Salt of complement factor b inhibitor, preparation method therefor and use thereof

Abstract

The present invention relates to the technical field of biology. Disclosed are a salt of a complement factor B inhibitor, a preparation method therefor and a use thereof. Specifically, the present invention provides a salt of a compound as shown in formula (A), a preparation method therefor and a use thereof.

Description

Salts of complement factor b inhibitors, methods of making and uses thereof

[0001] Cross-reference to related applications

[0002] This application claims the benefit of Chinese Patent Application No. CN202410904979.9, filed July 5, 2024; the entire contents of which are incorporated herein by reference. TECHNICAL FIELD

[0003] The present application belongs to the field of biotechnology, and specifically relates to salts of complement factor B inhibitors, methods of making and uses thereof. BACKGROUND

[0004] The complement system is part of the host innate immune system involved in lysing foreign cells, enhancing antigen phagocytosis, agglutinating antigen carriers, and attracting macrophages and neutrophils, and is an important innate immune component for the human body to resist infection by 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, tissues, or cells. The complement system is an important regulator of inflammatory reactions and tissue damage, and is 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] In healthy individuals, the AP pathway is kept in a low level of activation to monitor the status of the invasion 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 removal 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 low efficiency and the excessive stimulation of complement can be harmful to the human body and are associated with increased susceptibility to infection or non-infectious diseases. Complement dysfunction or overactivation has been linked to certain autoimmune, inflammatory and neurodegenerative diseases, as well as ischemia-reperfusion injury and cancer. For example, activation of the alternative pathway of the complement cascade contributes to the production of C3a and C5a (both 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 (Factor B, FB) is a key protein involved in AP activation, and inhibiting FB activity can prevent AP pathway activation without interfering with CP and LP pathways, which can avoid increasing the risk of infection due to complement system inhibition. PCT / CN2024 / 071419 provides a class of complement factor B inhibitors. The crystal structure of the active pharmaceutical ingredient often affects the chemical stability of the drug. Different crystalline forms, preparation methods and storage conditions may lead to changes in the crystal structure of the compound, and sometimes other morphological crystal forms are also produced. Therefore, in-depth study of the polymorphism of the compound and obtaining a crystal form with stable chemical properties are of great significance for the development of drugs suitable for industrial production and with good biological activity. SUMMARY

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

[0008] The purpose of the present application is to provide a salt of a compound represented by formula A, a preparation method and uses thereof, wherein the structure of formula A is as follows:

[0009] The chemical name of the compound represented by formula A is 4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid.

[0010] In one aspect, the present application provides a salt represented by formula I:

[0011] Wherein:

[0012] M is an acid molecule, a base molecule or a basic cation;

[0013] n is 1 to 3.

[0014] In the present application, the salt is an acid salt or a base salt as conventional in the art.

[0015] In the present application, the acid salt is selected from a hydrochloride, a hydrobromide, a sulfate, a phosphate, a p-toluenesulfonate, a maleate, a tartrate or a citrate; preferably a hydrochloride, a phosphate or a sulfate.

[0016] In the present application, the base salt is selected from a sodium salt, a potassium salt, a calcium salt, a choline sulfate salt or a diethylamine salt; preferably a sodium salt or a calcium salt.

[0017] In some embodiments, a salt of the compound of Formula A is provided, the salt being selected from a sodium salt, a calcium salt, a hydrochloride, a phosphate or a sulfate.

[0018] In some embodiments, n is 1 to 2.

[0019] In some embodiments, n is 1, 2 or 3.

[0020] In some embodiments, n is 1 or 2.

[0021] In some embodiments, n is 1.

[0022] In some embodiments, n is 2.

[0023] In some embodiments, M is an acid molecule and n is 1 to 2; preferably n is 1.

[0024] In some embodiments, M is a basic cation and n is 1 to 2; preferably n is 1 or 2.

[0025] In some embodiments, a calcium salt of the compound of Formula I is provided.

[0026] In some embodiments, a calcium salt of the compound of Formula I is provided and n is 2.

[0027] In some embodiments, the calcium salt has the following structure:

[0028] In some embodiments, a crystalline form of a calcium salt of the compound of Formula II is provided.

[0029] In some embodiments, a crystalline form of a calcium salt of the compound of Formula II is provided, the X-ray powder diffraction pattern of which has diffraction peaks at 3.8°±0.2°, 5.2°±0.2°, 10.6°±0.2° and 11.3°±0.2° in terms of 2Θ.

[0030] Preferably, the crystal form of the calcium salt has X-ray powder diffraction patterns with diffraction peaks at 2θ of 3.8°±0.2°, 5.2°±0.2°, 7.5°±0.2°, 9.7°±0.2°, 10.6°±0.2° and 11.3°±0.2°.

[0031] More preferably, the crystal form of the calcium salt has X-ray powder diffraction patterns with diffraction peaks at 2θ of 3.8°±0.2°, 5.2°±0.2°, 7.5°±0.2°, 9.7°±0.2°, 10.6°±0.2°, 11.3°±0.2° and 12.4°±0.2°.

[0032] In some embodiments, the crystal form of the calcium salt, and its 2θ X-ray powder diffraction pattern are detailed in the table below:

[0033] Table 1: X-ray powder diffraction data of calcium salt crystal forms

[0034] In some embodiments, the X-ray powder diffraction pattern of the calcium salt crystal form, expressed at a 2θ angle, is shown in Figure 5.

[0035] In some embodiments, a phosphate of the compound shown in Formula I is provided.

[0036] In some embodiments, a phosphate of the compound shown in Formula I is provided, where n is 1.

[0037] In some implementations, the phosphate has the following structure:

[0038] In some embodiments, a crystal form of the phosphate of the compound shown in Formula III is provided.

