 (td, J = 10.4, 4.1 Hz, 1H), 3.57 (s, 1H), 3.57(s, 3H), 3.45 (q, J = 7.0 Hz, 2H), 3.22 – 3.13 (m, 1H), 2.35 (s, 3H), 1.96 (d, J = 13.6 Hz, 1H), 1.77 (dt, J = 21.9, 14.0 Hz, 3H), 1.63 – 1.51 (m, 1H), 1.43 –1.31 (m, 1H), 1.18 (t, J = 7.0 Hz, 3H). LCMS m / z = 424.2[M+1] + . Example 20b: 4-((1R,2R,5S)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indole-4-yl)oxy)cyclohexyl)benzoic acid and 4-((1S,2R,5R)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indole-4-yl)oxy)cyclohexyl)benzoic acid and 4-((1R,2S,5S)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indole-4-yl)oxy)cyclohexyl)benzoic acid A mixture of isomers was obtained with reference to Example 20a.

[0229] The isomer mixture was resolved by chiral SFC to obtain peaks 20b-1 (tr = 0.89 min), 20b-2 (tr = 1.22 min), 20b-3 (tr = 0.92 min), and 20b-4 (tr = 1.46 min). (Resolution method: 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) 20b-1,tr =0.89min 1 HNMR (400 MHz, DMSO- d 6) δ 10.80 (s, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.54(d, J = 8.2 Hz, 2H), 7.05 (t, J = 2.8 Hz, 1H), 6.60 (s, 1H), 5.59 (d, J = 2.1 Hz,1H), 4.64 (s, 1H), 3.84 (s, 1H), 3.55 (s, 3H), 3.45 (dd, J = 14.0, 7.0 Hz, 3H),2.33 (s, 3H), 2.14 (s, 1H), 1.88 (d, J = 13.1 Hz, 1H), 1.65 (d, J = 10.6 Hz, 2H),1.55 (s, 1H), 1.24 (s, 1H), 1.14 (t, J = 7.0 Hz, 3H). LCMS m / z= 424.1[M+1] + . 20b-2 ,t r =1.22min 1 HNMR (400 MHz, DMSO- d 6) 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). 20b-3 ,t r =0.92min 1 HNMR (400 MHz, DMSO- d 6) 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 = 11.6Hz, 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] + . 20b-4 ,tr=1.46min 1 HNMR (400 MHz, DMSO- d 6) δ 10.77 (s, 1H), 7.87 (d, J = 8.3 Hz, 2H), 7.52(d, J= 8.3 Hz, 2H), 7.03 (t, J = 2.7 Hz, 1H), 6.56 (s, 1H), 5.59 (dd, J = 2.8, 2.0Hz, 1H), 4.55 (s, 1H), 3.53 (dd, J = 7.0, 2.3 Hz, 1H), 3.50 (s, 3H), 3.47 (dd, J = 7.0, 2.3 Hz, 1H), 3.44 – 3.37 (m, 1H), 3.03 (d, J = 13.0 Hz, 1H), 2.30 (s,3H), 2.18 (dd, J = 24.2, 11.8 Hz, 1H), 1.98 (d, J = 11.6 Hz, 1H), 1.84 (dd, J =19.4, 8.1 Hz, 1H), 1.72 (t, J = 13.6 Hz, 2H), 1.39 (t, J = 13.0 Hz, 1H), 1.10 (t, J = 7.0 Hz, 3H). LCMS m / z = 424.1[M+1] + . 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

[0230] 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. Under ice-water bath conditions, N-chlorosuccinimide (103.0 mg) was added, followed by slow addition of 2M dilute hydrochloric acid (5 drops). 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 and purified by sand column chromatography (mobile phase: petroleum ether / ethyl acetate = 4 / 1 (V / V)) to give 88 mg of the title compound. b) Preparation of methyl benzoate (±)-rel-(2S,4S)-4-(4-ethoxy-1-((5-methoxy-7-methyl-1-tolyl-1H-indol-4-yl)sulfonyl)piperidin-2-yl)benzoate Methyl benzoate (±)-rel-(2S,4S)-4-(4-ethoxypiperidin-2-yl)benzoate (69.5 mg), triethylamine (80.1 mg), dichloromethane (5 mL), and 5-methoxy-7-methyl-1-tolyl-1H-indole-4-sulfonyl chloride (164 mg) were added to a reaction flask and stirred for 16 hours. The reaction mixture was diluted with water (40 mL) and extracted with dichloromethane (100 mL). The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain sintered precipitate. The sintered precipitate was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 2 / 1 (V / V)) to obtain 179 mg of the sample.

[0231] 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 in accordance with the method described in Example 17.

[0232] LCMS m / z = 473.1 [M+1] + 。

[0233] Enantiomers were separated by chiral SFC to obtain 21-1,t r =1.34min and 21-2,t r = 2.68 min (Separation method: 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) 21-1, tr=1.34min 1 HNMR (400 MHz, DMSO- d 6) δ 11.39 (s, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.55 – 7.42 (m, 3H), 6.94 (s, 1H), 6.91 (dd, J = 3.0, 2.0 Hz, 1H), 5.39 (s,1H), 3.90 (s, 3H), 3.84– 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 = 9.8 Hz, 1H), 1.47–1.42 (m, 2H), 0.99-0.96 (m, 3H). 21-2, tr=2.68min 1 HNMR (400 MHz, DMSO- d 6) δ 11.39 (s, 1H), 7.92 (d, J = 8.4 Hz, 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 = 12.4 Hz, 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 = 11.0 Hz, 1H), 1.51 –1.38 (m, 2H), 0.99–0.96 (m, 3H). Example 22: (±) (Z)-1 1 -((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-3-oxa-1(2,4)-piperazine-2(1,2-benzocyclohexanone-8-ene-2 4 carboxylic acid

[0234] a) Preparation of methyl 3-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzoate 10 g of methyl 4-bromo-3-hydroxybenzoate, 12.09 g of pinacol diborate, and 10.62 g of potassium acetate were added to a 500 mL two-necked flask. 150 mL of 1,4-dioxane was added, and the mixture was protected by nitrogen purging. 3.53 g of 1,1-bis(diphenylphosphine)ferrocene palladium dichloromethane complex was added. The mixture was stirred at 90 °C for 4 hours. The reaction solution was cooled to room temperature and quenched with water. The mixture was extracted three times with ethyl acetate (100 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 prepare slurry. The slurry was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to give 7.7 g of the title compound.

[0235] LCMS m / z=279.1 [M+H]+ . b) Preparation of methyl 3-hydroxy-4-(pyrazin-2-yl)benzoate 7.5 g of methyl 3-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzoate, 6.43 g of 2-bromopyrazine, and 8.57 g of sodium carbonate were added to a 500 mL two-necked flask. A mixed solvent of 1,4-dioxane / water (150 mL / 30 mL) was added, and the mixture was protected by nitrogen purging. 2.49 g of tetraphenylphosphine palladium was added, and the mixture was stirred at 100 °C for 4 hours. The mixture was then quenched with water, extracted three times with ethyl acetate (100 mL * 3), and the organic phases were combined. The mixture was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to prepare slurry. The slurry was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to give 3.7 g of the title compound.

[0236] LCMS m / z = 231.2[M+H]+. c) Preparation of (±)-3-hydroxy-4-(piperazin-2-yl)benzoate methyl ester 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 / carbon (1.3 g, 10%) were added. The mixture was purged with hydrogen, stirred overnight at room temperature, filtered, and the filtrate was concentrated under reduced pressure to give 3 g of the title compound.

[0237] LCMS m / z = 237.1[M+H]+. 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 purging. A solution of di-tert-butyl dicarbonate (1.55 g) in dichloromethane (10 mL) was then added dropwise. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to produce sand, and purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to obtain 2.5 g of the title compound.

[0238] LCMS m / z = 337.4[M+H]+. e) Preparation of tert-butyl piperazine-1-carboxylic acid (±) 2.3 g of (±)3-(2-hydroxy-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester was dissolved in N,N-dimethylformamide (50 mL), imidazole (931 mg) was added, nitrogen was used for purging protection, the mixture was cooled to 0 °C in an ice-water bath, tert-butyldimethylchlorosilane (2.06 g) and 4-dimethylaminopyridine (84 mg) were added, the mixture was stirred overnight at room temperature, water was added to quench the reaction, and the mixture was 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 obtain sintered sand, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 20 / 1 (V / V)) to give 2.2 g of the title compound.

[0239] LCMS m / z = 451.7[M+H]+. f) Preparation of tert-butyl 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 1.32 g of 4-(hydroxymethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester was dissolved in dichloromethane (30 mL), protected by nitrogen purging, and cooled to 0 °C in an ice-water bath. 2.07 g of dibromotriphenylphosphine was added in portions, and the mixture was stirred at 0 °C for 1.5 hours. Then, 1.7 g of (±) 3-(2-((tert-butyldimethylsilyl)oxy)-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester and 1.46 g of N,N-diisopropylethylamine were added, and the mixture was stirred at 0 °C for 1.5 hours. The reaction was quenched with water, and the mixture was 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 obtain sintered 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.

[0240] LCMS m / z = 725.0[M+H]+. 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) 2.4 g of (±)4-((4-(tert-butyloxycarbonyl)-2-(2-((tert-butyldimethylsilyl)oxy)-4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester was dissolved in tetrahydrofuran (50 mL) under nitrogen purging protection. Then, a tetrahydrofuran solution of tetrabutylammonium fluoride (5.6 mL, 1 mol / L) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was quenched with water, 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 obtain sintered sand, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to give 2 g of the title compound.

[0241] LCMS m / z = 610.7[M+H]+. Preparation of tert-butyl 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 2 g of 4-((4-(tert-butyloxycarbonyl)-2-(2-hydroxy-4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester was dissolved in N,N-dimethylformamide (30 mL), potassium carbonate (1.36 g) was added, nitrogen was used for protection, and then 6-bromohex-1-ene (1.07 g) was added. The mixture was stirred overnight at room temperature, the reaction was quenched with water, 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 obtain sintered sand, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to give 2 g of the title compound.

[0242] LCMS m / z = 692.9[M+H]+. i) Preparation of tert-butyl 4-((2-(2-(hexyl-5-en-1-oxy)-4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid 2 g of tert-butyl 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 was dissolved in methanol (50 mL), and 11 mL of 1,4-dioxane hydrochloric acid solution (4 M) was added. The mixture was stirred at room temperature for 2 hours, and the reaction solution was concentrated under reduced pressure to give 1.8 g of the title compound.

