Complement factor b inhibitors

Abstract

The invention provides a complement factor B inhibitor, the structure of the complement factor B inhibitor is basically shown in a general formula (I), and the definition of each substituent group in the formula is shown in the specification. The compound provided by the invention has obvious complement factor B inhibition activity, and can be used for preventing and / or treating complement factor B inhibitor mediated diseases or disease states. # imgabs0 #

Description

Complement factor B inhibitors Technical Field

[0001] The present invention belongs to the field of biomedicine, and particularly relates to a complement factor B inhibitor. Background Art

[0002] The complement system is part of the host innate immune system, involved in lysing foreign cells, enhancing antigen phagocytosis, agglutinating antigen-carrying agents, and attracting macrophages and neutrophils. It is a crucial component of the human innate immune system against infections by foreign pathogens, bacteria, and parasites. It also plays a crucial role in bridging innate and adaptive immunity. Complement is composed of plasma proteins, including soluble and membrane-bound proteins, and complement receptors. Complement is primarily produced by membrane proteins expressed in the liver or on the cell surface, and functions in plasma, tissues, or cells. The complement system is a crucial regulator of inflammatory responses and tissue damage, consisting of over 20 serum and cell surface proteins. The complement system includes intrinsic complement components and various regulatory proteins. Intrinsic complement components include C1 to 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).

[0003] Under normal physiological conditions in healthy individuals, the AP pathway maintains a low level of activation to monitor for invading foreign pathogens. Complement proteins are distributed on the surface of apoptotic cells, and complement activation is strictly regulated, serving only to clear apoptotic cells without further activating other innate or adaptive immune responses. In the event of infection with a foreign pathogen, the complement system is fully activated, generating inflammatory responses, opsonization, or phagocytosis, destroying the pathogen and ultimately activating the adaptive immune response. Both inefficient and overstimulated complement activation can be harmful to the human body and are associated with increased susceptibility to infection 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 of 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 the complement pathway (including the alternative complement pathway).

[0004] Complement factor B (FB) is a key protein involved in AP activation. Inhibiting FB activity can prevent AP activation without interfering with the CP and LP pathways, thereby avoiding the increased risk of infection caused by complement system inhibition. Therefore, the search for novel and effective small molecule inhibitors of complement factor B is an important research direction for drug development in the context of various diseases caused by complement abnormalities.

[0005] Summary of the Invention

[0006] The object of the present invention is to provide a new 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 represented by general formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of general formula (I) is as follows:

[0008] in:

[0009] X is selected from CH2, NH, S, O or

[0010] Y and Z are each independently selected from CH or N;

[0011] When X is CH2, Z is N;

[0012] R 1 is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl or C3-C6 heterocyclyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally substituted with halogen, oxo, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl or C3-C6 halocycloalkyl;

[0013] R 2 is hydrogen, or R 1 and R 2 Together with the atoms to which they are attached, they form a C10-15 heterocyclic group, which is optionally substituted with halogen;

[0014] R 3 is selected from C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted by deuterium or halogen.

[0015] In a preferred embodiment of the present invention, the compound represented by general formula (I), its isomer or pharmaceutically acceptable salt thereof is further represented by general formula (II-1), (II-2) or (II-3):

[0016] in:

[0017] X, Y, R 1、R 3 As mentioned above;

[0018] P is selected from CH2, NH, S or O;

[0019] R 4 Selected from hydrogen, halogen or C1-C3 alkyl;

[0020] m is 0, 1 or 2.

[0021] In a preferred embodiment of the present invention, the compound represented by general formula (I), its isomer or pharmaceutically acceptable salt thereof is further represented by general formula (II-1-1) or (II-1-2):

[0022] in:

[0023] X, Y, R 1 、R 3 As defined above.

[0024] In a preferred embodiment of the present invention, the compound represented by general formula (I), its isomer or pharmaceutically acceptable salt thereof is further represented by general formula (II-2-1) or (II-2-2):

[0025] in:

[0026] X, Y, R 1 、R 3 As defined above. In a further preferred embodiment of the present invention, Y is selected from CH or N; preferably CH.

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

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

[0029] In a preferred embodiment of the present invention, the compound represented by general formula (I), its isomer or pharmaceutically acceptable salt thereof is further represented by general formula (III-1) or (III-2):

[0030] in:

[0031] X, R 1 、R 3 As defined above.

[0032] In a preferred embodiment of the present invention, the compound represented by general formula (I), its isomer or pharmaceutically acceptable salt thereof is further represented by general formula (III-1-1), (III-1-2), (III-1-3) or (III-1-4):

[0033] in:

[0034] X, R 1 、R 3 As defined above.

[0035] In a preferred embodiment of the present invention, the compound represented by general formula (I), its isomer or pharmaceutically acceptable salt thereof, is further represented by general formula (III-2-1), (III-2-2), (III-2-3), (III-2-4), (III-2-5), (III-2-6), (III-2-7) or (III-2-8):

[0036] in:

[0037] X, R 1 、R 3 As defined above.

[0038] In a further preferred embodiment of the present invention, X is selected from NH, S, O or

[0039] In a further preferred embodiment of the present invention, X is selected from CH2, S or O; preferably S or O.

[0040] In a preferred embodiment of the present invention, X is selected from CH2.

[0041] In a preferred embodiment of the present invention, X is selected from S.

[0042] In a preferred embodiment of the present invention, X is selected from O.

[0043] In a preferred embodiment of the present invention, X is selected from NH.

[0044] In a preferred embodiment of the present invention, X is selected from

[0045] In a preferred embodiment of the present invention, Z is selected from CH or N.

[0046] In a preferred embodiment of the present invention, Z is selected from N.

[0047] In a preferred embodiment of the present invention, Z is selected from CH.

[0048] In a further preferred embodiment of the present invention, R 1 Selected from C1-C3 alkyl, C1-C3 alkoxy, C3-C4 cycloalkyl or C3-C4 heterocyclyl, wherein the C1-C3 alkyl or C3-C4 cycloalkyl is optionally substituted by fluorine, chlorine, bromine, iodine, oxo, C1-C3 haloalkyl, C3-C4 cycloalkyl, C3-C4 heterocyclyl or C3-C4 halocycloalkyl.

[0049] In a preferred embodiment of the present invention, R 1 is selected from C1-C3 alkyl, C1-C3 alkoxy, C3-C4 cycloalkyl or C3-C4 heterocyclyl, wherein the C1-C3 alkyl or C3-C4 cycloalkyl is optionally substituted with 1, 2 or 3 substituents selected from fluorine, chlorine, bromine, iodine, oxo, C1-C3 haloalkyl, C3-C4 cycloalkyl, C3-C4 heterocyclyl or C3-C4 halocycloalkyl.

[0050] In a preferred embodiment of the present invention, R 1 The C1-C3 alkyl group is optionally substituted with 1, 2 or 3 substituents selected from fluorine, chlorine, bromine and iodine.

[0051] In a preferred embodiment of the present invention, the C1-C3 fluoroalkyl group is selected from fluoromethyl, difluoromethyl or trifluoromethyl, preferably trifluoromethyl.

[0052] In a preferred embodiment of the present invention, R 1 is selected from C3-C4 cycloalkyl, wherein the C3-C4 cycloalkyl is optionally substituted with 1, 2 or 3 substituents selected from C1-C3 fluoroalkyl.

[0053] In a further preferred embodiment of the present invention, R 1 is selected from methyl, ethyl, propyl, ethoxy, cyclobutyl or oxetane, wherein the ethyl, propyl or cyclobutyl is optionally substituted by fluoro, oxo, trifluoromethyl, cyclopropyl, fluorocyclopropyl or oxetane.

[0054] In a further preferred embodiment of the present invention, R 1 is selected from methyl, ethyl, propyl, ethoxy, cyclobutyl or oxetane, wherein the ethyl, propyl or cyclobutyl is optionally substituted with 1, 2 or 3 substituents selected from fluoro, oxo, trifluoromethyl, cyclopropyl, fluorocyclopropyl or oxetane.

[0055] In a further preferred embodiment of the present invention, R 1 is selected from methyl, ethyl or propyl, wherein the methyl, ethyl or propyl is optionally substituted by 1, 2 or 3 fluorine groups. 1 Selected from Preferred More preferred

[0056] In a further preferred embodiment of the present invention, R 1 Selected from

[0057] In a further preferred embodiment of the present invention, R 3 is selected from C1-C3 alkyl or C3-C4 cycloalkyl, wherein the C1-C3 alkyl is optionally substituted by deuterium, fluorine, chlorine, bromine or iodine.

[0058] In a further preferred embodiment of the present invention, R 3 is selected from C1-C3 alkyl or C3-C4 cycloalkyl, wherein the C1-C3 alkyl is optionally substituted by 1, 2 or 3 substituents selected from deuterium, fluorine, chlorine, bromine or iodine. In a further preferred embodiment of the present invention, R 3 is selected from methyl or cyclopropyl, said methyl being optionally substituted by deuterium or fluorine.

[0059] In a further preferred embodiment of the present invention, R 3 is selected from methyl or cyclopropyl, said methyl being optionally substituted with 1, 2 or 3 substituents selected from deuterium or fluorine.

[0060] In a further preferred embodiment of the present invention, R 3 Selected from methyl, -CD3, -CF3 or Preferably methyl, -CD3, -CF3 or Methyl is preferred.

[0061] In a further preferred embodiment of the present invention, P is selected from CH2, NH, S or O; preferably O.

[0062] In a further preferred embodiment of the present invention, R 4 is selected from fluorine, chlorine, bromine or iodine; preferably fluorine.

[0063] In a further preferred embodiment of the present invention, R 4 Selected from hydrogen.

[0064] In a further preferred embodiment of the present invention, m is 0, 1 or 2; preferably 2.

[0065] In a further preferred embodiment of the present invention, the compound, its isomer or pharmaceutically acceptable salt thereof has the following structure:

[0066] The present invention provides the following compounds, their isomers or pharmaceutically acceptable salts:

[0067] In a further preferred embodiment of the present invention, the compound, its isomer or pharmaceutically acceptable salt thereof has the following structure:

[0068] The present invention provides the following compounds, their isomers or pharmaceutically acceptable salts:

[0069] In a further preferred embodiment of the present invention, the compound, its isomer or pharmaceutically acceptable salt thereof has the following structure:

[0070] In a further preferred embodiment of the present invention, the compound, its isomer or pharmaceutically acceptable salt thereof has the following structure:

[0071] In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-2 ...

[0072] Chromatographic column: Lux Cellulose-4 4.6*50mm, 3μm;

[0073] Mobile phase A: supercritical CO2; mobile phase B: methanol;

[0074] Gradient: 10% to 50% flow for 2.0 min, 50% hold for 1.0 min;

[0075] Detection wavelength: 220nm.

[0076] In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[ ...

[0077] Chromatographic column: Lux Cellulose-4 4.6*50mm, 3μm;

[0078] Mobile phase A: supercritical CO2; mobile phase B: methanol;

[0079] Gradient: 10% to 50% flow for 2.0 min, 50% hold for 1.0 min;

[0080] Detection wavelength: 220nm.

[0081] In a preferred embodiment, the compound The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-1-yl]-1-nitropropene ...

[0082] Chromatographic column: 4250*20mm,10μm;

[0083] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol);

[0084] Flow rate: 70 mL / min;

[0085] Mobile phase ratio: A:B = 75:25;

[0086] Detection wavelength: 214nm.

[0087] In a preferred embodiment, the compound The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-2 ...

[0088] Chromatographic column: 4250*20mm, 10μm;

[0089] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol);

[0090] Mobile phase ratio: A:B = 75:25;

[0091] Detection wavelength: 214nm.

[0092] In a preferred embodiment, the compound The isomers of α-hydroxy-1-[ ...

[0093] Chromatographic column: CHIRALPAK IE-3 4.6*50mm, 3μm;

[0094] Mobile phase A: (n-hexane: dichloromethane = 3:1) (0.1% diethylamine); Mobile phase B: isopropanol; A:B = 80:20;

[0095] Flow rate: 1.0 mL / min;

[0096] Detection wavelength: 220 / 254 dual wavelength detection.

[0097] In a preferred embodiment, the compound The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-1-yl]-1-nitropropene ...

[0098] Chromatographic column: CHIRALPAK IE-3 4.6*50mm, 3μm;

[0099] Mobile phase A: (n-hexane: dichloromethane = 3:1) (0.1% diethylamine); Mobile phase B: isopropanol; A:B = 80:20;

[0100] Flow rate: 1.0 mL / min;

[0101] Detection wavelength: 220 / 254 dual wavelength detection.

[0102] In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[ ...]]]]]]]]]]]]]]]]]]]]]]

[0103] Chromatographic column: 250*20mm,10μm;

[0104] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 75:25;

[0105] Flow rate: 70 mL / min;

[0106] Detection wavelength: 214nm.

[0107] In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-2 ...

[0108] Chromatographic column: 250*20mm,10μm;

[0109] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 75:25;

[0110] Flow rate: 70 mL / min;

[0111] Detection wavelength: 214nm.

[0112] In a preferred embodiment, the compound The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-2 ...

[0113] Chromatographic column: 250*20mm,10μm;

[0114] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 70:30;

[0115] Flow rate: 100 mL / min;

[0116] Detection wavelength: 214nm.

[0117] In a preferred embodiment, the compound The isomers of α-hydroxy-1-[ ...]]]]]]]]]]]]]]]]]]]]]]]]

[0118] Chromatographic column: 250*20mm,10μm;

[0119] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 70:30;

[0120] Flow rate: 100 mL / min;

[0121] Detection wavelength: 214nm.

[0122] In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-1-yl]-1-nitropropene ...

[0123] Chromatographic column: 250*20mm,10μm;

[0124] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 75:25;

[0125] Flow rate: 100 mL / min;

[0126] Detection wavelength: 214nm.

[0127] In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[ ...

[0128] Chromatographic column: 250*20mm,10μm;

[0129] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 75:25;

[0130] Flow rate: 100 mL / min;

[0131] Detection wavelength: 214nm.

[0132] In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[ ...

[0133] Chromatographic column: 250*20mm 10μm;

[0134] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 75:25;

[0135] Flow rate: 100 mL / min;

[0136] Detection wavelength: 214nm.

[0137] In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[ ...

[0138] Chromatographic column: 250*20mm,10μm;

[0139] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 75:25;

[0140] Flow rate: 100 mL / min;

[0141] Detection wavelength: 214nm.

[0142] In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-2 ...

[0143] Chromatographic column: 250*25mm,10μm;

[0144] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 75:25;

[0145] Flow rate: 100 mL / min;

[0146] Detection wavelength: 214nm.

[0147] In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-1-yl]-1-nitropropene ...

[0148] Chromatographic column: 250*25mm,10μm;

[0149] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 75:25;

[0150] Flow rate: 100 mL / min;

[0151] Detection wavelength: 214nm.

[0152] In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-2 ...

[0153] Chromatographic column: 250*20mm,10μm;

[0154] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 75:25;

[0155] Flow rate: 100 mL / min;

[0156] Detection wavelength: 214nm.

[0157] In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-1-yl]-1-nitropropene ...

[0158] Chromatographic column: 250*20mm,10μm;

[0159] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 75:25;

[0160] Flow rate: 100 mL / min;

[0161] Detection wavelength: 214nm.

[0162] In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-2 ...

[0163] Chromatographic column: 250*20mm,10μm;

[0164] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 75:25;

[0165] Flow rate: 100 mL / min;

[0166] Detection wavelength: 214nm.

[0167] In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[ ...]]]]]]]]]]]]]]]]]]]

[0168] Chromatographic column: 250*20mm,10μm;

[0169] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 75:25;

[0170] Flow rate: 100 mL / min;

[0171] Detection wavelength: 214nm.

[0172] In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-2 ...

[0173] Chromatographic column: 250*20mm,10μm;

[0174] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 75:25;

[0175] Flow rate: 100 mL / min;

[0176] Detection wavelength: 214nm.

[0177] In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-2 ...

[0178] Chromatographic column: 250*20mm,10μm;

[0179] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 75:25;

[0180] Flow rate: 100 mL / min;

[0181] Detection wavelength: 214nm.

[0182] In a preferred embodiment of the present invention, the compound The isomers of α-Hydroxy-1-[4-[4-(2-oxo-1-yl)-1-nitropropene]-2 ...

[0183] Chromatographic column: 250*20mm,10μm;

[0184] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 70:30;

[0185] Flow rate: 100 mL / min;

[0186] Detection wavelength: 214nm.

[0187] In a preferred embodiment of the present invention, the compound The isomers of α-Hydroxy-1-[4-[4-(4-oxo-1-yl)-1-nitropropene]-2 ...

[0188] Chromatographic column: 250*20mm,10μm;

[0189] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 70:30;

[0190] Flow rate: 100 mL / min;

[0191] Detection wavelength: 214nm.

[0192] In a preferred embodiment of the present invention, the compound The isomers of α-Hydroxy-1-[4-[4-(4-oxo-1-yl)-1-nitropropene]-2 ...

[0193] Chromatographic column: 250*20mm,10μm;

[0194] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 70:30;

[0195] Flow rate: 100 mL / min;

[0196] Detection wavelength: 214nm.

[0197] In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-1-yl]-1-nitropropene ...

[0198] Chromatographic column: 250*20mm,10μm;

[0199] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 70:30;

[0200] Flow rate: 100 mL / min;

[0201] Detection wavelength: 214nm.

[0202] In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-2 ...

[0203] Chromatographic column: 250*20mm,10μm;

[0204] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 75:25;

[0205] Flow rate: 100 mL / min;

[0206] Detection wavelength: 214nm.

[0207] In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-2 ...

[0208] Chromatographic column: 250*20mm,10μm;

[0209] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 75:25;

[0210] Flow rate: 100 mL / min;

[0211] Detection wavelength: 214nm.

[0212] In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-2 ...

[0213] Chromatographic column: 250*20mm,10μm;

[0214] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 50:50;

[0215] Flow rate: 100 mL / min;

[0216] Detection wavelength: 214nm.

[0217] In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-2 ...

[0218] Chromatographic column: 250*20mm,10μm;

[0219] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 50:50;

[0220] Flow rate: 100 mL / min;

[0221] Detection wavelength: 214nm.

[0222] In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-2 ...

[0223] Chromatographic column: 250*20mm 10μm;

[0224] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 50:50;

[0225] Flow rate: 100 mL / min;

[0226] Detection wavelength: 214nm.

[0227] In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-2 ...

[0228] Chromatographic column: 250*20mm,10μm;

[0229] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 50:50;

[0230] Flow rate: 100 mL / min;

[0231] Detection wavelength: 214nm.

[0232] In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-2 ...

[0233] Chromatographic column: 250*20mm,10μm;

[0234] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 55:45;

[0235] Flow rate: 70 mL / min;

[0236] Detection wavelength: 214nm.

[0237] In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-2 ...

[0238] Chromatographic column: 250*20mm,10μm;

[0239] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 55:45;

[0240] Flow rate: 70 mL / min;

[0241] Detection wavelength: 214nm.

[0242] In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-2 ...

[0243] Chromatographic column: 250*20mm,10μm;

[0244] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 55:45;

[0245] Flow rate: 70 mL / min;

[0246] Detection wavelength: 214nm.

[0247] In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-2 ...

[0248] Chromatographic column: 250*20mm,10μm;

[0249] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 55:45;

[0250] Flow rate: 70 mL / min;

[0251] Detection wavelength: 214nm.

[0252] In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[ ...

[0253] Chromatographic column: 250*20mm, 10μm;

[0254] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 70:30;

[0255] Flow rate: 100 mL / min;

[0256] Detection wavelength: 214nm.

[0257] Detection wavelength: 214 nm. In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-2 ...

[0258] Chromatographic column: 250*20mm,10μm;

[0259] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 70:30;

[0260] Flow rate: 100 mL / min;

[0261] Detection wavelength: 214nm.

[0262] Detection wavelength: 214 nm In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-2 ...

[0263] Chromatographic column: 250*20mm,10μm;

[0264] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 70:30;

[0265] Flow rate: 100 mL / min;

[0266] Detection wavelength: 214nm.

[0267] Detection wavelength: 214 nm In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-2 ...

[0268] Chromatographic column: 250*20mm,10μm;

[0269] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol); A:B: 70:30;

[0270] Flow rate: 100 mL / min;

[0271] Detection wavelength: 214nm.

[0272] In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-1-yl]-1-nitropropene ...

[0273] Chromatographic column: 250*20mm,10μm;

[0274] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / l ammonia methanol); A:B: 75:25;

[0275] Flow rate: 120 mL / min;

[0276] Detection wavelength: 214nm.

[0277] In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-1-yl]-1-nitropropene ...

[0278] Chromatographic column: 250*20mm,10μm;

[0279] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / l ammonia methanol); A:B: 75:25;

[0280] Flow rate: 120 mL / min;

[0281] Detection wavelength: 214nm.

[0282] Detection wavelength: 214 nm. In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-2 ...

[0283] Chromatographic column: 250*20mm,10μm;

[0284] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / l ammonia methanol); A:B: 75:25;

[0285] Flow rate: 120 mL / min;

[0286] Detection wavelength: 214nm.

[0287] Detection wavelength: 214 nm. In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-2 ...

[0288] Chromatographic column: 250*20mm,10μm;

[0289] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / l ammonia methanol); A:B: 75:25;

[0290] Flow rate: 120 mL / min;

[0291] Detection wavelength: 214nm.

[0292] In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-2 ...

[0293] Chromatographic column: 250*20mm,10μm;

[0294] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / l ammonia methanol); A:B: 55:45;

[0295] Flow rate: 70 mL / min;

[0296] Detection wavelength: 214nm.

[0297] In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-2 ...

[0298] Chromatographic column: 250*20mm,10μm;

[0299] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / l ammonia methanol); A:B: 55:45;

[0300] Flow rate: 70 mL / min;

[0301] Detection wavelength: 214nm.

[0302] In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-2 ...

[0303] Chromatographic column: CHIRALPAK-IG 2*25cm;

[0304] Mobile phase A: n-hexane (0.1% formic acid); Mobile phase B: ethanol: dichloromethane = 1:1; A:B: = 1:1;

[0305] Flow rate: 20 mL / min;

[0306] Detection wavelength: 220 / 254nm.

[0307] In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-2 ...

[0308] Chromatographic column: CHIRALPAK-IG 2*25cm,;

[0309] Mobile phase A: n-hexane (0.1% formic acid); Mobile phase B: ethanol: dichloromethane = 1:1; A:B: = 1:1;

[0310] Flow rate: 20 mL / min;

[0311] Detection wavelength: 220 / 254nm.

[0312] In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[ ...

[0313] Chromatographic column: CHIRALPAK-IG 2*25cm,;

[0314] Mobile phase A: n-hexane (0.1% formic acid); Mobile phase B: ethanol: dichloromethane = 1:1; A:B: = 1:1;

[0315] Flow rate: 20 mL / min;

[0316] Detection wavelength: 220 / 254nm.

[0317] In a preferred embodiment of the present invention, the compound The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-1-yl]-1-nitropropene ...

[0318] Chromatographic column: CHIRALPAK-IG 2*25cm,;

[0319] Mobile phase A: n-hexane (0.1% formic acid); Mobile phase B: ethanol: dichloromethane = 1:1; A:B: = 1:1;

[0320] Flow rate: 20 mL / min;

[0321] Detection wavelength: 220 / 254nm.

[0322] An intermediate for preparing the above compound or its salt, the structure of which is shown below:

[0323] In a preferred embodiment of the present invention, the intermediate The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-2 ...

[0324] Chromatographic column: 250*4.6mm,5μm;

[0325] Mobile phase A: n-hexane; mobile phase B: ethanol; A:B: 90:10;

[0326] Flow rate: 1 mL / min;

[0327] Detection wavelength: 254nm.

[0328] In a preferred embodiment of the present invention, the intermediate The isomers of α-hydroxy-1-[3-[3-(2-[2-(2-methyl-1-oxo-1-yl)-1-nitropropene]-1-yl]-1-nitropropene ...

[0329] Chromatographic column: 250*4.6mm,5μm;

[0330] Mobile phase A: n-hexane; mobile phase B: ethanol; A:B: 90:10;

[0331] Flow rate: 1 mL / min;

[0332] Detection wavelength: 254nm.

