Dosage composition of complement factor b inhibitor

Abstract

The present invention belongs to the field of biotechnology. Disclosed is a dosage composition of a complement factor B inhibitor. Specifically, the present invention provides a pharmaceutical composition comprising a compound represented by formula I, an isomer thereof, or a pharmaceutically acceptable salt thereof in a unit dosage form, wherein the mass of the compound or the pharmaceutically acceptable salt thereof is 5-1500 mg based on the free base.

Description

Dose compositions of complement factor b inhibitors

[0001] Cross-reference to related applications

[0002] This application claims the benefit of Chinese Patent Application No. CN202410905165.7, filed July 05, 2024; the entire contents of which are incorporated herein by reference. TECHNICAL FIELD

[0003] The present invention belongs to the field of biotechnology, in particular to dose compositions of complement factor B inhibitors. BACKGROUND

[0004] The complement system is part of the host innate immune system that participates in the lysis of foreign cells, enhances antigen phagocytosis, agglutinates antigen carriers, and attracts macrophages and neutrophils, and is an important innate immune component for the human body to resist infections of exogenous pathogens, bacteria, and parasites, etc. At the same time, the complement system is also an important component of the connection between innate immunity and adaptive immunity. Complement is composed of Ife plasma proteins, including soluble proteins, membrane-bound proteins, and complement receptors, and is mainly produced by membrane proteins expressed on the liver or cell surface, and plays a role in the plasma, tissue, or cells. The complement system is an important regulator of inflammatory reactions and tissue damage, composed of more than 20 serum proteins and cell surface proteins. The complement system includes complement intrinsic components and various regulatory proteins. The complement intrinsic components include C1-C9, of which C3 has the highest content. The complement system is mainly activated through three pathways: the classical pathway (CP), the lectin pathway (LP), and the alternative pathway (AP).

[0005] Under normal physiological conditions in healthy individuals, the AP pathway is always in a low level of activation state to monitor the invasion state of foreign pathogens at any time. Complement proteins are distributed on the surface of apoptotic cells, and complement activation is strictly regulated, only for the clearance of apoptotic cells, without further activating other innate immune or adaptive immune responses. In the case of infection of foreign pathogens, the complement system is fully activated, producing inflammatory reactions, opsonization, or phagocytosis, etc., to destroy pathogens and ultimately activate adaptive immune responses. Both the inefficiency and the excessive stimulation of complement can be harmful to the human body and are associated with increased susceptibility to infections or non-infectious diseases, and dysfunction or overactivation of complement 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 of which are 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.

[0006] Complement Factor B (FB) is a key protein involved in the activation of AP, inhibiting FB activity can prevent the activation of AP pathway, and does not interfere with CP and LP pathways, which can avoid the risk of increased infection due to complement system inhibition. PCT / CN2024 / 071419 provides a class of complement factor B inhibitors. SUMMARY

[0007] All the contents involved in the patent PCT / CN2024 / 071419 are added to the present application by citation.

[0008] The purpose of the present application is to provide a pharmaceutical composition in unit dosage form of a complement factor B inhibitor.

[0009] In one aspect, the present application provides a pharmaceutical composition in unit dosage form comprising a compound represented by formula I, an isomer thereof or a pharmaceutically acceptable salt thereof, and the structure of formula (I) is as follows:

[0010] Wherein:

[0011] The compound or its pharmaceutically acceptable salt is 5-1500mg in free base.

[0012] X is selected from S or O;

[0013] R 1 selected from C1-C6 alkyl, said C1-C6 alkyl is optionally substituted by halogen;

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

[0015] In a preferred aspect of the present application, the compound represented by general formula (I) is further represented by general formula (I-1), (I-2), (I-3) or (I-4):

[0016] Wherein:

[0017] X, R 1 , R 3 are as defined above.

[0018] In a preferred aspect of the present application, X is selected from S.

[0019] In a preferred aspect of the present application, X is selected from O.

[0020] In a further preferred aspect of the present application, R 1selected from the group consisting of C1-C3 alkyl, said C1-C3 alkyl being optionally substituted with 1, 2, or 3 substituents selected from the group consisting of fluorine, chlorine, bromine, or iodine.

[0021] In a preferred embodiment of the present application, R 1 selected from the group consisting of C1-C3 alkyl, said C1-C3 alkyl being optionally substituted with 1, 2, or 3 substituents selected from the group consisting of fluorine, chlorine, bromine, or iodine.

[0022] In a further preferred embodiment of the present application, R 1 selected from the group consisting of methyl, ethyl, or propyl, said methyl, ethyl, or propyl being optionally substituted with 1, 2, or 3 fluorine.

[0023] In a further preferred embodiment of the present application, R 1 selected from the group consisting of

[0024] In a further preferred embodiment of the present application, R 1 selected from the group consisting of

[0025] In a further preferred embodiment of the present application, R 3 selected from the group consisting of C1-C3 alkyl, said C1-C3 alkyl being optionally substituted with deuterium, fluorine, chlorine, bromine, or iodine.

[0026] In a further preferred embodiment of the present application, R 3 selected from the group consisting of C1-C3 alkyl, said C1-C3 alkyl being optionally substituted with 1, 2, or 3 substituents selected from the group consisting of deuterium, fluorine, chlorine, bromine, or iodine.

[0027] In a further preferred embodiment of the present application, R 3 selected from the group consisting of methyl, said methyl being optionally substituted with deuterium or fluorine.

[0028] In a further preferred embodiment of the present application, R 3 selected from the group consisting of methyl, said methyl being optionally substituted with 1, 2, or 3 substituents selected from the group consisting of deuterium or fluorine.

[0029] In a further preferred embodiment of the present application, R 3 selected from the group consisting of methyl, -CD3, or preferably methyl.

[0030] In a further preferred embodiment of the present application, the compound has the following structure:

[0031] In a further preferred embodiment of the present application, the compound has the following structure:

[0032] In a further preferred embodiment of the present application, the compound has the following structure:

[0033] In a further preferred embodiment of the present application, the compound has the following structure:

[0034] In a preferred embodiment of the present application, the isomer of the compound is resolved by chiral SFC with a retention time of 1.95 min, and the specific resolution method is as follows:

[0035] Column: 250*20mm, 10pm;

[0036] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonium methanol); A:B:75:25;

[0037] Flow rate: 100 mL / min;

[0038] Detection wavelength: 214 nm.

[0039] In a preferred embodiment of the present application, the isomer of the compound is resolved by chiral SFC with a retention time of 2.73 min, and the specific resolution method is as follows:

[0040] Column: 250*25mm, 10pm;

[0041] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonium methanol); A:B:75:25;

[0042] Flow rate: 100 mL / min;

[0043] Detection wavelength: 214 nm.

[0044] In a preferred embodiment of the present application, the isomer of the compound is resolved by chiral SFC with a retention time of 2.00 min, and the specific resolution method is as follows:

[0045] Column: 250*20mm, 10pm;

[0046] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonium methanol); A:B:75:25;

[0047] Flow rate: 100 mL / min;

[0048] Detection wavelength: 214 nm.

[0049] In a preferred aspect of the present application, the isomer of compound is resolved by chiral SFC with a retention time of 3.60 min, and the specific resolution method is as follows:

[0050] Column: 250*20mm, 10μm;

[0051] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonium methanol); A:B: 70:30;

[0052] Flow rate: 100 mL / min;

[0053] Detection wavelength: 214 nm.

[0054] In a preferred aspect of the present application, the isomer of compound is resolved by chiral SFC with a retention time of 1.39 min, and the specific resolution method is as follows:

[0055] Column: 250*20mm, 10μm;

[0056] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonium methanol); A:B: 75:25;

[0057] Flow rate: 100 mL / min;

[0058] Detection wavelength: 214 nm.

[0059] In a preferred aspect of the present application, the isomer of compound is resolved by chiral SFC with a retention time of 2.40 min, and the specific resolution method is as follows:

[0060] Column: 250*20mm, 10μm;

[0061] Mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonium methanol); A:B: 75:25;

[0062] Flow rate: 100 mL / min;

[0063] Detection wavelength: 214 nm.

[0064] Another aspect of the present application provides a pharmaceutical composition comprising a unit dosage form of a compound represented by formula II or a pharmaceutically acceptable salt thereof, and the structure of formula (II) is as follows:

[0065] wherein:

[0066] The compound or pharmaceutically acceptable salt thereof is present in an amount of 5-1500 mg as free base;

[0067] R 1 selected from

[0068] In a preferred embodiment of the application, the compound has the structure:

[0069] In a preferred embodiment of the application, the compound has the structure:

[0070] In a preferred embodiment of the application, the compound has the structure:

[0071] In a preferred embodiment of the application, the compound or pharmaceutically acceptable salt thereof is present in an amount of 10-1200 mg as free base in the unit dosage form of the pharmaceutical composition.

[0072] In a preferred embodiment of the application, the compound or pharmaceutically acceptable salt thereof is present in an amount of 20-1200 mg as free base in the unit dosage form of the pharmaceutical composition.

[0073] In a preferred embodiment of the application, the compound or pharmaceutically acceptable salt thereof is present in an amount of 25-1200 mg as free base in the unit dosage form of the pharmaceutical composition.

[0074] In a preferred embodiment of the application, the compound or pharmaceutically acceptable salt thereof is present in an amount of 50-1000 mg as free base in the unit dosage form of the pharmaceutical composition.

[0075] In a preferred embodiment of the application, the compound or pharmaceutically acceptable salt thereof is present in an amount of 50-800 mg as free base in the unit dosage form of the pharmaceutical composition.

[0076] In a preferred embodiment of the application, the compound or pharmaceutically acceptable salt thereof is present in an amount of 75-600 mg as free base in the unit dosage form of the pharmaceutical composition.

[0077] In a preferred embodiment of the application, the compound or pharmaceutically acceptable salt thereof is present in an amount of 100-600 mg as free base in the unit dosage form of the pharmaceutical composition.

[0078] In a preferred embodiment of the application, the pharmaceutical composition in unit dosage form contains 100-400 mg of the compound or a pharmaceutically acceptable salt thereof as free base.

[0079] In a preferred embodiment of the application, the pharmaceutical composition in unit dosage form contains 100-200 mg of the compound or a pharmaceutically acceptable salt thereof as free base.

[0080] In a preferred embodiment of the application, the pharmaceutical composition in unit dosage form contains 25 mg of the compound or a pharmaceutically acceptable salt thereof as free base.

[0081] In a preferred embodiment of the application, the pharmaceutical composition in unit dosage form contains 50 mg of the compound or a pharmaceutically acceptable salt thereof as free base.

[0082] In a preferred embodiment of the application, the pharmaceutical composition in unit dosage form contains 100 mg of the compound or a pharmaceutically acceptable salt thereof as free base.

[0083] In a preferred embodiment of the application, the pharmaceutical composition in unit dosage form contains 150 mg of the compound or a pharmaceutically acceptable salt thereof as free base.

[0084] In a preferred embodiment of the application, the pharmaceutical composition in unit dosage form contains 200 mg of the compound or a pharmaceutically acceptable salt thereof as free base.

[0085] In a preferred embodiment of the application, the pharmaceutical composition in unit dosage form contains 250 mg of the compound or a pharmaceutically acceptable salt thereof as free base.

[0086] In a preferred embodiment of the application, the pharmaceutical composition in unit dosage form contains 300 mg of the compound or a pharmaceutically acceptable salt thereof as free base.

[0087] In a preferred embodiment of the application, the pharmaceutical composition in unit dosage form contains 350 mg of the compound or a pharmaceutically acceptable salt thereof as free base.

[0088] In a preferred embodiment of the application, the pharmaceutical composition in unit dosage form contains 400 mg of the compound or a pharmaceutically acceptable salt thereof as free base.

[0089] In a preferred embodiment of the application, the pharmaceutical composition in unit dosage form contains 500 mg of the compound or a pharmaceutically acceptable salt thereof as free base.

[0090] In a preferred embodiment of the present application, the compound or its pharmaceutically acceptable salt in the unit dosage form of the pharmaceutical composition has a mass of 600 mg as free base.

[0091] In a preferred embodiment of the present application, the compound or its pharmaceutically acceptable salt in the unit dosage form of the pharmaceutical composition has a mass of 900 mg as free base.

[0092] In a preferred embodiment of the present application, the compound or its pharmaceutically acceptable salt in the unit dosage form of the pharmaceutical composition has a mass of 1200 mg as free base.

[0093] In a preferred embodiment of the present application, the mass of the compound or its pharmaceutically acceptable salt as free base in the unit dosage form of the pharmaceutical composition accounts for 0.1% to 99.9% of the total mass of the pharmaceutical composition; preferably 5% to 90%; more preferably 20% to 90%; further preferably 25% to 85.7%; and more further preferably 50% to 60%.

[0094] In a preferred embodiment of the present application, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers, and the mass of the pharmaceutically acceptable carrier(s) accounts for 0.1% to 99.9% of the total mass of the pharmaceutical composition; preferably 5% to 90%; and more preferably 10% to 75%.

[0095] In the present application, the pharmaceutical composition can be administered by any applicable route or method, such as orally or parenterally (e.g., intravenously).

[0096] In the present application, the unit dosage form of the pharmaceutical composition is a solid preparation or a liquid preparation.

[0097] In a preferred embodiment of the present application, the unit dosage form of the pharmaceutical composition is a solid preparation.

[0098] In a preferred embodiment of the present application, the unit dosage form of the pharmaceutical composition is a tablet.

[0099] In a preferred embodiment of the present application, the unit dosage form of the pharmaceutical composition is a dry suspension.

[0100] In another aspect, the present application also provides use of the aforementioned unit dosage form of the pharmaceutical composition in the preparation of a medicament for preventing and / or treating a complement factor B-mediated disease or condition.

[0101] In another aspect, the present application also provides a method for preventing and / or treating a complement factor B mediated disease or condition, comprising administering to a subject in need thereof an effective amount of the aforementioned pharmaceutical composition in unit dosage form.

[0102] In another aspect, the present application also provides the aforementioned pharmaceutical composition in unit dosage form of the present application for preventing and / or treating a complement factor B mediated disease or condition.

[0103] In another aspect, the present application also provides the aforementioned pharmaceutical composition in unit dosage form for use in preventing and / or treating a complement factor B mediated disease or condition in a subject in need thereof.