[0243] LCMS m / z = 592.7[M+H]+. Preparation of tert-butyl 4-(4-allyl-2-(2-(hexyl-5-en-1-oxy)-4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid 4-((2-(2-(hexyl-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) and 3-bromoprop-1-ene (0.98 g) were dissolved in acetonitrile (40 mL), and triethylamine (1.64 g) was added. The mixture was purged under nitrogen protection and stirred overnight at room temperature. The reaction was quenched with water, extracted three times with ethyl acetate (30 mL * 3), and the organic phases were combined. The mixture was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain sintered sand, and purified by column chromatography (mobile phase: dichloromethane / methanol = 50 / 1 (V / V)) to give 1.2 g of the title compound.

[0244] LCMS m / z = 632.8[M+H]+. 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-benzocyclohexanone-8-ene-2 4 Preparation of carboxylic esters 4-(4-allyl-2-(2-(hexyl-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), and Grubbs 1st (130 mg) was added. Under nitrogen purging protection, the mixture was stirred at 80 °C for 18 hours. The reaction solution was concentrated under reduced pressure to prepare sand, and purified by column chromatography (mobile phase: dichloromethane / methanol = 10 / 1 (V / V)) to give 175 mg of the title compound.

[0245] l) (±) (Z)-1 1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-3-oxa-1(2,4)-piperazine-2(1,2-benzocyclohexanone-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-benzocyclohexanone-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, 2 N) was added. The mixture was stirred at 70 °C for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, diluted with water, and the pH was adjusted to 7 with dilute hydrochloric acid. The mixture was extracted three times with ethyl acetate, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The filtrate was then concentrated under reduced pressure to prepare sintered sand, which was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 5 mg of the title compound.

[0246] 1 H NMR (400 MHz, DMSO- d6 ) δ 10.84 (s, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.44 (s, 1H), 7.28 (s, 1H), 6.76 – 6.64 (m, 1H), 6.62 (s, 1H), 5.45 (t, J = 10.5 Hz, 1H), 5.29 (s, 1H), 4.25 (s, 1H), 4.16 (d,J = 9.3 Hz, 1H), 3.95 (t, J = 10.9 Hz, 2H), 3.77 (d, J = 11.9 Hz, 1H), 3.74(s, 3H), 2.90 (d, J = 11.5 Hz, 2H), 2.75 (d, J = 11.3 Hz, 1H), 2.68 (d, J =17.4 Hz, 2H), 2.43 (s, 3H), 2.33 (d, J = 11.7 Hz, 2H), 1.91 (s, 2H), 1.66 (s,1H), 1.30 – 1.08 (m, 4H). LCMS m / z = 490.6 [M+1]+. 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)-piperidine-2(1,2)-benzocyclohexanone-8-ene-2 4 carboxylic acid

[0247] a) Preparation of methyl 3-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzoate 25 g of methyl 4-bromo-3-hydroxybenzoate, 30.23 g of pinacol diborate, and 26.55 g of potassium acetate were added to a 500 mL three-necked flask, followed by 350 mL of 1,4-dioxane. Under nitrogen purging protection, 4.42 g of [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex was added. The mixture was heated to 90 °C and stirred for 4 hours. The mixture was quenched with 300 mL of water and extracted three times with 200 mL of ethyl acetate. 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 prepare slurry. The slurry was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to obtain 30 g of the title compound.

[0248] LCMS m / z=279.1 [M+H]+. b) Preparation of tert-butyl 5-(2-hydroxy-4-(methoxycarbonyl)phenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylic acid 19 g of methyl 3-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzoate, 12.58 g of tert-butyl 5-bromo-4-oxo-3,4-dihydropyridine-1(2H)-carboxylic acid, and 18.88 g of potassium carbonate were added to a three-necked flask. Then, 1,4-dioxane / water (300 mL / 100 mL) was added. Under nitrogen purging protection, 4.42 g of tetraphenylphosphine palladium was added. The mixture was heated to 60 °C and stirred for 4 hours. The mixture was quenched with water (300 mL) and 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 prepare slurry. The slurry was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to give 7.5 g of the title compound.

[0249] LCMS m / z=348.4 [M+H]+. c) Preparation of tert-butyl (3R,4S)-4-hydroxy-3-(2-hydroxy-4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid At 0°C, anhydrous formic acid (30 mL) was added dropwise to triethylamine (43 mL) to prepare a solution for later use (temperature controlled at 5-10°C). 7.5 g of 5-(2-hydroxy-4-(methoxycarbonyl)phenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester and 1.36 g of RuCl(p-cymene)[(S,S)-Ts-DPEN] were added to the reaction flask. Then, the prepared anhydrous formic acid and triethylamine solution was added to the reaction flask, and nitrogen gas was introduced. The reaction mixture was subjected to displacement, and the temperature was slowly raised to room temperature. The mixture was stirred overnight, and 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 around 10°C. Water (200 mL) was added to quench the reaction, and ethyl acetate (150 mL * 3) was used for extraction. The mixture was washed with saturated brine (200 mL * 1), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to prepare slag. The slag was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 20 / 3 (V / V)) to obtain 2 g of the title compound.

[0250] LCMS m / z = 352.4 [M+H]+. d) Preparation of tert-butyl (3R,4S)-3-(2-(hex-5-en-1-oxy)-4-(methoxycarbonyl)phenyl)-4-hydroxypiperidine-1-carboxylic acid (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). The mixture was purged under nitrogen protection and stirred overnight at room temperature. The mixture was then quenched with water (100 mL) and extracted with ethyl acetate (100 mL * 3). The organic phases were combined, washed with saturated brine (100 mL * 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to prepare slurry. The slurry was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 20 / 3 (V / V)) to obtain 1.55 g of the title compound.

[0251] LCMS m / z = 434.5[M+H]+. 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-oxy)-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 under nitrogen purging protection. Anhydrous tetrahydrofuran (40 mL) was added, and diisopropyl azodicarbonate (868 mg) was added dropwise at 0 °C. The reaction system was slowly heated to room temperature and stirred overnight. The reaction was quenched with water (100 mL), extracted with ethyl acetate (100 mL * 3), and the organic phases were combined. The mixture was washed with saturated brine (100 mL * 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain granules, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 20 / 1 (V / V)) to give 550 mg of the title compound.

[0252] LCMS m / z = 693.9[M+H]+. f) Preparation of tert-butyl 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 530 mg 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 was added to 1,4-dioxane (3 mL), followed by 3 mL of 1,4-dioxane hydrochloric acid solution (4 M). The mixture was stirred at room temperature for 2 hours under nitrogen protection. The mixture was then neutralized with 30 mL of saturated sodium bicarbonate solution and extracted with 3 x 50 mL of ethyl acetate. The organic phases were combined, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain 440 mg of the title compound.

[0253] LCMS m / z = 593.7[M+H]+ . 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), followed by the addition of triethylamine (440 mg) and 3-bromoprop-1-ene (264 mg). The mixture was stirred overnight at 50 °C, quenched with water (50 mL), extracted with ethyl acetate (50 mL * 3), and the organic phases were combined. The mixture was washed with saturated brine (50 mL * 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain slag, and purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 350 mg of the title compound.

[0254] LCMS m / z = 633.8[M+H]+. 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)-piperidine-2(1,2)benzocyclohexanone-8-ene-2 4 Preparation of carboxylic esters 350 mg 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 was added to dichloromethane (350 mL), followed by the addition of Grubbs 1st (228 mg). The mixture was then subjected to nitrogen purging and stirred at 40 °C for 18 hours. The reaction solution was concentrated under reduced pressure to obtain sintered sand, which was then purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 130 mg of the title compound.

[0255] LCMS m / z = 605.7[M+H]+. i) (1 3 R, 1 4 R, Z)-1 4 -((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-3-oxa-1(3,1)-piperidine-2(1,2)-benzocyclohexanone-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)-piperidine-2(1,2)benzocyclohexanone-8-ene-2 4The carboxylic acid ester (35 mg) was dissolved in a tetrahydrofuran / methanol (3 mL / 3 mL) mixture, and lithium hydroxide aqueous solution (3 mL, 2 N) was added. The mixture was stirred at 70 °C for 2 hours, concentrated under reduced pressure to dryness, and the pH was adjusted to neutral by adding dilute hydrochloric acid aqueous solution. 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 prepare slag. The slag was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 6.1 mg of the title compound. 1 H NMR (400 MHz, DMSO -d6 ) δ 10.87 (d, J =9.4 Hz, 1H), 7.90 (dd, J = 30.1, 7.7 Hz, 1H), 7.57 (t, J = 7.3 Hz, 1H), 7.40 (dd, J = 20.6, 12.0 Hz, 2H), 7.24 – 7.17 (m, 1H), 6.71 (d, J = 16.0 Hz, 1H), 5.43 (s,1H), 4.93 (d, J = 34.3 Hz, 1H), 4.09 (s, 1H), 3.79 (t, J = 15.9 Hz, 3H), 2.39 (d, J = 5.7 Hz, 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]+.

[0256] Example 24: (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 -Formic acid

[0257] 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)benzoic acid cyclodecane-2 4 Preparation of formate 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)-piperidine-2(1,2)benzocyclohexanone-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, stirred overnight at room temperature, filtered with diatomaceous earth, and the filtrate was distilled under reduced pressure to dryness to give 45 mg of the title compound.

[0258] LCMS m / z=607.4 [M+H]+.

[0259] 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 formic acid 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)benzoic acid cyclodecane-2 4 Formate (50 mg) was dissolved in a tetrahydrofuran / methanol (3 mL / 3 mL) mixture, and lithium hydroxide aqueous solution (3 mL, 2 N) was added. The mixture was stirred at 70 °C for 2 hours, concentrated under reduced pressure to dryness, and the pH was adjusted to neutral by adding dilute hydrochloric acid aqueous solution. 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 prepare slag. The slag was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 5.1 mg of the title compound.