[0333] In a preferred embodiment of the present invention, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of any of the above compounds, isomers thereof or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers.

[0334] The pharmaceutical composition of the present invention can be administered by any applicable route or method, for example, by oral or parenteral (e.g., intravenous) administration. For oral administration, the pharmaceutical composition of the present invention is generally provided in the form of tablets, capsules or solutions. Tablets may comprise a compound of the present invention, an isomer thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The carrier includes but is not limited to a diluent, a disintegrant, a binder, a lubricant, a colorant or a preservative. Capsules include hard capsules and soft capsules.

[0335] For parenteral administration, the pharmaceutical composition of the present invention can be administered by intravenous injection, intramuscular injection or subcutaneous injection. It is usually provided in a sterile aqueous solution or suspension or lyophilized powder, and the appropriate pH and isotonicity are adjusted.

[0336] In a preferred embodiment of the present invention, the present invention also provides the use of any one of the above compounds, isomers or pharmaceutically acceptable salts thereof in the preparation of a medicament for preventing and / or treating diseases or disease states mediated by complement factor B.

[0337] In a preferred embodiment of the present invention, the present invention also provides a method for preventing and / or treating diseases or disease states mediated by complement factor B, which comprises administering a compound of the present invention, an isomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention to an individual in need thereof.

[0338] 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), renal system-related diseases, respiratory system diseases, and cardiovascular diseases.

[0339] In a preferred embodiment of the present invention, the disease or condition mediated by complement factor B is arthritis.

[0340] Related definitions

[0341] As used herein and unless otherwise specified, the terms "comprises," "includes," "has," "contains," and their grammatical equivalents should generally be understood as open-ended and non-limiting, e.g., not excluding other unlisted elements or steps.

[0342] Unless otherwise specified, the following terms used in the specification and claims have the following meanings:

[0343] The compounds of the present invention may be asymmetric, for example, having one or more chiral centers. Unless otherwise indicated, the compounds of the present invention may be any one isomer or a mixture of two or more isomers. The compounds of the present invention include isomers (e.g., stereoisomers), enantiomers, diastereomers, racemates, or mixtures of two or more isomers of the compounds.

[0344] The term "isomer" refers to different compounds that have the same molecular formula but different arrangements and configurations of the atoms. "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, the term is used to refer to a racemic mixture. The use of "rel" indicates that the diastereomeric orientation is known, but the absolute stereochemistry is not. For example, the designation "rel-3S,4S" as used herein indicates that the relative stereochemistry at the 3 and 4 positions is either 3S,4S or 3R,4R. For purposes of the present invention, the order of the aliphatic ring positions is as follows: Absolute stereochemistry is not determined, but optical rotation and / or chiral chromatography conditions will show which isomers are present. "Diastereomers" are stereoisomers with at least two asymmetric atoms but that are not 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 with R or S. Compounds whose absolute configuration is unknown can be designated as (+) or (-) based on the direction in which they rotate plane polarized light (right- or left-handed) at the wavelength of the sodium D line or the retention time when separated by chiral chromatography. Some compounds described herein contain one or more asymmetric centers or axes, and therefore can produce enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- or represented by (+) or (-) symbols in terms of absolute stereochemistry. The present 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 substituents can be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituents 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, and racemic mixtures and other mixtures thereof. Compounds of the present invention containing asymmetric carbon atoms can be isolated in optically pure form or as mixtures of two or more isomers. Optically pure forms can be resolved from mixtures of two or more isomers or synthesized using chiral starting materials or chiral reagents.

[0345] The "compounds" of the present invention also include tautomeric forms. Tautomeric forms result from the exchange of a single bond for an adjacent double bond accompanied by the migration of a proton. The term "tautomer" or "tautomeric form" refers to isomers of different functional groups that are in dynamic equilibrium at room temperature and can readily interconvert.

[0346] The isomer mixtures obtainable according to the present invention can be separated into the individual isomers in a known manner by a person skilled in the art; diastereomers can be separated, for example, by partitioning between multiphase solvent mixtures, recrystallization, and / or chromatography, for example, on silica gel, or by medium-pressure liquid chromatography, for example using a reversed-phase column, and racemates can be separated, for example, by salt formation with an optically pure salt-forming agent and separation (for example, by fractional crystallization) of the thus obtainable diastereomer mixture, or by chromatography on an optically active column material. Intermediates and end products can be worked up and / or purified according to standard methods, for example, using chromatography, distribution methods, (re)crystallization, etc. At all reaction stages, the isomer mixtures formed can be separated into the individual isomers, for example, diastereomers or enantiomers, or into any desired isomer mixtures, for example, racemates or diastereomer mixtures.

[0347] Absolute stereochemistry and / or optical rotation are provided as appropriate for embodiments of the present invention. The present invention is concerned with all stereochemical forms of the compounds provided herein. In some cases, the compound contains two or more chiral centers. The relative stereochemistry of these compounds is identified by NMR research and / or X-ray diffraction. In these cases, the prefix "rel" is used, followed by the R / S nomenclature to identify these compounds. Obviously, if "rel" is used, R / S only provides relative stereochemical information (e.g., trans or cis), not absolute stereochemistry. In some cases, the relative stereochemistry of the diastereoisomer pair is not determined, so when only one isomer is separated and / or available, enantiomers are indicated / distinguished according to the retention time under the given HPLC conditions. The same sample usually has the same retention time, but there may be certain operational errors. When a person of ordinary skill in the art uses the same instrument and detection method to detect samples obtained using the corresponding method, the retention time error is usually within ±0.2 min, preferably within ±0.1 min. Different technicians using different instruments may occasionally have a few retention time errors outside this range. For example, errors within ±0.5 min; or within ±0.3 min; or within ±0.2 min should all be considered to belong to the same substance. Therefore, retention time errors within ±0.5 min, ±0.3 min, ±0.2 min or ±0.1 min can be interpreted as being within the scope of protection of the present invention.

[0348] In cases where individual diastereomers are identified as racemic, but the relative stereochemistry is not determined, the compound is named using the symbol "(±)" and the designation "Diastereomer-1" or "Diastereomer-2" if only one isomer is isolated and / or available.

[0349] In the present invention, Indicates the absolute configuration of a stereocenter. in Refers to the chemical bond connection. When it appears in a bicyclic or polycyclic ring When the connection position is uncertain, it means that the connection site is limited to Any atom in the monocyclic ring, as long as the valence permits.

[0350] The structures of the compounds of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of a compound, the absolute configuration can be confirmed by conventional techniques in the art, such as single crystal X-ray diffraction (SARD).

[0351] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both occurring and not occurring.

[0352] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0353] The term "substituted" means that any one or more (e.g., 1, 2, 3, or 4, etc.) hydrogen atoms on a particular group are replaced by a substituent, which may be the same or different, as long as the valence of the particular group is normal and the compound after the substitution is stable. For example, "substituted with halogen" means that any one or more (e.g., 1, 2, 3, or 4, etc.) hydrogen atoms on a particular group are replaced by the same or different halogens, as long as the valence of the particular group is normal and the compound after the substitution is stable.

[0354] As used herein, numerical ranges refer to each integer within the given range. For example, "C1-C6" means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms; "C1-C3" means that the group may have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.

[0355] 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 include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, n-hexyl, 2-hexyl, 3-hexyl, and the like.

[0356] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen atom (fluorine, chlorine, bromine, iodine). For example, the term "C1-C6 haloalkyl" refers to a haloalkyl group containing 1 to 6 carbon atoms. Examples include, but are not limited to, trifluoromethyl and trifluoroethyl.

[0357] The term "cycloalkyl" refers to a monocyclic saturated hydrocarbon system with no heteroatoms and no double bonds. Examples of the term "C3-C6 cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0358] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent. The term "C3-C6 membered heterocyclyl" refers to a group containing 3 to 6 carbon atoms as ring atoms, wherein one or more heteroatoms selected from nitrogen, oxygen or sulfur as ring atoms, preferably 1 to 3 heteroatoms; the term "C10-15 heterocyclyl" refers to a group containing 10 to 15 carbon atoms as ring atoms, wherein one or more heteroatoms selected from nitrogen, oxygen or sulfur as ring atoms, preferably 1 to 3 heteroatoms, preferably 11 or 12 carbon atoms as ring atoms, and 1 or 2 heteroatoms selected from oxygen or nitrogen as ring atoms.

[0359] The term "pharmaceutically acceptable" means that a carrier, vehicle, excipient, diluent, and / or formed salt is generally chemically or irrationally compatible with the other ingredients constituting a pharmaceutical dosage form and physiologically compatible with the receptor.

[0360] The term "pharmaceutically acceptable carrier" refers to any carrier that is non-irritating to the body and does not impair the biological activity and properties of the active compound. This includes, but is not limited to, any diluent, disintegrant, binder, glidant, or wetting agent commonly used in the art for human or animal use.

[0361] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness of the free acid and base of a particular compound without any adverse biological effects. Examples include acid addition salts (including organic and inorganic acids) or base addition salts (including organic and inorganic bases), and may also include zwitterionic salts, as well as quaternary ammonium salts, such as alkylammonium salts. The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or a mixture of the two.

[0362] The term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a drug or pharmaceutical agent that is non-toxic but can achieve the desired effect. The exact dosage will vary depending on a variety of factors, such as subject-dependent variables (e.g., age, immune system health, etc.), the disease or illness, and the treatment being administered.

[0363] The term "pharmaceutical composition" means a composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable ingredient selected from the following depending on the mode of administration and the nature of the dosage form, including but not limited to: carriers, diluents, adjuvants, excipients, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, dispersants, temperature-sensitive materials, temperature regulators, adhesives, stabilizers, suspending agents, etc.

[0364] The drugs or pharmaceutical compositions of the present disclosure can be administered orally, topically, parenterally, or mucosally (e.g., buccally, by inhalation, or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers. It is generally desirable to use the oral route. The active agent can be administered orally in the form of capsules, tablets, and the like.

[0365] The medicine or pharmaceutical composition of the present disclosure can be delivered parenterally, that is, administered intravenously (iv), intracerebroventricularly (icv), subcutaneously (sc), intraperitoneally (ip), intramuscularly (im), subcutaneously (sd) or intradermally (id), by direct injection, for example, through rapid bolus injection or continuous infusion. The formulation for injection can be presented in unit dosage form, for example, in an ampoule or multi-dose container with an added preservative. The composition can be in the form of an excipient, a suspension, a solution or an emulsion in an oil or aqueous vehicle, and can include formulation agents such as anti-settling agents, stabilizers and / or dispersants. Alternatively, the active ingredient can be reconstituted with a suitable carrier (e.g., sterile pyrogen-free water) before use in powder form.

[0366] The medicaments or pharmaceutical compositions of the present disclosure may also be formulated for rectal administration, for example, as suppositories or retention enemas (eg, containing conventional suppository bases such as cocoa butter or other glycerides).

[0367] The term "treating" includes inhibiting, alleviating, preventing or eliminating one or more symptoms or side effects associated with the disease, condition or disorder being treated.

[0368] The abbreviations used in the claims and the specification have the following meanings: M: mol / L DMSO: dimethyl sulfoxide DMSO-d6: deuterated dimethyl sulfoxide DEA: diethylamine DCM: dichloromethane IPA: isopropyl alcohol FA: formic acid 1 H NMR: proton nuclear magnetic resonance HPLC: high performance liquid chromatography LCMS: liquid chromatography-mass spectrometry M: molar MEOH: methanol m / z: mass-to-charge ratio SFC: supercritical fluid chromatography V / V: volume / volume BRIEF DESCRIPTION OF THE DRAWINGS

[0369] FIG1 is a graph showing the arthritis score of Example 13a-2 in the collagen antibody-induced arthritis experiment in mice in Experimental Example 4;

[0370] FIG2 is a graph showing the change in footpad thickness of Example 13a-2 in the collagen antibody-induced mouse arthritis experiment in Experimental Example 4;

[0371] FIG3 is a graph showing the AUC changes in the CAIA mouse model efficacy study in Experimental Example 5;

[0372] FIG4 is the crystal structure of the compound 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid in Experimental Example 6;

[0373] FIG5 is the crystal structure of the 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;

[0374] FIG6 is the crystal structure of the compound (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester in Experimental Example 8. DETAILED DESCRIPTION

[0375] The preparation method of compound of the present invention is described in more detail below, but these specific preparation methods do not constitute any restriction to the scope of the present invention.In addition, reaction conditions such as the amount of reactant, solvent, alkali, compound used, reaction temperature, reaction times etc. are not limited to the following example.

[0376] The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art. Such a combination can be easily performed by those skilled in the art.

[0377] 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 commercial products.

[0378] 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

[0379] a) Preparation of methyl 4-(pyrazin-2-yl)benzoate

[0380] (4-(Methoxycarbonyl)phenyl)boric acid (2 g), 1,4-dioxane (100 mL), and water (20 mL) were added to a (250 mL) two-necked flask, followed by sodium carbonate (3.53 g) and tetrakis(triphenylphosphine palladium) (1.28 g). Nitrogen was replaced for protection, and 2-chloropyrazine (1.91 g) was added. The mixture was stirred at 100°C for 4.5 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to make sand, and purified by column chromatography (mobile phase: dichloromethane / methanol = 10 / 1 (V / V)) to obtain 2.04 g of the title compound.

[0381] b) Preparation of methyl (±) 4-(piperazin-2-yl)benzoate

[0382] Methyl 4-(pyrazin-2-yl)benzoate (1 g) was dissolved in a mixed solvent of acetic acid / methanol (28 ml / 14 mL), and palladium acetate (105 mg) and palladium / carbon (350 mg) were added. The atmosphere was replaced with hydrogen, and the mixture was stirred at room temperature overnight. The mixture was filtered through celite and the filtrate was evaporated to dryness to obtain 0.9 g of the title compound.

[0383] c) Preparation of tert-butyl (±) 3-(4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

[0384] Methyl (±) 4-(piperazin-2-yl)benzoate (480 mg) was added to a 50 mL two-necked flask, and dichloromethane (30 mL) and triethylamine (661.54 mg) were added. After nitrogen displacement protection, di-tert-butyl dicarbonate (475.59 mg) was added and stirred at room temperature for 1 hour. After quenching with water, the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and sanded. The mixture was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 300 mg of the title compound.

[0385] d) Preparation of tert-butyl (±)-4-((4-(tert-butoxycarbonyl)-2-(4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0386] tert-Butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (270.9 mg) was added to a 50 mL two-necked flask, and 1,2-dichloroethane (10 mL) was added, followed by tert-butyl (±)-3-(4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (300 mg). The mixture was replaced with nitrogen and cooled to 0°C in an ice bath. Sodium triacetoxyborohydride (396.9 mg) was added, and the mixture was stirred overnight at room temperature. After quenching with water, the mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and sanded, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (v / v)) to give 380 mg of the title compound.

[0387] e) Preparation of tert-butyl (±)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate

[0388] Add tert-butyl (±)-4-((4-(tert-butoxycarbonyl)-2-(4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (150 mg) to a 25 mL two-necked flask, followed by methanol (5 mL) and a 4M hydrogen chloride solution in 1,4-dioxane (5 mL). Replace the mixture with nitrogen and stir at room temperature for 2 h. Concentrate under reduced pressure to obtain 120 mg of the title compound.

[0389] f) Preparation of tert-butyl (±)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-propylpiperazin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate

[0390] Tert-butyl (±)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (70 mg) was added to a 15 mL sealed tube, and acetonitrile (8 mL), 1-bromopropane (52 mg), and triethylamine (86.1 mg) were added. The mixture was stirred at 50°C overnight. The reaction solution was concentrated under reduced pressure to prepare sand and purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 40 mg of the title compound.

[0391] g) Preparation of (±)4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-propylpiperazin-2-yl)benzoic acid

[0392] Tert-butyl (±)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-propylpiperazin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (40 mg) was dissolved in a mixed solvent of dichloromethane / methanol (2 mL / 2 mL), and 1N aqueous lithium hydroxide solution (1 mL) was added, and the mixture was stirred at 70°C for 1 hour. The reaction solution was directly dried by rotary evaporation, dissolved in water, and the pH was adjusted to neutral with dilute hydrochloric acid. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to prepare sand. The mixture was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 9 mg of the title compound.

[0393] 1 HNMR(400MHz,DMSO-d6)δ10.82(s,1H),7.96(s,2H),7.62(s,2H),7.25(t,J=2.7Hz ,1H),6.65(s,1H),6.44(s,1H),3.70(s,3H),3.56(d,J=11.9Hz,2H),3.25-3.13(m, 2H),2.70(t,J=9.2Hz,2H),2.41(s,3H),2.18(dd,J=18.8,11.5Hz,2H),1.98(d,J=7 .5Hz,2H),1.87(t,J=10.9Hz,1H),1.37(dt,J=12.0,6.1Hz,2H),0.85-0.80(m,3H).

[0394] LCMS m / z=422.2[M+1] +

[0395] Chiral SFC separation of the (±)4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-propylpiperazin-2-yl)benzoic acid enantiomers afforded 1-1,t r =2.06min and 1-2,t r = 2.34 min. (Specific separation method is as follows: chromatographic column: Lux Cellulose-4 4.6*50 mm, 3 μm; mobile phase A: supercritical CO2; mobile phase B: methanol; gradient: 10% to 50% for 2.0 minutes, 50% for 1.0 minute; detection wavelength: 220 nm)

[0396] 1-1,t r =2.06min

[0397] 1HNMR (400MHz, DMSO-d6) δ10.82(s,1H),7.97(d,J=8.3Hz,2H),7.69(d,J=6.7Hz,2H),7.25( t,J=2.7Hz,1H),6.66(s,1H),6.53-6.35(m,1H),3.71(s,3H),3.56(d,J=11.8Hz,1H),3.38( s,1H),3.23(d,J=11.8Hz,1H),2.71(t,J=10.0Hz,2H),2.63(d,J=11.4Hz,1H),2.42(s,3H), 2.26-2.10(m,3H),1.93(dt,J=21.0,10.9Hz,2H),1.47-1.30(m,2H),0.82(t,J=7.3Hz,3H).

[0398] 1-2,t r =2.34min

[0399] 1 HNMR (400MHz, DMSO-d6) δ10.82(s,1H),7.97(d,J=8.3Hz,2H),7.69(d,J=6.7Hz,2H),7.25(s ,1H),6.66(s,1H),6.52-6.35(m,1H),3.71(s,3H),3.56(d,J=11.8Hz,1H),3.39(d,J=10.4H z,1H),3.23(d,J=11.8Hz,1H),2.71(t,J=10.2Hz,2H),2.63(d,J=11.4Hz,1H),2.42(s,3H), 2.28-2.09(m,3H),1.93(dt,J=21.2,11.1Hz,2H),1.46-1.29(m,2H),0.82(t,J=7.3Hz,3H).

[0400] Example 2: (±)4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-propionylpiperazin-2-yl)benzoic acid

[0401] Prepare by referring to the preparation method of Example 1, except that 1-bromopropane in step f) is replaced by propionyl chloride.

[0402] 1HNMR (400MHz, DMSO-d6) δ12.94 (s, 1H), 10.85 (s, 1H), 8.01 (d, J = 6.4Hz, 2H), 7. 73(dd,J=16.2,7.7Hz,2H),7.27(s,1H),6.67(s,1H),6.42(d,J=8.7Hz,1H),4.2 6(s,1H),3.72(s,3H),3.57(s,2H),3.23(d,J=11.9Hz,2H),3.04-2.92(m,1H),2 .67-2.61(m,2H),2.43(s,3H),2.26(s,1H),1.99(s,2H),0.98(t,J=7.4Hz,3H).

[0403] LCMS m / z=436.2[M+1] +

[0404] Example 3: (±)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(oxetan-3-yl)piperazin-2-yl)benzoic acid

[0405] a) Preparation of tert-butyl (±)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(oxetan-3-yl)piperazin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate

[0406] Tert-butyl (±)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (70 mg) was dissolved in 1,2-dichloroethane (8 mL) and added to a 25 mL two-necked flask. Sodium triacetoxyborohydride (120.2 mg) was then added, and the mixture was cooled to 0°C in an ice bath. The mixture was purged with nitrogen for protection, and oxetane-3-one (20.44 mg) was added and stirred overnight. The reaction solution was concentrated under reduced pressure and sanded, and purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 50 mg of the title compound.

[0407] b) Preparation of (±)4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(oxetane-3-yl)piperazin-2-yl)benzoic acid

[0408] Tert-butyl (±)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(oxetane-3-yl)piperazin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (50 mg) was dissolved in a mixed solution of tetrahydrofuran / methanol (2 mL / 2 mL), and 1N aqueous lithium hydroxide solution (1 mL) was added, and the mixture was stirred at 70 ° C. for 3 h. The reaction solution was directly dried by rotary evaporation, dissolved in water, and the pH was adjusted to neutral with dilute hydrochloric acid. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to make sand. The mixture was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 22 mg of the title compound.

[0409] 1 HNMR(400MHz,DMSO-d6)δ10.83(s,1H),7.97(d,J=8.0Hz,2H),7.68(d,J=6.1Hz ,2H),7.25(s,1H),6.66(s,1H),6.43(s,1H),4.51-4.43(m,2H),4.40(t,J=5.8 Hz,2H),3.71(s,3H),3.58(d,J=11.8Hz,2H),3.24(d,J=11.8Hz,2H),2.67(s,1 H),2.66-2.55(m,2H),2.42(s,3H),2.24(t,J=10.6Hz,1H),1.92-1.81(m,2H).

[0410] LCMS m / z=436.2[M+1] + .

[0411] Example 4: (±)4-(4-(cyclopropylmethyl)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperazin-2-yl)benzoic acid

[0412] Prepare by referring to the preparation method of Example 1, except that 1-bromopropane in step f) is replaced by (bromomethyl)cyclopropane.

[0413] 1HNMR(400MHz,DMSO-d6)δ10.82(s,1H),7.97(d,J=8.2Hz,2H),7.69(s,2H),7.26(s,1H),6.66(s,1 H),6.45(s,1H),3.71(s,3H),3.56(d,J=11.8Hz,1H),3.23(d,J=11.7Hz,1H),2.84(dd,J=19.7,10 .8Hz,2H),2.64(d,J=11.5Hz,1H),2.42(s,3H),2.23(t,J=10.7Hz,1H),2.14(d,J=6.4Hz,2H),1.9 9(dt,J=22.0,11.1Hz,2H),1.24(s,1H),0.78(s,1H),0.40(d,J=7.8Hz,2H),0.04(d,J=7.8Hz,2H).

[0414] LCMS m / z=434.3[M+1] + .

[0415] Example 5: (±)4-(4-((2,2-difluorocyclopropyl)methyl)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperazin-2-yl)benzoic acid

[0416] The preparation method was carried out according to Example 1, except that 1-bromopropane in step f) was replaced by 2-(bromomethyl)-1,1-difluorocyclopropane.

[0417] 1 HNMR(400MHz,DMSO-d6)δ12.87(s,1H),10.84(s,1H),7.98(d,J=7.7Hz,2H),7.71(s,2H),7.2 6(t,J=2.5Hz,1H),6.66(s,1H),6.45(d,J=2.0Hz,1H),3.72(s,3H),3.57(d,J=11.1Hz,1H),3. 41(s,1H),3.24(d,J=11.8Hz,2H),2.78(d,J=15.2Hz,2H),2.66(d,J=11.2Hz,1H),2.43(s,3H) ,2.37-2.15(m,2H),2.15-1.93(m,2H),1.79(d,J=6.3Hz,1H),1.60-1.46(m,1H),1.12(s,1H).

[0418] LCMS m / z=470.3[M+1] + .

[0419] 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

[0420] The preparation method was carried out according to Example 1, except that 1-bromopropane in step f) was replaced with 1,1-difluoro-2-iodoethane.

[0421] 1 HNMR (400MHz, DMSO-d6) δ10.83(s,1H),7.97(d,J=8.2Hz,2H),7.68(d,J=6.5Hz,2H),7.25(t,J=2.7Hz, 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=10.6Hz,1H) ,3.22(d,J=11.9Hz,1H),2.78(dd,J=21.1,10.5Hz,2H),2.69-2.57(m,3H),2.42(s,3H),2.26(d,J=10.9Hz,3H).

[0422] LCMS m / z=444.2[M+1] + .