[0104] In a preferred embodiment of the present application, the complement factor B mediated disease or condition is selected from one or more of ophthalmic diseases, autoimmune diseases (including arthritis), diseases related to the kidney system, diseases of the respiratory system, cardiovascular diseases.

[0105] In some specific embodiments, the complement factor B mediated disease or condition is arthritis.

[0106] In some specific embodiments, the complement factor B mediated disease or condition is Paroxysmal Nocturnal Hemoglobinuria (PNH).

[0107] In some specific embodiments, the compound or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof in an amount of 10-1200 mg in mass as free base.

[0108] In a preferred embodiment of the present application, the compound or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof in an amount of 20-1200 mg in mass as free base.

[0109] In a preferred embodiment of the present application, the compound or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof in an amount of 25-1200 mg in mass as free base.

[0110] In a preferred embodiment of the present application, the compound or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof in an amount of 50-1000 mg in mass as free base.

[0111] In a preferred embodiment of the present application, the compound or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof in an amount of 50-800 mg in mass as free base.

[0112] In a preferred embodiment of the present application, the compound or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof in an amount of 100-600 mg in mass as a free base.

[0113] In a preferred embodiment of the present application, the compound or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof in an amount of 100-400 mg in mass as a free base.

[0114] In a preferred embodiment of the present application, the compound or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof in an amount of 100-200 mg in mass as a free base.

[0115] In some embodiments, the pharmaceutical composition in unit dosage form is administered orally.

[0116] In some embodiments, the pharmaceutical composition in unit dosage form is administered parenterally.

[0117] In some embodiments, the pharmaceutical composition in unit dosage form is administered intravenously.

[0118] Related Definitions

[0119] Unless otherwise defined, the following terms used in the specification and claims have the following meanings:

[0120] As used herein and unless otherwise indicated, the terms "comprising," "including," "having," "containing," and their grammatical variants, are generally understood to be open-ended and non-limiting, e.g., not excluding additional unrecited elements or steps.

[0121] Unless otherwise defined, the following terms used in the specification and claims have the following meanings:

[0122] The "compounds" of the present application can be asymmetric, e.g., having one or more chiral centers. Unless otherwise indicated, the "compounds" of the present application can be any one of the isomers or a mixture of two or more isomers. The "compounds" of the present application include isomers (e.g., stereoisomers), enantiomers, diastereomers, racemates, or mixtures of two or more isomers of the described compounds.

[0123] The term "isomers" refers to different compounds that have the same molecular formula, but different arrangements of atoms. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of one another. A 1 : 1 mixture of a pair of enantiomers is a "racemic" mixture. The term is used to refer to a racemic mixture where appropriate. The use of "rel" indicates that the diastereomeric orientation is known, but the absolute stereochemistry is not. For example, the name "rel-3S,4S" as used herein means that the relative stereochemistry at the 3 and 4 positions is either 3S,4S or 3R,4R. In the present application, the order of the aliphatic ring positions is as follows: Absolute stereochemistry is not specified but optical rotation and / or chiral chromatographic conditions will indicate which isomer is present. "Diastereomers" are stereoisomers that have at least two asymmetric atoms, but are not mirror images of each other. Absolute stereochemistry is assigned based on the Cahn- Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by R or S notation. Resolved compounds whose absolute configuration is not known or is a mixture of (R)- and (S)-forms can be designated (+) or (-), depending on the direction (right or left) in which they rotate plane-polarized light at the sodium D line wavelength (589 nm). Some of the compounds described herein contain one or more asymmetric centers or axes and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (S)- or as (+) or (-) if appropriate. The present application includes all such possible isomers, including racemates, optically pure forms, and mixtures thereof. Optical activity (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents or resolved by 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 ring, the cycloalkyl substituents can have a cis- or trans-configuration. That is, the compounds of the present application include but are not limited to cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)-isomers, as well as racemic mixtures and other mixtures thereof. Compounds of the present application containing an asymmetric carbon atom can be isolated in optically active form or as a mixture of isomers. The optically active forms can be obtained by resolution of a mixture of isomers or by synthesis using chiral starting materials or chiral reagents.

[0124] The present application "compounds" also include tautomeric forms. Tautomeric forms arise from the exchange of a single bond and the adjacent double bond together with the migration of a proton. The term "tautomer" or "tautomeric forms" refers to different functional group isomers that are in dynamic equilibrium at room temperature and can rapidly interconvert.

[0125] The skilled person can separate isomeric mixtures obtainable according to the application into the individual isomers in known manner; diastereomers can be separated, for example, by partitioning between a mixture of heterogeneous solvents, by recrystallization and / or by chromatography, for example silica gel chromatography or by medium pressure liquid chromatography, for example using a reversed phase column, racemates can be separated, for example, by forming a salt with an optically pure salt-forming reagent and separating (for example by fractional crystallization) the diastereomeric mixture of non- optical isomers thus obtainable or by chromatography on an optically active column material. The intermediates and end products can be worked up and / or purified according to standard methods, for example using chromatography, partitioning, (re)crystallization, etc. At all stages of the reaction, the isomeric mixtures formed can be separated into the individual isomers, for example diastereomers or enantiomers, or into any desired isomeric mixture, for example a racemate or a diastereomeric mixture.

[0126] Absolute stereochemistry and / or optical rotation are provided for embodiments of the application where appropriate. The present application contemplates all stereochemical forms of the compounds provided herein. In some instances, the compounds contain two or more chiral centers. The relative stereochemistry of these compounds is identified by NMR studies and / or X-ray diffraction. In these instances, the prefix "rel" is used followed by the R / S nomenclature. It is understood that if "rel" is used, the R / S provides only relative stereochemical information (e.g., trans or cis) and does not indicate absolute stereochemistry. In some instances, the relative stereochemistry of a pair of diastereomers is not determined, and thus when only one isomer is isolated and / or available, the enantiomers are designated / distinguished according to retention time under the HPLC conditions given. The same sample will generally have the same retention time, but there can be some operator error, and retention times will generally be within ± 0.2 min, preferably within ± 0.1 min, when samples obtained by the corresponding method are tested using the same instrument and detection method by an ordinarily skilled person; a few retention times can occasionally be outside this range when different instruments are used by different technicians, e.g., within ± 0.5 min; or ± 0.3 min; or ± 0.2 min; and retention times within ± 0.5 min, ± 0.3 min, ± 0.2 min, or ± 0.1 min of each other are to be construed as the same substance, and thus retention times within ± 0.5 min, ± 0.3 min, ± 0.2 min, or ± 0.1 min of each other are to be construed as within the scope of the present application.

[0127] In instances where a pair of diastereomers is identified as racemic, but the relative stereochemistry is not determined, the compound is named with the symbol "(±)" and the names "diastereomer-1" or "diastereomer-2" if only one isomer is isolated and / or available.

[0128] In the present application, the term "enantiomer" is used to refer to a pair of molecules that are mirror images of each other and are not superimposable. The term "diastereomer" is used to refer to a pair of molecules that are not mirror images of each other and are not superimposable. The term "racemate" is used to refer to a mixture of equal amounts of enantiomers. The term "diastereomeric mixture" is used to refer to a mixture of equal amounts of diastereomers. "R" or "S" configuration. "R" or "S" configuration. "R" or "S" configuration. "R" or "S" configuration. "R" or "S" configuration. "R" or "S" configuration.

[0129] The compounds of the present application can be confirmed by conventional methods well known to those skilled in the art. If the present application relates to the absolute configuration of a compound, the absolute configuration can be determined by conventional techniques in the art, such as single crystal X-ray diffraction (SARD). "R" or "S" configuration.

[0130] The term "optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and this description includes instances where the event or circumstance occurs and instances where it does not. "R" or "S" configuration.

[0131] The term "halogen" means fluorine, chlorine, bromine, and iodine. "R" or "S" configuration.

[0132] The term "substituted" means that any one or more (e.g., 1, 2, 3, or 4, etc.) hydrogen atoms of a particular group are replaced with a substituent group, which can be the same or different, as long as the valency of the particular group is normal and the substituted compound is stable. For example, "substituted with halogen" means that any one or more (e.g., 1, 2, 3, or 4, etc.) hydrogen atoms of a particular group are replaced with the same or different halogen, as long as the valency of the particular group is normal and the substituted compound is stable. "R" or "S" configuration.

[0133] The numerical ranges recited herein are inclusive of the integers within the given range. For example, "C1-C6" means that the group can 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 can have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms. "R" or "S" configuration.

[0134] The term "alkyl" means a saturated aliphatic hydrocarbon group, including straight-chain or branched-chain saturated hydrocarbon groups that have the number of carbon atoms designated. For example, the term "C1-C6alkyl" includes C1alkyl, C2alkyl, C3alkyl, C4alkyl, C5alkyl, C6alkyl, and examples include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, n-hexyl, 2-hexyl, 3-hexyl, and the like. "R" or "S" configuration.

[0135] The term "pharmaceutically acceptable" means that the carrier, vehicle, adjuvant, diluent, and / or salt is generally chemically and / or physically compatible with the other ingredients of a pharmaceutical formulation and physiologically acceptable to the recipient thereof. "R" or "S" configuration.

[0136] The term "pharmaceutically acceptable carrier" means those carriers that do not cause an undesirable physiological effect(s) when administered to a subject, and that do not abrogate the biological activity and properties of the active compounds. This includes, but is not limited to, any of the conventional diluents, disintegrants, binders, glidants, wetting agents that are commonly used in the art for use in humans or animals.

[0137] The term "pharmaceutically acceptable salt" means a salt that retains the biological effectiveness and properties of the free acids and bases of the specific compound and that is not biologically undesirable. For example, pharmaceutically acceptable acid or base salts that are commonly used in the art, wherein the acid salts include conventional organic or inorganic salts that include, but are not limited to, p-toluenesulfonic acid, maleic acid, citric acid, or tartaric acid; wherein the inorganic acid salts include, but are not limited to, hydrobromic acid, hydrochloric acid, sulfuric acid, or phosphoric acid, preferably hydrochloric acid, sulfuric acid, or phosphoric acid; wherein the base salts include, but are not limited to, sodium, potassium, calcium, choline, or diethylamine salts, preferably sodium or calcium salts, and can also include zwitterions, and quaternary ammonium salts, such as alkyl ammonium salts. The pharmaceutically acceptable salts of the present application can be synthesized from the parent compound that contains an acidic or basic moiety by conventional chemical methods. Generally, such salts are prepared either by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two; the appropriate organic solvent being, for example, methanol, ethanol, DMSO, acetonitrile, dioxane, tetrahydrofuran, or acetone.

[0138] "Subject" as used herein refers to an animal, including, but not limited to, primates (e.g., humans), cows, pigs, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. As used herein, the terms "subject" and "patient" are used interchangeably, e.g., to refer to a mammal or human; as used herein, "patient" generally refers to a human.

[0139] The term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a drug or pharmaceutical agent to produce a desired effect, without being toxic to the subject. The precise amount will vary depending on a variety of factors, such as subject-dependent variables (e.g., age, immune system health, etc.), disease or illness, and the treatment being administered.

[0140] 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 group consisting of carriers, diluents, adjuvants, excipients, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweetening agents, flavoring agents, flavorants, antibacterial agents, antifungal agents, lubricants, dispersing agents, temperature-sensitive materials, temperature-regulating agents, adhesion agents, stabilizing agents, suspending agents, and the like, depending on the mode and nature of the dosage form.

[0141] The pharmaceutical or pharmaceutical composition of the present disclosure can be delivered parenterally, i.e., by intravenous (i.v.), intracerebroventricular (i.c.v.), subcutaneous (s.c.), intraperitoneal (i.p.), intramuscular (i.m.), subdermal (s.d.), or intradermal (i.d.) administration, by direct injection, e.g., bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient can be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0142] The pharmaceutical or pharmaceutical composition of the present disclosure can also be formulated for rectal administration, e.g., as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

[0143] The term "treatment" includes inhibiting, alleviating, preventing or eliminating one or more symptoms or side effects associated with the disease, disorder or condition being treated.

[0144] The term "complement factor B-mediated disease or disease state" refers to a class of pathological processes in which abnormal activation or dysregulation of the alternative pathway (AP) of the complement system is a central driving mechanism for the onset and progression of the disease, and complement factor B (FB), as a key zymogen rate-limiting protease of this pathway, plays an indispensable, directly promoting or exacerbating role in the pathological damage in which its activity, expression level or functional status. Examples of complement factor B-mediated diseases or disease states include, but are not limited to, ophthalmic diseases, autoimmune diseases, diseases related to the kidney system, respiratory system diseases, cardiovascular diseases, arthritis, paroxysmal nocturnal hemoglobinuria, etc.

[0145] The abbreviations used in the claims and specification have the following meanings: M: mol / L. DMSO: dimethyl sulfoxide. DMSO-d6: deuterated dimethyl sulfoxide. DEA: diethylamine. DCM: dichloromethane. IPA: isopropyl alcohol. FA: formic acid. 1HNMR: nuclear magnetic resonance hydrogen spectrum. HPLC: high performance liquid chromatography. LCMS: liquid chromatography-mass spectrometry. MEOH: methanol. m / z: mass-to-charge ratio. SFC: supercritical fluid chromatography. V / V: volume / volume. Tris: Tris (tris-hydroxymethyl aminomethane) buffer salt. MgCl2: magnesium chloride. Chaps: 3-[3-(cholamidopropyl)dimethylammonio]propanesulfonate. PBS: phosphate buffered saline. Tween80: Tween 80. w / v: mass concentration. Bid: twice a day. BRIEF DESCRIPTION OF DRAWINGS

[0146] Figure 1 is a crystal structure of compound 1a-2 in Experimental Example 1;

[0147] Figure 2 is a crystal structure of compound 2a-2 in Experimental Example 2;

[0148] Figure 3 is a crystal structure of compound (3R, 4S)-4-hydroxy-3-(4- (methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester in Experimental Example 3.