[0260] 1 H NMR (400 MHz, DMSO -d6) δ 10.86 (s, 1H), 7.85 (d, J = 7.5 Hz, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.45 (s, 1H), 7.20 (s, 1H), 6.74 (s, 1H), 6.38 (s,1H), 4.84 (d, J = 7.9 Hz, 1H), 4.21 (s, 1H), 3.83 (s, 3H), 3.25 (d, J = 10.5Hz, 3H), 2.71 (d, J = 9.7 Hz, 2H), 2.40 (s, 3H), 2.10 (d, J = 11.2 Hz, 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, 17.4 Hz, 4H). LCMS m / z = 493.3[M+H]+. 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

[0261] a) Preparation of tert-butyl 5-(difluoromethoxy)-4-formyl-7-methyl-1H-indole-1-carboxylic acid 1.5 g of 4-formyl-5-hydroxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester was dissolved in 25 mL of dichloromethane and added to a two-necked flask. Under nitrogen purging protection, the mixture was cooled to 0 °C in an ice-water bath. 12.23 g of potassium hydroxide aqueous solution was added dropwise. After stirring for 5 minutes, a 5 mL solution of difluorobromomethyltrimethylsilane (3.32 g) in dichloromethane was added dropwise. The reaction was carried out at 0 °C for 2 hours. The reaction was quenched with 50 mL of water and extracted with 3 x 50 mL of dichloromethane. The organic phases were combined, washed with 1 x 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain sintered sand, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to give 670 mg of the title compound.

[0262] LCMS m / z=326[M+H]+.

[0263] b) Preparation of tert-butyl 5-(difluoromethoxy)-4-hydroxy-7-methyl-1H-indole-1-carboxylic acid 670 mg of 5-(difluoromethoxy)-4-formyl-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester was dissolved in 20 mL of dichloromethane and added to a 100 mL two-necked flask. Under nitrogen purging protection, 3.55 g of m-chloroperoxybenzoic acid was added at 0 °C and the reaction was carried out at room temperature for 3 hours. The reaction was quenched by adding sodium bisulfite aqueous solution, 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 obtain sand, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 4 / 1 (V / V)) to give 170 mg of the title compound.

[0264] LCMS m / z=314.2[M+H]+.

[0265] 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 120 mg of 5-(difluoromethoxy)-4-hydroxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester, (±)-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-necked flask under nitrogen purging protection. Anhydrous tetrahydrofuran (10 mL) was added, and diisopropyl azodicarbonate (155 mg) was added dropwise at 0 °C. The mixture was slowly heated to room temperature and stirred overnight. The mixture was quenched with water (20 mL), extracted with dichloromethane (20 mL * 3), and the organic phases were combined. The mixture was washed with saturated brine (20 mL * 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain sintered sand, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 4 / 1 (V / V)) to give 137 mg of the title compound.

[0266] LCMS m / z=631.3[M+H]+.

[0267] 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 1,4-dioxane hydrogen chloride solution (10 mL, 4 M) was added. Under nitrogen purging protection, the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to dryness under reduced pressure to give 150 mg of the title compound.

[0268] LCMS m / z=531[M+H]+.

[0269] 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, followed by N,N-diisopropylethylamine (137 mg). The mixture was stirred overnight at 70 °C, quenched with 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 obtain sand, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 4 / 1 (V / V)) to give 140 mg of the title compound.

[0270] LCMS m / z=627[M+H]+.

[0271] 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 lithium hydroxide aqueous solution (5 mL, 2N) was added. The mixture was stirred at 70 °C for 2 hours, concentrated under reduced pressure to dryness, and the pH was adjusted to neutral by adding dilute hydrochloric acid aqueous solution. The mixture was extracted with ethyl acetate (10 mL*3), and the organic phases were combined. The mixture was washed with saturated brine (20 mL*1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to prepare slurry. The slurry was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 130 mg of the enantiomer of the title compound.

[0272] 1 H NMR (400 MHz, DMSO -d6 ) δ 11.16 (s, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 8.2 Hz, 2H), 7.28 (t, J = 2.7 Hz, 1H), 6.94 – 6.54 (m, 2H), 6.21 (s,1H), 4.59 – 4.47 (m, 1H), 3.56 (t, J = 6.1 Hz, 1H), 3.19 – 3.07 (m, 1H), 2.91(dd, J = 21.7, 10.3 Hz, 2H), 2.56 (d, J = 6.9 Hz, 2H), 2.36 (s, 3H), 2.12 (t, J =10.6 Hz, 1H), 1.77 (d, J = 8.8 Hz, 1H), 1.69 (d, J = 9.1 Hz, 1H), 1.43 (dd, J =7.8, 5.5 Hz, 2H). LCMS m / z = 513.2[M+1]+. The enantiomers 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 resolved by chiral SFC to obtain 25-1, tr = 1.69 min and 25-2, tr = 2.40 min. (Resolution method: 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) 25-1, tr=1.69min 1 H NMR (400 MHz, DMSO -d6 ) δ 11.18 (s, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 8.2 Hz, 2H), 7.28 (t, J = 2.7 Hz, 1H), 6.72 (dd, J = 89.3, 62.3 Hz,2H), 6.27 – 6.14 (m, 1H), 4.53 (td, J = 9.6, 4.3 Hz, 1H), 3.55 (dd, J = 17.3,11.2 Hz, 1H), 3.12 (td, J = 10.0, 3.7 Hz, 1H), 2.91 (dd, J = 23.0, 11.6 Hz, 2H),2.56 (dd, J = 15.0, 8.3 Hz, 2H), 2.42 – 2.31 (m, 3H), 2.11 (dd, J = 20.1, 8.8 Hz, 1H), 1.73 (q, J = 10.7 Hz, 2H), 1.51 (d, J = 2.7 Hz, 2H). 25-2, tr=2.40min. 1 H NMR (400 MHz, DMSO) δ 11.19 (s, 1H), 7.89 (d, J= 8.3 Hz, 2H), 7.57(d, J = 8.3 Hz, 2H), 7.28 (t, J = 2.8 Hz, 1H), 6.72 (dd, J = 89.4, 62.1 Hz, 2H),6.21 (dd, J = 3.0, 2.0 Hz, 1H), 4.53 (td, J = 9.8, 4.5 Hz, 1H), 3.56 (t, J = 6.1Hz, 1H), 3.12 (td, J = 10.4, 3.9 Hz, 1H), 2.91 (dd, J = 23.0, 11.4 Hz, 2H), 2.64– 2.53 (m, 2H), 2.41 – 2.33 (m, 3H), 2.11 (dd, J = 19.4, 9.1 Hz, 1H), 1.82 –1.63 (m, 2H), 1.49 – 1.36 (m, 2H). Example 26: 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5-(methoxy-d3)-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid

[0273] a) Preparation of 5-hydroxy-7-methyl-1H-indole-4-carboxaldehyde 5.0 g of 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester was added to a 250 mL two-necked flask under ice-water bath conditions, followed by 130 mL of dichloromethane. Under nitrogen purging protection, 21.66 g of boron tribromide was added dropwise, and the mixture was slowly heated to room temperature and reacted overnight. The reaction solution was poured into ice water, filtered, and the filter cake was washed with dichloromethane, chlorine solution, saturated sodium bicarbonate, and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain sand, and purified by column chromatography (mobile phase: petroleum ether / dichloromethane = 3 / 2 (V / V)) to give 1.2 g of the title compound.

[0274] LCMS m / z=176.1 [M+H]+.

[0275] b) Preparation of tert-butyl 5-(difluoromethoxy)-4-hydroxy-7-methyl-1H-indole-1-carboxylic acid 1.2 g of 5-hydroxy-7-methyl-1H-indole-4-carboxaldehyde was added to 40 mL of dichloromethane, followed by 4.48 g of ditert-butyl dicarbonate and 334 mg of 4-dimethylaminopyridine. The mixture was then stirred overnight at room temperature under nitrogen purging protection. The reaction solution was concentrated to dryness under reduced pressure, and 30 mL of methanol and 10 g of potassium carbonate were added. The mixture was stirred at room temperature for 1 hour. The pH was adjusted to weakly acidic with dilute hydrochloric acid, and water and ethyl acetate were added for extraction and separation. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain sintered precipitate, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 85 / 15 (V / V)) to give 1.56 g of the title compound.

[0276] LCMS m / z=276.1 [M+H]+.

[0277] c) Preparation of tert-butyl 4-formyl-5-(methoxy-d3)-7-methyl-1H-indole-1-carboxylic acid 1.4 g of 5-(difluoromethoxy)-4-hydroxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester, 20 mL of N,N-dimethylformamide, 2.21 g of deuterated iodomethane, and 2.11 g of potassium carbonate were added to a reaction flask and reacted overnight at room temperature. The reaction was quenched by adding water (30 mL), extracted with ethyl acetate (30 mL x 3), and the organic phases were combined. The mixture was washed with saturated brine (30 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain slag. The slag was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 85 / 15 (V / V)) to give 873 mg of the title compound.

[0278] LCMS m / z=293.2 [M+H]+.

[0279] d) Preparation of tert-butyl 4-hydroxy-5-(methoxy-d3)-7-methyl-1H-indole-1-carboxylic acid 800 mg of 4-formyl-5-(methoxy-d3)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester, 5 mL of tetrahydrofuran, and 15 mL of methanol were added to a reaction flask. The mixture was cooled in an ice-water bath, and hydrogen peroxide (5 mL) and sulfuric acid (0.5 mL) were added dropwise. The mixture was stirred in an ice-water bath for 2.5 hours. The reaction was quenched by slowly adding saturated sodium sulfite solution. The mixture was extracted with ethyl acetate (30 mL * 3), and the organic phases were combined. The mixture was washed with saturated brine (30 mL * 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to prepare slag. The slag was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 90 / 10 (V / V)) to obtain 723 mg of the enantiomer of the title compound.

[0280] 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 enantiomers of (±)-rel-(3S,4R)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester were resolved by chiral chromatography to yield (3S,4R)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (t r =20.33min) and (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (t r =16.51 min), 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 Experiment 8. (Resolution method: Column: DAICELCHIRALPAK® IC 250*4.6mm, 5 μm; Mobile phase A: n-hexane; Mobile phase B: ethanol; A:B:90:10; Flow rate: 1 mL / min; Detection wavelength: 254 nm) (3S,4R)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester 1 H NMR (400 MHz, DMSO -d6 ) δ 7.88 (d, J = 8.3 Hz, 2H), 7.42 (d, J =8.3 Hz, 2H), 4.75 (d, J = 4.2 Hz, 1H), 4.00 (d, J = 14.8 Hz, 1H), 3.84 (s,3H), 3.77 (d, J = 11.7 Hz, 2H), 3.34 (s, 1H), 3.16 (s, 1H), 2.82 (d, J = 11.1Hz, 1H), 1.69 (dd, J = 19.9, 3.0 Hz, 2H), 1.39 (s, 9H). (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester 1 H NMR (400 MHz, DMSO -d6) δ 7.88 (d, J = 8.3 Hz, 2H), 7.42 (d, J =8.3 Hz, 2H), 4.75 (d, J = 4.1 Hz, 1H), 4.00 (d, J = 14.8 Hz, 1H), 3.82 (d, J= 15.6 Hz, 3H), 3.76 (d, J = 11.9 Hz, 2H), 3.37 (s, 1H), 3.16 (s, 1H), 2.82 (d, J = 11.1 Hz, 1H), 1.81 – 1.59 (m, 2H), 1.39 (s, 9H). 200 mg of tert-butyl 4-hydroxy-5-(methoxy-d3)-7-methyl-1H-indole-1-carboxylic acid, 250.8 mg of (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester, and 187.7 mg of triphenylphosphine were added to a 50 mL three-necked flask under nitrogen purging protection. Anhydrous tetrahydrofuran (20 mL) was added, and diisopropyl azodicarbonate (144.7 mg) was added dropwise under an ice-water bath. The reaction system was slowly heated to room temperature and stirred overnight. The reaction was quenched with water (20 mL), extracted with ethyl acetate (20 mL x 3), and the organic phases were combined. The mixture was washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to prepare sinter. The sinter was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 90 / 10 (V / V)) to give 171 mg of the title compound.