[0423] Chiral SFC separation of the (±)4-(4-(2,2-difluoroethyl)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperazin-2-yl)benzoic acid enantiomers afforded 6-1,t r =4.90min and 6-2,t r =6.20min. (Separation method: Chromatographic column: 4250*20mm, 10μm; Mobile phase A: supercritical CO2; Mobile phase B: methanol (+0.1% 7.0mol / L ammonia methanol); Flow rate: 70mL / min; Mobile phase ratio: A:B = 75:25; Detection wavelength: 214nm

[0424] 6-1,t r =4.90min

[0425] 1HNMR(400MHz,DMSO-d6)δ10.82(s,1H),7.96(d,J=8.0Hz,2H),7.65(s,2H) ,7.25(t,J=2.7Hz,1H),6.66(s,1H),6.43(s,1H),6.31-5.91(m,1H),3.71( s,3H),3.57(d,J=12.0Hz,1H),3.40(s,1H),3.22(d,J=11.8Hz,1H),2.78(d d,J=21.5,10.3Hz,2H),2.72-2.58(m,3H),2.42(s,3H),2.30-2.17(m,3H).

[0426] LCMS m / z=444.2[M+1] + .

[0427] 6-2,t r =6.20min

[0428] 1 HNMR(400MHz,DMSO-d6)δ12.90(s,1H),10.83(s,1H),7.99(d,J=8.4Hz,2H),7.70(d,J= 7.1Hz, 2H), 7.26 (t, J=2.7Hz, 1H), 6.66 (s, 1H), 6.44 (dd, J=2.8, 2.0Hz, 1H), 6.11 (tt, J= 55.7,4.3Hz,1H),3.71(s,3H),3.57(d,J=11.8Hz,1H),3.42(d,J=8.2Hz,1H),3.24(d,J= 11.8Hz,1H),2.82(d,J=10.8Hz,1H),2.79-2.59(m,4H),2.42(s,3H),2.31-2.14(m,3H).

[0429] LCMS m / z=444.2[M+1] + .

[0430] Example 7: (±)4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(oxetan-2-ylmethyl)piperazin-2-yl)benzoic acid

[0431] The preparation method was carried out according to Example 1, except that 1-bromopropane in step f) was replaced with 2-iodomethyloxetane.

[0432] 1HNMR(400MHz,DMSO)δ8.01(d,J=8.2Hz,2H),7.68(d,J=7.8Hz,2H),7.29(s,1H),6 .68(s,1H),6.47(s,1H),5.00(s,1H),4.64(d,J=5.0Hz,1H),4.56-4.46(m,2H),4. 34(s,1H),3.78(s,3H),3.62-3.52(m,2H),3.29(d,J=8.4Hz,2H),2.86(d,J=11.9H z,2H),2.73(s,1H),2.66(d,J=4.4Hz,3H),2.39(s,2H),2.13(s,1H),1.30(s,1H).

[0433] LCMS m / z=450[M+1] + .

[0434] Example 8: (±)4-(4-((1-fluorocyclopropyl)methyl)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperazin-2-yl)benzoic acid

[0435] a) Preparation of (1-fluorocyclopropyl)methanol

[0436] 1-Fluorocyclopropane-1-carboxylic acid (520 mg) was dissolved in tetrahydrofuran (20 mL), and the atmosphere was replaced with nitrogen. 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 obtain 420 mg of the title compound.

[0437] b) Preparation of (1-fluorocyclopropyl)methyl-4-methylbenzenesulfonate

[0438] (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 at room temperature overnight. The reaction solution was concentrated under reduced pressure and sanded. The mixture was purified by column chromatography (mobile phase: petroleum ether and ethyl acetate = 20 / 1 (V / V)) to obtain 230 mg of the title compound.

[0439] 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-carboxylate

[0440] tert-Butyl 5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (50 mg) and (1-fluorocyclopropyl)methyl-4-methylbenzenesulfonate (230 mg, 0.9 mmol) were added to a sealed tube, followed by N,N-dimethylformamide (10 mL) and sodium hydroxide (20 mg). The mixture was stirred at 70°C overnight. The reaction solution was cooled to room temperature and concentrated under reduced pressure to prepare sand. The mixture was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 12 mg of the title compound.

[0441] d) Preparation of (±)4-(4-((1-fluorocyclopropyl)methyl)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperazin-2-yl)benzoic acid

[0442] Tert-butyl (±)-4-((4-((1-fluorocyclopropyl)methyl)-2-(4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (12 mg) was dissolved in a mixed solution of anhydrous tetrahydrofuran (3 mL) and methanol (3 mL), and 1N aqueous lithium hydroxide solution (0.5 mL) was added. The mixture was heated to 70°C and reacted for 3 h. After dissolution with water, the pH was adjusted to neutral with dilute hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to prepare sand. The mixture was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 3.45 mg of the title compound.

[0443] 1 HNMR(400MHz,DMSO-d6)δ7.97(d,J=7.6Hz,2H),7.64(s,2H),7.32(d,J=3.1H z,1H),6.64(s,1H),6.44(s,1H),4.72(d,J=20.5Hz,2H),3.73(s,3H),3.52(d ,J=10.7Hz,2H),3.25-3.12(m,2H),2.80(s,1H),2.66(s,3H),2.33(s,1H),2 .12-1.91(m,2H),1.46(s,1H),1.04(d,J=19.0Hz,2H),0.87(d,J=7.0Hz,2H).

[0444] LCMS m / z=452.2[M+1] + .

[0445] 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

[0446] The preparation method was referred to Example 8, except that the (1-fluorocyclopropyl)methyl-4-methylbenzenesulfonate in step c) was replaced with 3,3,3-trifluoropropyl-4-methylbenzenesulfonate.

[0447] 1 HNMR(400MHz,DMSO-d6)δ12.87(s,1H),10.83(s,1H),7.98(d,J=8.1Hz,2H),7.71(s, 2H),7.28(s,1H),6.66(s,1H),6.44(s,1H),3.71(s,3H),3.57(d,J=11.8Hz,1H),3.4 9-3.39(m,2H),3.23(d,J=11.8Hz,2H),2.77(dd,J=19.2,10.5Hz,2H),2.69-2.59(m, 1H),2.46(d,J=10.1Hz,1H),2.42(s,3H),2.21(t,J=10.9Hz,1H),2.10-1.91(m,3H).

[0448] LCMS m / z=476.2[M+1] + .

[0449] 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 afford 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)

[0450] 9-1,tr=2.31min

[0451] 1HNMR (400MHz, DMSO-d6) δ10.82(s,1H),7.94(d,J=8.3Hz,2H),7.62(d,J=6.6Hz,2H),7. 25(t,J=2.7Hz,1H),6.66(s,1H),6.43(s,1H),3.71(s,3H),3.57(d,J=11.8Hz,2H),3.22 (d,J=11.8Hz,2H),2.84(q,J=7.2Hz,2H),2.76(dd,J=17.2,11.2Hz,2H),2.63(d,J=11. 5Hz,1H),2.45(d,J=9.8Hz,1H),2.42(s,3H),2.20(t,J=10.5Hz,1H),2.10-1.92(m,2H).

[0452] 9-2,t r =3.57min

[0453] 1 HNMR (400MHz, DMSO-d6) δ10.82(s,1H),7.94(d,J=8.3Hz,2H),7.61(d,J=6.3Hz,2H ),7.25(t,J=2.7Hz,1H),6.66(s,1H),6.47-6.38(m,1H),3.71(s,3H),3.57(d,J=11 .8Hz,2H),3.21(d,J=11.8Hz,2H),2.82(dd,J=14.5,7.2Hz,2H),2.77-2.69(m,2H), 2.63(d,J=11.5Hz,1H),2.45(d,J=9.7Hz,1H),2.42(s,3H),2.19(t,J=10.4Hz,1H), 2.01(dt,J=20.7,10.2Hz,2H).

[0454] 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

[0455] The preparation method was referred to Example 3, except that the oxetane-3-one in step a) was replaced with 3-(trifluoromethyl)cyclobutane-1-one.

[0456] 1HNMR(400MHz,DMSO-d6)δ10.83(s,1H),7.98(d,J=8.1Hz,2H),7.68(d,J=7.3Hz,2H) ,7.26(s,1H),6.66(s,1H),6.44(s,1H),3.71(s,3H),3.57(d,J=11.9Hz,1H),3.43(d ,J=8.7Hz,2H),3.24(d,J=12.0Hz,3H),3.20-3.07(m,3H),2.79(t,J=11.7Hz,2H),2 .62(d,J=11.1Hz,1H),2.46-2.37(m,4H),2.35(d,J=11.6Hz,1H),2.28-2.19(m,1H).

[0457] LCMS m / z=502.2[M+1] + .

[0458] The enantiomers of (±)4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(3-(trifluoromethyl)cyclobutyl)piperazin-2-yl)benzoic acid were resolved by chiral SFC to afford 10-1, t r =2.12min and 10-2,t r =3.03min. (Separation method: Chromatographic column: 250*20mm, 10μm; Mobile phase A: supercritical CO2; Mobile phase B: methanol (+0.1% 7.0mol / L ammonia methanol); A:B ratio: 75:25; Flow rate: 70mL / min; Detection wavelength: 214nm)

[0459] 10-1,t r =2.12min

[0460] 1 HNMR(400MHz,DMSO-d6)δ10.82(s,1H),7.96(d,J=8.2Hz,2H),7.67(s,2H),7.2 5(s,1H),6.65(s,1H),6.43(s,1H),3.70(s,3H),3.57(d,J=11.7Hz,2H),3.23( d,J=11.7Hz,2H),2.84-2.74(m,1H),2.65(d,J=13.1Hz,3H),2.42(s,3H),2.18 (dd,J=18.3,9.4Hz,3H),2.03-1.93(m,1H),1.83(dd,J=19.4,8.6Hz,3H).LCMS m / z = 502.2 [M + 1] + .

[0461] 10-2,t r =3.03min

[0462] 1 HNMR (400MHz, DMSO-d6) δ10.82 (s, 1H), 7.95 (d, J = 8.0Hz, 2H), 7.65 (s, 2H), 7. 25(s,1H),6.65(s,1H),6.43(s,1H),3.70(s,3H),3.57(d,J=11.8Hz,2H),3.22 (d,J=11.9Hz,2H),2.83(d,J=9.1Hz,1H),2.65(d,J=12.1Hz,3H),2.42(s,3H) ,2.18(d,J=26.6Hz,3H),2.03-1.93(m,1H),1.83(dd,J=19.6,9.5Hz,3H).LCMS m / z=502.2[M+1] + .

[0463] 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.

[0464] The preparation method was referred to Example 8, except that the (1-fluorocyclopropyl)methyl-4-methylbenzenesulfonate in step c) was replaced with 2,2,2-trifluoroethyl trifluoromethanesulfonate.

[0465] 1 HNMR(400MHz,DMSO-d6)δ10.83(s,1H),7.96(d,J=8.4Hz,2H),7.66(d,J=7.5Hz,2 H),7.26(t,J=2.7Hz,1H),6.66(s,1H),6.44(dd,J=2.8,2.0Hz,1H),3.71(s,3H),3 .57(d,J=11.8Hz,1H),3.47-3.40(m,1H),3.22(s,1H),3.19-3.07(m,2H),2.79(t, J=12.1Hz,2H),2.67(d,J=11.5Hz,1H),2.46-2.31(m,5H),2.23(t,J=10.7Hz,1H).

[0466] LCMS m / z=462.2[M+1]+ .

[0467] Chiral SFC separation of the (±)4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(2,2,2-trifluoroethyl)piperazin-2-yl)benzoic acid enantiomers afforded 11-1,t r =1.08min and 11-2,t r =2.24min. (Separation method: Chromatographic column: 250*20mm, 10μm; Mobile phase A: supercritical CO2; Mobile phase B: MEOH (+0.1% 7.0mol / L ammonia methanol); A:B ratio: 70:30; Flow rate: 100mL / min; Detection wavelength: 214nm)

[0468] 11-1,t r =1.08min

[0469] LCMS m / z=462.2[M+1] + .

[0470] 1 HNMR(400MHz,DMSO-d6)δ10.83(s,1H),7.98(d,J=8.4Hz,2H),7.68(d,J=7.5Hz,2H) ,7.26(t,J=2.7Hz,1H),6.66(s,1H),6.44(dd,J=2.8,2.0Hz,1H),3.71(s,3H),3.57 (d,J=11.8Hz,1H),3.47-3.40(m,1H),3.26-3.20(m,1H),3.19-3.07(m,2H),2.79(t ,J=12.1Hz,2H),2.62(d,J=11.5Hz,1H),2.46-2.31(m,5H),2.23(t,J=10.7Hz,1H).

[0471] 11-2,t r =2.24min

[0472] 1HNMR(400MHz,DMSO-d6)δ10.83(s,1H),7.98(d,J=8.4Hz,2H),7.69(d,J=7.3Hz,2H ),7.26(t,J=2.7Hz,1H),6.66(s,1H),6.47-6.37(m,1H),3.71(s,3H),3.57(d,J=1 1.8Hz,1H),3.46-3.40(m,1H),3.24(d,J=11.9Hz,1H),3.19-3.08(m,2H),2.79(t, J=11.8Hz,2H),2.62(d,J=11.4Hz,1H),2.46-2.31(m,5H),2.23(t,J=10.5Hz,1H).

[0473] LCMS m / z=462.2[M+1] + .

[0474] Example 12: (±)4-(4-(3,3-difluorocyclobutyl)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperazin-2-yl)benzoic acid

[0475] The preparation method was referred to Example 3, except that the oxetane-3-one in step a) was replaced with 3,3-difluorocyclobutane-1-one.

[0476] 1 HNMR (400MHz, DMSO-d6) δ10.82(s,1H),7.97(d,J=7.8Hz,2H),7.69(s,2H),7.19(s,1H),6.66(s,1H),6.43(s,1H),3.71(s,3H),3.58(d,J=12.4 Hz,1H),3.35(s,1H),3.23(d,J=11.9Hz,1H),2.67(s,3H),2.61(s,1H), 2.42(s,2H),2.33(s,1H),2.21(s,2H),2.07-1.94(m,2H),1.45(s,3H).

[0477] LCMS m / z=470.2[M+1] + .

[0478] Example 13: 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 and 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

[0479] a) Preparation of tert-butyl (±) 3-(4-(methoxycarbonyl)phenyl)-4-oxopiperidine-1-carboxylate

[0480] Tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (50 g), (4-(methoxycarbonyl)phenyl)boric acid (48.52 g), nickel (II) trifluoromethanesulfonate (3.21 g), 1,10-phenanthroline (1.62 g), potassium carbonate (49.62 g), and 1,4-dioxane (500 mL) were added to a reaction flask, replaced with nitrogen for protection, and stirred at 80°C for 16 h. The reaction solution was diluted with water (500 mL) and extracted with ethyl acetate (3×500 mL). The organic phases were separated, combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to make sand. The mixture was purified by column chromatography (mobile phase: petroleum ether, ethyl acetate = 5 / 1 (V / V)) to obtain 32 g of the title compound.

[0481] 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

[0482] Tert-butyl (±) 3-(4-(methoxycarbonyl)phenyl)-4-oxopiperidine-1-carboxylate (30 g) was added to a reaction flask, and methanol (300 mL) was added. Under nitrogen protection, sodium borohydride (10.21 g) was added in batches at 0°C, and stirred at room temperature for 1 hour. Water (500 mL) was added under an ice bath to quench the reaction, and the mixture was extracted with ethyl acetate (3×500 mL). The liquids were separated, and the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to make sand. The title compounds were purified by column chromatography (mobile phase: petroleum ether, ethyl acetate = 3 / 1 (V / V)) according to the corresponding elution gradient to obtain 8.9 g and 21.3 g, respectively.

[0483] (±)-rel-(3S,4R)-tert-Butyl 4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate

[0484] 1 HNMR (400MHz, DMSO-d6) δ7.88(d,J=8.4Hz,2H),7.43(d,J=8.4Hz,2H),4.75(d,J=4.2Hz,1H),3.99(d,J=7.8Hz,1H),3.84(s ,3H),3.77(d,J=12.4Hz,2H),3.49(d,J=14.2Hz,1H),3.16(s,1H),2.83(d,J=11.2Hz,1H),1.71-1.64(m,2H),1.39(s,9H).

[0485] (±)-rel-(3S,4S)-tert-butyl 4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate

[0486] 1 HNMR (400MHz, DMSO-d6) δ7.90(d,J=8.3Hz,2H),7.42(d,J=8.3Hz,2H),4.71(d,J=6.0Hz,1H),4.03(q,J=7.1Hz,1H),3.97 (d,J=11.8Hz,1H),3.85(s,3H),3.83-3.72(m,2H),2.89(s,2H),1.99(s,1H),1.89(dd,J=12.4,3.8Hz,1H),1.40(s,9H).

[0487] 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

[0488] a) Preparation of (±)-rel-(3S,4S)-4-((1-(tert-butyloxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0489] tert-Butyl 4-hydroxy-5-methoxy-7-methyl-1H-indole-1-carboxylate (10.06 g), tert-butyl (±)-rel-(3S,4R)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate (8.4 g), triphenylphosphine (23.82 g), and anhydrous tetrahydrofuran (200 mL) were added to a three-necked flask, replaced with nitrogen for protection, and diisopropyl azodicarboxylate (18.33 g) was added dropwise at 0°C. The reaction system was warmed to room temperature and reacted for 16 hours. The reaction was diluted with water (500 mL) and extracted with ethyl acetate (3×200 mL). The liquids were separated, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to make sand. The product was purified by column chromatography (mobile phase: petroleum ether, ethyl acetate = 5 / 1 (V / V)) to obtain 22 g of the title compound.

[0490] 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

[0491] Dissolve (±)-rel-(3S,4S)-4-((1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (10 g) in 4 M hydrochloric acid in 1,4-dioxane (70 mL), stir at room temperature for 4 hours, and concentrate under reduced pressure to obtain the residue, which is 16 g of the title compound.

[0492] LCMS m / z=495.4[M+1] + .

[0493] 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

[0494] (±)-rel-(3S,4S)-5-methoxy-4-((3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (8 g) and N,N-diisopropylethylamine (8.4 mL) were added to a reaction flask, tetrahydrofuran (80 mL) was added, and 2,2-difluoroethyl trifluoromethanesulfonate (10.4 g) was added. The mixture was replaced 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 and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate 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 12.4 g of the title compound.

[0495] 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

[0496] (±)-rel-(3S,4S)-4-((1-(2,2-difluoroethyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (6.2 g) was added to a reaction flask, and methanol (120 mL), lithium hydroxide (7.8 g), and water (40 mL) were added. The mixture was replaced with nitrogen and stirred at 70°C for 16 hours. The reaction solution was adjusted to pH = 6 with dilute hydrochloric acid (3 M), diluted with water (100 mL) and extracted with ethyl acetate (3×500 mL). The organic phases were separated, and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to prepare sand and purified by column chromatography (mobile phase: dichloromethane methanol 5 / 1 (V / V)) to obtain 7.6 g of the title compound enantiomer.

[0497] LCMS m / z=445[M+1] + .

[0498] 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 give 4-((3S,4S)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid (13a-1,t r =1.19 min) and 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid (13a-2,t r =1.95min), 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 of Experimental Example 6. (Separation method: chromatographic column: 250*20mm, 10μm; Mobile phase A: supercritical CO2; Mobile phase B: methanol (+0.1% 7.0mol / L ammonia methanol); A:B ratio: 75:25; Flow rate: 100mL / min; Detection wavelength: 214nm)

[0499] 4-((3S,4S)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid

[0500] 1 HNMR(400MHz,DMSO-d6)δ10.83(s,1H),7.90(d,J=8.2Hz,2H),7.56(d,J=8 .1Hz,2H),7.20-7.13(m,1H),6.62(s,1H),6.30-5.96(m,2H),4.48-4.38(m ,1H),3.60(s,3H),3.29(s,1H),3.12(s,1H),2.93(dd,J=23.7,11.6Hz,2H ),2.78(t,J=15.5Hz,2H),2.34(d,J=8.9Hz,3H),2.28(s,1H),1.70(s,2H).

[0501] LCMS m / z=445.1[M+1] + .

[0502] 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid

[0503] 1 HNMR (400MHz, DMSO-d6) δ10.83(s,1H),7.88(d,J=8.1Hz,2H),7.51(d,J=8.1Hz,2H),7.16(t,J=2.7Hz,1H),6.62(s,1H),6.29-5.97(m,2H),4.51 -4.39(m,1H),3.60(s,3H),3.38(d,J=3.5Hz,1H),3.09(s,1H),2.95-2.8 7(m,2H),2.75(d,J=15.6Hz,2H),2.36(s,3H),2.26(s,1H),1.69(s,2H).

[0504] LCMS m / z=445.1[M+1] + .

[0505] 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

[0506] Prepare with reference to the preparation method of Example 13a, except that the (±)-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.

[0507] Chiral SFC separation of the (±)-rel-(3S,4R)-4-(1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid enantiomers afforded 13b-1, r =1.29min and 13b-2,t r =4.00min(Separation method: Chromatographic column: 250*20mm10μm; Mobile phase A: supercritical CO2; Mobile phase B: methanol (+0.1% 7.0mol / L ammonia methanol); A:B ratio: 75:25; Flow rate: 100mL / min; Detection wavelength: 214nm)

[0508] 13b-1,t r =1.29min

[0509] 1 HNMR (400MHz, DMSO-d6) δ10.83(s,1H),7.89(d,J=8.3Hz,2H),7.57(d,J=8.4Hz,2H),7.09(t,J=2.7Hz,1H),6. 61(s,1H),6.38-5.99(m,1H),5.73(s,1H),4.65(s,1H),3.55(s,3H),3.18(dd,J=22.7,10.9Hz,2H),2.88(dd,J =17.7,12.0Hz,4H),2.67(s,1H),2.34(s,3H),1.66(s,2H).

[0510] LCMS m / z=445.1[M+1] + .

[0511] 13b-2,t r =4.00min

[0512] 1 HNMR(400MHz,DMSO-d6)δ13.09-12.27(m,1H),10.83(s,1H),7.90(d,J=8.3H z,2H),7.58(d,J=8.3Hz,2H),7.09(t,J=2.8Hz,1H),6.61(s,1H),6.37-6.02 (m,1H),5.77-5.71(m,1H),4.66(s,1H),3.55(s,3H),3.21(dd,J=24.5,13.9 Hz,2H),2.96-2.83(m,4H),2.66(d,J=10.6Hz,1H),2.34(s,3H),1.66(s,2H).

[0513] LCMS m / z=445.1[M+1] + .

[0514] 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 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 and 4-((3R,4S)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid

[0515] 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

[0516] 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

[0517] Reference Example 13 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: (±)-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 (6.3 g) was added. N-Diisopropylethylamine (6.6 mL) was added to the reaction flask, followed by tetrahydrofuran (80 mL), and then 2,2,2-trifluoroethyl trifluoromethanesulfonate (8.9 g). The mixture was replaced 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 liquids were separated, and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to make sand, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to obtain 5 g of the title compound.

[0518] LCMS m / z=577.1[M+H] + .

[0519] 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

[0520] (±)-rel-(3S,4S)-5-methoxy-4-((3-(4-(methoxycarbonyl)phenyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (5 g) was added to a reaction flask, and methanol (120 mL), lithium hydroxide (6.25 g), and water (100 mL) were added. The mixture was replaced with nitrogen and stirred at 70°C for 16 hours. The reaction solution was adjusted to pH = 6 with dilute hydrochloric acid (3 M), diluted with water (100 mL) and extracted with ethyl acetate (3×500 mL). The organic phases were separated, and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to prepare sand and purified by column chromatography (mobile phase: dichloromethane methanol 5 / 1 (V / V)) to obtain 1.7 g of the title compound enantiomer.