[0149] Figure 4 is a graph of arthritic score of Example 1a-2 in collagen antibody-induced mouse arthritis experiment in Experimental Example 7;

[0150] Figure 5 is a graph of footpad thickness change of Example 1a-2 in collagen antibody-induced mouse arthritis experiment in Experimental Example 7;

[0151] Figure 6 is a graph of AUC change in efficacy study of CAIA mouse model in Experimental Example 8. DETAILED DESCRIPTION

[0152] The preparation methods of the compounds of the present application are described in more detail below, but these specific preparation methods do not constitute any limitation on the scope of the present application. In addition, the reaction conditions such as the reactants, solvents, bases, the amount of the compounds used, the reaction temperature, the reaction time, etc. are not limited to the following examples.

[0153] The compounds of the present application can also be optionally prepared by combining various synthetic methods described in the present specification or known in the art, and such combination can be easily performed by those skilled in the art.

[0154] The raw materials and equipment used in the detailed description of the present application are known products, and can be obtained by purchasing commercially available products, unless otherwise specified.

[0155] Example 1: 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 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

[0156] a) Preparation of (±) tert-butyl 3-(4-(methoxycarbonyl)phenyl)-4-oxopiperidine-1- carboxylate

[0157] tert-Butyl 3-bromo-4-oxopiperidine-1-carboxylate (50 g), (4-(methoxycarbonyl)phenyl)boronic acid (48.52 g), nickel(II) trifluoromethanesulfonate (3.21 g), 1,10- phenanthroline (1.62 g), potassium carbonate (49.62 g), 1,4-dioxane (500 mL) were added into a reaction flask, which was protected by nitrogen, stirred at 80 °C for 16 h, the reaction solution was diluted with water (500 mL), extracted with ethyl acetate (3 x 500 mL), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a sand, which was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to give the title compound 32 g.

[0158] b) Preparation of (±)-rel-(3S,4R)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1- carboxylate and (±)-rel-(3S,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1- carboxylate

[0159] (±) tert-Butyl 3-(4-(methoxycarbonyl)phenyl)-4-oxopiperidine-1-carboxylate (30 g) was added into a reaction flask, methanol (300 mL) was added, sodium borohydride (10.21 g) was added portionwise at 0 °C under nitrogen protection, stirred at room temperature for 1 h, the reaction was quenched by the addition of water (500 mL) in an ice bath, extracted with ethyl acetate (3 x 500 mL), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a sand, which was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 3 / 1 (V / V)) to give the title compounds 8.9 g and 21.3 g, respectively.

[0160] (±)-rel-(3S,4R)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1 - carboxylic acid tert-butyl ester

[0161] 1 HNMR (400 MHz, DMSO-d6) δ 7.88 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 4.75 (d, J = 4.2 Hz, 1H), 3.99 (d, J = 7.8 Hz, 1H), 3.84 (s, 3H), 3.77 (d, J = 12.4 Hz, 2H), 3.49 (d, J = 14.2 Hz, 1H), 3.16 (s, 1H), 2.83 (d, J = 11.2 Hz, 1H), 1.71 - 1.64 (m, 2H), 1.39 (s, 9H).

[0162] (±)-rel-(3S,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1 - carboxylic acid tert-butyl ester

[0163] 1 HNMR (400 MHz, DMSO-d6) δ 7.90 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 8.3 Hz, 2H), 4.71 (d, J = 6.0 Hz, 1H), 4.03 (q, J = 7.1 Hz, 1H), 3.97 (d, J = 11.8 Hz, 1H), 3.85 (s, 3H), 3.83 - 3.72 (m, 2H), 2.89 (s, 2H), 1.99 (s, 1H), 1.89 (dd, J = 12.4, 3.8 Hz, 1H), 1.40 (s, 9H).

[0164] Compound 1a: 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

[0165] a) Preparation of (±)-rel-(3S,4S)-4-((1-(tert-butoxycarbonyl)-3-(4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-methoxy-7-methyl-1H-indole-1- carboxylic acid tert-butyl ester

[0166] (±)-rel-(3S,4S)-4-((l-(2,2-difluoroethyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4- yl)oxy)-5-methoxy-7-methyl-lH-indole-l-carboxylic acid tert-butyl ester (8 g), N,N- diisopropylethylamine (8.4 mL) were added to a reaction flask, tetrahydrofuran (80 mL) was added, followed by the addition of 2,2-difluoroethyl trifluoromethanesulfonate (10.4 g), the reaction was protected by nitrogen gas, stirred at 70 °C for 2 hours, the reaction solution was diluted with water (500 mL) and extracted with ethyl acetate (3 x 200 mL), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to give a sand, which was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to give the title compound 12.4 g.

[0167] b) Preparation of (±)-rel-(3S,4S)-5-methoxy-4-((3-(4-(methoxycarbonyl)phenyl)piperidin-4- yl)oxy)-7-methyl-lH-indole-l-carboxylic acid tert-butyl ester

[0168] (±)-rel-(3S,4S)-4-((l-(2,2-difluoroethyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4- yl)oxy)-5-methoxy-7-methyl-lH-indole-l-carboxylic acid tert-butyl ester (8 g), N,N- diisopropylethylamine (8.4 mL) were added to a reaction flask, tetrahydrofuran (80 mL) was added, followed by the addition of 2,2-difluoroethyl trifluoromethanesulfonate (10.4 g), the reaction was protected by nitrogen gas, stirred at 70 °C for 2 hours, the reaction solution was diluted with water (500 mL) and extracted with ethyl acetate (3 x 200 mL), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to give a sand, which was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to give the title compound 12.4 g.

[0169] LCMS m / z = 495.4 [M+1] + .

[0170] c) Preparation of (±)-rel-(3S,4S)-4-((l-(2,2-difluoroethyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4- yl)oxy)-5-methoxy-7-methyl-lH-indole-l-carboxylic acid tert-butyl ester

[0171] (±)-rel-(3S,4S)-4-((l-(2,2-difluoroethyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4- yl)oxy)-5-methoxy-7-methyl-lH-indole-l-carboxylic acid tert-butyl ester (8 g), N,N- diisopropylethylamine (8.4 mL) were added to a reaction flask, tetrahydrofuran (80 mL) was added, followed by the addition of 2,2-difluoroethyl trifluoromethanesulfonate (10.4 g), the reaction was protected by nitrogen gas, stirred at 70 °C for 2 hours, the reaction solution was diluted with water (500 mL) and extracted with ethyl acetate (3 x 200 mL), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to give a sand, which was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to give the title compound 12.4 g.

[0172] 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

[0173] (±)-rel-(3S,4S)-4-((1-(2,2-difluoroethyl)-3-(4-(methoxy carbonyl)phenyl)piperidin-4- yl)oxy)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (6.2 g) was added to a reaction flask, methanol (120 mL), lithium hydroxide (7.8 g), water (40 mL) were added, protected by nitrogen gas replacement, stirred at 70 °C for 16 hours, the reaction solution was adjusted to pH = 6 with dilute hydrochloric acid (3M), diluted with water (100 mL) and extracted with ethyl acetate (3 x 500 mL), the organic phase was separated, combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to sand, purified by column chromatography (mobile phase: dichloromethane methanol 5 / 1 (V / V)) to give the title compound enantiomer 7.6 g.

[0174] LCMS m / z = 445 [M+1] + .

[0175] The (±)-rel-(3S,4S)-4-(1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4- yl)oxy)piperidin-3-yl)benzoic acid enantiomers were resolved by chiral SFC to give compound 1a-1 (t r = 1.19 min) and compound 1a-2 (t r = 1.95 min), the absolute stereochemical configuration of 1a-2 was confirmed by X-ray single crystal diffraction of experimental example 1 to be 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid. (Resolution method: chromatographic column: 250*20mm, 10μm; mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonium methanol); A:B:75:25; flow rate: 100 mL / min; detection wavelength: 214 nm)

[0176] 4-((3S,4S)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)piperidin-3- yl)benzoic acid

[0177] 1HNMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 7.90 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H), 7.20 - 7.13 (m, 1H), 6.62 (s, 1H), 6.30 - 5.96 (m, 2H), 4.48 - 4.38 (m, 1H), 3.60 (s, 3H), 3.29 (s, 1H), 3.12 (s, 1H), 2.93 (dd, J = 23.7, 11.6 Hz, 2H), 2.78 (t, J = 15.5 Hz, 2H), 2.34 (d, J = 8.9 Hz, 3H), 2.28 (s, 1H), 1.70 (s, 2H).

[0178] LCMS m / z = 445.1 [M+1] + .

[0179] 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4- yl)oxy)piperidin-3-yl)benzoic acid

[0180] 1 HNMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 7.88 (d, J = 8.1 Hz, 2H), 7.51 (d, J = 8.1 Hz, 2H), 7.16 (t, J = 2.7 Hz, 1H), 6.62 (s, 1H), 6.29 - 5.97 (m, 2H), 4.51 - 4.39 (m, 1H), 3.60 (s, 3H), 3.38 (d, J = 3.5 Hz, 1H), 3.09 (s, 1H), 2.95 - 2.87 (m, 2H), 2.75 (d, J = 15.6 Hz, 2H), 2.36 (s, 3H), 2.26 (s, 1H), 1.69 (s, 2H).

[0181] LCMS m / z = 445.1 [M+1] + .

[0182] Compound 1b: 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

[0183] Reference the preparation method of compound 1a, replace (±)-rel-(3S,4R)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester in step a) with (±)-rel-(3S,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester.

[0184] The enantiomers of (±)-rel-(3S,4R)-4-(1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid were resolved by chiral SFC to obtain compound 1b-1, t r = 1.29 min) and compound 1b-2, t r = 4.00 min). (Resolution method: chromatographic column: 250*20mm 10μm; mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonium methanol); A:B:75:25; flow rate: 100 mL / min; detection wavelength: 214 nm)

[0185] Compound 1b-1, t r = 1.29 min

[0186] 1 HNMR (400MHz, DMSO-d6) δ 10.83 (s, 1H), 7.89 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.09 (t, J = 2.7 Hz, 1H), 6.61 (s, 1H), 6.38-5.99 (m, 1H), 5.73 (s, 1H), 4.65 (s, 1H), 3.55 (s, 3H), 3.18 (dd, J = 22.7, 10.9 Hz, 2H), 2.88 (dd, J = 17.7, 12.0 Hz, 4H), 2.67 (s, 1H), 2.34 (s, 3H), 1.66 (s, 2H).

[0187] LCMS m / z = 445.1 [M+1] + .

[0188] Compound 1b-2, t r = 4.00 min

[0189] 1HNMR (400 MHz, DMSO-d6) δ 13.09 - 12.27 (m, 1H), 10.83 (s, 1H), 7.90 (d, J = 8.3 Hz, 2H), 7.58 (d, J = 8.3 Hz, 2H), 7.09 (t, J = 2.8 Hz, 1H), 6.61 (s, 1H), 6.37 - 6.02 (m, 1H), 5.77 - 5.71 (m, 1H), 4.66 (s, 1H), 3.55 (s, 3H), 3.21 (dd, J = 24.5, 13.9 Hz, 2H), 2.96 - 2.83 (m, 4H), 2.66 (d, J = 10.6 Hz, 1H), 2.34 (s, 3H), 1.66 (s, 2H).

[0190] LCMS m / z = 445.1 [M+1] + .

[0191] Example 2: Preparation of 4-((3S,4S)-4-((5-methoxy-7-methyl-lH-indol-4- yl)oxy)-l-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid and 4-((3R,4R)-4-((5- methoxy-7-methyl-lH-indol-4-yl)oxy)-l-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid and 4-((3S,4R)-4-((5-methoxy-7-methyl-lH-indol-4-yl)oxy)-l-(2,2,2- trifluoroethyl)piperidin-3-yl)benzoic acid and 4-((3R,4S)-4-((5-methoxy-7-methyl- lH-indol-4-yl)oxy)-l-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid

[0192] Compound 2a: 4-((3S,4S)-4-((5-methoxy-7-methyl-lH-indol-4-yl)oxy)-l-(2,2,2- trifluoroethyl)piperidin-3-yl)benzoic acid and 4-((3R,4R)-4-((5-methoxy-7-methyl- lH-indol-4-yl)oxy)-l-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid

[0193] a) Preparation of (±)-rel-(3S,4S)-5-methoxy-4-((3-(4- (methoxycarbonyl)phenyl)-l-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)-7-methyl-lH- indole-1-carboxylic acid tert-butyl ester

[0194] Reference compound 1 preparation of (±)-rel-(3S,4S)-5-methoxy-4-((3-(4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-lH-indole-l-carboxylic acid tert-butyl ester, (±)-rel-(3S,4S)-5-methoxy-4-((3-(4-(methoxycarbonyl)phenyl)piperidin-4- yl)oxy)-7-methyl-lH-indole-l-carboxylic acid tert-butyl ester (6.3 g), N,N- diisopropylethylamine (6.6 mL) were added to a reaction flask, tetrahydrofuran (80 mL) was added, followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (8.9 g), the reaction was protected by nitrogen replacement, stirred at 70 °C for 2 hours, the reaction solution was diluted with water (500 mL) and extracted with ethyl acetate (3 x 200 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give sand, which was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to give the title compound 5 g.

[0195] LCMS m / z = 577.1 [M+H] + .

[0196] b) Preparation of 4-((3S,4S)-4-((5-methoxy-7-methyl-lH-indol-4-yl)oxy)-l-(2,2,2- trifluoroethyl)piperidin-3-yl)benzoic acid and 4-((3R,4R)-4-((5-methoxy-7-methyl- lH-indol-4-yl)oxy)-l-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid

[0197] (±)-rel-(3S,4S)-5-methoxy-4-((3-(4-(methoxycarbonyl)phenyl)-l-(2,2,2- trifluoroethyl)piperidin-4-yl)oxy)-7-methyl-lH-indole-l-carboxylic acid tert-butyl ester (5 g) was added to a reaction flask, methanol (120 mL), lithium hydroxide (6.25 g), water (100 mL) were added, the reaction was protected by nitrogen replacement, 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 x 500 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give sand, which was purified by column chromatography (mobile phase: dichloromethane / methanol 5 / 1 (V / V)) to give the title compound enantiomer 1.7 g.