[0281] f) Preparation of tert-butyl 5-(methoxy-d3)-4-(((3R,4R)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylic acid 171 mg of tert-butyl 4-(((3R,4R)-1-(tert-butyloxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-(methoxy-d3)-7-methyl-1H-indole-1-carboxylic acid was dissolved in 2 mL of 1,4-dioxane. 1 mL of 1,4-dioxane hydrochloric acid solution (4 M) was added, and the mixture was stirred at room temperature for 3.5 hours under nitrogen purging protection. 10 mL of saturated sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with 3 x 20 mL of ethyl acetate. The organic phases were combined, washed with 1 x 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 141 mg of the title compound.

[0282] LCMS m / z=498.3 [M+H]+.

[0283] g) Preparation of tert-butyl 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 75 mg 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 was added to a 50 mL reaction flask, followed by 5 mL of tetrahydrofuran and 78.8 mg of N,N-diisopropylethylamine. The mixture was then purged with nitrogen and 97 mg of 2,2-difluoroethyltrifluoromethanesulfonate was added. The mixture was stirred overnight at 50 °C. The reaction solution was concentrated under reduced pressure and evaporated to dryness to obtain sintered sand. The sintered sand was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 90 / 10 (V / V)) to give 61 mg of the title compound.

[0284] 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 60 mg 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 was dissolved in tetrahydrofuran / methanol (2 mL / 2 mL), and lithium hydroxide aqueous solution (1 mL, 2N) was added. The mixture was stirred at 70 °C for 3.5 hours, concentrated under reduced pressure to dryness, and the pH was adjusted to neutral by adding dilute hydrochloric acid aqueous solution. The mixture was extracted with ethyl acetate (10 mL*3), and the organic phases were combined. The mixture was washed with saturated brine (20 mL*1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to prepare slurry. The slurry was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 25.2 mg of the title compound.

[0285] 1 H NMR (400 MHz, DMSO -d6) δ 12.80 (s, 1H), 10.83 (s, 1H), 7.91 (d, J= 8.2 Hz, 2H), 7.58 (d, J = 8.2 Hz, 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, 9.0 Hz, 1H), 3.13 (td, J =10.2, 3.8 Hz, 1H), 2.93 (dd, J = 23.5, 11.9 Hz, 2H), 2.78 (t, J = 15.5 Hz, 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]+.

[0286] 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

[0287] Prepared according to the preparation method of Example 26, except that 2,2-difluoroethyltrifluoromethanesulfonate in step g is replaced with 2,2,2-trifluoroethyltrifluoromethanesulfonate.

[0288] 1 H NMR (400 MHz, DMSO- d6 ) δ 12.76 (s, 1H), 10.84 (s, 1H), 7.91 (d, J= 7.9 Hz, 2H), 7.58 (d, J = 7.9 Hz, 2H), 7.17 (s, 1H), 6.62 (s, 1H), 6.18 (s,1H), 4.49 – 4.45 (m, 1H), 3.26 (d, J = 10.1 Hz, 3H), 3.15 (d, J = 10.0 Hz,1H), 2.95 (t, J = 13.0 Hz, 2H), 2.68 (t, J = 11.1 Hz, 1H), 2.36 (s, 3H), 1.71(s, 2H). LCMS m / z=466.2 [M+H]+. 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

[0289] 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 80 mg of 5-(difluoromethoxy)-4-hydroxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester, 172 mg of (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester, and 134 mg of triphenylphosphine were added to a 25 mL three-necked flask under nitrogen purging protection. Anhydrous tetrahydrofuran (10 mL) was added, and diisopropyl azodicarbonate (104 mg) was added dropwise under an ice-water bath. The reaction system was slowly heated to room temperature and stirred overnight. The reaction was quenched with water (20 mL), extracted with ethyl acetate (20 mL * 3), and the organic phases were combined. The mixture was washed with saturated brine (20 mL * 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to prepare sintered precipitate. The sintered precipitate was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 90 / 10 (V / V)) to give 80 mg of the title compound.

[0290] LCMS m / z=631.3 [M+H]+.

[0291] b) Preparation of tert-butyl 5-(difluoromethoxy)-4-(((3R,4R)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylic acid 80 mg of 4-((3R,4R)-1-(tert-butyloxycarbonyl)-3-((4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester was dissolved in 5 mL of 1,4-dioxane. 5 mL of 1,4-dioxane hydrochloric acid solution (4 M) was added, and the mixture was stirred at room temperature for 3.5 hours under nitrogen purging protection. 10 mL of saturated sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with 3 x 20 mL of ethyl acetate. The organic phases were combined, washed with 1 x 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 65 mg of the title compound.

[0292] LCMS m / z=531 [M+H]+.

[0293] c) Preparation of tert-butyl 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 37 mg of 5-(difluoromethoxy)-4-(((3R,4R)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester was added to a 50 mL reaction flask, followed by 5 mL of tetrahydrofuran and 36 mg of N,N-diisopropylethylamine. The mixture was then purged with nitrogen and 49 mg of 2,2,2-trifluoroethyltrifluoromethanesulfonate was added. The mixture was stirred at 50 °C for 2 hours. The reaction solution was concentrated under reduced pressure and evaporated to dryness to obtain sinter. The sinter was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 90 / 10 (V / V)) to give 28 mg of the title compound.

[0294] d) 4-((3R,4R)-4-((5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid 28 mg 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 was dissolved in tetrahydrofuran / methanol (5 mL / 5 mL), and lithium hydroxide aqueous solution (5 mL, 2N) was added. The mixture was stirred at 70 °C for 2 hours, concentrated under reduced pressure to dryness, and the pH was adjusted to neutral by adding dilute hydrochloric acid aqueous solution. The mixture was extracted with ethyl acetate (10 mL*3), and the organic phases were combined. The mixture was washed with saturated brine (20 mL*1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to prepare sintered precipitate. The sintered precipitate was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 12 mg of the title compound.

[0295] 1 H NMR (400 MHz, DMSO- d6) δ 12.83 (s, 1H), 11.17 (s, 1H), 7.89 (d, J= 8.3 Hz, 2H), 7.57 (d, J = 8.3 Hz, 2H), 7.29 (t, J = 2.8 Hz, 1H), 6.94-6.56(t, 1H), 6.67 (s, 1H), 6.28 – 6.21 (m, 1H), 4.56 (td, J = 9.5, 4.8 Hz, 1H), 3.24 (d, J = 10.2 Hz, 1H), 3.19 – 3.11 (m, 1H), 2.96 (t, J = 12.7 Hz, 2H),2.74 (t, J = 11.4 Hz, 1H), 2.36 (s, 3H), 1.80 – 1.66 (m, 2H), 1.23 (s, 2H). LCMS m / z=499 [M+H]+. Example 29: 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid

[0296] Prepared according to the preparation method of Example 28, except that 2,2,2-trifluoroethyltrifluoromethanesulfonate in step g is replaced with 2,2-difluoroethyltrifluoromethanesulfonate.

[0297] 1 H NMR (400 MHz, DMSO -d6) δ 12.77 (s, 1H), 11.17 (s, 1H), 7.89 (d, J= 8.3 Hz, 2H), 7.57 (d, J = 8.3 Hz, 2H), 7.28 (t, J = 2.8 Hz, 1H), 6.94-6.56(t, 1H), 6.67 (s, 1H), 6.29-6.01 (tt, J = 4.2 Hz, 1H), 6.22 (dd, J = 2.9, 2.0Hz, 1H), 4.53 (td, J = 9.7, 5.0 Hz, 1H), 3.14 (td, J = 10.4, 3.9 Hz, 1H),2.94 (dd, J = 20.9, 10.8 Hz, 2H), 2.79 (td, J = 15.9, 3.0 Hz, 2H), 2.56 (t, J= 11.3 Hz, 1H), 2.36 (s, 3H), 1.74 (d, J = 3.7 Hz, 1H), 1.25 (d, J = 9.2 Hz,2H). LCMS m / z=481 [M+H]+. Example 30: 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((7-methyl-5-(trifluoromethoxy)-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid

[0298] 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 1.49 g of 4-hydroxy-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester, 1.2 g of (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester, and 1.13 g of triphenylphosphine were added to a 100 mL three-necked flask under nitrogen purging protection. Anhydrous tetrahydrofuran (40 mL) was added, and diisopropyl azodicarbonate (869 mg) was added dropwise under an ice-water bath. The reaction system was slowly heated to room temperature and stirred overnight. The reaction was quenched with water (20 mL), extracted with ethyl acetate (20 mL * 3), and the organic phases were combined. The mixture was washed with saturated brine (20 mL * 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to prepare sinter. The sinter was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 85 / 15 (V / V)) to give 1.1 g of the title compound.

[0299] b) Preparation of methyl 4-((3R,4R)-4-((5-hydroxy-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoate 1.1 g of 4-(((3R,4R)-1-(tert-butyloxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester was added to a reaction flask, protected by nitrogen purging, and dichloromethane (20 mL) was added. Boron tribromide (187.7 mg) was added dropwise under an ice-water bath. The reaction system was slowly raised to room temperature and the reaction was continued for about 6 hours. Triethylamine was added dropwise to the reaction under an ice-water bath until the solution was weakly basic. The reaction solution was concentrated to dryness under reduced pressure to give 0.8 g of the title compound.

[0300] LCMS m / z=381.2 [M+H]+.