[0521] Chiral SFC resolution of the enantiomers 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 afforded 4-((3S,4S)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid (14a-1, t r =1.87 min) and 4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid (14a-2,t r =2.73min), 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 of Experimental Example 7. (Separation method: chromatographic column: 250*25mm, 10μm; Mobile phase A: supercritical CO2; Mobile phase B: methanol (+0.1% 7.0mol / L ammonia methanol); A:B: 75:25; Flow rate: 100mL / min; Detection wavelength: 214nm)

[0522] 14a-1,t r =1.87min

[0523] 1 HNMR(400MHz,DMSO-d6)δ10.84(s,1H),7.89(d,J=8.2Hz,2H),7.55(d,J=8.2Hz,2H) ,7.17(t,J=2.8Hz,1H),6.63(s,1H),6.21-6.16(m,1H),4.47(dd,J=16.1,7.7Hz,1H) ,3.60(s,3H),3.24(d,J=3.5Hz,2H),3.16-3.08(m,1H),2.94(t,J=12.7Hz,2H),2.67 (t,J=11.2Hz,1H),2.47-2.41(m,1H),2.34(d,J=11.4Hz,3H),1.70(d,J=3.6Hz,2H).

[0524] LCMS m / z=463.1[M+H] + .

[0525] 14a-2,t r =2.73min

[0526] 1 HNMR(400MHz,DMSO-d6)δ10.81(s,1H),7.86(d,J=8.2Hz,2H),7.51(d,J=8.2Hz,2H ),7.14(t,J=2.8Hz,1H),6.59(s,1H),6.15(dd,J=3.0,2.0Hz,1H),4.44(dd,J=16. 1,7.8Hz,1H),3.57(s,3H),3.20(d,J=3.6Hz,2H),3.12-3.05(m,1H),2.89(d,J=13 .0Hz,2H),2.64(t,J=11.3Hz,1H),2.42(s,1H),2.32(s,3H),1.67(d,J=3.5Hz,2H).

[0527] LCMS m / z=463.1[M+H] + .

[0528] 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

[0529] Prepare with reference to the preparation method of Example 14a, except that the (±)-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.

[0530] 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 afforded 14b-1, r =1.06min and 14b-2,t r =2.37min(Separation method: Chromatographic column: 250*20mm, 10μm; Mobile phase A: supercritical CO2; Mobile phase B: methanol (+0.1% 7.0mol / L ammonia methanol); A:B ratio: 75:25; Flow rate: 100mL / min; Detection wavelength: 214nm)

[0531] 14b-1,t r =1.06min

[0532] 1 HNMR(400MHz,DMSO-d6)δ10.83(s,1H),7.89(d,J=8.3Hz,2H),7.56(d,J=8.3Hz,2H),7.09(t,J=2.8Hz,1H),6.61(s,1H),5.71(dd,J=3.0,2.0Hz,1H),4.65(d,J=2.5Hz,1H),3.55(s,3H),3.42-3.36(m,2H),3.30-3.25(m,2H),3.14-3.07(m,1H),2.89(d,J=7.6Hz,1H),2.68(d,J=10.9Hz,1H),2.34(s,3H),1.65(s,2H).

[0533] LCMS m / z=463.1[M+H] + .

[0534] 14b-2,t r =2.37min

[0535] 1 HNMR(400MHz,DMSO-d6)δ10.84(s,1H),7.90(d,J=8.3Hz,2H),7.58(d,J=8.3Hz,2H),7.09(t,J=2.7Hz,1H),6.61(s,1H),5.72(dd,J=2.9,2.0Hz,1H),4.66(d,J=2.4Hz,1H),3.55(s,3H),3.44-3.36(m,2H),3.29(d,J=5.9Hz,2H),3.12(td,J=10.6,5.6Hz,1H),2.89(d,J=7.8Hz,1H),2.69(d,J=11.1Hz,1H),2.34(s,3H),1.66(s,2H).

[0536] LCMS m / z=463.1[M+H] + .

[0537] 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 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 and 4-((3R,4S)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid

[0538] 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

[0539] The preparation method was referred to Example 13a, except that 2,2-difluoroethyl trifluoromethanesulfonate in step c) was replaced with 3,3,3-trifluoropropyl trifluoromethanesulfonate.

[0540] 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 afforded 15a-1,t r =1.25min and 15a-2,t r =2.00min(Separation method: Chromatographic column: 250*20mm, 10μm; Mobile phase A: supercritical CO2; Mobile phase B: methanol (+0.1% 7.0mol / L ammonia methanol); A:B ratio: 75:25; Flow rate: 100mL / min; Detection wavelength: 214nm)

[0541] 15a-1,t r =1.25min

[0542] 1HNMR (400MHz, DMSO-d6) δ10.83(s,1H),7.91(d,J=8.1Hz,2H),7.58(d,J=8.1Hz,2H),7.17(t ,J=2.4Hz,1H),6.63(s,1H),6.17(s,1H),4.46(td,J=9.5,4.8Hz,1H),3.60(s,3H),3.12(td ,J=10.2,3.6Hz,1H),2.89(dd,J=24.1,10.3Hz,2H),2.57(dd,J=9.6,6.7Hz,2H),2.49(d,J= 13.4Hz, 2H), 2.36 (s, 3H), 2.30 (d, J = 11.0Hz, 1H), 2.07 (t, J = 10.1Hz, 1H), 1.79-1.64 (m, 2H).

[0543] LCMS m / z=475.0[MH] + .

[0544] 15a-2,t r =2.00min

[0545] 1 HNMR (400MHz, DMSO-d6) δ10.83(s,1H),7.91(d,J=8.1Hz,2H),7.58(d,J=8.2Hz,2H),7. 17(t,J=2.6Hz,1H),6.63(s,1H),6.17(s,1H),4.46(td,J=9.5,4.8Hz,1H),3.60(s,3H) ,3.12(td,J=10.2,3.7Hz,1H),2.93-2.83(m,2H),2.62-2.53(m,2H),2.52-2.45(m,2H) ,2.36(s,3H),2.31(t,J=11.1Hz,1H),2.05(dt,J=15.0,7.5Hz,1H),1.80-1.62(m,2H).

[0546] LCMS m / z=475.0[MH] + .

[0547] 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

[0548] The preparation method was referred to Example 13b, except that 2,2-difluoroethyl trifluoromethanesulfonate in step c) was replaced with 2,2,2-trifluoropropyl trifluoromethanesulfonate.

[0549] 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 afforded 15b-1, r =0.91min and 15b-2,t r =2.35min(Separation method: Chromatographic column: 250*20mm, 10μm; Mobile phase A: supercritical CO2; Mobile phase B: methanol (+0.1% 7.0mol / L ammonia methanol); A:B ratio: 75:25; Flow rate: 100mL / min; Detection wavelength: 214nm)

[0550] 15b-1,t r =0.91min

[0551] 1 HNMR(400MHz,DMSO-d6)δ12.88-12.26(m,1H),10.83(s,1H),7.90(d,J=8.3Hz,2H), 7.60(d,J=8.3Hz,2H),7.10(t,J=2.7Hz,1H),6.61(s,1H),5.76(s,1H),4.67(d,J=2 .5Hz,1H),3.54(s,3H),3.29(s,1H),3.24(s,1H),3.00(t,J=10.8Hz,1H),2.84(d,J =9.4Hz,1H),2.73-2.54(m,5H),2.33(dd,J=5.6,1.0Hz,3H),1.67(t,J=14.4Hz,2H).

[0552] 15b-2,tr=2.35min

[0553] 1HNMR(400MHz,DMSO-d6)δ12.66-11.86(m,1H),10.83(s,1H),7.90(d,J=7.9 Hz,2H),7.60(d,J=8.3Hz,2H),7.10(t,J=2.7Hz,1H),6.61(s,1H),5.76(s,1 H),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=24.2,22.4Hz,5H),2.37-2.32(m,3H),1.68(s,2H).

[0554] 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

[0555] a) Preparation of 1-bromo-2-methoxy-4-methyl-5-nitrobenzene

[0556] Dissolve 1-bromo-2-fluoro-4-methyl-5-nitrobenzene (100 g) in methanol (1 L), add sodium methoxide (25.6 g), replace with nitrogen, stir at 30°C for 16 hours, filter the reaction solution, and concentrate the filtrate under reduced pressure to obtain 73 g of the title compound.

[0557] b) Preparation of 4-bromo-5-methoxy-7-methyl-1H-indole

[0558] 1-Bromo-2-methoxy-4-methyl-5-nitrobenzene (73 g) was added to a 2L three-necked flask, and tetrahydrofuran (730 mL) was added. Under nitrogen protection, the temperature was lowered to -40°C, and vinylmagnesium bromide tetrahydrofuran solution (1750 mL, 1.3 M) was slowly added dropwise. The reaction solution was stirred at -40°C for 3 hours, quenched with aqueous ammonium chloride solution (200 mL), and extracted with ethyl acetate (3*200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to make sand. The mixture was purified by column chromatography (mobile phase: petroleum ether ethyl acetate = 20 / 1 (V / V)) to obtain 8.5 g of the title compound.

[0559] c) Preparation of 4-bromo-5-methoxy-7-methyl-1-toluenesulfonyl-1H-indole

[0560] 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 temperature was lowered to 0°C, p-toluenesulfonyl chloride (10.1 g) was added, and the mixture was 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 sand. The mixture was purified by column chromatography (mobile phase: petroleum ether, ethyl acetate = 5 / 1 (V / V)) to obtain 8.1 g of the title compound.

[0561] d) Preparation of S-(5-methoxy-7-methyl-1-toluenesulfonyl-1H-indol-4-yl)ethanesulfonate

[0562] S-(5-methoxy-7-methyl-1-tolyl-1H-indol-4-yl)ethanesulfonate (8 g), potassium thioacetate (2.55 g), tris(dibenzylidene-BASE acetone)dipalladium (9.29 g), a solution of 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (17.6 g), N,N-diisopropylethylamine (7.87 g), and 1,4-dioxane (120 mL) were added to a reaction flask and heated in a microwave at 140 ° C for 2 hours. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (300 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to make sand and purified by column chromatography (mobile phase: petroleum ether ethyl acetate = 5 / 1 (V / V)) to obtain 2.6 g of the title compound.

[0563] e) Preparation of 5-methoxy-7-methyl-1-toluenesulfonyl-1H-indole-4-thiol

[0564] 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 nitrogen was replaced for protection. The mixture was stirred at room temperature for 1 hour, and the reaction solution was diluted with 1N dilute hydrochloric acid (10 mL) and water (30 mL). The reaction solution was extracted with ethyl acetate (60 mL), and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 260 mg of the title compound.

[0565] LCMS m / z=348[M+1] + .

[0566] f) Preparation of (±)tert-butyl-3-(4-(methoxycarbonyl)phenyl)-4-(2-toluenesulfonylhydrazone)piperidine-1-carboxylate

[0567] Tert-butyl (±) 3-(4-(methoxycarbonyl)phenyl)-4-oxopiperidine-1-carboxylate (2.194 g) and 4-methylbenzenesulfonylhydrazide (1.838 g) were added to a reaction flask, followed by methanol (35 mL). The mixture was replaced with nitrogen and stirred at room temperature for 16 hours. The mixture was concentrated and evaporated to dryness under reduced pressure. The residue was purified by a reverse phase column (WelFlash C18-I, Regular C18 20-40 μm, 330 g; mobile phase A: 10 mmol formic acid / H2O, B: MeCN; flow rate: 150 mL / min; isocratic elution: 77.5% MeCN) to obtain 0.9 g of the title compound.

[0568] g) Preparation of tert-butyl (±)4-((5-methoxy-7-methyl-1-tolyl-1H-indol-4-yl)thio)-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate

[0569] 5-Methoxy-7-methyl-1-tosyl-1H-indole-4-thiol (260 mg), cesium carbonate (856 mg), 1,4-dioxane (10 mL), and (±) tert-butyl-3-(4-(methoxycarbonyl)phenyl)-4-(2-tosylhydrazone)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) and extracted with ethyl acetate (30 mL x 3). 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 prepare sand. The mixture was purified by column chromatography (mobile phase: petroleum ether, ethyl acetate = 5 / 1 (V / V)) to give 470 mg of the title compound.

[0570] h) Preparation of methyl (±) 4-(4-((5-methoxy-7-methyl-1-tolyl-1H-indol-4-yl)thio)piperidin-3-yl)benzoate

[0571] Tert-butyl (±)-4-((5-methoxy-7-methyl-1-tolyl-1H-indol-4-yl)thio)-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate (470 mg) was dissolved in 4 M hydrochloric acid solution in 1,4-dioxane (5.0 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain 220 mg of the title compound.

[0572] 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

[0573] Methyl (±) 4-(4-((5-methoxy-7-methyl-1-tolyl-1H-indol-4-yl)thio)piperidin-3-yl)benzoate (200 mg), N,N-diisopropylethylamine (226 mg), anhydrous tetrahydrofuran (10 mL), and 2,2-difluoroethyl trifluoromethanesulfonate (227 mg) were stirred at 70 ° C. for 2 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure and sanded, and purified by column chromatography (mobile phase: petroleum ether, ethyl acetate = 5 / 1 (V / V)) to give 190 mg of a diastereomeric mixture.

[0574] Chiral SFC separation of (±) methyl 4-(1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1-tolyl-1H-indol-4-yl)thio)piperidin-3-yl)benzoate afforded peaks -1, t r =2.24min, 64mg; Peak-2, t r =2.65min, 61mg; Peak-3, t r =2.55min, 60mg; Peak-4, t r =3.38min, 80mg (Separation method: Chromatographic column: 250*20mm, 10μm; Mobile phase A: supercritical CO2; Mobile phase B: methanol (+0.1% 7.0mol / L ammonia methanol); A:B ratio: 70:30; Flow rate: 100mL / min; Detection wavelength: 214nm)

[0575] Peak-1,t r =2.24min

[0576] 1HNMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 3.8 Hz, 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).

[0577] Peak - 2, t r = 2.65 min

[0578] 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).

[0579] Peak - 3, t r = 2.55 min

[0580] 1HNMR(400MHz, CDCl3)δ7.90(d,J=8.4Hz,2H),7.60(d,J=3.8Hz,1H),7.46(d,J=8.4Hz,2H), 7.33(d,J=8.2Hz,2H),7.19(d,J=8.2Hz,2H),6.49(d,J=3.8Hz,2H),5.90(tt,J=55.8,4.4Hz ,1H),3.92(s,3H),3.78-3.68(m,4H),3.39-3.31(m,1H),3.11(t,J=10.6Hz,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).

[0581] Peak-4,t r =3.38min

[0582] 1 HNMR(400MHz, CDCl3) δ7.89(d,J=8.4Hz,2H),7.60(d,J=3.8Hz,1H),7.46(d,J=8.4Hz,2H), 7.33(d,J=8.2Hz,2H),7.19(d,J=8.2Hz,2H),6.49(d,J=3.8Hz,2H),5.90(tt,J=55.8,4.4Hz ,1H),3.92(s,3H),3.78-3.69(m,4H),3.40-3.31(m,1H),3.12(t,J=10.6Hz,1H),2.99-2.82 (m,4H),2.67-2.64(m,1H),2.50(s,3H),2.35(s,3H),1.96-1.90(m,1H),1.78-1.74(m,1H).

[0583] j) Preparation of 4-((3S,4S)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)thio)piperidin-3-yl)benzoic acid, 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)thio)piperidin-3-yl)benzoic acid, 4-((3S,4R)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)thio)piperidin-3-yl)benzoic acid and 4-((3R,4S)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)thio)piperidin-3-yl)benzoic acid

[0584] Referring to step d) of Example 13a, the title four compounds were obtained respectively. The chiral HPLC analysis showed peak 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.

[0585] 16-1, t r =3.20min

[0586] 1 HNMR(400MHz,DMSO-d6)δ11.00(s,1H),7.86(d,J=8.2Hz,2H),7.40(d,J=8.0Hz, 2H),7.29(t,J=2.8Hz,1H),6.71(s,1H),6.32-6.29(m,1H),6.08(dd,J=57.9,53 .6Hz,1H),3.75(s,3H),2.85(dd,J=27.0,11.8Hz,4H),2.75-2.62(m,2H),2.44( s,3H),2.30(dd,J=19.8,8.3Hz,1H),2.15(t,J=11.6Hz,1H),1.67-1.47(m,2H).

[0587] 16-2, t r =3.60min

[0588] 1 HNMR(400MHz,DMSO-d6)δ11.01(s,1H),7.86(d,J=8.1Hz,2H),7.38(d,J=8.0 Hz,2H),7.30(t,J=2.8Hz,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=20.7,9.9Hz,1H),2.14(t,J=10.7Hz,1H),1.57(dd,J=35.0,9.4Hz,2H).

[0589] 16-3, t r =3.72min

[0590] 1HNMR(400MHz, DMSO-d6)δ10.98(s,1H),7.85(dd,J=14.8,8.2Hz,2H),7.43(d,J=8.1H z,2H),7.26(t,J=2.8Hz,1H),6.67(s,1H),6.34-5.95(m,2H),3.74(d,J=3.9Hz,1H),3 .69(s,3H),3.03(t,J=10.8Hz,2H),2.92(d,J=8.7Hz,2H),2.86-2.77(m,2H),2.54(d ,J=12.8Hz,1H),2.41(d,J=8.5Hz,3H),1.77(d,J=6.6Hz,1H),1.48(d,J=11.0Hz,1H).

[0591] 16-4, t r =5.48min

[0592] 1 HNMR(400MHz, DMSO-d6)δ10.98(s,1H),7.84(dd,J=14.4,8.3Hz,2H),7.42(d,J=8.0H z,2H),7.26(t,J=2.8Hz,1H),6.67(s,1H),6.34-5.99(m,2H),3.74(d,J=3.8Hz,1H),3 .70(s,3H),3.03(t,J=10.7Hz,2H),2.93(t,J=10.0Hz,2H),2.87-2.76(m,2H),2.54(d ,J=11.2Hz,1H),2.41(d,J=9.8Hz,3H),1.77(d,J=8.3Hz,1H),1.48(d,J=10.5Hz,1H).

[0593] 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

[0594] a) Preparation of 5-hydroxy-7-methyl-1H-indole-4-carbaldehyde

[0595] Tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (5.0 g) and dichloromethane (120 mL) were added to a two-necked flask, replaced with nitrogen, and aluminum chloride (23.04 g) was added in batches under ice bath and stirred for 10 minutes. The mixture was stirred at 40°C overnight. After the reaction cooled to room temperature, it was slowly poured into ice water and quenched with 3N dilute hydrochloric acid aqueous solution. The reaction was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to prepare sand. The mixture was purified by column chromatography (mobile phase: petroleum ether / dichloromethane = 3 / 7 (V / V)) to obtain 1.4 g of the title compound.

[0596] b) Preparation of tert-butyl 4-formyl-5-hydroxy-7-methyl-1H-indole-1-carboxylate

[0597] 5-Hydroxy-7-methyl-1H-indole-4-carbaldehyde (1.4 g), dichloromethane (40 mL), di-tert-butyl dicarbonate (5.23 g), and 4-dimethylaminopyridine (390 mg) were added to a reaction flask, replaced with nitrogen, and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to prepare sand, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 6 / 1 (v / v)) to obtain 2.03 g of the title compound.

[0598] c) Preparation of tert-butyl 4-formyl-5-(methoxy-d3)-7-methyl-1H-indole-1-carboxylate

[0599] To the mixture of tert-butyl 4-formyl-5-hydroxy-7-methyl-1H-indole-1-carboxylate (0.4 g), N,N-dimethylformamide (20 mL), potassium carbonate (602.4 mg) and deuterated iodomethane (631.8 mg) were stirred at room temperature overnight. Ethyl acetate and water were added and the mixture was extracted. The organic phases were combined and dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to prepare sand and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 9 / 1 (v / v)) to give 375 mg of the title compound.

[0600] d) Preparation of tert-butyl 4-hydroxy-5-(methoxy-d3)-7-methyl-1H-indole-1-carboxylate

[0601] Tert-butyl 4-formyl-5-(methoxy-d3)-7-methyl-1H-indole-1-carboxylate (350 mg), tetrahydrofuran (10 mL), and methanol (25 mL) were added to a reaction flask, and hydrogen peroxide (1.75 mL) was added dropwise under an ice-water bath, followed by concentrated sulfuric acid (0.2 mL). The mixture was reacted under an ice-water bath for 2.5 hours. Saturated sodium sulfite solution was slowly added under an ice-water bath to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to prepare sand. The mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 9 / 1 (V / V)) to give 310 mg of the title compound.

[0602] 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

[0603] Prepared with reference to the preparation method of Example 13a, except that tert-butyl 4-hydroxy-5-methoxy-7-methyl-1H-indole-1-carboxylate in step a) was replaced with tert-butyl 4-hydroxy-5-(methoxy-d3)-7-methyl-1H-indole-1-carboxylate. 2,2-difluoroethyl trifluoromethanesulfonate in step c) was replaced with 3,3,3-trifluoropropyl trifluoromethanesulfonate.

[0604] 1 HNMR(400MHz,DMSO-d6)δ12.80(s,1H),10.83(s,1H),7.91(d,J=8.2Hz,2H),7.58(d,J=8.3Hz,2 H),7.17(t,J=2.7Hz,1H),6.62(s,1H),6.16(d,J=2.0Hz,1H),4.45(td,J=9.5,4.8Hz,1H),3.11 (td,J=10.3,3.8Hz,1H),2.89(dd,J=22.7,10.0Hz,2H),2.56(dd,J=10.1,6.7Hz,2H),2.48-2.3 8(m,2H),2.36(s,3H),2.34-2.25(m,1H),2.07(t,J=10.4Hz,1H),1.68(dd,J=27.4,6.2Hz,2H).

[0605] LCMS m / z=480.3[M+1] + .

[0606] 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 afforded 17a-1,t r =0.88min and 17a-2,t r =1.39min(Separation method: Chromatographic column: 250*20mm 10μm; Mobile phase A: supercritical CO2; Mobile phase B: methanol (+0.1% 7.0mol / L ammonia methanol); A:B ratio: 75:25; Flow rate: 100mL / min; Detection wavelength: 214nm)

[0607] 17a-1,t r =0.88min

[0608] 1 HNMR(400MHz,DMSO-d6)δ12.98-12.11(m,1H),10.83(s,1H),7.90(d,J=8.1Hz ,2H),7.59(d,J=8.3Hz,2H),7.16(t,J=2.6Hz,1H),6.62(s,1H),6.15(s,1H),4 .45(d,J=4.9Hz,1H),3.29(s,1H),3.11(s,1H),2.89(dd,J=23.0,10.2Hz,2H) ,2.53(d,J=4.7Hz,4H),2.35(d,J=7.1Hz,3H),2.12-2.00(m,1H),1.72(s,2H).

[0609] 17a-2,t r =1.39min

[0610] 1 HNMR(400MHz,DMSO-d6)δ12.80(s,1H),10.83(s,1H),7.91(d,J=8.0Hz,2H),7.59 (d,J=8.0Hz,2H),7.17(t,J=2.6Hz,1H),6.62(s,1H),6.15(s,1H),4.45(d,J=4.9 Hz,1H),3.10(s,1H),2.91(dd,J=23.0,10.2Hz,2H),2.69-2.66(m,1H),2.55(d,J =4.7Hz,3H),2.36(d,J=7.1Hz,3H),2.34-2.31(m,1H),2.07(m,1H),1.72(s,2H).

[0611] 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

[0612] Prepare with reference to the preparation method of Example 17, except that 4-hydroxy-5-(methoxy-d3)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester is replaced with 4-hydroxy-7-methyl-5-(trifluoromethoxy)-1H-indole-1-carboxylic acid tert-butyl ester.

[0613] 1 HNMR(400MHz,DMSO-d6)δ10.80(s,1H),7.88(d,J=8.2Hz,2H),7.51(d,J=8.2 Hz,2H),7.14(s,1H),6.60(s,1H),6.08(s,1H),4.42(td,J=10.3,4.1Hz,1H) ,3.22-3.10(m,2H),2.34(s,3H),1.95(d,J=11.2Hz,1H),1.77(dt,J=21.8,1 3.9Hz, 3H), 1.63-1.48 (m, 1H), 1.37 (t, J = 13.3Hz, 1H), 1.18 (t, J = 7.0Hz, 3H).

[0614] LCMS m / z=530.1[M+1] + .

[0615] Example 19: 4-(1R,2R,5S)-(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 Benzoic acid and 4-(1R,2S,5R)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)thio)cyclohexyl)benzoic acid and 4-(1S,2R,5S)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)thio)cyclohexyl)benzoic acid and 4-(1R,2R,5R)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)thio)cyclohexyl)benzoic acid and 4-(1S,2S,5S)-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)thio)cyclohexyl)benzoic acid

[0616] a) Preparation of 8-ethoxy-1,4-dioxaspiro[4.5]decane

[0617] 1,4-Dioxaspiro[4.5]decan-8-ol (50 g) was dissolved in tetrahydrofuran (500 mL). Under nitrogen protection, sodium hydrogen hydride (15 g) was added at 0°C and stirred for 2 hours. Ethyl iodide (98.4 g) was added at 0°C and stirred at room temperature for 16 hours. The reaction was quenched with aqueous ammonium chloride solution and extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 65 g of the title compound.