[0039] In some embodiments, a phosphate form of the compound shown in Formula III is provided, the X-ray powder diffraction pattern of which has diffraction peaks at 2θ of 9.0°±0.2°, 9.8°±0.2°, 16.0°±0.2° and 18.0°±0.2°.

[0040] Preferably, the phosphate crystal form has X-ray powder diffraction patterns with diffraction peaks at 2θ of 9.0°±0.2°, 9.8°±0.2°, 16.0°±0.2°, 18.0°±0.2°, 23.1°±0.2° and 23.5°±0.2°.

[0041] More preferably, the crystalline form of the phosphate salt has an X-ray powder diffraction pattern with diffraction peaks at 9.0° ± 0.2°, 9.8° ± 0.2°, 15.3° ± 0.2°, 16.0° ± 0.2°, 18.0° ± 0.2°, 23.1° ± 0.2°, 23.5° ± 0.2°, and 24.2° ± 0.2° in terms of 2Θ.

[0042] Further preferably, the crystalline form of the phosphate salt has an X-ray powder diffraction pattern with diffraction peaks at 9.0° ± 0.2°, 9.8° ± 0.2°, 13.1° ± 0.2°, 15.3° ± 0.2°, 16.0° ± 0.2°, 18.0° ± 0.2°, 21.0° ± 0.2°, 23.1° ± 0.2°, 23.5° ± 0.2°, and 24.2° ± 0.2° in terms of 2Θ.

[0043] Still further preferably, the crystalline form of the phosphate salt has an X-ray powder diffraction pattern with diffraction peaks at 9.0° ± 0.2°, 9.8° ± 0.2°, 13.1° ± 0.2°, 15.3° ± 0.2°, 16.0° ± 0.2°, 16.7° ± 0.2°, 18.0° ± 0.2°, 21.0° ± 0.2°, 23.1° ± 0.2°, 23.5° ± 0.2°, 24.2° ± 0.2°, and 27.0° ± 0.2° in terms of 2Θ.

[0044] In some embodiments, the crystalline form of the phosphate salt has an X-ray powder diffraction pattern with 2Θ as shown in the following table:

[0045] Table 2: X-ray powder diffraction data for the crystalline form of the phosphate salt

[0046] In some embodiments, the crystalline form of the phosphate salt has an X-ray powder diffraction pattern with 2Θ as shown in the following table:

[0047] In some embodiments, a hydrochloride salt of the compound of Formula I is provided.

[0048] In some embodiments, a hydrochloride salt of the compound of Formula I is provided, and n is 1.

[0049] In some embodiments, the hydrochloride salt has the following structure:

[0050] In some embodiments, a crystalline form of a hydrochloride salt of the compound of Formula IV is provided.

[0051] In some embodiments, a crystalline form of a hydrochloride salt of the compound of Formula IV is provided, having an X-ray powder diffraction pattern with peaks at 7.6° ± 0.2°, 8.6° ± 0.2°, 11.4° ± 0.2°, and 17.4° ± 0.2° in terms of 2Θ.

[0052] Preferably, the crystalline form of the hydrochloride salt has an X-ray powder diffraction pattern with peaks at 7.6° ± 0.2°, 8.6° ± 0.2°, 11.4° ± 0.2°, 17.4° ± 0.2°, 19.6° ± 0.2°, and 23.1° ± 0.2° in terms of 2Θ.

[0053] More preferably, the crystalline form of the hydrochloride salt has an X-ray powder diffraction pattern with peaks at 7.6° ± 0.2°, 8.6° ± 0.2°, 11.4° ± 0.2°, 15.7° ± 0.2°, 17.4° ± 0.2°, 19.6° ± 0.2°, 22.8° ± 0.2°, and 23.1° ± 0.2° in terms of 2Θ.

[0054] Further preferably, the crystalline form of the hydrochloride salt has an X-ray powder diffraction pattern with peaks at 7.6° ± 0.2°, 8.6° ± 0.2°, 11.2° ± 0.2°, 11.4° ± 0.2°, 15.7° ± 0.2°, 17.4° ± 0.2°, 19.6° ± 0.2°, 22.8° ± 0.2°, 23.1° ± 0.2°, and 24.0° ± 0.2° in terms of 2Θ.

[0055] Still further preferably, the crystalline form of the hydrochloride salt has an X-ray powder diffraction pattern with peaks at 7.6° ± 0.2°, 8.6° ± 0.2°, 11.2° ± 0.2°, 11.4° ± 0.2°, 15.1° ± 0.2°, 15.7° ± 0.2°, 17.4° ± 0.2°, 19.6° ± 0.2°, 22.8° ± 0.2°, 23.1° ± 0.2°, 24.0° ± 0.2°, and 24.4° ± 0.2° in terms of 2Θ.

[0056] In some embodiments, the crystalline form of the hydrochloride salt has an X-ray powder diffraction pattern with peaks at 2Θ as shown in the following table:

[0057] Table 3: X-ray powder diffraction pattern data for the hydrochloride salt crystalline form

[0058] In some embodiments, the crystalline form of the hydrochloride salt has an X-ray powder diffraction pattern with peaks at 2Θ as shown in the following table:

[0059] In some embodiments, a sodium salt of the compound of Formula I is provided.

[0060] In some embodiments, a sodium salt of a compound of Formula I is provided, and n is 1.

[0061] In some embodiments, the sodium salt has the following structure:

[0062] In some embodiments, a sodium salt of a compound of Formula V is provided.

[0063] In some embodiments, the sodium salt is amorphous.

[0064] In some embodiments, the amorphous form of the sodium salt has an X-ray powder diffraction pattern, in terms of 2 theta angles, as shown in FIG. 8.

[0065] In some embodiments, the sodium salt is crystalline.

[0066] In some embodiments, a crystalline form of the sodium salt of a compound of Formula V is provided having an X-ray powder diffraction pattern with peaks at 5.2° ± 0.2°, 10.4° ± 0.2°, 20.8° ± 0.2°, and 26.1° ± 0.2° in terms of 2 theta angles.