[0301] c) Preparation of tert-butyl 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-hydroxy-7-methyl-1H-indole-1-carboxylic acid 0.8 g of 5-hydroxy-7-methyl-1H-indole-4-carboxaldehyde was added to dichloromethane (40 mL), followed by 2.0 g of ditert-butyl dicarbonate and 102 mg of 4-dimethylaminopyridine. The mixture was then purged under nitrogen protection and stirred overnight at room temperature. Water and ethyl acetate were added for extraction and separation. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 85 / 15 (V / V)) to give 447 mg of the title compound.

[0302] d) 4-(((3R,4R)-1-(tert-butyloxycarbonyl)-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-butyloxycarbonyl)-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]thiophene-5-onium trifluoromethanesulfonate (405 mg), and potassium carbonate (159.6 mg) were added to a reaction flask, followed by N,N-dimethylformamide (20 mL). The mixture was stirred overnight at room temperature, and the reaction was quenched with water (20 mL). The mixture was extracted with ethyl acetate (20 mL x 3), and the organic phases were combined. The mixture was washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain sintered sand. The sintered sand was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 90 / 10 (V / V)) to give 158 mg of the title compound.

[0303] e) 4-(((3R,4R)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-5-(trifluoromethoxy)-1H-indole-1-carboxylic acid tert-butyl ester 158 mg of tert-butyl 4-(((3R,4R)-1-(tert-butyloxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-5-(trifluoromethoxy)-1H-indole-1-carboxylic acid was dissolved in 5 mL of 1,4-dioxane. 1,4-dioxane hydrochloric acid solution (5 mL, 4 M) was added, and the mixture was stirred at room temperature for 3.5 hours under nitrogen purging protection. 10 mL of saturated sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with 3 x 20 mL ethyl acetate solutions. The organic phases were combined, washed with 1 x 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 105 mg of the title compound.

[0304] f) Preparation of tert-butyl 4-(((3R,4R)-1-(2,2-difluoroethyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-5-(trifluoromethoxy)-1H-indole-1-carboxylic acid 65 mg of 4-(((3R,4R)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-5-(trifluoromethoxy)-1H-indole-1-carboxylic acid tert-butyl ester was added to a 50 mL reaction flask, followed by 5 mL of tetrahydrofuran and 61 mg of N,N-diisopropylethylamine. The mixture was then purged with nitrogen and 75.8 mg of 2,2-difluoroethyltrifluoromethanesulfonate was added. The mixture was stirred overnight at 50 °C. The reaction solution was concentrated under reduced pressure and evaporated to dryness to obtain sinter. The sinter was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 80 / 20 (V / V)) to give 49 mg of the title compound.

[0305] 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 lithium hydroxide aqueous solution (5 mL, 2N) was added. The mixture was stirred at 70 °C for 3.5 hours, concentrated under reduced pressure to dryness, and the pH was adjusted to neutral by adding dilute hydrochloric acid aqueous solution. The mixture was extracted with ethyl acetate (10 mL*3), and the organic phases were combined. The mixture was washed with saturated brine (20 mL*1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to prepare slurry. The slurry was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 18.3 mg of the title compound.

[0306] 1 H NMR (400 MHz, DMSO- d6 ) δ 12.92 (s, 1H), 10.93 (s, 1H), 8.00 (d, J= 8.4 Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H), 7.25 (t, J = 2.8 Hz, 1H), 6.72 (s,1H), 6.44 – 6.02 (m, 2H), 4.45 (dd, J = 16.1, 9.5 Hz, 1H), 3.23 (td, J =10.7, 4.2 Hz, 1H), 3.03 (dd, J = 21.3, 10.7 Hz, 2H), 2.85 (dd, J = 33.4, 21.7Hz, 2H), 2.43 (d, J = 17.8 Hz, 3H), 2.39 (d, J = 14.4 Hz, 1H), 1.80 (s, 2H), 1.33 (s, 1H). LCMS m / z = 499.2[M+H]+. 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

[0307] Prepared according to the preparation method of Example 30, except that 2,2-difluoroethyltrifluoromethanesulfonate in step f is replaced with 2,2,2-trifluoroethyltrifluoromethanesulfonate.

[0308] 1 H NMR (400 MHz, DMSO- d6) δ 12.90 (s, 1H), 10.93 (s, 1H), 8.00 (d, J= 8.1 Hz, 2H), 7.68 (d, J = 8.1 Hz, 2H), 7.27 (s, 1H), 6.72 (s, 1H), 6.28 (s,1H), 4.58 (d, J = 7.4 Hz, 1H), 3.36 (d, J = 9.2 Hz, 3H), 3.24 (dd, J = 9.5,6.8 Hz, 1H), 3.05 (t, J = 12.4 Hz, 2H), 2.78 (t, J = 11.1 Hz, 1H), 2.45 (s,3H), 1.81 (s, 1H), 1.33 (s, 1H). LCMS m / z = 517.2[M+H]+. Example 32: 4-((2R,5S)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-1-yl)benzoic acid and 4-((2S,5R)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-1-yl)benzoic acid and 4-((2S,5S)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-1-yl)benzoic acid

[0309] a) Preparation of methyl 5-ethoxypyridine-2-carboxylic acid 49 g of methyl 5-hydroxypyridine-2-carboxylic acid, 54.90 g of iodoethane, and 66 g of potassium carbonate were added to a reaction flask, followed by 490 mL of N,N-dimethylformamide. The mixture was purged with nitrogen and stirred overnight at room temperature. The reaction was quenched with water and extracted with ethyl acetate (5 × 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.

[0310] LCMS m / z=182[M+H]+.

[0311] b) Preparation of (5-ethoxypyridin-2-yl)methanol 54 g of methyl 5-ethoxypyridine-2-carboxylic acid, 33.82 g of sodium borohydride, and 46.6 g of calcium chloride were added to a reaction flask, followed by 540 mL of ethanol. The mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure to obtain a residue, which was then added to water 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 obtain 36.9 g of the title compound.

[0312] LCMS m / z=154[M+H]+.

[0313] c) Preparation of 1-benzyl-5-ethoxy-2-(hydroxymethyl)pyridine-1-ammonium bromide (5-ethoxypyridin-2-yl)methanol (34.4 g) and benzyl bromide (57.61 g) were added to a reaction flask, followed by acetonitrile (344 mL). The mixture was stirred overnight at 90°C. 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.

[0314] LCMS m / z=244[M+H]+.

[0315] 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, followed by a mixture of methanol / tetrahydrofuran (200 mL / 200 mL). The mixture was cooled to -60°C, and sodium borohydride (11.6 g) was added. The mixture was stirred for 2 hours while slowly heating to room temperature. The reaction was quenched with water (200 mL), and the mixture was extracted with ethyl acetate (200 mL*3). The organic phases were combined, washed with saturated brine (200 mL*1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to prepare slurry. The slurry was purified by column chromatography (mobile phase: dichloromethane / methanol = 10 / 1 (V / V)) to give 29 g of the title compound.

[0316] LCMS m / z=248[M+H]+.

[0317] 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 a reaction flask, followed by tetrahydrofuran (311 mL). Sodium hydride (13.58 g) was added under ice bath conditions. The mixture was stirred at 0°C for 30 minutes, and then bromo(methoxy)methane (16.98 g) was added dropwise. The reaction was slowly brought to room temperature and stirred for 2 hours. The reaction was quenched with water / ice (20 mL), extracted with ethyl acetate (30 mL * 3), and the organic phases were combined. The mixture was washed with saturated brine (30 mL * 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain sintered precipitate. The sintered precipitate was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 (V / V)) to give 29 g of the title compound.

[0318] LCMS m / z=292[M+H]+.

[0319] 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 the addition of methanol (193 mL). The mixture was purged with hydrogen and stirred at room temperature for 3 hours. The mixture was then filtered, and the filter cake was washed with methanol (3 x 5 mL). The filtrate was concentrated to dryness under reduced pressure to give 16.2 g of the title compound.

[0320] LCMS m / z=204[M+H]+.

[0321] Preparation of methyl 4-(5-ethoxy-2-((methoxymethoxy)methyl)piperidin-1-yl)benzoate 5-ethoxy-2-((methoxymethoxy)methyl)piperidine (5 g), methyl 4-bromobenzoate (4.2 g), tris(dibenzylene-BASEacetone)palladium (2.55 g), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (4.59 g), and cesium carbonate (24.04 g) were added to a reaction flask, followed by toluene (50 mL). The mixture was purged with nitrogen and stirred at 100°C for 24 hours. The reaction solution was then concentrated under reduced pressure to obtain sintered precipitate, which was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 (V / V)) to give 5.6 g of the title compound.

[0322] LCMS m / z=338[M+H]+.

[0323] h) Preparation of methyl 4-(5-ethoxy-2-(hydroxymethyl)piperidin-1-yl)benzoate 5 g of methyl 4-(5-ethoxy-2-((methoxymethoxy)methyl)piperidin-1-yl)benzoate was dissolved in 20 mL of methanol, and a solution of 1,4-dioxane (4 M, 20.0 mL) of hydrogen chloride was added. The mixture was stirred at room temperature for 2 hours, and the reaction solution was concentrated to dryness under reduced pressure to give 3 g of the title compound. LCMS m / z = 294 [M+H]+.

[0324] i) Preparation of methyl 4-(5-ethoxy-2-formylpiperidin-1-yl)benzoate 4 g of methyl 4-(5-ethoxy-2-(hydroxymethyl)piperidin-1-yl)benzoate and 8.67 g of Dys-Martin oxidant were added to a reaction flask, followed by 40.0 mL of dichloromethane. The mixture was stirred at room temperature for 2 hours, filtered, and the filter cake was washed with 3 × 10 mL of dichloromethane. The filtrate was concentrated under reduced pressure to prepare sinter, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to give 3 g of the title compound.

[0325] LCMS m / z=292[M+H]+.

[0326] j) Preparation of methyl (Z)-4-(5-ethoxy-2-((2-toluenesulfonylhydrazine)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 overnight at room temperature. The reaction solution was concentrated under reduced pressure to obtain sand, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 (V / V)) to give 2.2 g of the title compound.

[0327] LCMS m / z=460 [M+H]+.

[0328] Preparation of k) (E)-4-((5-ethoxy-1-(4-(methoxycarbonyl)phenyl)piperidin-2-ylidene)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester Methyl (Z)-4-(5-ethoxy-2-((2-toluenesulfonylhydrazine)methyl)piperidin-1-yl)benzoate (600 mg), tert-butyl 4-bromo-5-methoxy-7-methylindole-1-carboxylic acid (666.2 mg), tris(dibenzyl-BASEacetone)dipalladium (135.1 mg), 2-dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl (62.2 mg), and lithium tert-butoxide (313.5 mg) were added to a reaction flask, followed by 1,4-dioxane (10 mL). The mixture was stirred at 100°C for 3 hours under nitrogen protection. 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 to dryness under reduced pressure to obtain 900 mg of the title compound.