[0618] b) Preparation of 4-ethoxycyclohexane-1-one

[0619] 8-Ethoxy-1,4-dioxaspiro[4.5]decane (65 g), dilute hydrochloric acid (3 M, 234 mL) and tetrahydrofuran (273 mL) were added to a reaction flask and stirred at 90°C for 2 hours. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (3×100 mL). The layers were separated and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 40 g of the title compound.

[0620] c) (±)-4-(5-ethoxy-2-oxocyclohexyl)benzoic acid ethyl ester (diastereomeric mixture)

[0621] 4-Ethoxycyclohexane-1-one (25 g), ethyl 4-iodobenzoate (48.5 g), tris(dibenzylidene-BASE acetone)dipalladium (16 g), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (20 g), cesium carbonate (115 g), and anhydrous 1,4-dioxane (500 mL) were added to the reaction flask, replaced with nitrogen for protection, stirred at 100 ° C for 16 hours, the reaction solution was cooled and filtered, the filtrate was diluted with water (150 mL), and extracted with ethyl acetate (3×150 mL), separated, and the combined organic layer was dried over anhydrous sodium sulfate, filtered and filtered, and the filtrate was concentrated under reduced pressure to make sand, and purified by column chromatography (mobile phase: petroleum ether ethyl acetate = 5 / 1 (V / V)) to obtain 14.2 g of the title compound.

[0622] d) Ethyl (±)-(5-ethoxy-2-(2-toluenesulfonylhydrazono)cyclohexyl)benzoate

[0623] Ethyl (±)-4-(5-ethoxy-2-oxocyclohexyl)benzoate (6.2 g), 4-methylbenzenesulfonylhydrazide (4.772 g) and toluene (60 mL) were added to a reaction flask, and the reaction was stirred at 50° C. for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was evaporated to dryness and diluted with water (80 mL). The mixture was extracted with ethyl acetate (100 mL). The organic layers were separated, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to prepare sand. The product was purified by column chromatography (mobile phase: petroleum ether, ethyl acetate = 5 / 1 (V / V)) with a reverse phase column (WelFlash C18-I, Regular C18 20-40 μm, 120 g; mobile phase A: 10 mmol L The reaction mixture was purified by elution with NH4HCO3 / H2O, B:MeCN; flow rate: 80 mL / min; gradient: 60% MeCN) to give the title compounds (±)-ethyl 4-(5-ethoxy-2-(2-toluenesulfonylhydrazono)cyclohexyl)benzoate (diastereomer-1, peak-1tr=1.9 min) and (±)-ethyl 4-(5-ethoxy-2-(2-toluenesulfonylhydrazono)cyclohexyl)benzoate (diastereomer-2, peak-2tr=2.0 min).

[0624] Peak 1: (±)-ethyl 4-(5-ethoxy-2-(2-tosylhydrazono)cyclohexyl)benzoate (diastereomer-1)

[0625] 1 H NMR (400MHz, DMSO-d6) δ10.06 (s, 1H), 7.85 (d, J = 8.2Hz, 2H), 7.19-7.13 (m, 6H),4.36(q,J=7.2Hz,2H),3.68-2.61(m,2H),3.46(q,J=7.0Hz,2H),2.86-2 .77(m,1H),2.36(s,3H),2.19(d,J=11.6Hz,1H),2.10(d,J=11.2Hz,1H),2.0 1-1.92(m,1H),1.73-1.64(m,1H),1.39-1.29(m,4H),1.07(t,J=7.0Hz,3H).

[0626] Peak-2: (±)-ethyl 4-(5-ethoxy-2-(2-tosylhydrazono)cyclohexyl)benzoate (diastereomer-2)

[0627] 1HNMR (400MHz, DMSO-d6) δ10.09(s,1H),7.84(d,J=8.3Hz,2H),7.27(d,J=8.3Hz,2H),7.16(dd,J= 14.9,8.2Hz,4H),4.35(q,J=7.1Hz,2H),3.77(dd,J=11.1,4.9Hz,1H),3.70(s,1H),3.51-3.43(m ,2H),2.48(d,J=4.7Hz,1H),2.38(s,4H),2.26-2.16(m,1H),2.14-2.06(m,1H),2.04-1.97(m,1H ),1.90(dd,J=13.6,3.8Hz,1H),1.73-1.61(m,1H),1.36(t,J=7.1Hz,3H),1.14(t,J=7.0Hz,3H).

[0628] Example 19a: 4-(1R,2R,5S)-(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

[0629] a) Preparation of ethyl (±)-4-(5-ethoxy-2-((5-methoxy-7-methyl-1-tolyl-1H-indol-4-yl)thio)cyclohexyl)benzoate

[0630] 5-Methoxy-7-methyl-1-tolyl-1H-indole-4-thiol (650 mg), (±)-4-(5-ethoxy-2-(2-tosylhydrazine)cyclohexyl)benzoic acid ethyl ester (diastereomer-1, peak-1tr=1.9 min) (1.286 g), 1,4-dioxane (30 mL), and cesium carbonate (2.134 g) were added to a reaction flask, replaced with nitrogen for protection, stirred at 110°C for 1 hour, diluted with water (50 mL), and extracted three times with ethyl acetate (150 mL). The liquids were separated, and the combined organic phases were washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to make sand, and purified by column chromatography (mobile phase: petroleum ether ethyl acetate = 10 / 1 (V / V)) to give 300 mg of the title compound.

[0631] b) Preparation of 4-(1R,2R,5S)-(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

[0632] Ethyl (±)-4-(5-ethoxy-2-((5-methoxy-7-methyl-1-tolyl-1H-indol-4-yl)thio)cyclohexyl)benzoate (300 mg) and LiOH (1.17 g) were added to a mixed solution of methanol / water (15 mL / 6 mL), and the reaction was stirred at 70°C for 16 hours. The reaction was concentrated under reduced pressure, and the residue was evaporated to dryness, diluted with water, and the pH was adjusted to neutral with 1N dilute hydrochloric acid. The product was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to prepare sand. The product was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 160 mg of the title isomer mixture.

[0633] LCMS m / z=438.1[M-1] + 。

[0634] Chiral SFC separation of the isomeric mixture afforded 19a-1,t r =5.45min and 19a-2,t r =6.03min,19a-3,t r =5.33min and 19a-4,t r =7.81min(Separation method: Chromatographic column: 250*20mm, 10μm; Mobile phase A: supercritical CO2; Mobile phase B: methanol (+0.1% 7.0mol / L ammonia methanol); A:B: 50:50; Flow rate: 100mL / min; Detection wavelength: 214nm)

[0635] 19a-1,t r =5.45min

[0636] 1HNMR(400MHz,DMSO-d6)10.98(s,1H),7.89(d,J=8.2Hz,2H),7.45(d,J=8.2Hz,2H),7.28(t,J=2.8Hz,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=13.5Hz,1H),1.87(d,J=11.8Hz,1H),1.70(dd,J=13.6,3.5Hz,1H),1.38(dd,J=23.5,12.3Hz,2H),1.03(t,J=7.0Hz,3H).

[0637] LCMS m / z=438.1[M-1] + .

[0638] 19a-2,t r =6.03min

[0639] 1 HNMR(400MHz,DMSO-d6)δ10.98(s,1H),7.89(d,J=8.2Hz,2H),7.45(d,J=8.2Hz,2H),7.28(t,J=2.8Hz,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=10.4Hz,1H),1.87(d,J=11.9Hz,1H),1.70(dd,J=13.2,3.2Hz,1H),1.38(dd,J=23.5,12.1Hz,2H),1.03(t,J=7.0Hz,3H).

[0640] LCMS m / z=438.1[M-1] + .

[0641] 19a-3,t r =5.33min

[0642] 1HNMR (400MHz, DMSO-d6) δ10.95(s,1H),7.90(d,J=8.2Hz,2H),7.38(d,J=8.2Hz,2H),7.24(t,J=2.8Hz,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).

[0643] LCMS m / z=438.1[M-1] + .

[0644] 19a-4, tr=7.81min

[0645] 1 HNMR (400MHz, DMSO-d6) δ10.96 (s, 1H), 7.82 (d, J = 8.1Hz, 2H), 7.26-7.22 ( m,2H),7.21(s,1H),6.66(s,1H),6.11-6.08(m,1H),3.70(s,1H),3.67(s, 3H),3.51(tdd,J=9.3,7.0,2.3Hz,3H),3.14(d,J=12.8Hz,1H),2.42(s,3H ),2.08-1.91(m,3H),1.55(dd,J=42.6,29.5Hz,3H),1.13(t,J=7.0Hz,3H).

[0646] LCMS m / z=438.1[M-1] + .

[0647] Example-19b: 4-(1R,2S,5R)-(5-Ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)thio)cyclohexyl)benzoic acid and 4-(1S,2R,5S)-(5-Ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)thio)cyclohexyl)benzoic acid and 4-(1R,2R,5R)-(5-Ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)thio)cyclohexyl)benzoic acid and 4-(1S,2S,5S)-(5-Ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)thio)cyclohexyl)benzoic acid

[0648] Prepared by referring to the preparation method of Example 19a:, replacing the (±)-4-(5-ethoxy-2-(2-toluenesulfonylhydrazono)cyclohexyl)benzoic acid ethyl ester (diastereomer-1) in step a) with (±)-4-(5-ethoxy-2-(2-toluenesulfonylhydrazono)cyclohexyl)benzoic acid ethyl ester (diastereomer-2).

[0649] Chiral SFC separation of the isomeric mixture afforded 19b-1,t r =5.14min and 19b-2,t r =5.73min,19b-3,t r =5.20min and 19b-4,t r =6.30min(Separation method: Chromatographic column: 250*20mm, 10μm; Mobile phase A: supercritical CO2; Mobile phase B: methanol (+0.1% 7.0mol / L ammonia methanol); A:B ratio: 55:45; Flow rate: 70mL / min; Detection wavelength: 214nm)

[0650] 19b-1,t r =5.14min

[0651] 1 HNMR (400MHz, DMSO-d6) δ10.97(s,1H),7.88(d,J=8.2Hz,2H),7.44(d,J=8.2Hz,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),3.1 9-3.12(m,1H),2.93(td,J=12.0,3.4Hz,1H),2.43(s,3H),1.90(d,J=11.4Hz,1H),1.75(d,J=13.8H z,1H),1.63(dd,J=23.8,11.8Hz,2H),1.44-1.40(m,1H),1.33-1.24(m,1H),1.14(t,J=7.0Hz,3H).

[0652] 19b-2,t r =5.73min

[0653] 1HNMR(400MHz,DMSO-d6)δ10.96(s,1H),7.87(d,J=8.0Hz,2H),7.39(d,J=8.2Hz,2H),7.27(t,J=2.8Hz,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=11.8,3.4Hz,1H),2.42(s,3H),1.89(d,J=11.4Hz,1H),1.73(d,J=13.8Hz,1H),1.63(t,J=12.2Hz,2H),1.44-1.37(m,1H),1.33-1.26(m,1H),1.13(t,J=7.0Hz,3H).

[0654] 19b-3,t r =5.20min

[0655] 1 HNMR(400MHz,DMSO-d6)δ10.95(s,1H),7.90(d,J=8.4Hz,2H),7.45(d,J=8.4Hz,2H),7.24(t,J=2.8Hz,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=13.4Hz,1H),1.33-1.25(m,1H),1.09(t,J=7.0Hz,3H).

[0656] 19b-4,t r =6.30min

[0657] 1HNMR(400MHz,DMSO-d6)δ10.96(s,1H),7.90(d,J=8.2Hz,2H),7.43(d,J=8.2Hz ,2H),7.24(t,J=2.7Hz,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=7.0Hz,2H),2.41(s,3H),2.28-2.09(m,2H),1.97 -1.81(m,2H),1.55(d,J=13.4Hz,1H),1.33-1.25(m,1H),1.09(t,J=7.0Hz,3H).

[0658] Example 20: 4-((1R,2S,5R)-5-Ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid and 4-((1S,2S,5S)-5-Ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid and 4-((1R,2R,5R)-5-Ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid and 4-((1S,2R,5S)-5-Ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid Benzoic acid and 4-((1R,2R,5S)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid and 4-((1S,2R,5R)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid and 4-((1R,2S,5S)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid and 4-((1S,2S,5R)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid

[0659] a)(±)-4-(5-ethoxy-2-oxocyclohexyl)benzoic acid ethyl ester (diastereomeric mixture)

[0660] The title compound (±)-4-(5-ethoxy-2-oxocyclohexyl)benzoic acid ethyl ester was obtained by referring to the preparation method of step c of Example 19. Purification by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) was performed according to the corresponding elution order to obtain (±)-4-(5-ethoxy-2-oxocyclohexyl)benzoic acid ethyl ester (diastereomer-1, peak-1t r=3.8 min) and (±)-ethyl 4-(5-ethoxy-2-oxocyclohexyl)benzoate (diastereomer-2, peak-2t r =3.5min)

[0661] (±)-4-(5-ethoxy-2-oxocyclohexyl)benzoic acid ethyl ester (diastereomer-1, peak-1t r =3.8min)

[0662] 1 HNMR(400MHz,DMSO-d6)δ7.88(d,J=8.1Hz,2H),7.30(t,J=8.2Hz,2H),4.34-4. 27(m,2H),4.05(dd,J=12.8,5.7Hz,1H),3.83(s,1H),3.54(dd,J=12.9,5.9Hz,2 H),2.77-2.65(m,1H),2.32-2.23(m,2H),2.18(dd,J=13.9,4.6Hz,2H),1.94(td ,J=13.3,6.6Hz,1H),1.32(dd,J=12.2,5.1Hz,3H),1.19(dt,J=7.1,5.6Hz,3H).

[0663] (±)-4-(5-ethoxy-2-oxocyclohexyl)benzoic acid ethyl ester (diastereomer-2, peak-2t r =3.5min)

[0664] 1 HNMR(400MHz,DMSO-d6)δ7.88(d,J=8.1Hz,2H),7.30(t,J=8.2Hz,2H),4.34-4. 27(m,2H),4.05(dd,J=12.8,5.7Hz,2H),3.83(s,2H),3.54(dd,J=12.9,5.9Hz,1 H),2.77-2.65(m,1H),2.32-2.23(m,2H),2.18(dd,J=13.9,4.6Hz,1H),1.94(td ,J=13.3,6.6Hz,1H),1.32(dd,J=12.2,5.1Hz,3H),1.19(dt,J=7.1,5.6Hz,3H).

[0665] Example 20a; 4-((1R,2S,5R)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid and 4-((1S,2S,5S)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid and 4-((1R,2R,5R)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid and 4-((1S,2R,5S)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid

[0666] a) Preparation of ethyl (±)-4-(5-ethoxy-2-hydroxycyclohexyl)benzoate

[0667] Ethyl (±)-4-(5-ethoxy-2-oxocyclohexyl)benzoate (diastereomer-1, peak-1t r =3.8min) (15g) was added to a three-necked flask, and tetrahydrofuran (300mL) was added under nitrogen protection. The reaction system was cooled to -78°C, and 1M lithium tri-sec-butylborohydride (103mL) was slowly added dropwise. The reaction was carried out at -78°C for 1 hour. The reaction solution was poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate (3*200mL). The organic phases were separated and combined, washed with a saturated aqueous solution of common salt (3*200mL), and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by sand column chromatography (mobile phase: petroleum ether / ethyl acetate = 8 / 1 (V / V)) to obtain 14g of the title compound.

[0668] b) Preparation of tert-butyl (±)-4-((4-ethoxy-2-(4-(ethoxycarbonyl)phenyl)cyclohexyl)oxy)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0669] Ethyl (±)-4-(5-ethoxy-2-hydroxycyclohexyl)benzoate (7.88 g), tert-butyl 4-hydroxy-5-methoxy-7-methyl-1H-indole-1-carboxylate (7.42 g), triphenylphosphine (14.14 g), and anhydrous tetrahydrofuran (400 mL) were added to a three-necked flask, replaced with nitrogen for protection, and diisopropyl azodicarboxylate (10.9 g) was added dropwise at 0°C. The reaction system was warmed to room temperature and reacted for 16 hours. The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (3×200 mL). The liquids were separated, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to make sand. The mixture was purified by column chromatography (mobile phase: petroleum ether ethyl acetate = 20 / 1 (V / V)) to obtain 4.2 g of the title compound.

[0670] c) Preparation of 4-((1R,2S,5R)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid, 4-((1S,2S,5S)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid, 4-((1R,2R,5R)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid, and 4-((1S,2R,5S)-5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid

[0671] The isomer mixture was obtained by hydrolysis in the same manner as in Example 17.

[0672] LCMS m / z=424.2[M+1] + .

[0673] Chiral SFC separation of the isomeric mixture afforded 20a-1, t r =4.70min and 20a-2,t r =4.80min,20a-3,t r =3.43min and 20a-4,t r =3.59min(Separation method: Chromatographic column: 250*20mm, 10μm; Mobile phase A: supercritical CO2; Mobile phase B: methanol (+0.1% 7.0mol / L ammonia methanol); A:B ratio: 70:30; Flow rate: 100mL / min; Detection wavelength: 214nm)

[0674] 20a-1,t r =4.70min

[0675] 1HNMR(400MHz,DMSO-d6)δ10.79(s,1H),7.90(d,J=8.2Hz,2H),7.57(d,J=8.2Hz,2H),7.05(t,J=2.6Hz,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=6.9Hz,2H),3.34(s,1H),2.46(d,J=13.7Hz,1H),2.33(s,3H),2.13(t,J=13.0Hz,1H),1.88(d,J=12.4Hz,1H),1.66(dd,J=25.0,13.2Hz,2H),1.54(d,J=12.7Hz,1H),1.14(t,J=7.0Hz,3H).

[0676] LCMS m / z=424.2[M+1] + .

[0677] 20a-2,t r =4.80min

[0678] 1 HNMR(400MHz,DMSO-d6)δ10.79(s,1H),7.90(d,J=8.1Hz,2H),7.56(d,J=8.1Hz,2H),7.05(t,J=2.6Hz,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=7.0Hz,2H),3.35(s,1H),2.46(d,J=13.7Hz,1H),2.33(s,3H),2.13(t,J=13.6Hz,1H),1.88(d,J=12.7Hz,1H),1.65(dd,J=24.9,13.8Hz,2H),1.53(d,J=11.8Hz,1H),1.14(t,J=7.0Hz,3H).

[0679] LCMS m / z=424.2[M+1] + .

[0680] 20a-3,t r =3.43min

[0681] 1HNMR(400MHz,DMSO-d6)δ12.64(s,1H),10.79(s,1H),7.89(d,J=8.1Hz,2H),7.54(d,J=8.2Hz,2H),7.14(t,J=2.6Hz,1H),6.60(s,1H),6.08(d,J=2.2Hz,1H),4.43(td,J=10.3,4.0Hz,1H),3.57(s,1H),3.56(s,3H),3.44(q,J=7.0Hz,2H),3.22-3.14(m,1H),2.34(s,3H),1.95(d,J=11.1Hz,1H),1.77(dt,J=21.9,14.3Hz,3H),1.60-1.50(m,1H),1.37(t,J=13.3Hz,1H),1.18(t,J=7.0Hz,3H).

[0682] LCMS m / z=424.2[M+1] + .

[0683] 20a-4,t r =3.59min

[0684] 1 HNMR(400MHz,DMSO-d6)δ13.29-11.95(m,1H),10.80(s,1H),7.90(d,J=8.2Hz,2H),7.55(d,J=8.2Hz,2H),7.14(t,J=2.7Hz,1H),6.60(s,1H),6.12-6.04(m,1H),4.43(td,J=10.4,4.1Hz,1H),3.57(s,1H),3.57(s,3H),3.45(q,J=7.0Hz,2H),3.22-3.13(m,1H),2.35(s,3H),1.96(d,J=13.6Hz,1H),1.77(dt,J=21.9,14.0Hz,3H),1.63-1.51(m,1H),1.43-1.31(m,1H),1.18(t,J=7.0Hz,3H).

[0685] LCMS m / z=424.2[M+1] + .

[0686] Example 20b: 4-((1R,2R,5S)-5-Ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid and 4-((1S,2R,5R)-5-Ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid and 4-((1R,2S,5S)-5-Ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid and 4-((1S,2S,5R)-5-Ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid

[0687] Referring to Example 20a, a mixture of isomers was obtained.

[0688] The isomeric mixture was separated 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 (Separation method: chromatographic column: 250*20mm, 10μm; Mobile phase A: supercritical CO2; Mobile phase B: methanol (+0.1% 7.0mol / l ammonia methanol); A:B ratio: 75:25; Flow rate: 120mL / min; Detection wavelength: 214nm)

[0689] 20b-1,t r =0.89min

[0690] 1 HNMR(400MHz,DMSO-d6)δ10.80(s,1H),7.89(d,J=8.2Hz,2H),7.54(d,J=8.2Hz,2H) ,7.05(t,J=2.8Hz,1H),6.60(s,1H),5.59(d,J=2.1Hz,1H),4.64(s,1H),3.84(s,1H ),3.55(s,3H),3.45(dd,J=14.0,7.0Hz,3H),2.33(s,3H),2.14(s,1H),1.88(d,J=1 3.1Hz,1H),1.65(d,J=10.6Hz,2H),1.55(s,1H),1.24(s,1H),1.14(t,J=7.0Hz,3H).

[0691] LCMS m / z=424.1[M+1] + .

[0692] 20b-2,t r =1.22min

[0693] 1 HNMR(400MHz,DMSO-d6)δ10.80(s,1H),7.91(d,J=8.2Hz,2H),7.58(d,J=8.3Hz,2H),7.06(t,J=2.8Hz,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=14.0,7.0Hz,3H),2.34(s,3H),2.15(s,1H),1.89(d,J=11.7Hz,1H),1.66(d,J=11.3Hz,2H),1.56(s,1H),1.24(s,1H),1.15(t,J=7.0Hz,3H).

[0694] 20b-3,t r =0.92min

[0695] 1 HNMR(400MHz,DMSO-d6)δ12.69(s,1H),10.81(s,1H),7.90(d,J=8.3Hz,2H),7.56(d,J=8.3Hz,2H),7.07(t,J=2.7Hz,1H),6.60(s,1H),5.62(dd,J=2.9,2.0Hz,1H),4.58(s,1H),3.56(dd,J=7.0,2.3Hz,1H),3.53(s,3H),3.50(dd,J=7.0,2.3Hz,1H),3.47-3.41(m,1H),3.06(d,J=13.2Hz,1H),2.33(s,3H),2.21(dd,J=24.3,11.6Hz,1H),2.01(d,J=11.6Hz,1H),1.94-1.83(m,1H),1.77(d,J=13.9Hz,2H),1.43(t,J=13.2Hz,1H),1.14(t,J=7.0Hz,3H).

[0696] LCMS m / z=424.1[M+1] + .

[0697] 20b-4,tr=1.46min

[0698] 1HNMR (400MHz, DMSO-d6) δ10.77(s,1H),7.87(d,J=8.3Hz,2H),7.52(d,J=8.3Hz,2H),7.03(t,J=2.7Hz,1H),6.5 6(s,1H),5.59(dd,J=2.8,2.0Hz,1H),4.55(s,1H),3.53(dd,J=7.0,2.3Hz,1H),3.50(s,3H),3.47(dd,J=7.0,2 .3Hz,1H),3.44-3.37(m,1H),3.03(d,J=13.0Hz,1H),2.30(s,3H),2.18(dd,J=24.2,11.8Hz,1H),1.98(d,J=11 .6Hz,1H),1.84(dd,J=19.4,8.1Hz,1H),1.72(t,J=13.6Hz,2H),1.39(t,J=13.0Hz,1H),1.10(t,J=7.0Hz,3H).

[0699] LCMS m / z=424.1[M+1] + .