[0067] Preferably, a crystalline form of the sodium salt has an X-ray powder diffraction pattern with peaks at 5.2° ± 0.2°, 9.0° ± 0.2°, 10.4° ± 0.2°, 15.6° ± 0.2°, 20.8° ± 0.2°, and 26.1° ± 0.2° in terms of 2 theta angles.

[0068] More preferably, a crystalline form of the sodium salt has an X-ray powder diffraction pattern with peaks at 5.2° ± 0.2°, 9.0° ± 0.2°, 10.4° ± 0.2°, 15.6° ± 0.2°, 20.8° ± 0.2°, 22.8° ± 0.2°, 26.1° ± 0.2°, and 39.9° ± 0.2° in terms of 2 theta angles.

[0069] Further preferably, a crystalline form of the sodium salt has an X-ray powder diffraction pattern with peaks at 5.2° ± 0.2°, 9.0° ± 0.2°, 10.4° ± 0.2°, 15.6° ± 0.2°, 18.8° ± 0.2°, 20.8° ± 0.2°, 22.8° ± 0.2°, 26.1° ± 0.2°, 29.1° ± 0.2°, and 39.9° ± 0.2° in terms of 2 theta angles.

[0070] More preferably, the crystal form of the sodium salt has an X-ray powder diffraction pattern with diffraction peaks at 5.2°±0.2°, 9.0±0.2°, 10.4°±0.2°, 15.6°±0.2°, 18.5°±0.2°, 18.8°±0.2°, 20.8°±0.2°, 22.8°±0.2°, 26.1°±0.2°, 29.1°±0.2°, 38.0°±0.2° and 39.9°±0.2° in terms of 2Θ.

[0071] In some embodiments, the crystal form of the sodium salt has an X-ray powder diffraction pattern as shown in the following table in terms of 2Θ:

[0072] Table 4: X-ray powder diffraction pattern data of the crystal form of the sodium salt

[0073] In some embodiments, the X-ray powder diffraction of the crystal form of the sodium salt has a pattern as shown in Figure 9 in terms of 2Θ angle.

[0074] In some embodiments, a sulfate salt of the compound of Formula I is provided.

[0075] In some embodiments, a sulfate salt of the compound of Formula I is provided, and n is 1-2.

[0076] In some embodiments, the sulfate salt has a structure as shown in VI, and n is 1-2.

[0077] In some embodiments, a sulfate salt of the compound of Formula VI is provided.

[0078] In some embodiments, a sulfate salt of the compound of Formula VI is provided in amorphous form.

[0079] In some embodiments, a sulfate salt of the compound of Formula VI is provided in a crystal form.

[0080] In another aspect, the present application also provides a method for preparing a salt of the compound of Formula I, comprising the step of salifying the compound of Formula A with an acid or a base.

[0081] In the present application, the preparation method includes, but is not limited to, anti-solvent addition method, anti-anti-solvent addition method, solvent evaporation method, gas-solid diffusion method, suspension stirring method and cooling crystallization method.

[0082] In some embodiments, the method for preparing a salt of the compound of Formula I comprises the steps of weighing an appropriate amount of the compound of Formula A, dissolving in a corresponding solvent, and salifying with an acid or a base.

[0083] In the present application, the solvent includes one or more of methanol, ethanol, acetone, ethyl acetate, isopropyl acetate, acetonitrile, chloroform, benzene, propyl alcohol, N,N-dimethylformamide, ethyl formate, n-heptane, and water; preferably one or more of ethanol, acetonitrile, and water.

[0084] In another aspect, the present application also provides a pharmaceutical composition comprising a therapeutically effective amount of a salt of the compound of Formula I.

[0085] In a preferred embodiment of the present application, the pharmaceutical composition comprises a therapeutically effective amount of a salt of the compound of Formula I, which is selected from a sodium salt, a calcium salt, a hydrochloride salt, a phosphate salt, or a sulfate salt.

[0086] In a preferred embodiment of the present application, the pharmaceutical composition comprises a therapeutically effective amount of a crystalline form of a salt of the compound of Formula I, which is selected from a sodium salt, a calcium salt, a hydrochloride salt, a phosphate salt, or a sulfate salt.

[0087] In another aspect, the present application also provides a pharmaceutical composition comprising a therapeutically effective amount of a salt of the compound of Formula I and a pharmaceutically acceptable carrier.

[0088] In a preferred embodiment of the present application, the pharmaceutical composition comprises a therapeutically effective amount of a crystalline form of a salt of the compound of Formula I and a pharmaceutically acceptable carrier.

[0089] In the present application, the pharmaceutical composition can be administered by any applicable route or method, such as orally or parenterally (e.g., intravenously). A therapeutically effective amount of the salt of the foregoing compound or the crystalline form thereof is from about 1 mg to 1 g / Kg body weight / day.

[0090] In another aspect, the present application also provides the use of the salt of the foregoing compound, the crystalline form of the salt, or the pharmaceutical composition thereof in the preparation of a medicament for preventing and / or treating a complement factor B-mediated disease or condition.

[0091] In another aspect, the present application also provides a method for preventing and / or treating a complement factor B-mediated disease or condition, which comprises administering to a subject in need thereof an effective amount of the salt of the foregoing compound, the crystalline form of the salt, or the pharmaceutical composition thereof.

[0092] In another aspect, the present application also provides the salt of the foregoing compound, the crystalline form of the salt, or the pharmaceutical composition of the present application for use in preventing and / or treating a complement factor B-mediated disease or condition.

[0093] In another aspect, the present application also provides the salt, the crystalline form of the salt, or the salt, the crystalline form of the salt prepared as previously described, or the composition as previously described for use in therapy.