[0198] Enantiomeric resolution of (±)-rel-(3S,4S)-4-(4-((5-methoxy-7-methyl-lH-indol-4- yl)oxy)-l-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid by chiral SFC to give compound 2a-1 (t r= 1.87 min) and compound 2a-2 (t r = 2.73 min), the absolute stereochemical configuration of 2a-2 was confirmed by X-ray single crystal diffraction of experimental example 2 to be 4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2- trifluoroethyl)piperidin-3-yl)benzoic acid. (Resolution method: chromatographic column: 250*25 mm, 10 μm; mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonium methanol); A:B:75:25; flow rate: 100 mL / min; detection wavelength: 214 nm)

[0199] Compound 2a-1, t r = 1.87 min

[0200] 1 HNMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.55 (d, J = 8.2 Hz, 2H), 7.17 (t, J = 2.8 Hz, 1H), 6.63 (s, 1H), 6.21 - 6.16 (m, 1H), 4.47 (dd, J = 16.1, 7.7 Hz, 1H), 3.60 (s, 3H), 3.24 (d, J = 3.5 Hz, 2H), 3.16 - 3.08 (m, 1H), 2.94 (t, J = 12.7 Hz, 2H), 2.67 (t, J = 11.2 Hz, 1H), 2.47 - 2.41 (m, 1H), 2.34 (d, J = 11.4 Hz, 3H), 1.70 (d, J = 3.6 Hz, 2H).

[0201] LCMS m / z = 463.1 [M+H] + .

[0202] Compound 2a-2, t r = 2.73 min

[0203] 1HNMR(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).

[0204] LCMS m / z = 463.1 [M+H] + .

[0205] Compound 2b(±)-rel-(3S,4R)-4-(4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid

[0206] The compound 2a was prepared by referring to the preparation method of compound 2a, except that (±)-rel-(3S,4S)-4-((1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester was replaced with (±)-rel-(3S,4R)-4-((1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester.

[0207] Compound 2b-1(t) was obtained by chiral SFC resolution of (±)-rel-(3S,4R)-4-(4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid. r =1.06min) and compound 2b-2 (t r =2.37 min). (Separation method: Column: 250*20mm, 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

[0208] Compound 2b-1,t r =1.06min

[0209] 1 HNMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 7.89 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 8.3 Hz, 2H), 7.09 (t, J = 2.8 Hz, 1H), 6.61 (s, 1H), 5.71 (dd, J = 3.0, 2.0 Hz, 1H), 4.65 (d, J = 2.5 Hz, 1H), 3.55 (s, 3H), 3.42 - 3.36 (m, 2H), 3.30 - 3.25 (m, 2H), 3.14 - 3.07 (m, 1H), 2.89 (d, J = 7.6 Hz, 1H), 2.68 (d, J = 10.9 Hz, 1H), 2.34 (s, 3H), 1.65 (s, 2H).

[0210] LCMS m / z = 463.1 [M+H] + .

[0211] Compound 2b-2, t r = 2.37 min

[0212] 1 HNMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 7.90 (d, J = 8.3 Hz, 2H), 7.58 (d, J = 8.3 Hz, 2H), 7.09 (t, J = 2.7 Hz, 1H), 6.61 (s, 1H), 5.72 (dd, J = 2.9, 2.0 Hz, 1H), 4.66 (d, J = 2.4 Hz, 1H), 3.55 (s, 3H), 3.44 - 3.36 (m, 2H), 3.29 (d, J = 5.9 Hz, 2H), 3.12 (td, J = 10.6, 5.6 Hz, 1H), 2.89 (d, J = 7.8 Hz, 1H), 2.69 (d, J = 11.1 Hz, 1H), 2.34 (s, 3H), 1.66 (s, 2H).

[0213] LCMS m / z = 463.1 [M+H] + .

[0214] Example 3: Preparation of 4-((3S,4S)-4-((5-methoxy-7-methyl-1H-indol-4- yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid and 4-((3R,4R)-4-((5- methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid and 4-((3S,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(3,3,3- trifluoropropyl)piperidin-3-yl)benzoic acid and 4-((3R,4S)-4-((5-methoxy-7-methyl- 1H-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid

[0215] Example 3a: (±)-rel-(3S,4S)-4-(4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(3,3,3- trifluoropropyl)piperidin-3-yl)benzoic acid

[0216] Reference is made to the preparation method of Example 1a, by replacing 2,2- difluoroethyl trifluoromethanesulfonate in step c) with 3,3,3-trifluoropropyl trifluoro- methanesulfonate.

[0217] (±)-rel-(3S,4S) 4-(4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(3,3,3- trifluoropropyl)piperidin-3-yl)benzoic acid was resolved by chiral SFC to give 3a-1 (t r = 1.25 min) and 3a-2 (t r = 2.00 min). (Resolution method: Column: Chiralpak® IC (250*20mm, 10μm); Mobile phase A: Supercritical CO2; Mobile phase B: Methanol (+0.1% 7.0mol / L ammonium methanol); A:B:75:25; Flow rate: 100 mL / min; Detection wavelength: 214nm) 250*20mm, 10μm; Mobile phase A: Supercritical CO2; Mobile phase B: Methanol (+0.1% 7.0mol / L ammonium methanol); A:B:75:25; Flow rate: 100 mL / min; Detection wavelength: 214nm)

[0218] 3a-1, t r = 1.25 min

[0219] 1HNMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 7.91 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 8.2 Hz, 2H), 7.17 (t, J = 2.6 Hz, 1H), 6.63 (s, 1H), 6.17 (s, 1H), 4.46 (td, J = 9.5, 4.8 Hz, 1H), 3.60 (s, 3H), 3.12 (td, J = 10.2, 3.7 Hz, 1H), 2.93 - 2.83 (m, 2H), 2.62 - 2.53 (m, 2H), 2.52 - 2.45 (m, 2H), 2.36 (s, 3H), 2.31 (t, J = 11.1 Hz, 1H), 2.05 (dt, J = 15.0, 7.5 Hz, 1H), 1.80 - 1.62 (m, 2H).

[0220] LCMS m / z = 475.0 [M-H] + .

[0221] 3a-2,t r = 2.00 min

[0222] 1 HNMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 7.91 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 8.2 Hz, 2H), 7.17 (t, J = 2.6 Hz, 1H), 6.63 (s, 1H), 6.17 (s, 1H), 4.46 (td, J = 9.5, 4.8 Hz, 1H), 3.60 (s, 3H), 3.12 (td, J = 10.2, 3.7 Hz, 1H), 2.93 - 2.83 (m, 2H), 2.62 - 2.53 (m, 2H), 2.52 - 2.45 (m, 2H), 2.36 (s, 3H), 2.31 (t, J = 11.1 Hz, 1H), 2.05 (dt, J = 15.0, 7.5 Hz, 1H), 1.80 - 1.62 (m, 2H).

[0223] LCMS m / z = 475.0 [M-H] + .

[0224] Example 3b: (±)-rel-(3S,4R)-4-(4-((5-methoxy-7-methyl-lH-indol-4-yl)oxy)-l-(3,3,3- trifluoropropyl)piperidin-3-yl)benzoic acid

[0225] Prepared according to the procedure of Example 1b, substituting 2,2,2-trifluoropropyl triflate for 2,2-difluoroethyl triflate in step c).

[0226] (±)-rel-(3S,4R)-4-(4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(3,3,3- trifluoropropyl)piperidin-3-yl)benzoic acid was prepared by chiral SFC resolution of (±)-rel-(3S,4R)-4-(4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(3,3,3- trifluoropropyl)piperidin-3-yl)benzoic acid to give 3b-1 (t r = 0.91 min) and 3b-2 (t r = 2.35 min). (Resolution method: Chiral column: Chiralpak® IC, 250*20 mm, 10 μm; mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonium hydroxide); A:B: 75:25; flow rate: 100 mL / min; detection wavelength: 214 nm) 250*20 mm, 10 μm; mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonium hydroxide); A:B: 75:25; flow rate: 100 mL / min; detection wavelength: 214 nm)

[0227] 3b-1, t r = 0.91 min

[0228] 1 HNMR (400 MHz, DMSO-d6) δ 12.88 - 12.26 (m, 1H), 10.83 (s, 1H), 7.90 (d, J = 8.3 Hz, 2H), 7.60 (d, J = 8.3 Hz, 2H), 7.10 (t, J = 2.7 Hz, 1H), 6.61 (s, 1H), 5.76 (s, 1H), 4.67 (d, J = 2.5 Hz, 1H), 3.54 (s, 3H), 3.29 (s, 1H), 3.24 (s, 1H), 3.00 (t, J = 10.8 Hz, 1H), 2.84 (d, J = 9.4 Hz, 1H), 2.73 - 2.54 (m, 5H), 2.33 (dd, J = 5.6, 1.0 Hz, 3H), 1.67 (t, J = 14.4 Hz, 2H).

[0229] 3b-2, tr = 2.35 min

[0230] 1HNMR (400 MHz, DMSO-d6) δ 12.66 - 11.86 (m, 1H), 10.83 (s, 1H), 7.90 (d, J = 7.9 Hz, 2H), 7.60 (d, J = 8.3 Hz, 2H), 7.10 (t, J = 2.7 Hz, 1H), 6.61 (s, 1H), 5.76 (s, 1H), 4.67 (s, 1H), 3.55 (s, 3H), 3.29 (s, 1H), 3.28 - 3.21 (m, 1H), 3.00 (s, 1H), 2.85 (s, 1H), 2.64 (dd, J = 24.2, 22.4 Hz, 5H), 2.37 - 2.32 (m, 3H), 1.68 (s, 2H).

[0231] Example 4: Preparation of 4-((3S,4S)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl- 1H-indol-4-yl)thio)piperidin-3-yl)benzoic acid and 4-((3R,4R)-1-(2,2-difluoroethyl)-4- ((5-methoxy-7-methyl-1H-indol-4-yl)thio)piperidin-3-yl)benzoic acid and 4-((3S,4R)- 1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)thio)piperidin-3-yl)benzoic acid and 4-((3R,4S)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4- yl)thio)piperidin-3-yl)benzoic acid

[0232] a) Preparation of 1-bromo-2-methoxy-4-methyl-5-nitrobenzene

[0233] 1-bromo-2-fluoro-4-methyl-5-nitrobenzene (100 g) was dissolved in methanol (1 L), and sodium methoxide (25.6 g) was added. The reaction was protected by nitrogen replacement, stirred at 30 °C for 16 hours, and the reaction was filtered, and the filtrate was concentrated under reduced pressure to give the title compound 73 g.

[0234] b) Preparation of 4-bromo-5-methoxy-7-methyl-1H-indole

[0235] Into a 2L three-necked flask, 1-bromo-2-methoxy-4-methyl-5-nitrobenzene (73g) was added, tetrahydrofuran (730ml) was added, the temperature was lowered to -40°C under nitrogen protection, vinyl magnesium bromide tetrahydrofuran solution (1750ml, 1.3M) was added dropwise slowly, the reaction solution was stirred at -40°C for 3 hours, the reaction was quenched with aqueous solution of ammonium chloride (200ml), and extracted with ethyl acetate (3*200ml), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give sand, which was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 20 / 1 (V / V)) to give the title compound 8.5g.

[0236] c) Preparation of 4-bromo-5-methoxy-7-methyl-l-tosyl-lH-indole

[0237] Into a reaction flask, 4-bromo-5-methoxy-7-methyl-lH-indole (8.5g) was added, potassium hydroxide (6.0g) was added, N,N-dimethylformamide (100ml) was added, the temperature was lowered to 0°C, p-toluenesulfonyl chloride (10.1g) was added, the temperature was raised to room temperature, and stirred for 16 hours, the reaction was quenched with water (50ml), extracted with ethyl acetate (100ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give sand, which was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to give the title compound 8.1g.

[0238] d) Preparation of S-(5-methoxy-7-methyl-l-tosyl-lH-indol-4-yl)ethanesulfonate

[0239] Into a reaction flask, a solution of S-(5-methoxy-7-methyl-l-tosyl-lH-indol-4-yl)ethanesulfonate (8g), potassium thioacetate (2.55g), tris(dibenzylidene-BASE acetone) dipalladium (9.29g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (17.6g), N,N-diisopropylethylamine (7.87g), 1,4-dioxane (120ml) was added, and heated in a microwave at 140°C for 2 hours, the reaction mixture was quenched with water (50ml), extracted with ethyl acetate (300ml), separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give sand, which was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to give the title compound 2.6g.

[0240] e) Preparation of 5-methoxy-7-methyl-l-tosyl-lH-indole-4-thiol

[0241] S-(5-methoxy-7-methyl-l-tolyl-lH-indol-4-yl) ethanesulfonate (300 mg) was dissolved in a mixture of tetrahydrofuran / methanol (1.5 mL / 3.0 mL), 1 N lithium hydroxide (1 mL) was added, the mixture was stirred at room temperature for 1 hour under nitrogen protection, the reaction was diluted with 1 N dilute hydrochloric acid (10 mL) and water (30 mL), extracted with ethyl acetate (60 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 260 mg.

[0242] LCMS m / z = 348 [M+1] + .

[0243] f) Preparation of (±) tert-butyl-3-(4-(methoxy carbonyl)phenyl)-4-(2- methylbenzenesulfonylhydrazide)piperidine-1-carboxylate

[0244] (±) tert-Butyl 3-(4-(methoxy carbonyl)phenyl)-4-oxopiperidine-1-carboxylate (2.194 g), 4-methylbenzenesulfonylhydrazide (1.838 g) were added to a reaction flask, methanol (35 mL) was added, stirred at room temperature for 16 hours under nitrogen protection, concentrated and evaporated under reduced pressure, the residue was purified by reverse phase column (WelFlash C18-I, Regular C18 20-40 μm, 330 g; mobile phase A: 10 mM formic acid / H2O, B: MeCN; flow rate: 150 mL / min; isocratic elution: 77.5% MeCN) to give the title compound 0.9 g.

[0245] g) Preparation of (±) tert-butyl 4-((5-methoxy-7-methyl-l-tolyl-lH-indol-4- yl)thio)-3-(4-(methoxy carbonyl)phenyl)piperidine-1-carboxylate

[0246] 5-methoxy-7-methyl-l-tolylsulfonyl-lH-indole-4-thiol (260 mg), cesium carbonate (856 mg), 1,4-dioxane (10 mL), (±) tert-butyl 3-(4-(methoxy carbonyl)phenyl)-4-(2- methylbenzenesulfonylhydrazide)piperidine-1-carboxylate (590 mg) were added to a reaction flask, stirred at 110 °C for 1 hour under nitrogen protection, the reaction was diluted with water (30 mL), extracted with ethyl acetate (30 mL x 3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to give the title compound 470 mg.