[0700] 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

[0701] a) Preparation of 5-methoxy-7-methyl-1-tolyl-1H-indole-4-sulfonyl chloride

[0702] 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 an ice-water bath, N-chlorosuccinimide (103.0 mg) was added, and 2M dilute hydrochloric acid (5 drops) was slowly added and stirred for 3.5 hours. The reaction 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 obtain 88 mg of the title compound.

[0703] b) Preparation of methyl (±)-rel-(2S,4S)-4-(4-ethoxy-1-((5-methoxy-7-methyl-1-tolyl-1H-indol-4-yl)sulfonyl)piperidin-2-yl)benzoate

[0704] Methyl (±)-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 was diluted with water (40 mL) and extracted with dichloromethane (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to make sand, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 2 / 1 (V / V)) to obtain 179 mg of the title compound.

[0705] 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

[0706] The enantiomers were obtained by hydrolysis in the same manner as in Example 17.

[0707] LCMS m / z=473.1[M+1] + 。

[0708] The enantiomers were separated by chiral SFC to give 21-1, t r =1.34min and 21-2,t r =2.68min(Separation method: Chromatographic column: 250*20mm, 10μm; Mobile phase A: supercritical CO2; Mobile phase B: methanol (+0.1% 7.0mol / L ammonia methanol); A:B: 55:45; Flow rate: 70mL / min; Detection wavelength: 214nm)

[0709] 21-1,tr=1.34min

[0710] 1HNMR (400MHz, DMSO-d6) δ11.39 (s, 1H), 7.92 (d, J = 8.4Hz, 2H), 7.55-7.42 (m, 3H),6.94(s,1H),6.91(dd,J=3.0,2.0Hz,1H),5.39(s,1H),3.90(s,3H),3.8 4-3.81(m,1H),3.30(s,2H),3.06(s,1H),2.95-2.89(m,1H),2.55(s,3H),2. 05-1.93(m,1H),1.68(d,J=9.8Hz,1H),1.47-1.42(m,2H),0.99-0.96(m,3H).

[0711] 21-2,tr=2.68min

[0712] 1 HNMR(400MHz,DMSO-d6)δ11.39(s,1H),7.92(d,J=8.4Hz,2H),7.54-7.42(m ,3H),6.94(s,1H),6.93-6.88(m,1H),5.39(s,1H),3.90(s,3H),3.83(d,J=1 2.4Hz,1H),3.30(s,2H),3.06(s,1H),2.95-2.89(m,1H),2.55(s,3H),2.02 -1.97(m,1H),1.68(d,J=11.0Hz,1H),1.51-1.38(m,2H),0.99-0.96(m,3H).

[0713] Example 22: (±)(Z)-11-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-3-oxa-1(2,4)-piperazine-2(1,2)-benzocyclohexanone-8-ene-24-carboxylic acid

[0714] a) Preparation of methyl 3-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

[0715] Methyl 4-bromo-3-hydroxybenzoate (10 g), pinacol diboron (12.09 g), and potassium acetate (10.62 g) were added to a (500 mL) two-necked flask, and 1,4-dioxane (150 mL) was added. After nitrogen replacement protection, 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride dichloromethane complex (3.53 g) was added and stirred at 90°C for 4 hours. The reaction solution was cooled to room temperature, quenched with water, and 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 make sand. The mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to obtain 7.7 g of the title compound.

[0716] LCMS m / z=279.1[M+H]+ .

[0717] b) Preparation of methyl 3-hydroxy-4-(pyrazin-2-yl)benzoate

[0718] Methyl 3-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (7.5 g), 2-bromopyrazine (6.43 g), and sodium carbonate (8.57 g) were added to a (500 mL) two-necked flask, and a mixed solvent of 1,4-dioxane / water (150 mL / 30 mL) was added. The mixture was replaced with nitrogen for protection, and tetrakistriphenylphosphine palladium (2.49 g) was added. The mixture was stirred at 100° C. for 4 hours, quenched with water, and 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 make sand. The mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to obtain 3.7 g of the title compound.

[0719] LCMS m / z=231.2[M+H]+.

[0720] c) Preparation of methyl (±) 3-hydroxy-4-(piperazin-2-yl)benzoate

[0721] Methyl 3-hydroxy-4-(pyrazin-2-yl)benzoate (3.7 g) was dissolved in methanol (200 mL), and palladium acetate (361 mg), acetic acid (19.3 g), and palladium on carbon (1.3 g, 10%) were added. The mixture was replaced with hydrogen once, stirred at room temperature overnight, filtered, and the filtrate was concentrated under reduced pressure to obtain 3 g of the title compound.

[0722] LCMS m / z=237.1[M+H]+.

[0723] d) Preparation of tert-butyl (±) 3-(2-hydroxy-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

[0724] Dissolve (±) methyl 3-hydroxy-4-(piperazin-2-yl)benzoate (2.8 g) in dichloromethane (100 mL), add triethylamine (1.8 g), replace with nitrogen for protection, add di-tert-butyl dicarbonate (1.55 g) in dichloromethane (10 mL) dropwise, stir at room temperature for 1 hour,

[0725] The reaction solution was concentrated under reduced pressure to prepare sand, and then purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to obtain 2.5 g of the title compound.

[0726] LCMS m / z=337.4[M+H]+.

[0727] e) Preparation of tert-butyl (±) 3-(2-((tert-butyldimethylsilyl)oxy)-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

[0728] Dissolve (±) tert-Butyl 3-(2-hydroxy-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (2.3 g) in N,N-dimethylformamide (50 mL), add imidazole (931 mg), replace with nitrogen for protection, cool to 0°C in an ice-water bath, add tert-butyldimethylsilyl chloride (2.06 g) and 4-dimethylaminopyridine (84 mg), stir at room temperature overnight, quench with water, extract three times with ethyl acetate (50 mL*3), combine the organic phases, wash three times with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure to make sand, and purify by column chromatography (mobile phase: petroleum ether / ethyl acetate = 20 / 1 (V / V)) to obtain 2.2 g of the title compound.

[0729] LCMS m / z=451.7[M+H]+.

[0730] f) Preparation of (±) tert-butyl 4-((4-(tert-butyloxycarbonyl)-2-(2-(((tert-butyldimethylsilyl)oxy)-4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0731] Tert-butyl 4-(hydroxymethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (1.32 g) was dissolved in dichloromethane (30 mL), replaced with nitrogen, and cooled to 0°C in an ice-water bath. Dibromotriphenylphosphine (2.07 g) was added in batches, and the mixture was stirred at 0°C for 1.5 hours. Tert-butyl (±) 3-(2-((tert-butyldimethylsilyl)oxy)-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (1.7 g) and N,N-diisopropylethylamine (1.46 g) were added, and the mixture was stirred at 0°C for 1.5 hours. Water was added to quench the reaction, and the mixture was extracted three times with dichloromethane (30 mL*3). The organic phases were combined, washed three times 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 2.5 g of the title compound.

[0732] LCMS m / z=725.0[M+H]+.

[0733] g) Preparation of (±) tert-butyl 4-((4-(tert-butoxycarbonyl)-2-(2-hydroxy-4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0734] Tert-butyl (±)-4-((4-(tert-butyloxycarbonyl)-2-(2-(((tert-butyldimethylsilyl)oxy)-4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (2.4 g) was dissolved in tetrahydrofuran (50 mL) and replaced with nitrogen for protection. Then, a solution of tetrabutylammonium fluoride in tetrahydrofuran (5.6 mL, 1 mol / L) was added and stirred at room temperature for 1 hour. The reaction was quenched by adding water and extracted three times with ethyl acetate (30 mL*3). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to make sand, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to give 2 g of the title compound.

[0735] LCMS m / z=610.7[M+H]+.

[0736] 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-carboxylate

[0737] Tert-butyl (±)-4-((4-(tert-Butyloxycarbonyl)-2-(2-hydroxy-4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (2 g) was dissolved in N,N-dimethylformamide (30 mL), potassium carbonate (1.36 g) was added, and nitrogen was replaced for protection. 6-bromohex-1-ene (1.07 g) was added and stirred at room temperature overnight. The reaction was quenched by adding water, and extracted three times with ethyl acetate (30 mL*3). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to make sand, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to give 2 g of the title compound.

[0738] LCMS m / z=692.9[M+H]+.

[0739] 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-carboxylate

[0740] 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-carboxylate (2 g) was dissolved in methanol (50 mL), and a 1,4-dioxane hydrochloric acid solution (11 mL, 4 M) was added. The mixture was stirred at room temperature for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain 1.8 g of the title compound.

[0741] LCMS m / z=592.7[M+H]+.

[0742] j) 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-carboxylate

[0743] Tert-butyl (±)-4-((2-(2-(hexyl-5-en-1-oxy)-4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (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 replaced with nitrogen for protection, and stirred at room temperature overnight. The reaction was quenched by adding water, and extracted three times with ethyl acetate (30 mL*3). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to make sand, and purified by column chromatography (mobile phase: dichloromethane / methanol = 50 / 1 (V / V)) to give 1.2 g of the title compound.

[0744] LCMS m / z=632.8[M+H]+.

[0745] k) Preparation of (±)methyl (Z)-11-((1-(tert-butoxycarbonyl)-5-methoxy-7-methyl-1H-indol-4-yl)methyl)-3-oxa-1(2,4)-piperazine-2(1,2)-benzocyclohexanone-8-ene-24-carboxylate

[0746] 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-carboxylate (200 mg) was dissolved in toluene (200 mL), and Grubbs 1st (130 mg) was added. The mixture was purged with nitrogen and stirred at 80°C for 18 hours. The reaction solution was concentrated under reduced pressure and sanded, and purified by column chromatography (mobile phase: dichloromethane / methanol = 10 / 1 (V / V)) to give 175 mg of the title compound.

[0747] Preparation of (±)(Z)-11-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-3-oxa-1(2,4)-piperazine-2(1,2)-benzocyclohexanone-8-ene-24-carboxylic acid

[0748] (±)Methyl (Z)-11-((1-(tert-butoxycarbonyl)-5-methoxy-7-methyl-1H-indol-4-yl)methyl)-3-oxa-1(2,4)-piperazine-2(1,2)-benzocyclohexanone-8-ene-24-carboxylate (175 mg) was dissolved in methanol / tetrahydrofuran (10 mL / 10 mL), and an aqueous solution of lithium hydroxide (10 mL, 2N) was added. The mixture was stirred at 70°C for 2 hours. The reaction 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. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and evaporated to dryness. The filtrate was concentrated under reduced pressure and sanded, and purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 5 mg of the title compound.

[0749] 1H NMR (400MHz, DMSO-d6) δ10.84(s,1H),7.99(d,J=7.9Hz,1H),7.62(d,J=8.0Hz,1H),7.44(s,1H),7.28(s,1H ),6.76-6.64(m,1H),6.62(s,1H),5.45(t,J=10.5Hz,1H),5.29(s,1H),4.25(s,1H),4.16(d,J=9.3Hz,1H), 3.95(t,J=10.9Hz,2H),3.77(d,J=11.9Hz,1H),3.74(s,3H),2.90(d,J=11.5Hz,2H),2.75(d,J=11.3Hz,1H) ,2.68(d,J=17.4Hz,2H),2.43(s,3H),2.33(d,J=11.7Hz,2H),1.91(s,2H),1.66(s,1H),1.30-1.08(m,4H).

[0750] LCMS m / z=490.6[M+1]+.

[0751] Example 23: (13R, 14R, Z)-14-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-3-oxa-1(3,1)-piperidin-2(1,2)-benzocyclohexanone-8-ene-24-carboxylic acid

[0752] a) Preparation of methyl 3-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

[0753] Methyl 4-bromo-3-hydroxybenzoate (25 g), pinacol diboron (30.23 g), and potassium acetate (26.55 g) were added to a 500 mL three-necked flask, and 1,4-dioxane (350 mL) was added. After nitrogen replacement protection, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (4.42 g) was added, and the mixture was heated to 90 ° C. and stirred for 4 hours. Water (300 mL) was added to quench the mixture, and the mixture was extracted three times with ethyl acetate (200 mL*3). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to make sand. The mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to obtain 30 g of the title compound.

[0754] LCMS m / z=279.1[M+H]+.

[0755] b) Preparation of tert-butyl 5-(2-hydroxy-4-(methoxycarbonyl)phenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate

[0756] Methyl 3-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (19 g), tert-butyl 5-bromo-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (12.58 g), and potassium carbonate (18.88 g) were added to a three-necked flask, and 1,4-dioxane / water (300 mL / 100 mL) was added. Nitrogen was replaced for protection, and tetrakistriphenylphosphine palladium (4.42 g) was added. The mixture was heated to 60° C. and stirred for 4 hours. Water (300 mL) was added to quench the mixture, and the mixture was extracted three times with ethyl acetate (200 mL*3). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to make sand. The mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to obtain 7.5 g of the title compound.

[0757] LCMS m / z=348.4[M+H]+.

[0758] c) Preparation of tert-butyl (3R, 4S)-4-hydroxy-3-(2-hydroxy-4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate

[0759] 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). Tert-butyl 5-(2-hydroxy-4-(methoxycarbonyl)phenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (7.5 g) and RuCl(p-cymene)[(S,S)-Ts-DPEN] (1.36 g) were added to the reaction flask. The prepared anhydrous formic acid and triethylamine solution was then added to the reaction flask. Nitrogen was added to the flask. After replacement, the temperature was slowly raised to room temperature and stirred overnight. The reaction system was cooled to 0-5°C in an ice-water bath. Triethylamine (5 mL) was slowly added to adjust the pH to weak alkaline. The temperature was controlled at about 10°C. Water (200 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (150 mL*3), washed with saturated brine (200 mL*1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to make sand. The mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 20 / 3 (V / V)) to obtain 2 g of the title compound.

[0760] LCMS m / z=352.4[M+H]+.

[0761] d) Preparation of tert-butyl (3R, 4S)-3-(2-(hex-5-en-1-oxy)-4-(methoxycarbonyl)phenyl)-4-hydroxypiperidine-1-carboxylate

[0762] Tert-butyl (3R, 4S)-4-hydroxy-3-(2-hydroxy-4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate (1.9 g), 6-bromohex-1-ene (1.59 g) and potassium carbonate (2.24 g) were added to a three-necked flask, and N,N-dimethylformamide (40 mL) was added. The mixture was replaced with nitrogen for protection, stirred at room temperature overnight, 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 make sand. The mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 20 / 3 (V / V)) to obtain 1.55 g of the title compound.

[0763] LCMS m / z=434.5[M+H]+.

[0764] e) Preparation of tert-butyl 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-carboxylate

[0765] Tert-butyl (3R,4S)-3-(2-(hex-5-en-1-oxy)-4-(methoxycarbonyl)phenyl)-4-hydroxypiperidine-1-carboxylate (1.55 g, 3.58 mmol), tert-butyl 4-hydroxy-5-methoxy-7-methyl-1H-indole-1-carboxylate (1.5 g), and triphenylphosphine (1.13 g) were added to a three-necked flask, replaced with nitrogen, and anhydrous tetrahydrofuran (40 mL) was added. Diisopropyl azodicarboxylate (868 mg) was added dropwise at 0°C. The reaction system was slowly warmed to room temperature and stirred overnight. Water (100 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (100 mL*3). The organic phases were combined, washed with saturated brine (100 mL*1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to make sand, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 20 / 1 (V / V)) to give 550 mg of the title compound.

[0766] LCMS m / z=693.9[M+H]+.

[0767] 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-carboxylate

[0768] tert-Butyl 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-carboxylate (530 mg) was added to 1,4-dioxane (3 ml), and 1,4-dioxane hydrochloric acid solution (3 mL, 4 M) was added. The mixture was stirred at room temperature under nitrogen protection for 2 hours, neutralized with saturated sodium bicarbonate solution (30 mL), and extracted with ethyl acetate (50 mL*3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to give 440 mg of the title compound.

[0769] LCMS m / z=593.7[M+H]+ .

[0770] g) Preparation of tert-butyl 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-carboxylate

[0771] 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-carboxylate (430 mg) was dissolved in acetonitrile (10 mL), followed by the addition of triethylamine (440 mg) and 3-bromoprop-1-ene (264 mg). The reaction was stirred at 50°C overnight, quenched with water (50 mL), and extracted with ethyl acetate (50 mL*3). The organic phases were combined, washed with saturated brine (50 mL*1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 350 mg of the title compound.

[0772] LCMS m / z=633.8[M+H]+.

[0773] h) methyl (1 3 R, 1 4 R, Z)-1 4 -((1-(tert-Butoxycarbonyl)-5-methoxy-7-methyl-1H-indol-4-yl)oxy)-3-oxa-1(3,1)-piperidin-2(1,2)-benzocyclohexanone-8-ene-2 4 Preparation of carboxylic acid esters

[0774] tert-Butyl 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-carboxylate (350 mg) was added to dichloromethane (350 mL), and Grubbs 1st (228 mg) was added. The mixture was purged with nitrogen and stirred at 40°C for 18 hours. The reaction solution was concentrated under reduced pressure and sanded, and purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 130 mg of the title compound.

[0775] LCMS m / z=605.7[M+H]+.

[0776] i)(1 3 R, 1 4 R, Z)-1 4 -((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-3-oxa-1(3,1)-piperidin-2(1,2)-benzocyclohexanone-8-ene-2 4 Preparation of carboxylic acids

[0777] The methyl group (1 3 R, 1 4 R, Z)-1 4 -((1-(tert-Butoxycarbonyl)-5-methoxy-7-methyl-1H-indol-4-yl)oxy)-3-oxa-1(3,1)-piperidin-2(1,2)-benzocyclohexanone-8-ene-2 4 The carboxylate (35 mg) was dissolved in a mixed solution of tetrahydrofuran / methanol (3 mL / 3 mL), and an aqueous lithium hydroxide solution (3 mL, 2N) was added. The mixture was stirred at 70 ° C for 2 hours, concentrated to dryness under reduced pressure, and a dilute aqueous hydrochloric acid solution was added to adjust the pH to neutral. The mixture was extracted with ethyl acetate (10 mL*3), and 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 sand. The mixture was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 6.1 mg of the title compound. 1H NMR (400MHz, DMSO-d6) δ10.87(d,J=9.4Hz,1H),7.90(dd,J=30.1,7.7Hz,1H),7.57(t,J= 7.3Hz,1H),7.40(dd,J=20.6,12.0Hz,2H),7.24-7.17(m,1H),6.71(d,J=16.0Hz,1H),5. 43(s,1H),4.93(d,J=34.3Hz,1H),4.09(s,1H),3.79(t,J=15.9Hz,3H),2.39(d,J=5.7Hz ,3H),2.23-2.15(m,1H),2.03-1.96(m,2H),1.30(s,3H),1.26(s,5H),1.23(s,6H).LCMS m / z=491.6[M+H]+.

[0778] Example 24: (13R, 14R)-14-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-3-oxa-1(3,1)-piperidine-2(1,2)-benzocyclohexane-24-carboxylic acid

[0779] 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)-piperidin-2(1,2)-benzoic acid cyclodecane-2 4 Preparation of formate

[0780] The methyl group (1 3 R, 1 4 R, Z)-1 4 -((1-(tert-Butoxycarbonyl)-5-methoxy-7-methyl-1H-indol-4-yl)oxy)-3-oxa-1(3,1)-piperidin-2(1,2)-benzocyclohexanone-8-ene-2 4 Carboxylate (60 mg) was dissolved in methanol (5 mL) and added to a three-necked flask. Palladium / carbon (35 mg, 10%) was added and replaced with hydrogen. The mixture was stirred at room temperature overnight and filtered through celite. The filtrate was evaporated to dryness under reduced pressure to obtain 45 mg of the title compound.

[0781] LCMS m / z = 607.4 [M+H]+.

[0782] b)(1 3 R, 1 4 R)-1 4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-3-oxa-1(3,1)-piperidin-2(1,2)-benzocyclohexane-2 4 - Preparation of formic acid

[0783] The methyl group (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)-piperidin-2(1,2)-benzoic acid cyclodecane-2 4 Formic acid ester (50 mg) was dissolved in a mixed solution of tetrahydrofuran / methanol (3 mL / 3 mL), and an aqueous lithium hydroxide solution (3 mL, 2N) was added. The mixture was stirred at 70°C for 2 hours, concentrated to dryness under reduced pressure, and a dilute aqueous hydrochloric acid solution was added to adjust the pH to neutral. The mixture was extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated brine (20 mL*1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to prepare sand. The mixture was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 5.1 mg of the title compound.

[0784] 1 H NMR (400MHz, DMSO-d6) δ10.86(s,1H),7.85(d,J=7.5Hz,1H),7.54(d,J=7.9Hz,1H),7.45(s ,1H),7.20(s,1H),6.74(s,1H),6.38(s,1H),4.84(d,J=7.9Hz,1H),4.21(s,1H),3.83(s,3H ),3.25(d,J=10.5Hz,3H),2.71(d,J=9.7Hz,2H),2.40(s,3H),2.10(d,J=11.2Hz,1H),1.98 (s,2H),1.83(s,1H),1.70(s,3H),1.55(s,2H),1.40(s,2H),1.30(dd,J=26.9,17.4Hz,4H).

[0785] LCMS m / z=493.3[M+H]+.

[0786] 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

[0787] a) Preparation of tert-butyl 5-(difluoromethoxy)-4-formyl-7-methyl-1H-indole-1-carboxylate

[0788] Tert-butyl 4-formyl-5-hydroxy-7-methyl-1H-indole-1-carboxylate (1.5 g) was dissolved in dichloromethane (25 mL) and added to a two-necked flask. The mixture was replaced with nitrogen and cooled to 0°C in an ice-water bath. Aqueous potassium hydroxide solution (12.23 g) was added dropwise. After stirring for 5 minutes, a solution of difluorobromomethyltrimethylsilane (3.32 g) in dichloromethane (5 mL) was added dropwise. The mixture was reacted at 0°C for 2 hours, quenched with water (50 mL), extracted with dichloromethane (50 mL*3), and the organic phases were combined, washed with saturated brine (50 mL*1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to give 670 mg of the title compound.

[0789] LCMS m / z=326 [M+H]+.

[0790] b) Preparation of tert-butyl 5-(difluoromethoxy)-4-hydroxy-7-methyl-1H-indole-1-carboxylate

[0791] Tert-butyl 5-(difluoromethoxy)-4-formyl-7-methyl-1H-indole-1-carboxylate (670 mg) was dissolved in dichloromethane (20 mL) and added to a 100 mL two-necked flask. The atmosphere was replaced with nitrogen and m-chloroperbenzoic acid (3.55 g) was added at 0°C. The mixture was reacted at room temperature for 3 hours. Aqueous sodium bisulfite solution was added to quench the reaction and extracted with ethyl acetate (50 mL*3). The organic phases were combined, washed with saturated brine (50 mL*1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 4 / 1 (V / V)) to give 170 mg of the title compound.

[0792] LCMS m / z = 314.2 [M+H] +.

[0793] c) Preparation of (±)-rel-(3S,4S)-4-((1-(tert-butyloxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0794] Tert-butyl 5-(difluoromethoxy)-4-hydroxy-7-methyl-1H-indole-1-carboxylate (120 mg), tert-butyl (±)-rel-(3S,4R)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate (193 mg), and triphenylphosphine (201 mg) were added to a 25 mL two-necked flask, replaced with nitrogen, and anhydrous tetrahydrofuran (10 mL) was added. Diisopropyl azodicarboxylate (155 mg) was added dropwise at 0°C, and the mixture was slowly warmed to room temperature and stirred overnight. Water (20 mL) was added to quench the mixture, and the mixture was extracted with dichloromethane (20 mL*3). The organic phases were combined, washed with saturated brine (20 mL*1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 4 / 1 (V / V)) to give 137 mg of the title compound.

[0795] LCMS m / z = 631.3 [M+H]+.

[0796] Preparation of tert-butyl (d)-rel-(3S,4S)-5-(difluoromethoxy)-4-((3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylate

[0797] (±)-rel-(3S,4S)-4-((1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (137 mg) was dissolved in methanol (15 mL), and a 1,4-dioxane hydrogen chloride solution (10 mL, 4 M) was added. The mixture was replaced with nitrogen and 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.

[0798] LCMS m / z=531 [M+H]+.

[0799] Preparation of e)(±)-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

[0800] (±)-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), and 3,3,3-trifluoropropyl trifluoromethanesulfonate (195.6 mg) was added, followed by N,N-diisopropylethylamine (137 mg). The mixture was stirred at 70°C overnight, quenched with water (20 mL), and 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, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 4 / 1 (V / V)) to give 140 mg of the title compound.