[0094] In another aspect, the present application also provides a salt, a crystalline form of the salt, or a composition as previously described for use in the prevention and / or treatment of a complement factor B mediated disease or condition.

[0095] In some embodiments, the complement factor B mediated disease or condition is selected from one or more of an ophthalmic disease, an autoimmune disease (including arthritis), a disease related to the kidney system, a disease of the respiratory system, a cardiovascular disease.

[0096] In some specific embodiments, the complement factor B mediated disease or condition is arthritis.

[0097] Related Definitions

[0098] Unless otherwise defined, the following terms used in the specification and claims have the following meanings:

[0099] The "X-ray powder diffraction pattern" in the present application is measured using Cu-Ka radiation. It is noted that in X-ray powder diffraction spectra (XPRD), the diffraction pattern obtained from a crystalline compound is often characteristic of the particular crystalline form, where the relative intensities of the bands, especially at low angles, can vary due to preferred orientation effects resulting from differences in crystallization conditions, particle size, and other measurement conditions. Therefore, the relative intensities of the diffraction peaks are not characteristic of the crystalline form in question. In determining whether a crystalline form is the same as a known crystalline form, more attention should be paid to the relative positions of the peaks rather than their relative intensities. In addition, for any given crystalline form, there can be slight errors in the positions of the peaks, which are also well known in the art of crystallography. For example, due to changes in temperature during analysis of the sample, movement of the sample, or calibration of the instrument, the positions of the peaks can shift, and the measurement error in 2Θ values is sometimes about ±0.5°, and sometimes about ±0.2°. Therefore, in determining each crystalline structure, this error should be taken into account, and when the positions of the key characteristic peaks shift by about ±0.5°, and especially by about ±0.2°, they can be recognized as the same crystalline form.

[0100] Differential scanning calorimetry (DSC) measures the transition temperature when a crystal absorbs or releases heat as its crystal structure changes or the crystal melts. For the same crystalline form of the same compound, the thermal transition temperature and melting point are typically within about 5°C, and usually within about 3°C, of each other in successive analyses. When a given DSC peak or melting point is described for a compound, it is intended to refer to the DSC peak or melting point ± 5°C. DSC provides a useful method for distinguishing between different crystalline forms. Different crystal forms can be identified by their different transition temperature profiles. It is noted that mixtures can have DSC peaks or melting points that vary over a greater range. In addition, because decomposition can occur during melting of a substance, the melting temperature is dependent on the rate of temperature increase.

[0101] Thermogravimetric analysis (TGA) refers to a thermal analysis technique that measures the relationship between the mass of a sample under test and the change in temperature under programmed temperature control. When a substance under test undergoes sublimation or vaporization during heating, it loses mass by evolving gas or losing crystallization water, causing the mass of the sample under test to change. At this time, the thermogravimetric curve is not a straight line but has a decline. By analyzing the thermogravimetric curve, it is possible to know at what temperature the substance under test changes, and from the amount of mass lost, it is possible to calculate how much mass has been lost.

[0102] Dynamic vapor sorption (DVS) refers to a method of measuring the amount of water vapor or organic vapor adsorbed or desorbed by a sample by weighing the sample before and after adsorption or desorption at a certain relative pressure using a microbalance (with an accuracy of up to one part in a million), and is often used to detect the hygroscopicity of a drug.

[0103] When referring to, for example, an XRD pattern, a DSC pattern, a TGA pattern, or a DVS pattern, the term "as shown" includes patterns that are not necessarily identical to those depicted herein, but fall within the limits of experimental error when considered by one of skill in the art.

[0104] As used herein, "subject" refers to an animal, including, but not limited to, a primate (e.g., a human), a cow, a pig, a sheep, a goat, a horse, a dog, a cat, a rabbit, a rat, or a mouse. As used herein, the terms "subject" and "patient" are used interchangeably, e.g., to refer to a mammal or a human.

[0105] The term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a drug or agent to provide the desired effect, without being toxic to the subject.

[0106] The term "pharmaceutically acceptable carrier" means those carriers which have no significant stimulating effect on the organism and do not impair the biological activity and properties of the active compound. It includes, but is not limited to, any diluent, disintegrant, binder, glidant, wetting agent permitted by the National Medical Products Administration for use in humans or animals.

[0107] DMSO: dimethyl sulfoxide.

[0108] DMSO-d6: deuterated dimethyl sulfoxide.

[0109] 1 H NMR: nuclear magnetic resonance hydrogen spectrum.

[0110] HPLC: high performance liquid chromatography.

[0111] m / z: mass-to-charge ratio.

[0112] SFC: supercritical fluid chromatography.

[0113] V / V: volume / volume.

[0114] Tris: Tris (tris-hydroxymethyl aminomethane) buffer salt.

[0115] MgCl2: magnesium chloride.

[0116] Chaps: 3-[3-(cholamidopropyl)dimethylammonio]propanesulfonate inner salt. PBS: phosphate buffer.

[0117] Methylcellulose: methylcellulose.

[0118] Tween80: Tween 80.

[0119] w / v: mass concentration.

[0120] Bid: twice a day. BRIEF DESCRIPTION OF DRAWINGS

[0121] Figure 1 is a crystal structure of compound 1a-2 in Example 1;

[0122] Figure 2 is an X-ray powder diffraction spectrum of the crystal form B of the compound of Formula A;

[0123] Figure 3 is a differential scanning calorimetry diagram of the crystal form B of the compound of Formula A;

[0124] Figure 4 is a thermogravimetric analysis diagram of the crystal form B of the compound of Formula A;

[0125] Figure 5 is an X-ray powder diffraction spectrum of the crystal form of the calcium salt of the compound of Formula I;

[0126] Figure 6 is an X-ray powder diffraction spectrum of the crystal form of the phosphate salt of the compound of Formula I;

[0127] Figure 7 is an X-ray powder diffraction pattern of a hydrochloride salt crystalline form of the compound of Formula I;

[0128] Figure 8 is an X-ray powder diffraction pattern of a sodium salt amorphous of the compound of Formula I;

[0129] Figure 9 is an X-ray powder diffraction pattern of a sodium salt crystalline form of the compound of Formula I. DETAILED DESCRIPTION

[0130] 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.