[0329] LCMS m / z=535[M+H]+.

[0330] l) Preparation of tert-butyl 4-((5-ethoxy-1-(4-(methoxycarbonyl)phenyl)piperidin-2-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid (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 and stirred at room temperature for 20 hours. The mixture was then concentrated under reduced pressure to obtain sand, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 (V / V)) to give 80 mg of the title compound.

[0331] LCMS m / z=537 [M+H]+.

[0332] Preparation of 4-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-1-yl)benzoic acid 80 mg of 4-((5-ethoxy-1-(4-(methoxycarbonyl)phenyl)piperidin-2-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester was added to a reaction flask, followed by 1.8 mL of lithium hydroxide aqueous solution (2N) and 1 mL of tetrahydrofuran. The mixture was stirred at 70°C for 30 hours. The residue was acidified to pH 4 with concentrated sulfuric acid. The precipitated solid was collected by filtration, and the filter cake was washed with water (3 x 5 mL) to give 32 mg of the title compound.

[0333] The isomer mixture was resolved by chiral SFC to obtain 32a-1 (tr = 5.47 min), 32a-2 (tr = 7.57 min), 32a-3 (tr = 10.6 min), and 32a-4 (tr = 15.2 min). (Resolution method: column: CHIRALPAK-IG2*25cm; mobile phase A: n-hexane (0.1% formic acid); mobile phase B: ethanol: dichloromethane = 1:1; A:B = 1:1; flow rate: 20 mL / min; detection wavelength: 220 / 254 nm) 32a-1, tr=5.47min 1 H NMR (400 MHz, DMSO- d6 ) δ 10.86 (s, 1H), 7.82 – 7.73 (m, 2H), 7.30(t, J = 2.8 Hz, 1H), 7.03 (d, J = 8.8 Hz, 2H), 6.71 (s, 1H), 6.44 (dd, J =3.1, 1.9 Hz, 1H), 4.30 (s, 1H), 3.88 (d, J = 13.9 Hz, 1H), 3.82 (s, 3H), 3.67(s, 1H), 3.49 – 3.41 (m, 2H), 3.21 (t, J = 11.8 Hz, 2H), 2.75 (dd, J = 12.7,4.1 Hz, 1H), 2.46 – 2.39 (m, 3H), 2.08 (dd, J = 14.7, 11.4 Hz, 1H), 1.66 (q, J = 15.2, 14.4 Hz, 2H), 1.15 (d, J = 8.2 Hz, 1H), 1.05 (t, J = 7.0 Hz, 3H). Lacking active hydrogen. 32a-2, tr = 7.57 min 1 H NMR (400 MHz, DMSO- d6) δ 12.04 (s, 1H), 10.86 (s, 1H), 7.77 (d, J= 8.9 Hz, 2H), 7.30 (t, J = 2.8 Hz, 1H), 7.03 (d, J = 8.8 Hz, 2H), 6.71 (s,1H), 6.49 – 6.40 (m, 1H), 4.30 (s, 1H), 3.88 (d, J = 14.3 Hz, 1H), 3.82 (s,3H), 3.67 (s, 1H), 3.45 (dt, J = 7.0, 3.3 Hz, 2H), 3.19 (d, J = 11.8 Hz, 2H),2.75 (dd, J = 12.8, 4.0 Hz, 1H), 2.43 (s, 3H), 2.08 (t, J = 13.3 Hz, 1H),1.73 – 1.59 (m, 2H), 1.15 (d, J = 13.0 Hz, 1H), 1.05 (t, J = 7.0 Hz, 3H). 32a-3,tr=10.6min 1 H NMR (400 MHz, DMSO- d6 ) δ 12.12 (s, 1H), 10.87 (s, 1H), 7.79 (d, J= 8.6 Hz, 2H), 7.30 (t, J = 2.9 Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H), 6.70 (s,1H), 6.37 (t, J = 2.4 Hz, 1H), 4.28 (d, J = 10.2 Hz, 1H), 3.88 (dd, J = 12.4,4.8 Hz, 1H), 3.80 (s, 3H), 3.60 (qd, J = 7.0, 4.9 Hz, 2H), 3.20 (t, J = 11.8Hz, 1H), 2.93 (t, J = 11.4 Hz, 1H), 2.71 (dd, J = 12.8, 4.3 Hz, 2H), 2.43 (s,3H), 1.87 (d, J = 11.0 Hz, 1H), 1.76 (p, J = 10.4 Hz, 1H), 1.49 – 1.37 (m,1H), 1.16 (t, J = 6.9 Hz, 3H). 32a-4,tr=15.2min 1 H NMR (400 MHz, DMSO- d6 ) δ 12.15 (s, 1H), 10.87 (s, 1H), 7.84 – 7.72(m, 2H), 7.30 (t, J = 2.8 Hz, 1H), 7.05 (d, J = 9.1 Hz, 2H), 6.70 (s, 1H),6.37 (dd, J = 3.2, 1.9 Hz, 1H), 4.29 (d, J = 9.3 Hz, 1H), 3.88 (dd, J = 12.4,4.8 Hz, 1H), 3.80 (s, 3H), 3.60 (qd, J = 6.9, 4.8 Hz, 2H), 3.18 (d, J = 11.7Hz, 2H), 2.93 (t, J = 11.4 Hz, 1H), 2.71 (dd, J = 12.7, 4.1 Hz, 1H), 2.43 (s,3H), 1.87 (d, J = 9.5 Hz, 1H), 1.76 (p, J = 11.6, 10.7 Hz, 1H), 1.43 (d, J =5.6 Hz, 2H), 1.16 (t, J = 7.0 Hz, 3H). 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

[0334] 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 tetrahydrofuran (5 mL), N,N'-carbonyldiimidazole (26.3 mg), and stirred at 50 °C for 2 hours. Then, hydrazine hydrochloride (14.8 mg) and 1,8-diazobisspirocyclic [5.4.0]undecyl-7-ene (41.2 mg) were added sequentially, and the reaction was carried out overnight at 50 °C. After cooling, 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 to dryness under reduced pressure to obtain 25 mg of the title compound.

[0335] LCMS m / z=477.2[M+H]+.

[0336] 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 acetonitrile (10 mL), N,N'-carbonyldiimidazole (12.8 mg), and 1,8-diazobisspirocyclic [5.4.0]undecyl-7-ene (32 mg). The mixture was heated to 50 °C and reacted overnight. The reaction solution was concentrated under reduced pressure to obtain sand, which was then purified by column chromatography (mobile phase: dichloromethane / methanol = 90 / 10 (V / V)) to give 14.4 mg of the title compound.

[0337] 1 H NMR (400 MHz, DMSO- d6) δ 12.43 (s, 1H), 10.83 (s, 1H), 7.76 (d, J= 8.2 Hz, 2H), 7.63 (d, J = 8.2 Hz, 2H), 7.17 (s, 1H), 6.63 (s, 1H), 6.20 (s,1H), 4.47 (dd, J = 15.4, 8.5 Hz, 1H), 3.61 (s, 3H), 3.23 (d, J = 10.0 Hz, 2H), 3.14 (td, J = 10.1, 3.6 Hz, 1H), 3.02 – 2.87 (m, 2H), 2.69 (t, J = 11.2Hz, 1H), 2.44 (s, 1H), 2.36 (s, 3H), 1.71 (d, J = 3.4 Hz, 2H). LCMS m / z = 503.2[M+H]+. Experimental Example 1: Human Complement Factor B TR-FRET Assay Competitive binding assays were performed using Cy5-labeled small molecule inhibitors (+) or (-)-2-((1E,3E,5E)-5-(1-(6-((2-(3-(4-((R)-3-amino-3-phenylpropionyl)-1-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazin-2-yl)phenoxy)ethyl)amino)-6-oxohexyl)-3,3-dimethyl-5-sulfodihydroindole-2-yl)pent-1,3-dien-1-yl)-1-ethyl-3,3-dimethyl-5-sulfo-3H-indole-1-onium (prepared according to Example 2 of Biological Study, CN201480050471.1) as probes to test the inhibitory activity of the compounds on complement factor B. Complement factor B (ComplementTech, A135) and EZ-Link TM Sulfo-NHS-LC-LC-Biotin (Thermo, 21338) was incubated on ice at a 1:20 ratio for 2 hours, followed by termination with 1 M Tris (pH 7.5). Then, 2 mL of Zeba solution was added. TMBiotin-labeled complement factor B was obtained by purification twice using desalt spincolumn (Thermo, 89890). In the experiment, biotin-labeled complement factor B at a final concentration of 25 nM was incubated with different concentrations of the compound in buffer (PBS containing 10 mM MgCl2 and 0.05% Chaps) at 4°C for 30 minutes. Cy5 fluorescently labeled probes and europium chelate-labeled streptavidin (PerkinElmer, AD0060) at final concentrations of 75 nM and 0.225 nM were added, and the reaction was carried out at 4°C for 2 hours. After the reaction, time-dependent fluorescence energy transfer (TR-FRET) data were read using a microplate reader (Tecan, SPARK; 337 nm excitation, 615 nm and 665 nm excitation) to determine the IC50. 50 The test results are shown in Table 1 below.

[0338] Reference standard LNP023: synthesized according to Example 26 of CN201480050471.1, with the following structure: .

[0339] Table 1: Inhibitory activity of compounds against complement factor B

[0340] Experimental Example 2: Serum Alternate Pathway Complement Deposition Experiment The inhibitory activity of compounds on the complement alternative pathway in human serum was detected using the Wieslab® Complement System Alternative Pathway Kit (WIESLAB® Complement system Alternative pathway AP330 RUO). Human serum was diluted 18-fold using the kit diluent Diluent. 130 μL of the diluted serum was added to each well of a 96-well plate. The appropriate concentration of the test compound was added using a compound titrator (Tecan, D300e). The test concentration of the test compound started at 10 μM, with 3-fold dilutions, 6 concentration points, and single-well assays. The DMSO ratio in all wells was uniformly adjusted to 0.1% using DMSO. Add 0.1% DMSO and 130 μL of diluted serum to the positive control wells, and add 0.1% DMSO and 130 μL of Diluent to the negative control wells. Pre-incubate at room temperature for 15 min. Transfer 100 μL of the incubated mixture to each well of a 96-well plate provided in the kit, incubate at 37°C for 60 min, discard the liquid in the wells, add 300 μL of the washing buffer provided in the kit to each well, wash 3 times, add 100 μL of the conjugate antibody provided in the kit to each well, and incubate at room temperature for 30 min. Remove the liquid in the wells, add 300 μL of the washing buffer provided in the kit to each well, wash 3 times, add 100 μL of substrate solution to each well, and incubate at room temperature for 30 min. Detect using a microplate reader (Tecan, SPARK), and read the absorbance value at 405 nm. Experimental data are shown in Table 2 below.