[0247] h) Preparation of (±) methyl 4-(4-((5-methoxy-7-methyl-l-tolyl-lH-indol-4- yl)thio)piperidin-3-yl)benzoate

[0248] (±) 4-((5-methoxy-7-methyl-1- tolyl-1H-indol-4-yl)thio)-3-(4- (methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (470 mg) was dissolved in 4M hydrochloric acid in 1,4-dioxane (5.0 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give the title compound 220 mg.

[0249] 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

[0250] (±) 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), 2,2-difluoroethyl trifluoromethanesulfonate (227 mg) were stirred at 70°C under nitrogen protection for 2 hours. The reaction solution was concentrated under reduced pressure to give a mixture of diastereoisomers 190 mg. Purification by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) gave the title compound 190 mg.

[0251] (±) methyl 4-(1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1-tolyl-1H-indol-4- yl)thio)piperidin-3-yl)benzoate was resolved by chiral SFC to give peak-1 (t r = 2.24 min) 64 mg; peak-2 (t r = 2.65 min) 61 mg; peak-3 (t r = 2.55 min) 60 mg; peak-4 (t r = 3.38 min) 80 mg. (Resolution method: chromatographic column: Chiralpak® AD-H 250*20 mm, 10 μm; mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonium methanolate); A:B: 70:30; flow rate: 100 mL / min; detection wavelength: 214 nm) 250*20 mm, 10 μm; mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonium methanolate); A:B: 70:30; flow rate: 100 mL / min; detection wavelength: 214 nm)

[0252] peak-1, t r = 2.24 min

[0253] 1HNMR (400 MHz, CDC13) 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).

[0254] Peak-2, t r = 2.65 min

[0255] 1 HNMR (400 MHz, CDC13) 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).

[0256] Peak-3, t r = 2.55 min

[0257] 1HNMR (400 MHz, CDC13) δ 7.90 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 3.8 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 7.19 (d, J = 8.2 Hz, 2H), 6.49 (d, J = 3.8 Hz, 2H), 5.90 (tt, J = 55.8, 4.4 Hz, 1H), 3.92 (s, 3H), 3.78 - 3.68 (m, 4H), 3.39 - 3.31 (m, 1H), 3.11 (t, J = 10.6 Hz, 1H), 2.99 - 2.81 (m, 4H), 2.67 - 2.64 (m, 1H), 2.50 (s, 3H), 2.35 (s, 3H), 1.96 - 1.90 (m, 1H), 1.78 - 1.74 (m, 1H).

[0258] Peak-4, t r = 3.38 min

[0259] 1 HNMR (400 MHz, CDC13) δ 7.90 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 3.8 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 7.19 (d, J = 8.2 Hz, 2H), 6.49 (d, J = 3.8 Hz, 2H), 5.90 (tt, J = 55.8, 4.4 Hz, 1H), 3.92 (s, 3H), 3.78 - 3.69 (m, 4H), 3.40 - 3.31 (m, 1H), 3.12 (t, J = 10.6 Hz, 1H), 2.99 - 2.82 (m, 4H), 2.67 - 2.64 (m, 1H), 2.50 (s, 3H), 2.35 (s, 3H), 1.96 - 1.90 (m, 1H), 1.78 - 1.74 (m, 1H).

[0260] j) Preparation of 4-((3S,4S)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H- indol-4-yl)thio)piperidin-3-yl)benzoic acid and 4-((3R,4R)-1-(2,2-difluoroethyl)-4- ((5-methoxy-7-methyl-1H-indol-4-yl)thio)piperidin-3-yl)benzoic acid and 4-((3S,4R)- 1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)thio)piperidin-3-yl)benzoic acid and 4-((3R,4S)-1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4- yl)thio)piperidin-3-yl)benzoic acid

[0261] The title compound 4-1 was obtained by the method described in step d) of example 1a. Chiral HPLC analysis peak time 4-1, t = 3.20 min; 4-2, t = 3.60 min; 4-3, t = 3.72 min; 4-4, t = 5.48 min. r r r r

[0262] 4-1, t = 3.20 min r

[0263] 1 HNMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.86 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.29 (t, J = 2.8 Hz, 1H), 6.71 (s, 1H), 6.32 - 6.29 (m, 1H), 6.08 (dd, J = 57.9, 53.6 Hz, 1H), 3.75 (s, 3H), 2.85 (dd, J = 27.0, 11.8 Hz, 4H), 2.75 - 2.62 (m, 2H), 2.44 (s, 3H), 2.30 (dd, J = 19.8, 8.3 Hz, 1H), 2.15 (t, J = 11.6 Hz, 1H), 1.67 - 1.47 (m, 2H).

[0264] 4-2, t = 3.60 min r

[0265] 1 HNMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.86 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.30 (t, J = 2.8 Hz, 1H), 6.71 (s, 1H), 6.32 - 6.29 (m, 1H), 6.23 - 5.91 (m, 1H), 3.76 (s, 3H), 2.92 - 2.78 (m, 4H), 2.74 - 2.63 (m, 2H), 2.45 (s, 3H), 2.30 (dd, J = 20.7, 9.9 Hz, 1H), 2.14 (t, J = 10.7 Hz, 1H), 1.57 (dd, J = 35.0, 9.4 Hz, 2H).

[0266] 4-3, t = 3.72 min r

[0267] 1 ​​​​​​​HNMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 7.85 (dd, J = 14.8, 8.2 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 7.26 (t, J = 2.8 Hz, 1H), 6.67 (s, 1H), 6.34 - 5.95 (m, 2H), 3.74 (d, J = 3.9 Hz, 1H), 3.69 (s, 3H), 3.03 (t, J = 10.8 Hz, 2H), 2.92 (d, J = 8.7 Hz, 2H), 2.86 - 2.77 (m, 2H), 2.54 (d, J = 12.8 Hz, 1H), 2.41 (d, J = 8.5 Hz, 3H), 1.77 (d, J = 6.6 Hz, 1H), 1.48 (d, J = 11.0 Hz, 1H).

[0268] 4-4, t r = 5.48 min

[0269] 1 HNMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 7.85 (dd, J = 14.8, 8.2 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 7.26 (t, J = 2.8 Hz, 1H), 6.67 (s, 1H), 6.34 - 5.95 (m, 2H), 3.74 (d, J = 3.9 Hz, 1H), 3.69 (s, 3H), 3.03 (t, J = 10.8 Hz, 2H), 2.92 (d, J = 8.7 Hz, 2H), 2.86 - 2.77 (m, 2H), 2.54 (d, J = 12.8 Hz, 1H), 2.41 (d, J = 8.5 Hz, 3H), 1.77 (d, J = 6.6 Hz, 1H), 1.48 (d, J = 11.0 Hz, 1H).

[0270] Example 5: Preparation of 4-((3S,4S)-4-((5-(methoxy-d3)-7-methyl-lH-indol-4- yl)oxy)-l-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid and 4-((3R,4R)-4-((5- (methoxy-d3)-7-methyl-lH-indol-4-yl)oxy)-l-(3,3,3-trifluoropropyl)piperidin-3- yl)benzoic acid

[0271] a) Preparation of 5-hydroxy-7-methyl-lH-indole-4-carbaldehyde

[0272] Into a two-necked flask, 4-formyl-5-methoxy-7-methyl-lH-indole-l- carboxylate tert-butyl ester (5.0 g), dichloromethane (120 mL) were added, and the flask was protected by nitrogen. Aluminium trichloride (23.04 g) was added portionwise under ice-bath, and stirred for 10 minutes. The reaction was stirred at 40 °C overnight. After the reaction was cooled to room temperature, it was poured into ice-water, and 3N diluted hydrochloric acid aqueous solution was added to quench the reaction. The reaction was extracted with ethyl acetate, and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a sand. The sand was purified by column chromatography (mobile phase: petroleum ether / dichloromethane = 3 / 7 (V / V)) to give the title compound 1.4 g.

[0273] b) Preparation of 4-formyl-5-hydroxy-7-methyl-lH-indole-l-carboxylate tert-butyl ester

[0274] Into a reaction flask, 5-hydroxy-7-methyl-lH-indole-4-carboxaldehyde (1.4 g), dichloromethane (40 mL), di-tert-butyl dicarbonate (5.23 g), 4-dimethylamino pyridine (390 mg) were added, and the flask was protected by nitrogen. The reaction was stirred at room temperature overnight. The reaction was concentrated under reduced pressure to give a sand. The sand was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 6 / 1 (V / V)) to give the title compound 2.03 g.

[0275] c) Preparation of 4-formyl-5-(methoxy-d3)-7-methyl-lH-indole-l-carboxylate tert-butyl ester

[0276] Into a reaction flask, 4-formyl-5-hydroxy-7-methyl-lH-indole-l-carboxylate tert-butyl ester (0.4 g), N,N-dimethylformamide (20 mL), potassium carbonate (602.4 mg), deuterated methyl iodide (631.8 mg) were added, and stirred at room temperature overnight. After ethyl acetate and water were added, the reaction was extracted and separated. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a sand. The sand was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 9 / 1 (V / V)) to give the title compound 375 mg.

[0277] d) Preparation of 4-hydroxy-5-(methoxy-d3)-7-methyl-lH-indole-l-carboxylate tert-butyl ester

[0278] Into a reaction flask, 4-formyl-5-(methoxy-d3)-7-methyl-lH-indole-l-carboxylate tert-butyl ester (350 mg), tetrahydrofuran (10 mL), methanol (25 mL) were added, and hydrogen peroxide (1.75 mL) was added dropwise under ice-water bath. Concentrated sulfuric acid (0.2 mL) was added dropwise under ice-water bath. The reaction was stirred at room temperature for 2.5 hours. Saturated sodium sulfite solution was added dropwise under ice-water bath to quench the reaction. The reaction was extracted with ethyl acetate, and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a sand. The sand was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 9 / 1 (V / V)) to give the title compound 310 mg.

[0279] Example 5a: 4-((3S,4S)-4-((5-(methoxy-d3)-7-methyl-lH-indol-4-yl)oxy)-l-(3,3,3- trifluoropropyl)piperidin-3-yl)benzoic acid and 4-((3R,4R)-4-((5-(methoxy-d3)-7- methyl-lH-indol-4-yl)oxy)-l-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid

[0280] Prepared according to the procedure of Example la, substituting 4-hydroxy-5-(methoxy- d3)-7-methyl-lH-indole-1-carboxylate tert-butyl ester for 4-hydroxy-5-methoxy-7- methyl-lH-indole-1-carboxylate tert-butyl ester in step a). Substitute 3,3,3- trifluoropropyl triflate for 2,2-difluoroethyl triflate in step c).

[0281] 1 HNMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 10.83 (s, 1H), 7.91 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 8.3 Hz, 2H), 7.17 (t, J = 2.7 Hz, 1H), 6.62 (s, 1H), 6.16 (d, J = 2.0 Hz, 1H), 4.45 (td, J = 9.5, 4.8 Hz, 1H), 3.11 (td, J = 10.3, 3.8 Hz, 1H), 2.89 (dd, J = 22.7, 10.0 Hz, 2H), 2.56 (dd, J = 10.1, 6.7 Hz, 2H), 2.48 - 2.38 (m, 2H), 2.36 (s, 3H), 2.34 - 2.25 (m, 1H), 2.07 (t, J = 10.4 Hz, 1H), 1.68 (dd, J = 27.4, 6.2 Hz, 2H).

[0282] LCMS m / z = 480.3 [M+1] + .

[0283] (±)-rel-(3S,4S)-4-(4-((5-(methoxy-d3)-7-methyl-lH-indol-4-yl)oxy)-l-(3,3,3- trifluoropropyl)piperidin-3-yl)benzoic acid was resolved by chiral SFC to give 5a-l (t r = 0.88 min) and 5a-2 (t r = 1.39 min). (Resolution method: Chiral column: Chiralpak IC, 4.6 x 150 mm, 5 micron; Mobile phase: 0.1% ammonium acetate in methanol; Flow rate: 1.0 mL / min; Detector: UV 220 nm). 250* 20 mm 10 pm; mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonium formate); A:B:75:25; flow rate: 100 mL / min; detection wavelength: 214 nm)

[0284] 5a-1,t r = 0.88 min

[0285] 1 HNMR (400 MHz, DMSO-d6) δ 12.98 - 12.11 (m, 1H), 10.83 (s, 1H), 7.90 (d, J = 8.1 Hz, 2H), 7.59 (d, J = 8.3 Hz, 2H), 7.16 (t, J = 2.6 Hz, 1H), 6.62 (s, 1H), 6.15 (s, 1H), 4.45 (d, J = 4.9 Hz, 1H), 3.29 (s, 1H), 3.11 (s, 1H), 2.89 (dd, J = 23.0, 10.2 Hz, 2H), 2.53 (d, J = 4.7 Hz, 4H), 2.35 (d, J = 7.1 Hz, 3H), 2.12 - 2.00 (m, 1H), 1.72 (s, 2H).

[0286] 5a-2,t r = 1.39 min

[0287] 1 HNMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 10.83 (s, 1H), 7.91 (d, J = 8.0 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H), 7.17 (t, J = 2.6 Hz, 1H), 6.62 (s, 1H), 6.15 (s, 1H), 4.45 (d, J = 4.9 Hz, 1H), 3.10 (s, 1H), 2.91 (dd, J = 23.0, 10.2 Hz, 2H), 2.69 - 2.66 (m, 1H), 2.55 (d, J = 4.7 Hz, 3H), 2.36 (d, J = 7.1 Hz, 3H), 2.34 - 2.31 (m, 1H), 2.07 (m, 1H), 1.72 (s, 2H).