[0131] The compounds of the present application can also be conveniently prepared by optionally combining various synthetic methods described in the present specification or known in the art, which can be easily performed by those skilled in the art.

[0132] The raw materials and apparatus used in the detailed description of the present application are all known products unless otherwise specified, and can be obtained by purchasing commercially available products.

[0133] Example 1: Preparation of 4-((3S,4S)-4-((5-methoxy-7-methyl-1H-indol-4- yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid and 4-((3R,4R)-4-((5- methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid and 4-((3S,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2- trifluoroethyl)piperidin-3-yl)benzoic acid and 4-((3R,4S)-4-((5-methoxy-7-methyl- 1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid

[0134] a) Preparation of (±) tert-butyl 3-(4-(methoxycarbonyl)phenyl)-4-oxopiperidine-1- carboxylate

[0135] Into a reaction flask was placed 3-bromo-4-oxopiperidine-l-carboxylic acid tert-butyl ester (50 g), (4-(methoxycarbonyl)phenyl)boronic acid (48.52 g), nickel(II) trifluoromethanesulfonate (3.21 g), 1,10-phenanthroline (1.62 g), potassium carbonate (49.62 g), 1,4-dioxane (500 mL), and the reaction was stirred at 80 °C for 16 h under a nitrogen atmosphere. The reaction was diluted with water (500 mL) and extracted with ethyl acetate (3 x 500 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a solid. The solid was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (v / v)) to give the title compound (32 g).

[0136] b) Preparation of (±)-rel-(3S,4R)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-l- carboxylic acid tert-butyl ester and (±)-rel-(3S,4S)-4-hydroxy-3-(4- (methoxycarbonyl)phenyl)piperidine-l-carboxylic acid tert-butyl ester

[0137] Into a reaction flask was placed (±) 3-(4-(methoxycarbonyl)phenyl)-4-oxopiperidine-l- carboxylic acid tert-butyl ester (30 g) and methanol (300 mL). Sodium borohydride (10.21 g) was added portionwise at 0 °C under a nitrogen atmosphere. The reaction was stirred at room temperature for 1 h. The reaction was quenched by the addition of water (500 mL) in an ice bath. The reaction was extracted with ethyl acetate (3 x 500 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a solid. The solid 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) according to the elution gradient.

[0138] (±)-rel-(3S,4R)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-l-carboxylic acid tert-butyl ester

[0139] 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).

[0140] (±)-rel-(3S,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-l-carboxylic acid tert-butyl ester

[0141] 1 HNMR (400MHz, DMSO-d6) δ7.90(d,J=8.3Hz,2H),7.42(d,J=8.3Hz,2H),4.71(d,J=6.0Hz,1H),4.03(q,J=7.1Hz,1H),3.97 (d,J=11.8Hz,1H),3.85(s,3H),3.83-3.72(m,2H),2.89(s,2H),1.99(s,1H),1.89(dd,J=12.4,3.8Hz,1H),1.40(s,9H).

[0142] Example 1a: 4-((3S,4S)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid and 4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid

[0143] Preparation of tert-butyl ester of a)(±)-rel-(3S,4S)-4-((1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid

[0144] 10.06 g of tert-butyl 4-hydroxy-5-methoxy-7-methyl-1H-indole-1-carboxylic acid, 8.4 g of (±)-rel-(3S,4R)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester, 23.82 g of triphenylphosphine, and 200 mL of anhydrous tetrahydrofuran were added to a three-necked flask under nitrogen purging protection. Diisopropyl azodicarbonate (18.33 g) was added dropwise at 0 °C. The reaction system was heated to room temperature and reacted for 16 hours. The reaction was diluted with water (500 mL), extracted with ethyl acetate (3 × 200 mL), separated, and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to prepare slurry. The slurry was purified by column chromatography (mobile phase: petroleum ether ethyl acetate = 5 / 1 (V / V)) to give 22 g of the title compound.

[0145] b)(±)-rel-(3S,4S)-5-methoxy-4-((3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester preparation

[0146] (±)-rel-(3S,4S)-4-((1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (10 g) was dissolved in 4 M hydrochloric acid in 1,4-dioxane (70 mL) and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to give a residue, which was the title compound 16 g.

[0147] LCMS m / z = 495.4 [M+1] + .

[0148] c) Preparation of (±)-rel-(3S,4S)-5-methoxy-4-((3-(4-(methoxycarbonyl)phenyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0149] (±)-rel-(3S,4S)-5-methoxy-4-((3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (6.3 g) and N,N-diisopropylethylamine (6.6 mL) were added to a reaction flask, tetrahydrofuran (80 mL) was added, and then 2,2,2-trifluoroethyl trifluoromethanesulfonate (8.9 g) was added. The reaction was protected by nitrogen replacement, stirred at 70°C for 2 hours, and then 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 a residue, which was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to give the title compound 5 g.

[0150] LCMS m / z = 577.1 [M+H] + .

[0151] d) Preparation of 4-((3S,4S)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid and 4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid

[0152] (±)-rel-(3S,4S)-5-methoxy-4-((3-(4-(methoxycarbonyl)phenyl)-1-(2,2,2- trifluoroethyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (5 g) was added to a reaction flask, methanol (120 mL), lithium hydroxide (6.25 g), water (100 mL) were added, protected by nitrogen gas, 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 give sand, purified by column chromatography (mobile phase: dichloromethane methanol 5 / 1 (V / V)) to give the title compound enantiomer 1.7 g.