[0341] Table 2: Serum complement deposition results via the alternative pathway

[0342] Experimental Example 3: Pharmacokinetic Study in Mice Experimental objective: To investigate the plasma pharmacokinetics of male ICR (CD-1) mice after a single intravenous injection and gavage administration of the compound of the present invention.

[0343] Laboratory animals: Male ICR (CD-1) mice, weighing 32-35 g; Supplier: Vital Rivers Laboratory Animal Technology Co., Ltd.

[0344] Experimental procedure: Injection (IV): Oral administration (PO): The dose was 10 mg / kg (solvent: water (containing 0.5% methylcellulose (w / v), 0.5% Tween 80 (v / v))).

[0345] Sample collection: At each set time point, 40 μL of whole blood was collected from the experimental animals via the orbital cavity. The whole blood sample was placed in an anticoagulant tube containing EDTA-K2. The whole blood sample was centrifuged at 1500 g for 10 min to separate the plasma. The supernatant plasma sample was collected into a sample tube for LC-MS / MS analysis.

[0346] Data analysis: using WinNonlin TM Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software uses a non-compartmental model to process plasma concentrations and calculates pharmacokinetic parameters Cl and T using the linear logarithmic trapezoidal method. 1 / 2 C max AUC 0-24 The results are shown in the table below.

[0347] Table 3: Results of Pharmacokinetic Studies

[0348] Experimental Example 4: Collagen Antibody-Induced Mouse Arthritis Model Experimental Objective: To investigate the pharmacological effects of the compounds of this invention on collagen antibody- and lipopolysaccharide-induced arthritis (CAIA) in BALB / c mice. Experimental Animals: Male BALB / c mice, 6-8 weeks old, 18-20 grams; Supplier: Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0349] Experimental procedure: 1. Induction of the mouse CAIA model: On day 0, all mice were injected intravenously with 0.15 mL of Arthrogen-CIA5 clone mixed type II collagen antibody (10 mg / mL, Chondrex); on day 3, mice were injected intraperitoneally with 0.2 mL of LPS (E. coli 0111:B4 lipopolysaccharide, 0.5 mg / mL; Chondrex).

[0350] 2. Administration: Table 4: Dosing groups and dosing regimens

[0351] a: An aqueous solution of 0.5% methylcellulose (w / v) and 0.5% Tween N80 (v / v). b: Administer the medication only once in the morning on the day of sample collection, and complete blood collection within 4 hours after administration. Data Analysis: Data were analyzed using Graphpad Prism with One-way ANOVA / Dunnett's and SPSS with Repeat Measurement ANOVA / Bonferroni statistical methods. P A value <0.05 is considered statistically significant.

[0352] Arthritis scoring: Starting from the day of modeling, the incidence of arthritis in the limbs of each group of animals was observed three times a week until the end of the experiment. Scoring was based on the severity of the lesions (redness and swelling) using a scale of 0-4. The scoring criteria were as follows: 0, no signs of erythema or swelling; 1, erythema or mild swelling in the midfoot (ankle); 2, erythema and mild swelling extending from the ankle to the midfoot; 3, erythema and moderate swelling from the ankle joint to the metatarsal joint; 4, erythema and severe redness and swelling from the toes or fingers to the ankle or wrist joint.

[0353] Joint swelling: Starting from the day of modeling, the thickness of the left and right footpads of the animals was measured three times a week using a micrometer (Mitutoyo, 0 - 25 mm, minimal 0.001 mm) until the end of the experiment.

[0354] Experimental results: Experimental data are shown in Tables 5 and 6. Figure 1 , Figure 2 .

[0355] Table 5: Arthritis Scores

[0356] Table 6: Footpad Thickness (mm)

[0357] Experimental conclusion: According to the scoring results, compared with the model group, the compounds of the present invention can significantly improve the degree of arthritis lesions and reduce joint swelling in the model animals, and the effect is better than LNP023.

[0358] Experimental Example 5: Pharmacodynamic Study of the Test Substance in a CAIA Mouse Model Experimental objective: To evaluate the efficacy of the test drug against collagen antibody and lipopolysaccharide-induced arthritis (CAIA) in BALB / c mice.

[0359] Laboratory animals: Male BALB / c mice, 6-8 weeks old, 18-20 grams; Supplier: Shanghai Jihui Laboratory Animal Breeding Co., Ltd. Experimental procedure: 1. Induction of the mouse CAIA model: On day 0, all mice were injected intravenously with 0.15 mL of Arthrogen-CIA5 clone mixed type II collagen antibody (10 mg / mL, Chondrex); on day 3, mice were injected intraperitoneally with 0.2 mL of LPS (E. coli 0111:B4 lipopolysaccharide, 0.5 mg / mL; Chondrex).

[0360] 2. Administration: Table 7: Dosing groups and dosing regimens

[0361] a: An aqueous solution of 0.5% methylcellulose (w / v) and 0.5% Tween 80 (v / v). Experimental data are expressed as mean ± standard error (mean ± SEM). Data were analyzed using Graphpad Prism with One-way ANOVA / Dunnett's and SPSS with Repeat Measurement ANOVA / Bonferroni statistical methods. P A value <0.05 is considered statistically significant.

[0362] Arthritis scoring: Starting from the day of modeling, the incidence of arthritis in the limbs of each group of animals was observed three times a week until the end of the experiment. Scoring was based on the severity of the lesions (redness and swelling) using a scale of 0-4. The scoring criteria were as follows: 0, no signs of erythema or swelling; 1, erythema or mild swelling in the midfoot (ankle); 2, erythema and mild swelling extending from the ankle to the midfoot; 3, erythema and moderate swelling from the ankle joint to the metatarsal joint; 4, erythema and severe redness and swelling from the toes or fingers to the ankle or wrist joint.

[0363] Arthritis score AUC: After the experiment, GraphPad Prism 8.4.3 software was used to analyze the mean arthritis score of each group of animals at each time point. The Area under curve of the XY analyses was selected to calculate the arthritis score AUC for each group of animals. The larger the AUC, the greater the severity of arthritis. The AUC experimental results are shown in Table 8. Figure 3 .

[0364] Table 8: Arthritis Scores AUC

[0365] Experimental conclusion: According to the scoring results, compared with the model group, the compound of the present invention can significantly improve the severity of arthritis lesions in the model animals, and the AUC score is significantly lower than that of LNP023.

[0366] Experiment Example 6: X-ray Single Crystal Diffraction Experiment Preparation method: Take 5 mg of 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 =1.95min) was placed in a small glass vial, and 0.6 ml of acetone / water (2:1, v / v) mixed solvent was added. After dissolving, it was filtered into another clean vial, sealed with sealing film and a small hole was made with a syringe needle. After standing at room temperature for 3 days to evaporate, a rod-shaped single crystal sample was obtained.

[0367] After integrating and restoring the diffraction data using the SAINT program, empirical absorption correction was performed on the data using the SADABS program. The single crystal structure was analyzed by direct method using SHELXT2014, and the structure was refined using least squares method. The hydrogen atom refinement process was obtained by isotropic calculation, and the hydrogen atoms on CH were obtained by calculated hydrogen addition, and the structure was refined using riding model. Figure 4 Table 9 below shows the single-crystal data for the monohydrate of 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid from Example 13a-2. The Flack constant is 0.10 (9), and C11 and C15 are R configurations.

[0368] Table 9: Single Crystal Diffraction Data

[0369] Experiment 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) was prepared in a 3 mL glass bottle. r =2.73 min) Saturated solution at high temperature (about 60 ℃) with acetonitrile (1 mL) as solvent. While hot, draw up the above clear solution with a 2 mL syringe and filter it with a hydrophilic PTFE needle filter (13 mm*0.45 μm). Transfer the filtrate to another clean 3 mL glass bottle and then transfer it to room temperature to stand. After one day, transparent single crystals are obtained.

[0370] After integrating and restoring the diffraction data using the SAINT program, empirical absorption correction was performed using the SADABS program. The single-crystal structure was analyzed using the SHELXT2014 direct method, and the structure was refined using the least squares method. The hydrogen atom refinement process was obtained by isotropic calculation, and the hydrogen atoms on CH were obtained by calculated hydrogen addition, and the structure was refined using a riding model. The Flack constant is 0.09 (10), and the chirality of C11 and C17 is R configuration. Figure 5 Table 10 below shows the single-crystal results of the acetonitrile solvate of 4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid in Example 14a-2.

[0371] Table 10: Single Crystal Diffraction Data

[0372] Experiment Example 8: X-ray Single Crystal Diffraction Experiment Preparation method: The compound (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (t) was prepared. r A saturated solution was prepared at a high temperature (approximately 50 °C) for 16.51 min, using ethanol / water (1:2, v / v) as the solvent, with a volume of 1 mL. The solution was then transferred to room temperature and allowed to stand for one day to obtain a transparent single crystal.

[0373] After integrating and restoring the diffraction data using the SAINT program, the data were empirically absorbed and corrected using the SADABS program. The single crystal structure was analyzed by direct method using SHELXT2014, and the structure was refined using least squares method. The hydrogen atom refinement process was obtained by isotropic calculation. The hydrogen atoms on N and O were obtained by residual electron density, and the hydrogen atoms on CH were obtained by calculated hydrogen addition. The structure was refined using a riding model. The Flack constant was 0.08(7), C10 was R configuration, and C14 was S configuration. Figure 6 Table 11 below shows the intermediate compound (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (t) obtained by resolution in step e) of Example 26. r The single crystal results of the dihydrate (16.51 min) were obtained.

[0374] Table 11: Single Crystal Diffraction Data

[0375] The foregoing description of specific exemplary embodiments of the invention is for illustrative and explanatory purposes. These descriptions are not intended to limit the invention to the precise forms disclosed, and it will be apparent that many changes and variations can be made in accordance with the foregoing teachings. The exemplary embodiments were chosen and described in order to explain the specific principles of the invention and its practical application, thereby enabling those skilled in the art to implement and utilize various different exemplary embodiments of the invention, as well as various different choices and variations. The scope of the invention is intended to be defined by the claims and their equivalents.