[0288] Example 6: 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

[0289] a) Preparation of tert-butyl 5-(difluoromethoxy)-4-formyl-7-methyl-lH-indole-l- carboxylate

[0290] Tert-butyl 4-formyl-5-hydroxy-7-methyl-lH-indole-l-carboxylate (1.5 g) was dissolved in dichloromethane (25 mL) and added to a two-necked flask, which was protected by nitrogen replacement, and cooled to 0 °C in an ice-water bath. Aqueous potassium hydroxide (12.23 g) was added dropwise, and the mixture was stirred for 5 min before a solution of difluorobromomethyltrimethylsilane (3.32 g) in dichloromethane (5 mL) was added dropwise. The reaction was allowed to proceed at 0 °C for 2 h, and then quenched by the addition of water (50 mL). The mixture was extracted with dichloromethane (50 mL x 3), and the combined organic phases were washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a solid, which was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to give the title compound 670 mg.

[0291] LCMS m / z = 326 [M+H]+.

[0292] b) Preparation of tert-butyl 5-(difluoromethoxy)-4-hydroxy-7-methyl-lH-indole-l- carboxylate

[0293] Tert-butyl 5-(difluoromethoxy)-4-formyl-7-methyl-lH-indole-l-carboxylate (670 mg) was dissolved in dichloromethane (20 mL) and added to a 100 mL two-necked flask, which was protected by nitrogen replacement. m-Chloroperoxybenzoic acid (3.55 g) was added at 0 °C, and the reaction was allowed to proceed at room temperature for 3 h. The reaction was quenched by the addition of aqueous sodium bisulfite, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a solid, which was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 4 / 1 (V / V)) to give the title compound 170 mg.

[0294] LCMS m / z = 314.2 [M+H]+.

[0295] c) Preparation of tert-butyl (±)-rel-(3S,4S)-4-((l-(tert-butoxycarbonyl)-3-(4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-(difluoromethoxy)-7-methyl-lH- indole-l-carboxylate

[0296] (±)-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), hydrogen chloride 1,4-dioxane solution (10 mL, 4M) was added, nitrogen was replaced, stirred at room temperature for 2 hours, the reaction solution was concentrated to dryness under reduced pressure to obtain the title compound 150 mg.

[0297] LCMS m / z = 631.3 [M+H]+.

[0298] d) Preparation of (±)-rel-(3S,4S)-5-(difluoromethoxy)-4-((3-(4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0299] (±)-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), hydrogen chloride 1,4-dioxane solution (10 mL, 4M) was added, nitrogen was replaced, stirred at room temperature for 2 hours, the reaction solution was concentrated to dryness under reduced pressure to obtain the title compound 150 mg.

[0300] LCMS m / z = 531 [M+H]+.

[0301] e) Preparation of (±)-rel-(3S,4S)-5-(difluoromethoxy)-4-((3-(4- (methoxycarbonyl)phenyl)-1-(3,3,3-trifluoropropyl)piperidin-4-yl)oxy)-7-methyl-1H- indole-1-carboxylic acid tert-butyl ester

[0302] (±)-rel-(3S,4S)-5-(Difluoromethoxy)-4-((3-(4-(methoxycarbonyl)phenyl)piperidin-4- yl)oxy)-7-methyl-lH-indole-l-carboxylate tert-butyl ester (150 mg) was dissolved in tetrahydrofuran (10 mL), 3,3,3-trifluoropropyl trifluoromethanesulfonate (195.6 mg) was added, then N,N-diisopropylethylamine (137 mg) was added, and it was stirred at 70 °C overnight. Water (20 mL) was added to quench, and dichloromethane (20 mL*3) was extracted. The organic phase was combined, washed with saturated brine (20 mL*1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give sand. Column chromatography purification (mobile phase: petroleum ether / ethyl acetate = 4 / 1 (V / V)) gave the title compound 140 mg.

[0303] LCMS m / z = 627 [M+H]+.

[0304] f) Preparation of 4-((3S,4S)-4-((5-(difluoromethoxy)-7-methyl-lH-indol-4-yl)oxy)-l-(3,3,3- trifluoropropyl)piperidin-3-yl)benzoic acid and 4-((3R,4R)-4-((5-(difluoromethoxy)-7- methyl-lH-indol-4-yl)oxy)-l-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid

[0305] (±)-rel-(3S,4S)-5-(Difluoromethoxy)-4-((3-(4-(methoxycarbonyl)phenyl)-l-(3,3,3- trifluoropropyl)piperidin-4-yl)oxy)-7-methyl-lH-indole-l-carboxylate tert-butyl ester (140 mg) was dissolved in tetrahydrofuran / methanol (10 mL / 10 mL), and aqueous lithium hydroxide solution (5 mL, 2N) was added. It was stirred at 70 °C for 2 hours, concentrated to dryness under reduced pressure, and diluted with dilute aqueous hydrochloric acid to adjust the pH to neutral. It was extracted with ethyl acetate (10 mL*3), and the organic phase was combined, washed with saturated brine (20 mL*1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give sand. Column chromatography purification (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) gave the title compound enantiomer 130 mg.

[0306] 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 8.2 Hz, 2H), 7.28 (t, J = 2.7 Hz, 1H), 6.94 - 6.54 (m, 2H), 6.21 (s, 1H), 4.59 - 4.47 (m, 1H), 3.56 (t, J = 6.1 Hz, 1H), 3.19 - 3.07 (m, 1H), 2.91 (dd, J = 21.7, 10.3 Hz, 2H), 2.56 (d, J = 6.9 Hz, 2H), 2.36 (s, 3H), 2.12 (t, J = 10.6 Hz, 1H), 1.77 (d, J = 8.8 Hz, 1H), 1.69 (d, J = 9.1 Hz, 1H), 1.43 (dd, J = 7.8, 5.5 Hz, 2H).

[0307] LCMS m / z = 513.2 [M+l]+.

[0308] The (±)-rel-(3S,4S)-4-(1-(2,2-difluoroethyl)-4-((5-methoxy-7-methyl-1H-indol-4- yl)oxy)piperidin-3-yl)benzoic acid enantiomers were resolved by chiral SFC to give 6-1 (tr = 1.69 min) and 6-2 (tr = 2.40 min). (Resolution method: Column: 250*20 mm, 10 μm; mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonium formate); A:B: 75:25; flow rate: 100 mL / min; detection wavelength: 214 nm)

[0309] 6-1, tr = 1.69 min

[0310] 1H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 8.2 Hz, 2H), 7.28 (t, J = 2.7 Hz, 1H), 6.72 (dd, J = 89.3, 62.3 Hz, 2H), 6.27 - 6.14 (m, 1H), 4.53 (td, J = 9.6, 4.3 Hz, 1H), 3.55 (dd, J = 17.3, 11.2 Hz, 1H), 3.12 (td, J = 10.0, 3.7 Hz, 1H), 2.91 (dd, J = 23.0, 11.6 Hz, 2H), 2.56 (dd, J = 15.0, 8.3 Hz, 2H), 2.42 - 2.31 (m, 3H), 2.11 (dd, J = 20.1, 8.8 Hz, 1H), 1.73 (q, J = 10.7 Hz, 2H), 1.51 (d, J = 2.7 Hz, 2H).

[0311] 6 -2, tr = 2.40 min.

[0312] 1 H NMR (400 MHz, DMSO) δ 11.19 (s, 1H), 7.89 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8.3 Hz, 2H), 7.28 (t, J = 2.8 Hz, 1H), 6.72 (dd, J = 89.4, 62.1 Hz, 2H), 6.21 (dd, J = 3.0, 2.0 Hz, 1H), 4.53 (td, J = 9.8, 4.5 Hz, 1H), 3.56 (t, J = 6.1 Hz, 1H), 3.12 (td, J = 10.4, 3.9 Hz, 1H), 2.91 (dd, J = 23.0, 11.4 Hz, 2H), 2.64 - 2.53 (m, 2H), 2.41 - 2.33 (m, 3H), 2.11 (dd, J = 19.4, 9.1 Hz, 1H), 1.82 - 1.63 (m, 2H), 1.49 - 1.36 (m, 2H).

[0313] Example 7: 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

[0314] a) Preparation of 5-hydroxy-7-methyl-1H-indole-4-carbaldehyde

[0315] Into a 250 mL flask, 4-formyl-5-methoxy-7-methyl-lH-indole-l-carboxylate tert-butyl ester (5.0 g) was added, followed by dichloromethane (130 mL), and then the flask was protected by nitrogen. Then, boron tribromide (21.66 g) was added dropwise, and the reaction was slowly warmed to room temperature overnight. The reaction solution was poured into ice water, and then filtered. The filter cake was washed with dichloromethane. The chloro solution was washed with saturated sodium bicarbonate and saturated brine, and then dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure to give a sand. The sand was purified by column chromatography (mobile phase: petroleum ether / dichloromethane = 3 / 2 (V / V)) to give the title compound 1.2 g.

[0316] LCMS m / z = 176.1 [M+H]+.

[0317] b) Preparation of 4-formyl-5-hydroxy-7-methyl-lH-indole-l-carboxylate tert-butyl ester

[0318] Into a 250 mL flask, 4-formyl-5-methoxy-7-methyl-lH-indole-l-carboxylate tert-butyl ester (5.0 g) was added, followed by dichloromethane (130 mL), and then the flask was protected by nitrogen. Then, boron tribromide (21.66 g) was added dropwise, and the reaction was slowly warmed to room temperature overnight. The reaction solution was poured into ice water, and then filtered. The filter cake was washed with dichloromethane. The chloro solution was washed with saturated sodium bicarbonate and saturated brine, and then dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure to give a sand. The sand was purified by column chromatography (mobile phase: petroleum ether / dichloromethane = 3 / 2 (V / V)) to give the title compound 1.2 g.

[0319] LCMS m / z = 276.1 [M+H]+.

[0320] c) Preparation of 4-formyl-5-(methoxy-d3)-7-methyl-lH-indole-l-carboxylate tert-butyl ester

[0321] Into a 250 mL flask, 4-formyl-5-methoxy-7-methyl-lH-indole-l-carboxylate tert-butyl ester (5.0 g) was added, followed by dichloromethane (130 mL), and then the flask was protected by nitrogen. Then, boron tribromide (21.66 g) was added dropwise, and the reaction was slowly warmed to room temperature overnight. The reaction solution was poured into ice water, and then filtered. The filter cake was washed with dichloromethane. The chloro solution was washed with saturated sodium bicarbonate and saturated brine, and then dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure to give a sand. The sand was purified by column chromatography (mobile phase: petroleum ether / dichloromethane = 3 / 2 (V / V)) to give the title compound 1.2 g.

[0322] LCMS m / z = 293.2 [M+H]+.

[0323] d) Preparation of 4-hydroxy-5-(methoxy-d3)-7-methyl-lH-indole-l- carboxylic acid tert-butyl ester

[0324] Into a reaction flask was placed 4-formyl-5-(methoxy-d3)-7-methyl-lH- indole-l-carboxylic acid tert-butyl ester (800 mg), tetrahydrofuran (5 mL), methanol (15 mL), and the mixture was cooled in an ice water bath. Hydrogen peroxide (5 mL) and sulfuric acid (0.5 mL) were added dropwise, and the mixture was stirred for an additional 2.5 hours in an ice water bath. The reaction was quenched by the slow addition of saturated sodium sulfite solution, and the mixture was extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with saturated brine (30 mL*1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 90 / 10 (V / V)) to give the title compound enantiomer 723 mg.

[0325] e) Preparation of 4-((3R,4R)-l-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-(methoxy-d3)-7-methyl-lH-indole-l-carboxylic acid tert-butyl ester

[0326] The enantiomers of (±)-rel-(3S,4R)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-l- carboxylic acid tert-butyl ester were separated by chiral column to give (3S,4R)-4-hydroxy-3-(4- (methoxycarbonyl)phenyl)piperidine-l-carboxylic acid tert-butyl ester (t r = 20.33 min) and (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-l-carboxylic acid tert-butyl ester (t r = 16.51 min), and the absolute stereochemical configuration of (3R,4S)-4-hydroxy-3-(4- (methoxycarbonyl)phenyl)piperidine-l-carboxylic acid tert-butyl ester was confirmed by X-ray single crystal diffraction of Experimental Example 3. (Separation method: column: 250*4.6 mm, 5 μm; mobile phase A: n-hexane; mobile phase B: ethanol; A:B:90:10; flow rate: 1 mL / min; detection wavelength: 254 nm)

[0327] (3S,4R)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-l-carboxylic acid tert-butyl ester

[0328] 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 8.3 Hz, 2H), 4.75 (d, J = 4.2 Hz, 1H), 4.00 (d, J = 14.8 Hz, 1H), 3.84 (s, 3H), 3.77 (d, J = 11.7 Hz, 2H), 3.34 (s, 1H), 3.16 (s, 1H), 2.82 (d, J = 11.1 Hz, 1H), 1.69 (dd, J = 19.9, 3.0 Hz, 2H), 1.39 (s, 9H).

[0329] (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-l-carboxylic acid tert-butyl ester

[0330] 1 H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 8.3 Hz, 2H), 4.75 (d, J = 4.2 Hz, 1H), 4.00 (d, J = 14.8 Hz, 1H), 3.84 (s, 3H), 3.77 (d, J = 11.7 Hz, 2H), 3.34 (s, 1H), 3.16 (s, 1H), 2.82 (d, J = 11.1 Hz, 1H), 1.69 (dd, J = 19.9, 3.0 Hz, 2H), 1.39 (s, 9H).

[0331] (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-l-carboxylic acid tert-butyl ester

[0332] f) Preparation of (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-l- carboxylic acid tert-butyl ester

[0333] 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), hydrochloric acid 1,4-dioxane solution (1 mL, 4M) was added, protected by nitrogen, stirred at room temperature for 3.5 hours, saturated sodium bicarbonate solution (10 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL*3), the combined organic phase was washed with saturated brine (20 mL*1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 141 mg.

[0334] LCMS m / z = 498.3 [M+H]+.

[0335] 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

[0336] tert-Butyl 5-(methoxy-d3)-4-(((3R,4R)-3-(4-(methoxycarbonyl)phenyl)piperidin-4- yl)oxy)-7-methyl-1H-indole-1-carboxylate (75 mg) was added to a 50 mL reaction bottle, tetrahydrofuran (5 mL) and N,N-diisopropylethylamine (78.8 mg) were added, protected by nitrogen, 2,2-difluoroethyl trifluoromethanesulfonate (97 mg) was added, stirred at 50°C overnight, the reaction solution was concentrated under reduced pressure and evaporated to dryness, purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 90 / 10 (V / V)) to give the title compound 61 mg.