[0153] (±)-rel-(3S,4S)-4-(4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2- trifluoroethyl)piperidin-3-yl)benzoic acid was resolved by chiral SFC to give 1a-1 (t r = 1.87 min) and 1a-2 (t r = 2.73 min), the absolute stereochemical configuration of 1a-2 was confirmed by X-ray single crystal diffraction of experimental example 1 as 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*25mm, 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)

[0154] 1a-1, t r = 1.87 min

[0155] 1H NMR (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), 2.47h2.41 (m, 1H), 2.34 (d, J = 11.4 Hz, 3H), 1.70 (d, J = 3.6 Hz, 2H).

[0156] LCMS m / z = 463.1 [M+H] + .

[0157] 1a-2,t r = 2.73 min

[0158] 1 H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 7.86 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H), 7.14 (t, J = 2.8 Hz, 1H), 6.59 (s, 1H), 6.15 (dd, J = 3.0, 2.0 Hz, 1H), 4.44 (dd, J = 16.1, 7.8 Hz, 1H), 3.57 (s, 3H), 3.20 (d, J = 3.6 Hz, 2H), 3.12h3.05 (m, 1H), 2.89 (d, J = 13.0 Hz, 2H), 2.64 (t, J = 11.3 Hz, 1H), 2.42 (s, 1H), 2.32 (s, 3H), 1.67 (d, J = 3.5 Hz, 2H).

[0159] LCMS m / z = 463.1 [M+H] + .

[0160] Example 1b: (±)-rel-(3S,4R)-4-(4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2- trifluoroethyl)piperidin-3-yl)benzoic acid

[0161] Prepared according to the procedure of Example 1a, substituting (±)-rel-(3S,4S)-4- hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester for (±)-rel-(3S,4R)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester in step a).

[0162] (±)-rel-(3S,4R)-4-(4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2- trifluoroethyl)piperidin-3-yl)benzoic acid was resolved by chiral SFC to give 1b-1 (t r = 1.06 min) and 1b-2 (t r = 2.37 min) (Resolution method: 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 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)

[0163] 1b-1, t r = 1.06 min

[0164] 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).

[0165] LCMS m / z = 463.1 [M+H] + .

[0166] 1b-2, t r = 2.37 min

[0167] 1HNMR (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).

[0168] LCMS m / z = 463.1 [M+H] + .

[0169] Experimental Example 1: X-ray single crystal diffraction experiment

[0170] Preparation method: prepare a saturated solution of compound 1a-2 at high temperature (about 60°C) in a 3 mL glass bottle, the solvent is acetonitrile (1 mL), while hot, use a 2 mL syringe to suck the clear solution, filter with a hydrophilic PTFE needle filter (13 mm*0.45 μm), transfer the filtrate to another clean 3 mL glass bottle, then transfer it to room temperature, and after one day, transparent single crystals are obtained.

[0171] After integrating and reducing the diffraction data using the SAINT program, the data is empirically corrected using the SADABS program; the single crystal structure is analyzed by direct method using SHELXT2014, and the structure is refined by least squares method, the hydrogen atom refinement process adopts isotropic calculation processing, the hydrogen atom on C-H is obtained by calculation and hydrogenation, and is refined by riding model. The Flack constant is: 0.09(10), and the chiralities of C11 and C17 are R configuration. Figure 1 and Table 5 below are the single crystal results of the acetonitrile solvate of compound 1a-2.

[0172] Structure description: single crystal X-ray diffraction and structure analysis show that the obtained single crystal is an acetonitrile solvate of 1a-2. The asymmetric unit of the crystal contains one molecule of 1a-2 and one molecule of acetonitrile, in which 1a-2 and acetonitrile form an acetonitrile solvate, and the structure is as follows:

[0173] Table 5: Single crystal diffraction data

[0174] Experimental Example 2: Human complement factor B TR-FRET assay

[0175] The inhibitory activity of the 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 CN201480050471.1) as probe. Complement factor B (Complement Tech, A135) was labeled with EZ-Link TM Sulfo-NHS-LC-LC-Biotin (Thermo, 21338) at a ratio of 1:20 on ice for 2 hours, and then 1M Tris (pH 7.5) was added to terminate the reaction. Subsequently, the biotin-labeled complement factor B was purified twice with 2 mL Zeba TM desalt spin column (Thermo, 89890). During the experiment, the biotin-labeled complement factor B at a final concentration of 25 nM was incubated with different concentrations of compounds in buffer (PBS containing 10 mM 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 h. After the reaction, the data of time-dependent fluorescence energy transfer (TR-FRET) were read on a microplate reader (Tecan, SPARK; excitation light at 337 nm, emission light at 615 nm and 665 nm) to determine IC 50 The test results are shown in Table 6 below.

[0176] Control LNP023: synthesized according to example 26 of CN201480050471.1, and the structure is as follows:

[0177] Table 6: Inhibitory activity of compounds on complement factor B

[0178] Experimental Example 3: Serum alternative pathway complement deposition experiment