[0801] LCMS m / z=627 [M+H]+.

[0802] 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

[0803] Tert-butyl (±)-rel-(3S,4S)-5-(difluoromethoxy)-4-((3-(4-(methoxycarbonyl)phenyl)-1-(3,3,3-trifluoropropyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylate (140 mg) was dissolved in tetrahydrofuran / methanol (10 mL / 10 mL), and aqueous lithium hydroxide solution (5 mL, 2N) was added. The mixture was stirred at 70°C for 2 hours, concentrated to dryness under reduced pressure, and diluted aqueous hydrochloric acid was added to adjust the pH to neutral. The mixture was extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated brine (20 mL*1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to prepare sand. The mixture was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 130 mg of the title compound enantiomer.

[0804] 1H NMR (400MHz, DMSO-d6) δ11.16(s,1H),7.89(d,J=8.2Hz,2H),7.57(d,J=8.2Hz,2H),7.28(t ,J=2.7Hz,1H),6.94-6.54(m,2H),6.21(s,1H),4.59-4.47(m,1H),3.56(t,J=6.1Hz,1H),3 .19-3.07(m,1H),2.91(dd,J=21.7,10.3Hz,2H),2.56(d,J=6.9Hz,2H),2.36(s,3H),2.12( t,J=10.6Hz,1H),1.77(d,J=8.8Hz,1H),1.69(d,J=9.1Hz,1H),1.43(dd,J=7.8,5.5Hz,2H).

[0805] LCMS m / z=513.2[M+1]+.

[0806] 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 separated by chiral SFC to give 25-1, tr = 1.69 min and 25-2, tr = 2.40 min. (Separation method: chromatographic column: 250*20mm, 10μm; Mobile phase A: supercritical CO2; Mobile phase B: methanol (+0.1% 7.0mol / L ammonia methanol); A:B ratio: 75:25; Flow rate: 100mL / min; Detection wavelength: 214nm)

[0807] 25-1,tr=1.69min

[0808] 1H NMR (400MHz, DMSO-d6) δ11.18(s,1H),7.89(d,J=8.2Hz,2H),7.57(d,J=8.2Hz,2H),7.28(t,J=2.7Hz ,1H),6.72(dd,J=89.3,62.3Hz,2H),6.27-6.14(m,1H),4.53(td,J=9.6,4.3Hz,1H),3.55(dd,J=17. 3,11.2Hz,1H),3.12(td,J=10.0,3.7Hz,1H),2.91(dd,J=23.0,11.6Hz,2H),2.56(dd,J=15.0,8.3Hz ,2H),2.42-2.31(m,3H),2.11(dd,J=20.1,8.8Hz,1H),1.73(q,J=10.7Hz,2H),1.51(d,J=2.7Hz,2H).

[0809] 25-2,tr=2.40min.

[0810] 1 H NMR (400MHz, DMSO) δ11.19(s,1H),7.89(d,J=8.3Hz,2H),7.57(d,J=8.3Hz,2H),7.28(t,J=2.8 Hz,1H),6.72(dd,J=89.4,62.1Hz,2H),6.21(dd,J=3.0,2.0Hz,1H),4.53(td,J=9.8,4.5Hz,1H) ,3.56(t,J=6.1Hz,1H),3.12(td,J=10.4,3.9Hz,1H),2.91(dd,J=23.0,11.4Hz,2H),2.64-2.53 (m,2H),2.41-2.33(m,3H),2.11(dd,J=19.4,9.1Hz,1H),1.82-1.63(m,2H),1.49-1.36(m,2H).

[0811] 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

[0812] a) Preparation of 5-hydroxy-7-methyl-1H-indole-4-carbaldehyde

[0813] In an ice-water bath, tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (5.0 g) was added to a 250 mL two-necked flask, and then dichloromethane (130 mL) was added. The mixture was replaced with nitrogen and boron tribromide (21.66 g) was added dropwise. The temperature was slowly raised to room temperature and the reaction was allowed to proceed overnight. The reaction solution was poured into ice water and filtered. The filter cake was washed with dichloromethane, the chlorine solution was washed with saturated sodium bicarbonate, and then with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to make sand, and purified by column chromatography (mobile phase: petroleum ether / dichloromethane = 3 / 2 (V / V)) to give 1.2 g of the title compound.

[0814] LCMS m / z = 176.1 [M+H]+.

[0815] b) Preparation of tert-butyl 5-(difluoromethoxy)-4-hydroxy-7-methyl-1H-indole-1-carboxylate

[0816] 5-Hydroxy-7-methyl-1H-indole-4-carbaldehyde (1.2 g) was added to dichloromethane (40 mL), followed by addition of di-tert-butyl dicarbonate (4.48 g) and 4-dimethylaminopyridine (334 mg). The mixture was replaced with nitrogen and stirred at room temperature overnight. The reaction solution was concentrated to dryness under reduced pressure, and methanol (30 mL) and potassium carbonate (10 g) were added. The mixture was stirred at room temperature for 1 hour, and the pH was adjusted to weak acidity with dilute hydrochloric acid. 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 1.56 g of the title compound.

[0817] LCMS m / z = 276.1 [M+H]+.

[0818] c) Preparation of tert-butyl 4-formyl-5-(methoxy-d3)-7-methyl-1H-indole-1-carboxylate

[0819] 5-(Difluoromethoxy)-4-hydroxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (1.4 g), N,N-dimethylformamide (20 mL), deuterated iodomethane (2.21 g) and potassium carbonate (2.11 g) were added to a reaction flask and reacted at room temperature overnight. Water (30 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL*3). The organic phases were combined, washed with saturated brine (30 mL*1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to make sand. The mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 85 / 15 (V / V)) to give 873 mg of the title compound.

[0820] LCMS m / z = 293.2 [M+H] +.

[0821] d) Preparation of tert-butyl 4-hydroxy-5-(methoxy-d3)-7-methyl-1H-indole-1-carboxylate

[0822] Tert-butyl 4-formyl-5-(methoxy-d3)-7-methyl-1H-indole-1-carboxylate (800 mg), tetrahydrofuran (5 mL), and methanol (15 mL) were added to a reaction flask, cooled in an ice-water bath, and hydrogen peroxide (5 mL) and sulfuric acid (0.5 mL) were added dropwise in sequence. The mixture was stirred for another 2.5 hours in an ice-water bath, and a saturated sodium sulfite solution was slowly added to quench the reaction. The mixture was extracted with ethyl acetate (30 mL*3), and the organic phases were combined, washed with saturated brine (30 mL*1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to make sand. The mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 90 / 10 (V / V)) to obtain 723 mg of the title compound enantiomer.

[0823] e) Preparation of tert-butyl 4-((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-(methoxy-d3)-7-methyl-1H-indole-1-carboxylate

[0824] The enantiomers of (±)-rel-(3S,4R)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester were separated by chiral chromatography to obtain (3S,4R)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (t r = 20.33 min) and tert-butyl (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate (t r =16.51min), 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 of Experimental Example 8. (Separation method: Chromatographic column: 250*4.6mm, 5μm; mobile phase A: n-hexane; mobile phase B: ethanol; A:B: 90:10; flow rate: 1mL / min; detection wavelength: 254nm)

[0825] tert-Butyl (3S,4R)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate

[0826] 1H NMR (400MHz, DMSO-d6) δ7.88(d,J=8.3Hz,2H),7.42(d,J=8.3Hz,2H),4.75(d,J=4.2Hz,1H),4.00(d,J=14.8Hz,1H),3.84(s ,3H),3.77(d,J=11.7Hz,2H),3.34(s,1H),3.16(s,1H),2.82(d,J=11.1Hz,1H),1.69(dd,J=19.9,3.0Hz,2H),1.39(s,9H).

[0827] tert-Butyl (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate

[0828] 1 H NMR (400MHz, DMSO-d6) δ7.88(d,J=8.3Hz,2H),7.42(d,J=8.3Hz,2H),4.75(d,J=4.1Hz,1H),4.00(d,J=14.8Hz,1H),3.82(d ,J=15.6Hz,3H),3.76(d,J=11.9Hz,2H),3.37(s,1H),3.16(s,1H),2.82(d,J=11.1Hz,1H),1.81-1.59(m,2H),1.39(s,9H).

[0829] Tert-butyl 4-hydroxy-5-(methoxy-d3)-7-methyl-1H-indole-1-carboxylate (200 mg), tert-butyl (3R, 4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate (250.8 mg), and triphenylphosphine (187.7 mg) were added to a 50 mL three-necked flask, replaced with nitrogen for protection, anhydrous tetrahydrofuran (20 mL) was added, and diisopropyl azodicarboxylate (144.7 mg) was added dropwise under ice-water bath. The reaction system was slowly warmed to room temperature and stirred overnight. Water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (20 mLl*1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to make sand. The mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 90 / 10 (V / V)) to give 171 mg of the title compound.

[0830] f) Preparation of tert-butyl 5-(methoxy-d3)-4-(((3R,4R)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylate

[0831] tert-Butyl 4-((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-(methoxy-d3)-7-methyl-1H-indole-1-carboxylate (171 mg) was dissolved in 1,4-dioxane (2 mL), and a 1,4-dioxane hydrochloric acid solution (1 mL, 4 M) was added. The mixture was replaced with nitrogen and stirred at room temperature for 3.5 hours. Saturated sodium bicarbonate solution (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (20 mL*1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 141 mg of the title compound.

[0832] LCMS m / z = 498.3 [M+H]+.

[0833] 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-carboxylate

[0834] 5-(Methoxy-d3)-4-(((3R,4R)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (75 mg) was added to a 50 mL reaction bottle, and tetrahydrofuran (5 mL) and N,N-diisopropylethylamine (78.8 mg) were added. Nitrogen was replaced for protection, and 2,2-difluoroethyl trifluoromethanesulfonate (97 mg) was added. The mixture was stirred at 50°C overnight. The reaction solution was concentrated under reduced pressure and evaporated to dryness, and then purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 90 / 10 (V / V)) to give 61 mg of the title compound.

[0835] h) Preparation of 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5-(methoxy-d3)-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid

[0836] 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-carboxylate (60 mg) was dissolved in tetrahydrofuran / methanol (2 mL / 2 mL), and an aqueous lithium hydroxide solution (1 mL, 2N) was added. The mixture was stirred at 70°C for 3.5 hours, concentrated to dryness under reduced pressure, and a dilute aqueous hydrochloric acid solution was added to adjust the pH to neutral. The mixture was extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated brine (20 mL*1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to prepare sand. The mixture was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 25.2 mg of the title compound.

[0837] 1 H NMR (400MHz, DMSO-d6) δ12.80 (s, 1H), 10.83 (s, 1H), 7.91 (d, J = 8.2Hz, 2H), 7.58 (d, J=8.2Hz,2H),7.17(s,1H),6.62(s,1H),6.17(s,1H),6.33-5.96(m,1H),4.45(dd,J =15.1,9.0Hz,1H),3.13(td,J=10.2,3.8Hz,1H),2.93(dd,J=23.5,11.9Hz,2H),2.7 8(t,J=15.5Hz,2H),2.36(s,3H),2.32-2.18(m,1H),2.08-1.91(m,1H),1.70(s,2H).

[0838] LCMS m / z = 448.2 [M+H]+.

[0839] 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

[0840] Prepare by referring to the preparation method of Example 26, except that 2,2-difluoroethyl trifluoromethanesulfonate in step g is replaced by 2,2,2-trifluoroethyl trifluoromethanesulfonate.

[0841] 1H NMR (400MHz, DMSO-d6) δ12.76(s,1H),10.84(s,1H),7.91(d,J=7.9Hz,2H),7.58(d,J=7.9Hz,2H),7.17(s,1H),6.62(s,1H),6.18(s,1H),4 .49-4.45(m,1H),3.26(d,J=10.1Hz,3H),3.15(d,J=10.0Hz,1H),2.95(t,J=13.0Hz,2H),2.68(t,J=11.1Hz,1H),2.36(s,3H),1.71(s,2H).

[0842] LCMS m / z=466.2[M+H]+.

[0843] 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

[0844] a) Preparation of tert-butyl 4-((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate

[0845] Tert-butyl 5-(difluoromethoxy)-4-hydroxy-7-methyl-1H-indole-1-carboxylate (80 mg), tert-butyl (3R, 4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate (172 mg), and triphenylphosphine (134 mg) were added to a 25 mL three-necked flask, replaced with nitrogen for protection, anhydrous tetrahydrofuran (10 mL) was added, and diisopropyl azodicarboxylate (104 mg) was added dropwise under ice-water bath. The reaction system was slowly warmed to room temperature and stirred overnight. Water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (20 mL*1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to make sand. The mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 90 / 10 (V / V)) to give 80 mg of the title compound.

[0846] LCMS m / z = 631.3 [M+H]+.

[0847] b) Preparation of tert-butyl 5-(difluoromethoxy)-4-(((3R,4R)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylate

[0848] Tert-butyl 4-((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate (80 mg) was dissolved in 1,4-dioxane (5 mL), and a 1,4-dioxane hydrochloric acid solution (5 mL, 4 M) was added. The mixture was replaced with nitrogen and stirred at room temperature for 3.5 hours. Saturated sodium bicarbonate solution (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (20 mL*1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 65 mg of the title compound.

[0849] LCMS m / z=531 [M+H]+.

[0850] 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-carboxylate

[0851] tert-Butyl 5-(difluoromethoxy)-4-(((3R,4R)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylate (37 mg) was added to a 50 mL reaction bottle, and tetrahydrofuran (5 mL) and N,N-diisopropylethylamine (36 mg) were added. Nitrogen was replaced for protection, and 2,2,2-trifluoroethyl trifluoromethanesulfonate (49 mg) was added. The mixture was stirred at 50 ° C for 2 hours. The reaction solution was concentrated under reduced pressure and evaporated to dryness, and then purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 90 / 10 (V / V)) to give 28 mg of the title compound.

[0852] d) 4-((3R,4R)-4-((5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid

[0853] 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-carboxylate (28 mg) was dissolved in tetrahydrofuran / methanol (5 mL / 5 mL), and an aqueous lithium hydroxide solution (5 mL, 2N) was added. The mixture was stirred at 70°C for 2 hours, concentrated to dryness under reduced pressure, and a dilute aqueous hydrochloric acid solution was added to adjust the pH to neutral. The mixture was extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated brine (20 mL*1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to prepare sand. The mixture was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 12 mg of the title compound.

[0854] 1 H NMR (400MHz, DMSO-d6) δ12.83(s,1H),11.17(s,1H),7.89(d,J=8.3Hz,2H),7.57(d, J=8.3Hz,2H),7.29(t,J=2.8Hz,1H),6.94-6.56(t,1H),6.67(s,1H),6.28-6.21(m,1 H),4.56(td,J=9.5,4.8Hz,1H),3.24(d,J=10.2Hz,1H),3.19-3.11(m,1H),2.96(t, J=12.7Hz,2H),2.74(t,J=11.4Hz,1H),2.36(s,3H),1.80-1.66(m,2H),1.23(s,2H).

[0855] LCMS m / z=499[M+H]+.

[0856] Example 29: 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid

[0857] Prepare by referring to the preparation method of Example 28, except that 2,2,2-trifluoroethyl trifluoromethanesulfonate in step g is replaced by 2,2-difluoroethyl trifluoromethanesulfonate.

[0858] 1 H NMR (400MHz, DMSO-d6) δ12.77(s,1H),11.17(s,1H),7.89(d,J=8.3Hz,2H),7.57(d,J=8.3Hz,2H),7.28 (t,J=2.8Hz,1H),6.94-6.56(t,1H),6.67(s,1H),6.29-6.01(tt,J=4.2Hz,1H),6.22(dd,J=2.9,2.0Hz, 1H),4.53(td,J=9.7,5.0Hz,1H),3.14(td,J=10.4,3.9Hz,1H),2.94(dd,J=20.9,10.8Hz,2H),2.79(td ,J=15.9,3.0Hz,2H),2.56(t,J=11.3Hz,1H),2.36(s,3H),1.74(d,J=3.7Hz,1H),1.25(d,J=9.2Hz,2H).

[0859] LCMS m / z=481[M+H]+.

[0860] Example 30: 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((7-methyl-5-(trifluoromethoxy)-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid

[0861] a) Preparation of tert-butyl 4-((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0862] Tert-butyl 4-hydroxy-5-methoxy-7-methyl-1H-indole-1-carboxylate (1.49 g), tert-butyl (3R, 4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate (1.2 g), and triphenylphosphine (1.13 mg) were added to a 100 mL three-necked flask, replaced with nitrogen for protection, anhydrous tetrahydrofuran (40 mL) was added, and diisopropyl azodicarboxylate (869 mg) was added dropwise under ice-water bath. The reaction system was slowly warmed to room temperature and stirred overnight. Water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (20 mL*1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to make sand. The mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 85 / 15 (V / V)) to give 1.1 g of the title compound.

[0863] b) Preparation of methyl 4-((3R,4R)-4-((5-hydroxy-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoate

[0864] tert-Butyl 4-((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-methoxy-7-methyl-1H-indole-1-carboxylate (1.1 g) was added to a reaction flask, and nitrogen was replaced for protection. Dichloromethane (20 mL) was added, and boron tribromide (187.7 mg) was added dropwise under ice-water bath. The reaction system was slowly warmed to room temperature and the reaction was continued for about 6 hours. Triethylamine was added dropwise to the reaction mixture under ice-water bath until it became weakly alkaline. The reaction solution was concentrated to dryness under reduced pressure to obtain 0.8 g of the title compound.

[0865] LCMS m / z = 381.2 [M+H] +.

[0866] 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-carboxylate

[0867] 5-Hydroxy-7-methyl-1H-indole-4-carbaldehyde (0.8 g) was added to dichloromethane (40 mL), followed by addition of di-tert-butyl dicarbonate (2.0 g) and 4-dimethylaminopyridine (102 mg). The mixture was replaced with nitrogen and stirred at room temperature overnight. Water and ethyl acetate were added to extract the solution, 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.

[0868] d) tert-Butyl 4-((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-5-(trifluoromethoxy)-1H-indole-1-carboxylate

[0869] Tert-butyl 4-((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-hydroxy-7-methyl-1H-indole-1-carboxylate (447 mg), 2,8-difluoro-5-(trifluoromethyl)-5H-dibenzo[B,D]thiophen-5-ium 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 at room temperature overnight, quenched by the addition of water (20 mL), and extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (20 mL*1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to prepare sand. The mixture was then purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 90 / 10 (v / v)) to afford 158 mg of the title compound.

[0870] e) tert-Butyl 4-(((3R,4R)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-5-(trifluoromethoxy)-1H-indole-1-carboxylate

[0871] Tert-butyl 4-((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-5-(trifluoromethoxy)-1H-indole-1-carboxylate (158 mg) was dissolved in 1,4-dioxane (5 mL), and a 1,4-dioxane hydrochloric acid solution (5 mL, 4 M) was added. The mixture was replaced with nitrogen and stirred at room temperature for 3.5 hours. Saturated sodium bicarbonate solution (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (20 mL*1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 105 mg of the title compound.

[0872] 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-carboxylate

[0873] Tert-butyl 4-(((3R,4R)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-5-(trifluoromethoxy)-1H-indole-1-carboxylate (65 mg) was added to a 50 mL reaction flask, and tetrahydrofuran (5 mL) and N,N-diisopropylethylamine (61 mg) were added. Nitrogen was replaced for protection, and 2,2-difluoroethyl trifluoromethanesulfonate (75.8 mg) was added. The mixture was stirred at 50 ° C. for 2 overnight. The reaction solution was concentrated under reduced pressure and evaporated to dryness, and then purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 80 / 20 (V / V)) to give 49 mg of the title compound.

[0874] g) 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((7-methyl-5-(trifluoromethoxy)-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid

[0875] Tert-butyl 4-(((3R,4R)-1-(2,2-difluoroethyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-5-(trifluoromethoxy)-1H-indole-1-carboxylate (49 mg) was dissolved in tetrahydrofuran / methanol (5 mL / 5 mL), and an aqueous lithium hydroxide solution (5 mL, 2N) was added. The mixture was stirred at 70°C for 3.5 hours, concentrated to dryness under reduced pressure, and a dilute aqueous hydrochloric acid solution was added to adjust the pH to neutral. The mixture was extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated brine (20 mL*1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to prepare sand. The mixture was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to give 18.3 mg of the title compound.

[0876] 1H NMR (400MHz, DMSO-d6) δ12.92(s,1H),10.93(s,1H),8.00(d,J=8.4Hz,2H),7.67(d,J=8 .4Hz,2H),7.25(t,J=2.8Hz,1H),6.72(s,1H),6.44-6.02(m,2H),4.45(dd,J=16.1,9.5 Hz,1H),3.23(td,J=10.7,4.2Hz,1H),3.03(dd,J=21.3,10.7Hz,2H),2.85(dd,J=33.4, 21.7Hz,2H),2.43(d,J=17.8Hz,3H),2.39(d,J=14.4Hz,1H),1.80(s,2H),1.33(s,1H).

[0877] LCMS m / z=499.2[M+H]+.

[0878] 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

[0879] Prepare by referring to the preparation method of Example 30, except that 2,2-difluoroethyl trifluoromethanesulfonate in step f is replaced by 2,2,2-trifluoroethyl trifluoromethanesulfonate.

[0880] 1 H NMR(400MHz,DMSO-d6)δ12.90(s,1H),10.93(s,1H),8.00(d,J=8.1Hz,2H) ,7.68(d,J=8.1Hz,2H),7.27(s,1H),6.72(s,1H),6.28(s,1H),4.58(d,J=7 .4Hz,1H),3.36(d,J=9.2Hz,3H),3.24(dd,J=9.5,6.8Hz,1H),3.05(t,J=1 2.4Hz,2H),2.78(t,J=11.1Hz,1H),2.45(s,3H),1.81(s,1H),1.33(s,1H).

[0881] LCMS m / z=517.2[M+H]+.

[0882] 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-((2R,5R)-5-Ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-1-yl)benzoic acid

[0883] a) Preparation of methyl 5-ethoxypyridine-2-carboxylate

[0884] Methyl 5-hydroxypyridine-2-carboxylate (49 g), iodoethane (54.90 g), and potassium carbonate (66 g) were added to a reaction flask, followed by N,N-dimethylformamide (490 mL). The mixture was replaced with nitrogen for protection and stirred at room temperature overnight. Water was added to quench the reaction and the mixture was 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 obtain 54 g of the title compound.

[0885] LCMS m / z=182 [M+H]+.

[0886] b) Preparation of (5-ethoxypyridin-2-yl)methanol

[0887] Methyl 5-ethoxypyridine-2-carboxylate (54 g), sodium borohydride (33.82 g), and calcium chloride (46.6 g) were added to a reaction flask, followed by ethanol (540 mL). The mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain a residue. Water was added and the mixture was 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.

[0888] LCMS m / z=154 [M+H]+.

[0889] c) Preparation of 1-benzyl-5-ethoxy-2-(hydroxymethyl)pyridinium-1-ammonium bromide

[0890] (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 at 90° C. overnight. The mixture was cooled to room temperature, and the precipitated solid was collected by filtration and washed with ethyl acetate (3 x 20 mL) to obtain 64 g of the title compound.

[0891] LCMS m / z=244 [M+H]+.

[0892] d) Preparation of (1-benzyl-5-ethoxy-3,6-dihydro-2H-pyridin-2-yl)methanol

[0893] 1-Benzyl-5-ethoxy-2-(hydroxymethyl)pyridinium-1-ammonium bromide (40 g) was added to a reaction flask, and a mixed solution of methanol / tetrahydrofuran (200 mL / 200 mL) was added. The temperature was cooled to -60°C, and sodium borohydride (11.6 g) was added. The mixture was stirred for 2 hours while slowly warming to room temperature. Water (200 mL) was added to quench the reaction, 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 make sand. The mixture was purified by column chromatography (mobile phase: dichloromethane / methanol = 10 / 1 (V / V)) to give 29 g of the title compound.

[0894] LCMS m / z=248 [M+H]+.