[0337] 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

[0338] 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), lithium hydroxide aqueous solution (1 mL, 2N) was added, stirred at 70°C for 3.5 hours, concentrated to dryness under reduced pressure, diluted with dilute hydrochloric acid aqueous solution to neutral pH, extracted with ethyl acetate (10 mL*3), the combined organic phase was washed with saturated brine (20 mL*1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 25.2 mg.

[0339] 1 H NMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 10.83 (s, 1H), 7.91 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 8.2 Hz, 2H), 7.17 (s, 1H), 6.62 (s, 1H), 6.17 (s, 1H), 6.33 - 5.96 (m, 1H), 4.45 (dd, J = 15.1, 9.0 Hz, 1H), 3.13 (td, J = 10.2, 3.8 Hz, 1H), 2.93 (dd, J = 23.5, 11.9 Hz, 2H), 2.78 (t, J = 15.5 Hz, 2H), 2.36 (s, 3H), 2.32 - 2.18 (m, 1H), 2.08 - 1.91 (m, 1H), 1.70 (s, 2H).

[0340] LCMS m / z = 448.2 [M+H]+.

[0341] Example 8: Preparation of 4-((3R,4R)-4-((5-(methoxy-d3)-7-methyl-1H-indol-4- yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid

[0342] Prepared according to the procedure of Example 7, substituting 2,2,2- trifluoroethyl trifluoromethanesulfonate for 2,2-difluoroethyl trifluoromethanesulfonate in step g.

[0343] 1 H NMR (400 MHz, DMSO-d6) δ 12.76 (s, 1H), 10.84 (s, 1H), 7.91 (d, J = 7.9 Hz, 2H), 7.58 (d, J = 7.9 Hz, 2H), 7.17 (s, 1H), 6.62 (s, 1H), 6.18 (s, 1H), 4.49 - 4.45 (m, 1H), 3.26 (d, J = 10.1 Hz, 3H), 3.15 (d, J = 10.0 Hz, 1H), 2.95 (t, J = 13.0 Hz, 2H), 2.68 (t, J = 11.1 Hz, 1H), 2.36 (s, 3H), 1.71 (s, 2H).

[0344] LCMS m / z = 466.2 [M+H]+.

[0345] Experimental Example 1: X-ray single crystal diffraction experiment

[0346] Preparation method: 5 mg of compound 1a-2 was taken in a glass vial, 0.6 ml of acetone / water (2:1, v / v) mixed solvent was added, after dissolution, filtered into another clean vial, sealed with sealing film and a small hole was pierced with a syringe needle, and a rod-shaped single crystal sample was obtained after standing at room temperature for 3 days.

[0347] After the diffraction data was integrated and reduced by the SAINT program, the data was empirically corrected by the SADABS program; the single crystal structure was analyzed by the direct method by SHELXT2014, and the structure was refined by the least square method, the hydrogen atom refinement process was obtained by isotropic calculation, and the hydrogen atom on C-H was obtained by calculation and hydrogenation, and was refined by the riding model. Figure 1 and Table 1 below are the single crystal data of the monohydrate of compound 1a-2. The Flack constant is 0.10(9), and C11 and C15 are R configuration.

[0348] Structure description: single crystal X-ray diffraction and structure analysis show that the obtained single crystal is a hydrate of 1a-2. The asymmetric unit of the crystal contains one molecule of 1a-2 and one molecule of water, wherein 1a-2 and water form a hydrate,

[0349] Table 1. Single crystal diffraction data

[0350] Experimental example 2: X-ray single crystal diffraction experiment

[0351] Preparation method: a saturated solution of compound 2a-2 at high temperature (about 60°C) was prepared in a 3 mL glass bottle, the solvent was acetonitrile (1 mL), and the clear solution was taken with a 2 mL syringe while hot, filtered with a hydrophilic PTFE needle filter (13 mm*0.45 μm), and the filtrate was transferred to another clean 3 mL glass bottle, then transferred to room temperature and stood for one day, and transparent single crystals were obtained.

[0352] After the diffraction data was integrated and reduced by the SAINT program, the data was empirically corrected by the SADABS program; the single crystal structure was analyzed by the direct method by SHELXT2014, and the structure was refined by the least square method, the hydrogen atom refinement process was obtained by isotropic calculation, and the hydrogen atom on C-H was obtained by calculation and hydrogenation, and was refined by the riding model. The Flack constant is: 0.09(10), and the chirality of C11 and C17 is R configuration. Figure 2 and Table 2 below are the single crystal results of the acetonitrile solvate of compound 2a-2.

[0353] Structure description:

[0354] Single crystal X-ray diffraction and structure analysis showed that the obtained single crystal was acetonitrile solvate of 2a-2. The asymmetric unit of the crystal contained one molecule of 2a-2, one molecule of acetonitrile, wherein 2a-2 and acetonitrile formed acetonitrile solvate,

[0355] Table 2. Single crystal diffraction data

[0356] Experimental Example 3: X-ray single crystal diffraction experiment

[0357] Preparation method: Compound (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1- carboxylic acid tert-butyl ester (t r = 16.51 min) was prepared by the following method: saturated solution at high temperature (about 50°C) with ethanol / water (1:2, v / v) as solvent, volume 1 mL. Then it was transferred to room temperature and left to stand, and transparent single crystals were obtained after one day.

[0358] After the integration reduction of the diffraction data by the SAINT program, the data was empirically corrected by the SADABS program; the single crystal structure was analyzed by the direct method by the SHELXT2014, and the structure was refined by the least square method, the hydrogen atom refinement process was obtained by isotropic calculation, the hydrogen atom on N and O was obtained by residual electron density, the hydrogen atom on C-H was obtained by calculation and hydrogenation, and was refined by the riding model. The Flack constant was 0.08(7), C10 was R configuration, and C14 was S configuration. Figure 3 and Table 3 below are the dihydrate single crystal results of the intermediate compound (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (t r = 16.51 min) obtained by the resolution of Example 7 step e).

[0359] Structure description:

[0360] Single crystal X-ray diffraction and structure analysis showed that the obtained single crystal was dihydrate of (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (t r = 16.51 min). The asymmetric unit of the crystal contained one molecule of (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (t r = 16.51 min), two molecules of water, wherein (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (t r = 16.51 min) and two molecules of water formed a hydrate,

[0361] Table 3. Single crystal diffraction data

[0362] Experimental Example 4: Human Complement Factor B TR-FRET Assay

[0363] The inhibitory activity of test compounds on complement factor B was tested in a competitive binding experiment using Cy5 fluorescently labeled small molecule inhibitor (+) or (-)-2-((1E,3E,5E)-5-(1-(6-((2-(3-(4-((R)-3-amino-3-phenylpropanoyl)-1-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazin-2-yl)phenoxy)ethyl)amino)-6-oxohexyl)-3,3-dimethyl-5-sulfonodihydroindol-2-ylidene)pent-1,3-dien-1-yl)-1-ethyl-3,3-dimethyl-5-sulfono-3H-indol-1-ium (prepared according to biological example 2 of reference CN201480050471.1) as probe. Complement factor B (Complement Tech, A135) was biotinylated using EZ-Link TM Sulfo-NHS-LC-LC-Biotin (Thermo, 21338) at a ratio of 1:20 on ice for 2 hours, then 1M Tris (pH 7.5) was added to terminate the reaction. Subsequently, the biotinylated complement factor B was purified twice with 2 mL Zeba TM desalt spin column (Thermo, 89890) to obtain the biotinylated complement factor B. During the experiment, the biotinylated complement factor B at a final concentration of 25 nM was incubated with different concentrations of compounds in buffer (PBS containing 10 mM MgCl2and 0.05% Chaps) at 4°C for 30 min. Cy5 fluorescently labeled probe and europium chelate labeled streptavidin (PerkinElmer, AD0060) at final concentrations of 75 nM and 0.225 nM, respectively, were added and reacted at 4°C for 2 hours. After the reaction, the time-dependent fluorescence energy transfer (TR-FRET) data were read on a microplate reader (Tecan, SPARK; 337 nm excitation light, 615 nm and 665 nm emission light) to determine the IC 50 , and the test results are shown in Table 4 below.

[0364] Control LNP023: synthesized according to example 26 of reference CN201480050471.1, and the structure is as follows:

[0365] Table 4. Inhibitory activity of compounds on complement factor B

[0366] Experimental Example 5: Serum Sustained Complement Deposition Assay

[0367] use Complement System Bypass Pathway Kit ( The Complement System Alternative Pathway (AP330RUO) assay was used to detect the inhibitory activity of compounds on the complement alternative pathway in human serum. Human serum was diluted 18-fold using Diluent, the kit diluent. 130 μL of the diluted serum was added to each well of a 96-well plate. The appropriate concentration of the test compound was added using a compound titrator (Tecan, D300e). The test concentration of the test compound started at 10 μM, with 3-fold dilutions, 6 concentration points, and single-well assays. The DMSO ratio in all wells was uniformly adjusted to 0.1% using DMSO. Add 0.1% DMSO and 130 μL of diluted serum to the positive control wells, and add 0.1% DMSO and 130 μL of diluent Diluent to the negative control wells. Pre-incubate at room temperature for 15 min. Transfer 100 μL of the incubated mixture to each well of a 96-well plate provided in the kit, incubate at 37°C for 60 min, discard the liquid in the wells, add 300 μL of the washing buffer provided in the kit to each well, wash 3 times, add 100 μL of the conjugated antibody Conjugate provided in the kit to each well, and incubate at room temperature for 30 min. Remove the liquid in the wells, add 300 μL of the washing buffer provided in the kit to each well, wash 3 times, add 100 μL of substrate solution to each well, and incubate at room temperature for 30 min. Detect using a microplate reader (Tecan, SPARK), and read the absorbance value at 405 nm. Experimental data are shown in Table 5 below.

[0368] Table 5. Serum alternative pathway complement deposition results

[0369] Experimental Example 6: Pharmacokinetic Study in Mice

[0370] Experimental objective: To investigate the plasma pharmacokinetics of male ICR (CD-1) mice after a single intravenous injection and gavage administration of the compound of the present invention.

[0371] Laboratory animals: Male ICR (CD-1) mice, weighing 32-35g; Supplier: Vital River Laboratory Animal Technology Co., Ltd.

[0372] Experimental procedure: Injection (IV): Oral administration (PO): The dose was 10 mg / kg (solvent: water (containing 0.5% methylcellulose (w / v) and 0.5% Tween 80 (v / v))).

[0373] Sample collection: At each set time point, 40 μL of whole blood was collected from the experimental animals via the orbital cavity. The whole blood sample was placed in an anticoagulant tube containing EDTA-K2. The whole blood sample was centrifuged at 1500g for 10 min to separate the plasma. The supernatant plasma sample was collected into a sample tube for LC-MS / MS analysis.

[0374] Data analysis: using WinNonlin TM Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software uses a non-compartmental model to process plasma concentrations and calculates pharmacokinetic parameters Cl and T using the linear logarithmic trapezoidal method. 1 / 2 C max AUC 0-24 The results are shown in the table below.

[0375] Table 6. Results of Pharmacokinetic Studies

[0376] Experimental Example 7: Collagen Antibody-Induced Mouse Arthritis Model

[0377] Experimental Objective: To investigate the efficacy of the compounds of this invention against collagen antibody- and lipopolysaccharide-induced arthritis (CAIA) in BALB / c mice. Experimental Animals: Male BALB / c mice, 6-8 weeks old, 18-20 grams; Supplier: Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0378] Experimental procedure:

[0379] 1. Induction of the mouse CAIA model: On day 0, all mice were injected via the tail vein with 0.15 mL of [a specific drug / method / treatment]. Five clones of mixed type II collagen antibody (10 mg / mL, Chondrex) were administered to mice via intraperitoneal injection on day 3. 0.2 mL of LPS (E. coli 0111:B4 lipopolysaccharide, 0.5 mg / mL, Chondrex) was injected into the mice.

[0380] 2. Administration:

[0381] Table 7. Dosing groups and dosing regimens

[0382] a: An aqueous solution of 0.5% methylcellulose (w / v) and 0.5% Tween 80 (v / v).

[0383] b: Administer the medication only once in the morning on the day of sample collection, and complete the blood data analysis within 4 hours after administration.

[0384] Data were analyzed using Graphpad Prism with One-way ANOVA / Dunnett's and SPSS with Repeat Measurement ANOVA / Bonferroni. A p-value < 0.05 was considered statistically significant.

[0385] Arthritis score: From the day of modeling, the incidence of arthritis of the limbs of animals in each group was observed three times a week until the end of the experiment. According to the different degrees (redness) of the lesions, the scores were scored according to the 0-4 standard. The scoring criteria are as follows: 0, no signs of redness or swelling; 1, redness or slight swelling of the middle foot (ankle); 2, redness and slight swelling from the ankle to the metatarsal joint; 3, redness and moderate swelling from the ankle joint to the metatarsal joint; 4, redness and severe swelling of the toes or fingers to the ankle or wrist joint.

[0386] Joint swelling: From the day of modeling, the thickness of the left and right foot pads of the animals was measured three times a week with a screw micrometer (Mitutoyo, 0-25mm, minimal 0.001mm) until the end of the experiment.

[0387] Experimental results: The experimental data are shown in Tables 8, 9 and Figures 4, 5.

[0388] Table 8. Arthritis score

[0389] Table 9. Foot pad thickness (mm)

[0390] Experimental conclusion: According to the scoring results, compared with the model group, the compounds of the application can significantly improve the degree of arthritis lesions in the model animals and reduce the swelling of the joints, and the effect is better than that of LNP023.

[0391] Experimental Example 8: Pharmacodynamic study of the test substances in a CAIA mouse model

[0392] Purpose of the experiment: To evaluate the pharmacodynamic effect of the test drug on collagen antibody and lipopolysaccharide-induced arthritis (CAIA) in BALB / c mice.

[0393] Experimental animals: BALB / c mice, male, 6-8 weeks old, 18-20 grams; supplier: Shanghai Jihui Experimental Animal Breeding Co., Ltd.

[0394] Experimental process:

[0395] 1. Induction of mouse CAIA model: On day 0, all mice were injected with 0.15 mL of 5. Clone mixed type II collagen antibody (10 mg / mL, Chondrex), 0.2 mL of LPS (E. coli 0111: B4 lipopolysaccharide, 0.5 mg / mL; Chondrex) was injected intraperitoneally into the mice on day 3.