[0179] The complement system alternative pathway kit (Complement Tech, A140) was used to test the inhibitory activity of the test compounds on the alternative pathway of the complement system. The test compounds were incubated with the complement system alternative pathway reagent at 37°C for 30 min, and then the fluorescence intensity of the reaction solution was measured on a microplate reader (Tecan, SPARK; excitation light at 337 nm, emission light at 615 nm and 665 nm) to determine IC ​Complement system Alternative pathway AP330 RUO) to detect the inhibitory activity of the compound on the complement alternative pathway in human serum. The human serum is diluted 18 times using the kit diluent Diluent, and the diluted serum is added to a 96-well plate at 130 μL / well. The compound titrator (Tecan, D300e) is used to add the corresponding concentration of the test compound. The test concentration of the test compound is 10 μM, which is diluted 3 times, 6 concentration points, single well detection, and all the drug addition holes are uniformly adjusted to 0.1% DMSO. The positive control hole adds 0.1% DMSO and 130 μL of diluted serum, and the negative control hole adds 0.1% DMSO and 130 μL of diluent Diluent. The pre-incubation is carried out at room temperature for 15 min; the mixture after incubation is transferred to a 96-well plate provided by the kit at 100 μL per well, and incubated at 37°C for 60 min. The liquid in the hole is discarded, 300 μL of washing solution in the kit is added to each hole, and washed 3 times. 100 μL of conjugate in the kit is added to each hole, and incubated at room temperature for 30 min. The liquid in the hole is removed, 300 μL of washing solution in the kit is added to each hole, and washed 3 times. 100 μL of substrate solution is added to each hole, and incubated at room temperature for 30 min. The enzyme-labeled instrument (Tecan, SPARK) is used for detection, and the absorbance value at 405 nm is read. The experimental data are shown in Table 7 below.

[0180] Table 7: Serum alternative pathway complement deposition results

[0181] Experimental Example 4: Mouse pharmacokinetic study test

[0182] Experimental purpose: To investigate the plasma pharmacokinetics of the compound of the application in male ICR (CD-1) mice after single intravenous injection and oral administration.

[0183] Experimental animals: Male ICR (CD-1) mice, body weight 32-35 g; supplier: Vivotek Laboratory Animal Technology Co., Ltd.

[0184] Experimental process: Injection administration (IV): oral administration (PO): the dose is 10 mg / kg (solvent: water (containing 0.5% methyl cellulose (w / v), 0.5% Tween 80 (v / v))).

[0185] Sample collection: The experimental animals were taken 40 μL of blood from the orbit at each set time point, and the whole blood sample was placed in an anticoagulant tube containing EDTA-K2. The whole blood sample was centrifuged at 1500 g for 10 min to separate the plasma, and the upper plasma sample was collected into a sample tube for LC-MS / MS analysis.

[0186] Data analysis: WinNonlinTM Non-compartmental analysis of plasma concentration data was performed using WinNonlin® Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software. Pharmacokinetic parameters Cl, T 1 / 2 , C max , AUC 0-24 were calculated using linear-log trapezoidal methods. Results are shown in the table below.

[0187] Table 8: Pharmacokinetic study results

[0188] Example 5: Efficacy study of the test substance in a CAIA mouse model

[0189] Objective: To evaluate the efficacy of the test substance on collagen antibody and lipopolysaccharide-induced arthritis (CAIA) in BALB / c mice.

[0190] Experimental animals: BALB / c mice, male, 6-8 weeks, 18-20 grams; supplier: Shanghai Jihui Experimental Animal Breeding Co., Ltd.

[0191] Experimental procedure:

[0192] 1. Induction of the mouse CAIA model: On day 0, all mice were injected intravenously with 0.15 mL of 5 gram clone mixture type II collagen antibody (10 mg / mL, Chondrex); on day 3, mice were injected intraperitoneally with 0.2 mL of LPS (E. coli 0111 :B4 lipopolysaccharide, 0.5 mg / mL; Chondrex).

[0193] 2. Drug administration:

[0194] Table 9: Drug administration groups and administration regimen

[0195] a: 0.5% methyl cellulose (w / v), 0.5% Tween 80 (v / v) in water

[0196] Experimental data are expressed as mean ± S.E.M. Data were analyzed by One-way ANOVA / Dunnett’s using Graphpad Prism and Repeat Measurement ANOVA / Bonferroni using SPSS. P < 0.05 was considered to be significantly different.

[0197] 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.

[0198] Score AUC: After the end of the experiment, the mean arthritis score of each group of animals was analyzed with the 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 10.

[0199] Table 10: Arthritis score AUC

[0200] Experimental conclusion: According to the score results, compared with the model group, the compound of the application can significantly improve the degree of arthritis of the model animals, and the score AUC is significantly lower than that of LNP023.

[0201] Experimental example 6: study on pharmaceutical salts and crystal forms

[0202] It is well known to those skilled in the art that when the above-mentioned compound is proved to have good complement factor B inhibition effect, its salt or crystal form often has the same pharmacological and pharmacodynamic activity. On this basis, the inventors further studied the physicochemical properties of the corresponding compound salt or crystal form, but the preparation and characterization of the following specific salt or crystal form does not represent a limitation on the scope of protection of the application. Those skilled in the art can obtain more salts or crystals of the compounds of the application based on the application, and these schemes are all protected schemes of the application. The specific information is as follows:

[0203] 1. Instrument test information

[0204] 1) X-ray powder diffraction (XRPD) parameters

[0205] Table 11: X-ray powder diffraction (XRPD) parameters

[0206] 2) Thermogravimetric analyzer parameters

[0207] Table 12: Thermogravimetric analyzer parameters

[0208] 3) Differential scanning calorimeter parameters

[0209] Table 13: Differential scanning calorimeter parameters

[0210] 2. Preparation of crystal form

[0211] 2.1 Preparation of crystal form B

[0212] 1. Into a 5-mL glass vial, 0.2 g of the compound of Formula A and 0.4 mL of acetone were added, and the temperature was raised to 50 °C until dissolved, then the temperature was lowered to room temperature and stirred for 0.5 h, then 1.2 mL of n-heptane was added and stirred for 1 h, and the temperature was lowered to 4 ± 5 °C and stirred for 2-4 h, and then filtered under suction, and the wet filter cake was placed in a 40 ± 5 °C desiccator for 15-16 h under reduced pressure. The product was collected, and the yield was 85.5%. After detection and analysis, the XRPD results of crystal form B are shown in Figure 2, the DSC results are shown in Figure 3, and the TGA results are shown in Figure 4.