Claims

1. Compounds represented by general formula (I), their isomers, or pharmaceutically acceptable salts thereof: in: X is selected from CH2, NH, S, O, or ; Y and Z are each independently selected from CH or N; And when X is CH2, Z is N; R 1 Selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl or C3-C6 heterocyclic groups, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally substituted with halogen, oxo, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 heterocyclic or C3-C6 halocycloalkyl; R 2 It is hydrogen, or R 1 and R 2 The atoms bonded to them form C10-15 heterocyclic groups, which are optionally substituted with halogens; R 3 It is selected from C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted with deuterium or halogen.

2. The compound, its isomer, or a pharmaceutically acceptable salt thereof according to claim 1, wherein, The compounds are shown as those of general formulas (II-1), (II-2), or (II-3): in: X, Y, R 1 R 3 As defined in claim 1; P is selected from CH2, NH, S, or O; R 4 Selected from hydrogen, halogens, or C1-C3 alkyl groups; m can be 0, 1, or 2.

3. The compound, its isomer, or a pharmaceutically acceptable salt thereof according to claim 1, wherein, The compounds are shown as those of general formula (II-1-1) or (II-1-2): in: X, Y, R 1 R 3 As defined in claim 1.

4. The compound, its isomer, or a pharmaceutically acceptable salt thereof according to claim 1, wherein, The compounds are shown as those of general formula (II-2-1) or (II-2-2): in: X, Y, R 1 R 3 As defined in claim 1.

5. The compound, its isomer, or a pharmaceutically acceptable salt thereof according to claim 1, wherein, The compounds are shown as general formula (III-1) or (III-2): in: X, R 1 R 3 As defined in claim 1; Preferably, the compound, its isomers, or pharmaceutically acceptable salts thereof are represented by general formulas (III-1-1), (III-1-2), (III-1-3), or (III-1-4): in: X, R 1 R 3 As defined in claim 1.

6. The compound, its isomer, or a pharmaceutically acceptable salt thereof according to claim 1, wherein, The compounds are shown in general formulas (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): in: X, R 1 R 3 As defined in claim 1.

7. The compound, its isomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, wherein, X is selected from CH2, S, or O; preferably S or O. Y is selected from CH or N; CH is preferred. Z is selected from CH or N; N is preferred. R 1 It is selected from C1-C3 alkyl, C1-C3 alkoxy, C3-C4 cycloalkyl or C3-C4 heterocyclic groups, wherein the C1-C3 alkyl or C3-C4 cycloalkyl is optionally substituted with fluorine, chlorine, bromine, iodine, oxo, C1-C3 haloalkyl, C3-C4 cycloalkyl, C3-C4 heterocyclic or C3-C4 halocycloalkyl; Preferably, R 1 The group is selected from C1-C3 alkyl, C1-C3 alkoxy, C3-C4 cycloalkyl or C3-C4 heterocyclic groups, wherein the C1-C3 alkyl or C3-C4 cycloalkyl is optionally substituted by 1, 2 or 3 substituents selected from fluorine, chlorine, bromine, iodine, oxo, C1-C3 haloalkyl, C3-C4 cycloalkyl, C3-C4 heterocyclic or C3-C4 halocycloalkyl; Preferably, R 1 The molecule is selected from methyl, ethyl, propyl, ethoxy, cyclobutyl or oxetane, wherein the ethyl, propyl or cyclobutyl is optionally substituted with fluorine, oxo, trifluoromethyl, cyclopropyl, fluorocyclopropyl or oxetane; Preferably, R 1 The ethyl, propyl, ethoxy, cyclobutyl or oxetane are selected from methyl, ethyl, propyl, ethoxy, cyclobutyl or oxetane, wherein the ethyl, propyl or cyclobutyl is optionally substituted by 1, 2 or 3 substituents selected from fluorine, oxo, trifluoromethyl, cyclopropyl, fluorocyclopropyl or oxetane. More preferably, R 1 Selected from , , , , , , , , , , , or Preferred , , or More preferably , or Further preferably, R 1 Selected from ; R 3 Selected from C1-C3 alkyl or C3-C4 cycloalkyl, wherein the C1-C3 alkyl group is optionally substituted with deuterium, fluorine, chlorine, bromine or iodine; preferably, R 3 Selected from methyl or cyclopropyl, wherein the methyl group is optionally substituted with deuterium or fluorine; Preferably, R 3 Selected from methyl or cyclopropyl, wherein the methyl group is optionally substituted by one, two or three substituents selected from deuterium or fluorine; More preferably, R 3 Selected from methyl, -CD3, -CF3 or Further optimization of methyl groups; P is selected from CH2, NH, S, or O; O is preferred. R 4 Selected from fluorine, chlorine, bromine, or iodine; fluorine is preferred; m can be 0, 1, or 2; 2 is preferred.

8. The compound, its isomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, wherein, X is selected from NH, S, O, or ; Y is selected from CH or N; CH is preferred. Z is selected from CH or N; N is preferred. R 1 It is selected from C1-C3 alkyl, C1-C3 alkoxy, C3-C4 cycloalkyl or C3-C4 heterocyclic groups, wherein the C1-C3 alkyl or C3-C4 cycloalkyl is optionally substituted with fluorine, chlorine, bromine, iodine, oxo, C1-C3 haloalkyl, C3-C4 cycloalkyl, C3-C4 heterocyclic or C3-C4 halocycloalkyl; Preferably, R 1 The group is selected from methyl, ethyl, propyl, ethoxy, cyclobutyl, or oxetane, wherein the ethyl, propyl, or cyclobutyl group is optionally substituted with fluorine, oxo, trifluoromethyl, cyclopropyl, fluorocyclopropyl, or oxetane; more preferably, R 1 Selected from , , , , , , , , , , , or Preferred , , or More preferably , or Further preferably, R 1 Selected from ; R 3 Selected from C1-C3 alkyl or C3-C4 cycloalkyl, wherein the C1-C3 alkyl group is optionally substituted with deuterium, fluorine, chlorine, bromine or iodine; preferably, R 3 Selected from methyl or cyclopropyl, wherein the methyl group is optionally substituted with deuterium or fluorine; more preferably, R 3 Selected from methyl, -CD3, -CF3 or Further optimization of methyl groups; P is selected from CH2, NH, S, or O; O is preferred. R 4 Selected from fluorine, chlorine, bromine, or iodine; fluorine is preferred; m can be 0, 1, or 2; 2 is preferred.

9. The compound, its isomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, wherein, X is selected from S or O; O is preferred. Y is selected from CH; Z is selected from N; R 1 The alkyl group is selected from C1-C3 alkyl groups, wherein the C1-C3 alkyl group is optionally substituted by one, two or three substituents selected from fluorine, chlorine, bromine or iodine; Preferably, R 1 Selected from methyl, ethyl, or propyl, wherein the methyl, ethyl, or propyl group is optionally substituted with 1, 2, or 3 fluorine atoms; more preferably... , or Further preferably, R 1 Selected from ; R 3 Selected from C1-C3 alkyl groups, wherein the C1-C3 alkyl groups are optionally substituted with deuterium, fluorine, chlorine, bromine or iodine; preferably, R 3 Selected from methyl, wherein the methyl group is optionally substituted with deuterium or fluorine; more preferably, R 3 Selected from methyl, -CD3, -CF3 or More preferably, R 3 Selected from methyl or -CD3; methyl is further preferred.

10. The following compounds, their isomers, or pharmaceutically acceptable salts thereof, wherein, The compound has the following structure: or .

11. The following compounds, their isomers, or pharmaceutically acceptable salts thereof, wherein, The compound has the following structure: or .

12. A compound or a pharmaceutically acceptable salt thereof, wherein, The compound is a compound. The isomer of "" was separated by chiral SFC, with a retention time of 1.95 min. The specific separation method is as follows: 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: 214nm.

13. A compound or a pharmaceutically acceptable salt thereof, wherein, The compound is a compound. The isomer of "" was separated by chiral SFC, with a retention time of 2.73 min. The specific separation method is as follows: Column: DAICELCHIRALPAK® 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: 214nm.

14. A compound or a pharmaceutically acceptable salt thereof, wherein, The compound is a compound. The isomer of "" was separated by chiral SFC, with a retention time of 2.00 min. The specific separation method is as follows: 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: 214nm.

15. A compound or a pharmaceutically acceptable salt thereof, wherein, The compound is a compound. The isomer of "" was analyzed by chiral SFC, and the retention time was 3.60 min. The specific analytical method is as follows: 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: 70:30; Flow rate: 100 mL / min; Detection wavelength: 214nm.

16. A compound or a pharmaceutically acceptable salt thereof, wherein, The compound is a compound. The isomer of "" was separated by chiral SFC, with a retention time of 1.39 min. The specific separation method is as follows: 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: 214nm.

17. A compound or a pharmaceutically acceptable salt thereof, wherein, The compound is a compound. The isomer of "" was separated by chiral SFC, with a retention time of 6.30 min. The specific separation method is as follows: 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: 55:45; Flow rate: 70 mL / min; Detection wavelength: 214nm.

18. An intermediate for preparing the compound of any one of claims 1-11, its isomers or pharmaceutically acceptable salts thereof, or the compound of any one of claims 12-17 or its pharmaceutically acceptable salts thereof, wherein the structure is specifically as follows: 。 19. The intermediate according to claim 18, wherein, intermediate The isomer of "" was separated by chiral SFC, with a retention time of 20.33 min. The specific separation method is as follows: Chromatographic column: DAICELCHIRALPAK® IC 250*4.6mm, 5 μm; Mobile phase A: n-hexane; Mobile phase B: ethanol; A:B: 90:10; Flow rate: 1 mL / min; Detection wavelength: 254nm.

20. The intermediate according to claim 18, wherein, intermediate The isomer of "" was separated by chiral SFC, with a retention time of 16.51 min. The specific separation method is as follows: Chromatographic column: DAICELCHIRALPAK® IC 250*4.6mm, 5 μm; Mobile phase A: n-hexane; Mobile phase B: ethanol; A:B: 90:10; Flow rate: 1 mL / min; Detection wavelength: 254nm.

21. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1-11, an isomer thereof or a pharmaceutically acceptable salt thereof, or the compound of any one of claims 12-17 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

22. Use of the compound, its isomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1-11, or the compound or a pharmaceutically acceptable salt thereof according to any one of claims 12-17, or the pharmaceutical composition of claim 21 in the preparation of a medicament for the prevention and / or treatment of complement factor B-mediated diseases or disease states; Preferably, the disease or disease state mediated by complement factor B is selected from one or more of ophthalmic diseases, autoimmune diseases, kidney-related diseases, respiratory diseases, and cardiovascular diseases; arthritis is preferred.

Images