[0396] 2. Drug administration:

[0397] Table 10. Drug administration groups and administration scheme

[0398] a: 0.5% methylcellulose (w / v), 0.5% Tween 80 (v / v) in water

[0399] The experimental data are expressed as mean ± S.E.M. The data were analyzed by One-way ANOVA / Dunnett’s of Graphpad Prism and Repeat Measurement ANOVA / Bonferroni of SPSS. P < 0.05 was considered to be significantly different.

[0400] Arthritis score: From the day of modeling, the incidence of arthritis in the limbs of animals in each group was observed three times a week until the end of the experiment. According to the different degrees of lesions (redness), the scores were scored according to the 0-4 standard. The scoring criteria are as follows: 0, no signs of redness or swelling; 1, redness or slight swelling of the middle foot (ankle); 2, redness and slight swelling from the ankle to the middle foot; 3, redness and moderate swelling from the ankle joint to the metatarsal joint; 4, redness and severe swelling of the toes or fingers to the ankle or wrist joint.

[0401] Score AUC: After the end of the experiment, the mean arthritis scores of animals in each group were analyzed with each time point using GraphPad Prism 8.4.3 software, and the Area under curve of XY analyses was selected to calculate the arthritis score AUC of each group of animals. The greater the AUC, the greater the severity of arthritis. The AUC experimental results are shown in Table 11.

[0402] Table 11. Arthritis score AUC

[0403] Experimental conclusion: According to the score results, compared with the model group, the compound of the application can significantly improve the degree of arthritis lesions in model animals, and the score AUC is significantly lower than that of LNP023.

[0404] Experimental Example 9: Preparation Example

[0405] The following provides an exemplary formulation of the present application, and it is understood that the following formulation can be prepared by conventional preparation methods well known to those skilled in the art.

[0406] Preparation Example 1

[0407] Table 12. Tablets containing 25 mg of compound 2a-2

[0408] a) Compound 2a-2, pregelatinized starch, mannitol, cross-linked polyvinylpyrrolidone, and hydroxypropyl cellulose were added to the hopper of a mixer and mixed until uniform.

[0409] b) adding sodium stearyl fumarate to the above mixture and mixing until uniform;

[0410] c) compressing the mixture into tablets using a suitable punch;

[0411] d) adding the film coating pre-blend (gastroresistant) to purified water to make a coating solution. Coating the tablets in a high efficiency coater, stopping when the target weight gain is achieved and drying.

[0412] Preparation Example 2

[0413] Table 13. Tablets containing 100 mg of Compound 1a-2

[0414] Prepared according to the procedure of Preparation Example 1.

[0415] Preparation Example 3

[0416] Table 14. Tablets containing 150 mg of Compound 2a-2

[0417] Prepared according to the procedure of Preparation Example 1.

[0418] Preparation Example 4

[0419] Table 15. Tablets containing 200 mg of Compound 2a-2

[0420] Prepared according to the procedure of Preparation Example 1.

[0421] Preparation Example 5

[0422] Table 16. Tablets containing 250 mg of Compound 2a-2

[0423] Prepared according to the procedure of Preparation Example 1.

[0424] Preparation Example 6

[0425] Table 17. Tablets containing 300 mg of Compound 2a-2

[0426] Prepared according to the procedure of Preparation Example 1.

[0427] Preparation Example 7

[0428] Table 18. Tablets containing 350 mg of Compound 2a-2

[0429] Prepared according to the procedure of Preparation Example 1.

[0430] Preparation Example 8

[0431] Table 19. Tablets containing 400 mg of Compound 2a-2

[0432] Prepared according to the procedure of Preparation 1.

[0433] Preparation 9

[0434] Table 20. Tablets containing 500 mg of Compound 1a-2

[0435] Prepared according to the procedure of Preparation 1.

[0436] Preparation 10

[0437] Table 21. Tablets containing 600 mg of Compound 1a-2

[0438] Prepared according to the procedure of Preparation 1.

[0439] Preparation 11

[0440] Table 22. Dry suspension containing 900 mg of Compound 1a-2

[0441] a) Compound 1a-2, mannitol, sodium stearyl fumarate were added to the blender hopper and mixed until uniform;

[0442] b) The mixture was filled into aluminum bags to form a dry suspension.

[0443] Preparation 12

[0444] Table 23. Dry suspension containing 1200 mg of Compound 2a-2

[0445] Prepared according to the procedure of Preparation 11.

[0446] Example 10: A multicenter, randomized, open-label Phase II clinical trial to evaluate the efficacy and safety of Compound 2a-2 in the treatment of patients with paroxysmal nocturnal hemoglobinuria

[0447] This study is a multicenter, randomized, open-label Phase II clinical trial that plans to enroll 24 patients with paroxysmal nocturnal hemoglobinuria and allocate them in a 1 : 1 ratio to Group A or Group B, approximately 12 patients in each group. Patients in Group A will start receiving Compound 2a-2 treatment at a dose of 100 mg once a day on Day 1; patients in Group B will start receiving Compound 2a-2 treatment at a dose of 200 mg once a day on Day 1. The study will include an 8-week screening period, a 12-week treatment period, and an extended treatment period. After the end of the 12-week treatment, patients who have benefited will enter the extended treatment period.

[0448] The subjects return to the hospital for visit at V3(D1), V4(D8), V5(D15), V6(D22), V7(D29), V8(D43), V9(D57), V10(D71), V11(D85), and complete the relevant examinations according to the visit week number, and perform the corresponding PK, PD blood sample collection, and evaluate the safety and effectiveness.

[0449] The study population is paroxysmal nocturnal hemoglobinuria patients who have not received complement inhibitor treatment.

[0450] Some subjects have completed the 12-week (D85) visit. Hemoglobin (HB) and lactate dehydrogenase (LDH) are the pharmacodynamic indexes of this experiment, which are used to evaluate the efficacy of 2a-2 compound in treating PNH patients. High LDH level indicates that the subject may have hemolysis, and low HB level indicates that the subject may have hemolytic anemia.

[0451] Subject 1 in the 100mg dose group has a baseline HB of 79g / L, and a 12-week HB of 111g / L, which is 32g / L higher than the baseline; the baseline LDH is 1627U / L, the 2-week LDH is 252U / L, and the 12-week LDH is 345U / L.

[0452] Subject 2 in the 100mg dose group has a baseline HB of 67g / L, and a 12-week HB of 111g / L, which is 44g / L higher than the baseline; the baseline LDH is 858U / L, the 2-week LDH is 179U / L, and the 12-week LDH is 184U / L.

[0453] Subject 3 in the 100mg dose group has a baseline HB of 88g / L, and a 12-week HB of 128g / L, which is 40g / L higher than the baseline; the baseline LDH is 1188U / L, the 2-week LDH is 223U / L, and the 12-week LDH is 234U / L.

[0454] The HB of these 3 subjects at 12 weeks is increased by ≥20g / L compared with the baseline, and is close to the normal level. At 2 weeks, the LDH is basically close to the normal range, hemolysis is controlled, and can be maintained to 12 weeks.

Claims

1. A pharmaceutical composition comprising a unit dosage form of a compound represented by Formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, the structure of Formula (I) being represented by: ###00001### (I) ​ wherein: the compound or a pharmaceutically acceptable salt thereof has a mass of 5-1500 mg as free base; X is selected from S or O; R 1 selected from C1-C6alkyl, said C1-C6alkyl being optionally substituted with halogen; R 3 selected from C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy. In some embodiments, R1is selected from C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6 2. The pharmaceutical composition in unit dosage form according to claim 1, wherein, The compounds of general formula (I) are further represented by general formulae (I-1), (I-2), (I-3) or (I-4): wherein: X, R 1 , R 3 As defined in claim 1.

3. The pharmaceutical composition in unit dosage form according to claim 1, wherein, R 1 is selected from C1-C3 alkyl, said C1-C3 alkyl being optionally substituted with fluorine, chlorine, bromine or iodine; preferably, R 1 is selected from C1-C3 alkyl, said C1-C3 alkyl being optionally substituted with 1, 2 or 3 substituents selected from fluorine, chlorine, bromine or iodine; more preferably, R 1 is selected from methyl, ethyl or propyl, said methyl, ethyl or propyl being optionally substituted with 1, 2 or 3 fluorines; further preferably, R 1 is selected from most preferably, R 1 is selected from R 3 is selected from C1-C3 alkyl, said C1-C3 alkyl is optionally substituted with deuterium, fluoro, chloro, bromo, or iodo; preferably, R 3 is selected from C1-C3 alkyl, said C1-C3 alkyl is optionally substituted with 1, 2, or 3 substituents selected from deuterium, fluoro, chloro, bromo, or iodo; more preferably, R 3 is selected from methyl, said methyl is optionally substituted with deuterium or fluoro; further preferably, R 3 is selected from methyl, said methyl is optionally substituted with 1, 2, or 3 substituents selected from deuterium or fluoro; more further preferably, R 3 is selected from methyl, -CD3, or Most preferably, R 3 is selected from methyl.

4. The pharmaceutical composition in unit dosage form according to claim 1, wherein, The compound has the structure: Preferably, the compound has the structure: More preferably, the compound has the structure:

5. A pharmaceutical composition comprising a unit dosage form of a compound of Formula II: ###00002### or a pharmaceutically acceptable salt thereof. wherein: the compound or a pharmaceutically acceptable salt thereof has a mass of 5-1500 mg as free base; R 1 selected from 6. The pharmaceutical composition in unit dosage form according to claim 5, wherein, The compound has the structure:

7. The unit dosage form of pharmaceutical composition according to claim 1 or 5, wherein, the compound or a pharmaceutically acceptable salt thereof has a mass of 10-1200 mg as free base; preferably 20-1200 mg; more preferably 25-1200 mg; further preferably 50-1000 mg; more further preferably 50-800 mg; again further preferably 75-600 mg; again further preferably 100-600 mg; most preferably 100-400 mg; particularly preferably 100-200 mg.

8. The unit dosage form of pharmaceutical composition according to claim 1 or 5, wherein, the compound or a pharmaceutically acceptable salt thereof has a mass of 0.1%-99.9% as free base of the total mass of the pharmaceutical composition; preferably 5%-90%; more preferably 20%-90%; further preferably 25%-85.7%; more further preferably 50%-60%; Preferably, the pharmaceutical composition in unit dosage form further comprises one or more pharmaceutically acceptable carriers, which have a mass of 0.1%-99.9% of the total mass of the pharmaceutical composition; preferably 5%-90%; more preferably 10%-75%.

9. The pharmaceutical composition in unit dosage form according to any one of claims 1-8, wherein the pharmaceutical composition in unit dosage form is a solid formulation or a liquid formulation; preferably, the pharmaceutical composition in unit dosage form is a solid formulation, a tablet or a dry suspension.

10. Use of the pharmaceutical composition in unit dosage form according to any one of claims 1-9 for the preparation of a medicament for the prevention and / or treatment of a complement factor B mediated disease or condition; preferably, the complement factor B mediated disease or condition is selected from one or more of an ophthalmic disease, an autoimmune disease, a disease related to the kidney system, a disease of the respiratory system, a cardiovascular disease; more preferably, the complement factor B mediated disease or condition is arthritis or paroxysmal nocturnal hemoglobinuria.

11. The pharmaceutical composition in unit dosage form according to any one of claims 1-9 for the prevention and / or treatment of a complement factor B mediated disease or condition; preferably, the complement factor B mediated disease or condition is selected from one or more of an ophthalmic disease, an autoimmune disease, a disease related to the kidney system, a disease of the respiratory system, a cardiovascular disease; more preferably, the complement factor B mediated disease or condition is arthritis or paroxysmal nocturnal hemoglobinuria.

12. Use of the pharmaceutical composition in unit dosage form according to any one of claims 1-9 for the prevention and / or treatment of a complement factor B mediated disease or condition in a subject in need thereof; preferably, the complement factor B mediated disease or condition is selected from one or more of an ophthalmic disease, an autoimmune disease, a disease related to the kidney system, a disease of the respiratory system, a cardiovascular disease; more preferably, the complement factor B mediated disease or condition is arthritis or paroxysmal nocturnal hemoglobinuria.

13. A method of preventing and / or treating a disease or condition mediated by complement factor B, wherein, The method comprises administering to a subject in need thereof an effective amount of the unit dosage form of the pharmaceutical composition of any one of claims 1-9; preferably, the complement factor B-mediated disease or condition is selected from one or more of an ophthalmic disease, an autoimmune disease, a disease related to the kidney system, a disease of the respiratory system, a cardiovascular disease; more preferably, the complement factor B-mediated disease or condition is arthritis paroxysmal hemoglobinuria.

14. The method of claim 13, wherein, The method comprises administering to a subject in need thereof the compound or a pharmaceutically acceptable salt thereof in an amount of 10-1200 mg as free base; preferably, administering to a subject in need thereof the compound or a pharmaceutically acceptable salt thereof in an amount of 20-1200 mg as free base; more preferably, administering to a subject in need thereof the compound or a pharmaceutically acceptable salt thereof in an amount of 25-1200 mg as free base; further preferably, administering to a subject in need thereof the compound or a pharmaceutically acceptable salt thereof in an amount of 50-1000 mg as free base; more further preferably, administering to a subject in need thereof the compound or a pharmaceutically acceptable salt thereof in an amount of 50-800 mg as free base; again further preferably, administering to a subject in need thereof the compound or a pharmaceutically acceptable salt thereof in an amount of 75-600 mg as free base; again further preferably, administering to a subject in need thereof the compound or a pharmaceutically acceptable salt thereof in an amount of 100-600 mg as free base; most preferably, administering to a subject in need thereof the compound or a pharmaceutically acceptable salt thereof in an amount of 100-400 mg as free base; particularly preferably, administering to a subject in need thereof the compound or a pharmaceutically acceptable salt thereof in an amount of 100-200 mg as free base.

15. The method of claim 13 or 14, wherein, The unit dosage form of the pharmaceutical composition is administered orally; or the unit dosage form of the pharmaceutical composition is administered parenterally; or the unit dosage form of the pharmaceutical composition is administered intravenously.

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