[0895] e) Preparation of 1-benzyl-5-ethoxy-2-((methoxymethoxy)methyl)-1,2,3,6-tetrahydropyridine

[0896] (1-Benzyl-5-ethoxy-3,6-dihydro-2H-pyridin-2-yl)methanol (28 g) was added to the reaction flask, followed by tetrahydrofuran (311 mL), and sodium hydride (13.58 g) was added under ice bath, and stirred at 0°C for 30 minutes. Then, bromo(methoxy)methane (16.98 g) was added dropwise, and the reaction was slowly warmed to room temperature and stirred for 2 hours. Water / ice (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL*3). The organic phases were combined, washed with saturated brine (30 mL*1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to make sand, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 (V / V)) to obtain 29 g of the title compound.

[0897] LCMS m / z=292 [M+H]+.

[0898] f) Preparation of 5-ethoxy-2-((methoxymethoxy)methyl)piperidine

[0899] 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 methanol (193 mL). The atmosphere was replaced with hydrogen and stirred at room temperature for 3 hours. The mixture was filtered and the filter cake was washed with methanol (3 x 5 mL). The filtrate was concentrated to dryness under reduced pressure to obtain 16.2 g of the title compound.

[0900] LCMS m / z=204 [M+H]+.

[0901] g) Preparation of methyl 4-(5-ethoxy-2-((methoxymethoxy)methyl)piperidin-1-yl)benzoate

[0902] 5-Ethoxy-2-((methoxymethoxy)methyl)piperidine (5 g), methyl 4-bromobenzoate (4.23), tris(dibenzylidene-BASE acetone)dipalladium (2.55 g), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (4.59 g), and cesium carbonate (24.04 g) were added to a reaction flask, and toluene (50 mL) was added. The mixture was replaced with nitrogen for protection and stirred at 100° C. for 24 hours. The reaction solution was concentrated under reduced pressure to make sand and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 (V / V)) to obtain 5.6 g of the title compound.

[0903] LCMS m / z=338 [M+H]+.

[0904] h) Preparation of methyl 4-(5-ethoxy-2-(hydroxymethyl)piperidin-1-yl)benzoate

[0905] Methyl 4-(5-ethoxy-2-((methoxymethoxy)methyl)piperidin-1-yl)benzoate (5 g) was dissolved in methanol (20 mL). A solution of hydrogen chloride in 1,4-dioxane (4 M, 20.0 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to dryness under reduced pressure to obtain 3 g of the title compound. LCMS m / z = 294 [M+H]+.

[0906] i) Preparation of methyl 4-(5-ethoxy-2-formylpiperidin-1-yl)benzoate

[0907] Methyl 4-(5-ethoxy-2-(hydroxymethyl)piperidin-1-yl)benzoate (4 g) and Dess-Martin periodinane (8.67 g) were added to a reaction flask, followed by dichloromethane (40.0 mL). The mixture was stirred at room temperature for 2 hours, filtered, and the filter cake was washed with dichloromethane (3×10 mL). The filtrate was concentrated under reduced pressure to prepare sand, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to give 3 g of the title compound.

[0908] LCMS m / z=292 [M+H]+.

[0909] j) Preparation of methyl (Z)-4-(5-ethoxy-2-((2-toluenesulfonylhydrazide)methyl)piperidin-1-yl)benzoate

[0910] Methyl 4-(5-ethoxy-2-formylpiperidin-1-yl)benzoate (2 g) and p-toluenesulfonylhydrazide (1.4 g) were dissolved in methanol (20 mL) and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to prepare 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.

[0911] LCMS m / z=460 [M+H]+.

[0912] k) Preparation of tert-butyl (E)-4-((5-ethoxy-1-(4-(methoxycarbonyl)phenyl)piperidin-2-ylidene)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0913] Methyl (Z)-4-(5-ethoxy-2-((2-toluenesulfonylhydrazide)methyl)piperidin-1-yl)benzoate (600), tert-butyl 4-bromo-5-methoxy-7-methylindole-1-carboxylate (666.2), tris(dibenzylidene-BASE acetone)dipalladium (135.1 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (62.2 mg), and lithium tert-butoxide (313.5 mg) were added to a reaction flask, followed by the addition of 1,4-dioxane (10 mL). Under nitrogen protection, the mixture was stirred at 100°C for 3 hours, 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.

[0914] LCMS m / z=535 [M+H]+.

[0915] 1) Preparation of tert-butyl 4-((5-ethoxy-1-(4-(methoxycarbonyl)phenyl)piperidin-2-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0916] (E)-tert-Butyl 4-((5-ethoxy-1-(4-(methoxycarbonyl)phenyl)piperidin-2-ylidene)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (900 mg), sodium cyanoborohydride (126.9 mg), acetic acid (1.35 mL), and methanol (13.5 mL) were added to a reaction flask, stirred at room temperature for 20 hours, concentrated under reduced pressure to make sand, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 (V / V)) to give 80 mg of the title compound.

[0917] LCMS m / z=537 [M+H]+.

[0918] m) Preparation of 4-(5-ethoxy-2-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-1-yl)benzoic acid

[0919] Tert-butyl 4-((5-ethoxy-1-(4-(methoxycarbonyl)phenyl)piperidin-2-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (80 mg) was added to a reaction flask, followed by addition of aqueous lithium hydroxide solution (1.8 mL, 2N) and tetrahydrofuran (1 mL). The mixture was stirred at 70°C for 30 hours. The residue was acidified with concentrated sulfuric acid to pH 4. 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.

[0920] The isomeric mixture was separated 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 (Separation method: chromatographic column: CHIRALPAK-IG 2*25 cm; 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).

[0921] 32a-1,tr=5.47min

[0922] 1 H NMR (400MHz, DMSO-d6) δ10.86 (s, 1H), 7.82-7.73 (m, 2H), 7.30 (t, J = 2.8Hz, 1H), 7.03 (d, J = 8.8Hz, 2H), 6.71(s,1H),6.44(dd,J=3.1,1.9Hz,1H),4.30(s,1H),3.88(d,J=13.9Hz,1H),3.82(s,3H),3.67(s,1H ), 3.49-3.41(m,2H),3.21(t,J=11.8Hz,2H),2.75(dd,J=12.7,4.1Hz,1H),2.46-2.39(m,3H),2.08(dd,J=14.7,11.4Hz,1H),1.66(q,J=15.2,14.4Hz,2H),1.15(d,J=8.2Hz,1H),1.05(t,J=7.0Hz,3H). Lack of active hydrogen

[0923] 32a-2,tr=7.57min

[0924] 1H NMR(400MHz,DMSO-d6)δ12.04(s,1H),10.86(s,1H),7.77(d,J=8.9Hz,2H),7.30(t,J=2.8Hz,1H),7.03(d,J=8.8Hz,2H),6.71(s,1H),6.49-6.40(m,1H),4.30(s,1H),3.88(d,J=14.3Hz,1H),3.82(s,3H),3.67(s,1H),3.45(dt,J=7.0,3.3Hz,2H),3.19(d,J=11.8Hz,2H),2.75(dd,J=12.8,4.0Hz,1H),2.43(s,3H),2.08(t,J=13.3Hz,1H),1.73-1.59(m,2H),1.15(d,J=13.0Hz,1H),1.05(t,J=7.0Hz,3H).

[0925] 32a-3,tr=10.6min

[0926] 1 H NMR(400MHz,DMSO-d6)δ12.12(s,1H),10.87(s,1H),7.79(d,J=8.6Hz,2H),7.30(t,J=2.9Hz,1H),7.05(d,J=8.8Hz,2H),6.70(s,1H),6.37(t,J=2.4Hz,1H),4.28(d,J=10.2Hz,1H),3.88(dd,J=12.4,4.8Hz,1H),3.80(s,3H),3.60(qd,J=7.0,4.9Hz,2H),3.20(t,J=11.8Hz,1H),2.93(t,J=11.4Hz,1H),2.71(dd,J=12.8,4.3Hz,2H),2.43(s,3H),1.87(d,J=11.0Hz,1H),1.76(p,J=10.4Hz,1H),1.49-1.37(m,1H),1.16(t,J=6.9Hz,3H).

[0927] 32a-4,tr=15.2min

[0928] 1H NMR (400MHz, DMSO-d6) δ12.15(s,1H),10.87(s,1H),7.84-7.72(m,2H),7.30(t,J=2.8Hz,1H),7.05(d,J=9.1H z,2H),6.70(s,1H),6.37(dd,J=3.2,1.9Hz,1H),4.29(d,J=9.3Hz,1H),3.88(dd,J=12.4,4.8Hz,1H),3.80(s,3 H),3.60(qd,J=6.9,4.8Hz,2H),3.18(d,J=11.7Hz,2H),2.93(t,J=11.4Hz,1H),2.71(dd,J=12.7,4.1Hz,1H), 2.43(s,3H),1.87(d,J=9.5Hz,1H),1.76(p,J=11.6,10.7Hz,1H),1.43(d,J=5.6Hz,2H),1.16(t,J=7.0Hz,3H).

[0929] 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

[0930] a) Preparation of 4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzohydrazide

[0931] 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) and N,N'-carbonyldiimidazole (26.3 mg). The mixture was stirred at 50°C for 2 hours, and hydrazine hydrochloride (14.8 mg) and 1,8-diazobisspiro[5.4.0]undec-7-ene (41.2 mg) were added in sequence. The reaction was continued at 50°C overnight, the temperature was lowered, 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.

[0932] LCMS m / z = 477.2 [M+H]+.

[0933] 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

[0934] 4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzohydrazide (25 mg) was added to a reaction flask, followed by acetonitrile (10 mL), N,N'-carbonyldiimidazole (12.8 mg), and 1,8-diazobisspiro[5.4.0]undec-7-ene (32 mg). The mixture was heated to 50°C and reacted overnight. The reaction solution was concentrated under reduced pressure and sanded, and then purified by column chromatography (mobile phase: dichloromethane / methanol = 90 / 10 (V / V)) to give 14.4 mg of the title compound.

[0935] 1 H NMR (400MHz, DMSO-d6) δ12.43(s,1H),10.83(s,1H),7.76(d,J=8.2Hz,2H),7.63( d,J=8.2Hz,2H),7.17(s,1H),6.63(s,1H),6.20(s,1H),4.47(dd,J=15.4,8.5Hz, 1H),3.61(s,3H),3.23(d,J=10.0Hz,2H),3.14(td,J=10.1,3.6Hz,1H),3.02-2.8 7(m,2H),2.69(t,J=11.2Hz,1H),2.44(s,1H),2.36(s,3H),1.71(d,J=3.4Hz,2H).

[0936] LCMS m / z=503.2[M+H]+.

[0937] Experimental Example 1: Human complement factor B TR-FRET assay

[0938] The inhibitory activity of the compounds against complement factor B was tested in a competitive binding experiment using Cy5 fluorescently 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-sulfoindolin-2-ylidene)penta-1,3-dien-1-yl)-1-ethyl-3,3-dimethyl-5-sulfo-3H-indol-1-ium (prepared with reference to Biological Example 2 of CN201480050471.1) as probes. Complement factor B (ComplementTech, A135) and EZ-Link TM After incubation on ice for 2 hours, 1 M Tris (pH 7.5) was added to terminate the reaction. TM Biotin-labeled complement factor B was purified twice using a desalt spin column (Thermo, 89890). During the experiment, biotin-labeled complement factor B at a final concentration of 25 nM was incubated with different concentrations of compounds in a buffer solution (PBS containing 10 mM MgCl2 and 0.05% Chaps) at 4°C for 30 minutes. Cy5 fluorescent-labeled probes and europium chelate-labeled streptavidin (PerkinElmer, AD0060) were added at final concentrations of 75 nM and 0.225 nM, respectively, and reacted at 4°C for 2 hours. After the reaction, the time-dependent fluorescence energy transfer (TR-FRET) data was read on a microplate reader (Tecan, SPARK; 337 nm excitation light, 615 nm and 665 nm excitation light) to determine the IC 50 , the test results are shown in Table 1 below.

[0939] Reference substance LNP023: synthesized with reference to Example 26 of CN201480050471.1, with the following structure:

[0940] Table 1 Inhibitory activity of compounds against complement factor B

[0941] Experimental Example 2: Serum Alternative Pathway Complement Deposition Experiment

[0942] use Complement System Alternative Pathway Kit ( Complement system alternative pathway AP330 RUO) was used to test the inhibitory activity of compounds against the alternative complement pathway in human serum. Human serum was diluted 18-fold using the kit's diluent, Diluent. 130 μL of diluted serum was added to a 96-well plate at a rate of 130 μL / well. The test compound was then titrated using a compound titrator (Tecan, D300e). The starting concentration of the test compound was 10 μM, and the assay was performed using 3-fold dilutions at six concentration points in a single-well assay. DMSO was uniformly adjusted to 0.1% in all wells. Positive control wells were pre-incubated with 0.1% DMSO and 130 μL of diluted serum, while negative control wells were pre-incubated with 0.1% DMSO and 130 μL of Diluent. The mixture was transferred to a 96-well plate provided in the kit at 100 μL per well and incubated at 37°C for 60 minutes. The liquid was discarded, and 300 μL of the kit's wash buffer was added to each well, washed three times, followed by 100 μL of the conjugated antibody Conjugate provided in the kit per well, incubated at room temperature for 30 minutes. The liquid was removed, and 300 μL of the kit's wash buffer was added to each well, washed three times, followed by 100 μL of the substrate solution per well, incubated at room temperature for 30 minutes. The absorbance was read at 405 nm using a microplate reader (Tecan, SPARK). The experimental data are shown in Table 2 below.

[0943] Table 2 Complement deposition results of serum alternative pathway

[0944] Experimental Example 3: Pharmacokinetic Study in Mice

[0945] Experimental purpose: To investigate the plasma pharmacokinetics of the compound of the present invention in male ICR (CD-1) mice after single intravenous injection and oral administration.

[0946] Experimental animals: male ICR (CD-1) mice, weighing 32-35 g; supplier: Weitong Lihua Laboratory Animal Technology Co., Ltd.

[0947] Experimental procedure: Injection (IV): Oral administration (PO): The dose is 10 mg / kg (solvent: water (containing 0.5% methylcellulose (w / v) and 0.5% Tween 80 (w / v))).

[0948] Sample Collection: 40 μL of blood was collected from the experimental animals via the orbital orbital ventricle at each designated time point. The whole blood samples were placed in anticoagulant tubes containing EDTA-K2. The whole blood samples were centrifuged at 1500 g for 10 min to separate the plasma. The upper plasma layer was collected into a sample tube for LC-MS / MS analysis.

[0949] Data analysis: WinNonlin TM The non-compartmental model of the pharmacokinetic software Version 6.3 (Pharsight, Mountain View, CA) was used to process plasma concentrations, and the pharmacokinetic parameters Cl and T were calculated using the linear-log trapezoidal method. 1 / 2 ,C max ,AUC 0-24 , the results are shown in the table below.

[0950] Table 3 Pharmacokinetic study results

[0951] Experimental Example 4: Collagen Antibody-Induced Mouse Arthritis Model

[0952] Objective: To investigate the pharmacological effects of the compounds of this invention on collagen antibody- and lipopolysaccharide-induced arthritis (CAIA) in BALB / c mice. Animals: Male BALB / c mice, 6-8 weeks old, 18-20 g; Supplier: Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.

[0953] Experimental process:

[0954] 1. Induction of the mouse CAIA model: On day 0, all mice were injected with 0.15 mL of Arthrogen-CIA 5 clone mixed type II collagen antibody (10 mg / mL, Chondrex) via the tail vein. On day 3, mice were injected intraperitoneally with 0.2 mL of LPS (E. coli 0111: B4 lipopolysaccharide, 0.5 mg / mL; Chondrex).

[0955] 2. Administration:

[0956] Table 4 Dosage groups and dosing regimens a: 0.5% methylcellulose (w / v), 0.5% Tween N80 (v / v) aqueous solution b: The drug was administered only once in the morning on the day of collection, and blood collection data analysis was completed within 4 hours after administration:

[0957] Data were analyzed using One-way ANOVA / Dunnett's in Graphpad Prism and Repeated Measurement ANOVA / Bonferroni in SPSS. P < 0.05 was considered significant.

[0958] Arthritis Scoring: Starting from the day of modeling, the limbs of each group of animals were observed three times a week for the development of arthritis until the end of the experiment. Scoring was performed on a scale of 0 to 4, depending on the severity of the lesions (redness and swelling). The scoring criteria were as follows: 0, no signs of erythema or swelling; 1, erythema or mild swelling of the midfoot (ankle); 2, erythema and mild swelling extending from the ankle to the midfoot; 3, erythema and moderate swelling from the ankle to the metatarsal joints; 4, erythema and severe redness and swelling from the toes or fingers to the ankle or wrist.

[0959] Joint swelling: Starting from the day of modeling, the thickness of the left and right foot pads of the animals was measured using a screw micrometer (Mitutoyo, 0-25 mm, minimal 0.001 mm) three times a week until the end of the experiment.

[0960] Experimental results: The experimental data are shown in Table 5, Table 6 and Figure 1, Figure 2.

[0961] Table 5 Arthritis score

[0962] Table 6 Foot pad thickness (mm)

[0963] Experimental conclusion: According to the scoring results, compared with the model group, the compounds of the present invention can significantly improve the severity of arthritis in model animals and reduce joint swelling, and the effect is better than LNP023.

[0964] Experimental Example 5: Efficacy Study of the Test Substance in CAIA Mouse Model

[0965] Experimental purpose: To evaluate the efficacy of the test drug on collagen antibody and lipopolysaccharide-induced arthritis (CAIA) in BALB / c mice.

[0966] Experimental animals: BALB / c mice, male, 6-8 weeks, 18-20 g; Supplier: Shanghai Jihui Experimental Animal Breeding Co., Ltd.

[0967] Experimental process:

[0968] 1. Induction of the mouse CAIA model: On day 0, all mice were injected with 0.15 mL of Arthrogen-CIA 5 clone mixed type II collagen antibody (10 mg / mL, Chondrex) via the tail vein. On day 3, mice were injected intraperitoneally with 0.2 mL of LPS (E. coli 0111: B4 lipopolysaccharide, 0.5 mg / mL; Chondrex).

[0969] 2. Administration:

[0970] Table 7 Dosage groups and dosing regimens a: 0.5% methylcellulose (w / v), 0.5% Tween 80 (v / v) aqueous solution

[0971] Experimental data are expressed as mean ± standard error (SEM). Data were analyzed using One-way ANOVA / Dunnett's in Graphpad Prism and Repeat Measurement ANOVA / Bonferroni in SPSS. P < 0.05 was considered significant.

[0972] Arthritis Scoring: Starting from the day of modeling, the limbs of each group of animals were observed three times a week for the development of arthritis until the end of the experiment. Scoring was performed on a scale of 0 to 4, depending on the severity of the lesions (redness and swelling). The scoring criteria were as follows: 0, no signs of erythema or swelling; 1, erythema or mild swelling of the midfoot (ankle); 2, erythema and mild swelling extending from the ankle to the midfoot; 3, erythema and moderate swelling from the ankle to the metatarsal joints; 4, erythema and severe redness and swelling from the toes or fingers to the ankle or wrist.

[0973] Scoring AUC: After the experiment, GraphPad Prism 8.4.3 software was used to analyze the mean arthritis score for each group of animals at each time point. Using the Area under the curve (AUC) function in the XY analysis mode, the AUC for the arthritis score was calculated for each group. A higher AUC indicates greater arthritis severity. The AUC results are shown in Table 8 and Figure 3.

[0974] Table 8 Arthritis score AUC

[0975] Experimental conclusion: According to the scoring results, compared with the model group, the compound of the present invention can significantly improve the degree of arthritis in the model animals, and the scoring AUC is significantly lower than that of LNP023.

[0976] Experimental Example 6: X-ray single crystal diffraction experiment

[0977] 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 glass vial, and 0.6ml of acetone / water (2:1, v / v) mixed solvent was added. After dissolution, it was filtered into another clean vial, sealed with a sealing film, and a small hole was pierced with a syringe needle. After standing at room temperature for evaporation for 3 days, a rod-shaped single crystal sample was obtained.

[0978] After the diffraction data were integrated and reduced using the SAINT program, the data were empirically corrected for absorption using the SADABS program. The single crystal structure was directly solved using SHELXT2014 and refined using the least squares method. The hydrogen atom refinement process was obtained using isotropic calculations. The hydrogen atoms on CH were obtained by computational hydrogenation and refined using a riding model. Figure 4 and Table 9 below are 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 of Example 13a-2. The Flack constant was 0.10(9), and C11 and C15 were in the R configuration.

[0979] Table 9 Single crystal diffraction data

[0980] Experimental Example 7: X-ray single crystal diffraction experiment

[0981] Preparation method: Compound 4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid (14a-2,t r =2.73 min) at a high temperature (about 60° C.), the solvent being acetonitrile (1 mL). The clear solution was drawn up with a 2 mL syringe while still hot, and filtered through a hydrophilic PTFE syringe filter (13 mm*0.45 μm). The filtrate was transferred to another clean 3 mL glass bottle, which was then transferred to room temperature and allowed to stand. A transparent single crystal was obtained after one day.

[0982] After the diffraction data were integrated and reduced using the SAINT program, the data were empirically corrected for absorption using the SADABS program. The single crystal structure was directly resolved using SHELXT2014, and the structure was refined using the least squares method. The hydrogen atom refinement process was obtained using isotropic calculations. The hydrogen atoms on CH were obtained by computational hydrogenation and refined using a riding model. The Flack constant was 0.09 (10), and the chirality of C11 and C17 was R configuration. Figure 5 and Table 10 below are 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 of Example 14a-2.

[0983] Table 10 Single crystal diffraction data

[0984] Experimental Example 8: X-ray single crystal diffraction experiment

[0985] Preparation method: Prepare the compound (3R, 4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (t r =16.51min) at high temperature (about 50°C) to form a saturated solution in 1 mL of ethanol / water (1:2, v / v). The solution was then transferred to room temperature and allowed to stand for one day, yielding a transparent single crystal.

[0986] After the diffraction data were integrated and reduced using the SAINT program, the data were empirically corrected for absorption using the SADABS program; the single crystal structure was directly resolved using SHELXT2014, and the structure was refined using the least squares method. The hydrogen atom refinement process was performed using isotropic calculations. The hydrogen atoms on N and O were obtained through residual electron density, and the hydrogen atoms on CH were obtained through calculated hydrogenation, and the riding model was used for refinement. The Flack constant was 0.08 (7), C10 was R-configuration, and C14 was S-configuration. Figure 6 and Table 11 below are the intermediate compounds (3R, 4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (t r =16.51min) of the dihydrate single crystal result.

[0987] Table 11 Single crystal diffraction data

[0988] The foregoing descriptions of specific exemplary embodiments of the present invention are for purposes of illustration and description. These descriptions are not intended to limit the invention to the precise forms disclosed, and it is apparent that many variations and modifications are possible in light of the foregoing teachings. The exemplary embodiments have been selected and described for the purpose of explaining the specific principles of the invention and their practical application, thereby enabling those skilled in the art to realize and utilize a variety of exemplary embodiments of the invention and various options and modifications. The scope of the invention is intended to be defined by the claims and their equivalents.

Claims

1. A compound represented by general formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof: in: X is selected from CH2, NH, S, O or Y and Z are each independently selected from CH or N; When X is CH2, Z is N; R 1 is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl or C3-C6 heterocyclyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally substituted with halogen, oxo, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl or C3-C6 halocycloalkyl; R 2 is hydrogen, or R 1 and R 2 The atoms to which they are attached form a C10-15 heterocyclic group, which is optionally substituted with halogen; R 3 Selected from C1-C6 alkyl or C3-C6 cycloalkyl, the C1-C6 alkyl is optionally substituted by deuterium or halogen.

2. The compound according to claim 1, its isomer or a pharmaceutically acceptable salt thereof, wherein: The compound is represented by the general formula (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, halogen or C1-C3 alkyl; m is 0, 1 or 2.

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

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

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

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

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

9. The following compound, its isomer or its pharmaceutically acceptable salt, wherein: The compound has the following structure:

10. The following compound, its isomer or its pharmaceutically acceptable salt, wherein: The compound has the following structure:

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

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

13. The use according to claim 12, wherein The disease or disease state mediated by complement factor B is selected from one or more of ophthalmic diseases, autoimmune diseases, kidney system-related diseases, respiratory system diseases, and cardiovascular diseases; preferably arthritis.

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