[0213] 2.2 Preparation of calcium salt crystal form

[0214] Into a 20-mL glass vial, 700 mg of the compound of Formula A crystal form B, 62 mg of sodium hydroxide, and 14 mL of water were added, and the temperature was controlled at 30 ± 5 °C, and stirred until dissolved, and the solution was ready for use.

[0215] Into the above vial, 2.5 mL of calcium chloride aqueous solution (10% wt) was added, and the temperature was raised to 45 ± 5 °C, and stirred, and filtered under suction, and blown to near dryness under nitrogen. The wet filter cake was slurried with 5 mL of acetonitrile for 1 h. It was filtered under suction, and the filter cake was placed in a 50 ± 5 °C desiccator for 12 h under reduced pressure, and the product was collected. After detection and analysis, the XRPD results of the calcium salt crystal form are shown in Figure 5.

[0216] 2.3 Preparation of phosphate salt crystal form

[0217] Into a 60-mL glass vial, 2.5 g of the compound of Formula A crystal form B and 25 mL of acetonitrile were added in sequence, and stirred until dissolved at a temperature of 55 ± 5 °C. 503.3 mg of phosphoric acid (98% wt) was added, and the temperature was lowered to 35 ± 5 °C, and stirred magnetically (200 r / min) for 1 h. Seed crystals were added, and the temperature was maintained and stirred for 2 h. It was filtered under suction, and the filter cake was placed in a 45 ± 5 °C desiccator for 13 h under reduced pressure. The product was collected. After detection and analysis, the XRPD results of the phosphate salt crystal form are shown in Figure 6.

[0218] 2.4 Preparation of hydrochloride salt crystal form

[0219] Into a 30-mL glass vial, 3.0 g of the compound of Formula A, Form B, and 9.0 mL of absolute ethanol were added in sequence, and stirred magnetically at 25 ± 5 °C. 805.0 mg of hydrochloric acid-ethanol solution (30% wt) was added, and the solution was stirred at 25 ± 5 °C until clear. 10.0 mL of n-heptane and seed crystals were added, and the mixture was stirred for 2 h. The mixture was suction filtered, and the wet filter cake was slurried with 10.0 mL of 98% ethyl acetate / water at 45 ± 5 °C for 1 h. The mixture was suction filtered, and the filter cake was dried at 50 ± 5 °C under reduced pressure for 12 h. The product was collected. The XRPD results of the hydrochloride salt Form are shown in FIG. 7.

[0220] 2.5 Preparation of sodium salt

[0221] 1) Preparation of sodium salt amorphous

[0222] Into a 100-mL glass vial, 2 g of the compound of Formula A, Form B, 23.4 mL of methyl tert-butyl ether, and 173 mg of sodium hydroxide were added, and the mixture was warmed until clear. After the solution was clear, the mixture was cooled to 25 °C and stirred, and then 70 mL of n-heptane was added, and the mixture was stirred. The mixture was suction filtered and dried at 40 ± 5 °C under reduced pressure for 18 h. The XRPD results of the sodium salt are shown in FIG. 8.

[0223] 2) Preparation of sodium salt Form

[0224] Into a 10-mL glass vial, 0.5 g of the sodium salt amorphous and 8 mL of 1,4-dioxane were added, and the mixture was stirred at 4 °C, and a solid was precipitated. The XRPD results of the sodium salt Form are shown in FIG. 9.

[0225] 2.6 Preparation of sulfate salt

[0226] Into a 10-mL glass vial, 300 mg of the compound and 3 mL of ethyl acetate were added in sequence, and the mixture was stirred at room temperature until dissolved. 713.3 mg (wt: 9.09%) of sulfuric acid-methyl tert-butyl ether solution was added dropwise, and a solid was rapidly precipitated.

[0227] 3. Summary of salt forms characterization

[0228] The characterization results of the calcium salt, the phosphate salt, and the hydrochloride salt were summarized, and the results are shown in the following table. The molar ratio of the acid to base in the salt formation was determined by ion chromatography.

[0229] Conditions for calcium salt determination:

[0230] The chromatographic conditions used a cation exchange column (Dionex Ionpac CS12A, 4 x 250 mm, or a chromatographic column with equivalent performance); the detector was a conductivity detector; the detection mode was suppressed conductivity detection; the column temperature was 30 °C; the injection volume was 25 μL; and 20 mM methanesulfonic acid aqueous solution was used as the eluent at a flow rate of 0.9 mL per minute.

[0231] Salt, phosphate, sulfate detection conditions:

[0232] Chromatographic conditions An anion exchange column (Dionex Ionpac AS19, 4 x 250 mm column, Dionex Ionpac AG19, 4 x 50 mm guard column, or a chromatographic column of equivalent performance); a conductivity detector; suppressed conductivity detection; column temperature 30 °C; injection volume 25 μL; 30 mM aqueous potassium hydroxide as eluent at a flow rate of 1.0 mL per minute.

[0233] Table 14

[0234] The foregoing description of specific exemplary embodiments of the application has been presented for the purposes of illustration and description. It is not intended to be exhaustive or to limit the application to the precise form disclosed, and various modifications and variations are possible in light of the above teachings. It is intended that the application encompass all such modifications and variations as fall within the scope of the claims and their equivalents. The claims are intended to cover all changes and modifications of the application which fall within the scope of the claims, along with all equivalent arrangements.

Claims

1. A salt of the structure shown in Formula I: ###00001### Formula I wherein: M is an acid molecule, a base molecule or a basic cation; n is 1-3; preferably, n is 1, 2 or 3; preferably, n is 1 or 2; more preferably, n is 1; more preferably, n is 2; Preferably, M is an acid molecule, and n is 1-2; preferably n is 1; Preferably, M is a basic cation, and n is 1-2; preferably n is 1 or 2.

2. The salt of claim 1, characterized in that, The salt is an acid salt or a base salt; The acid salt is selected from a hydrochloride, a hydrobromide, a sulfate, a phosphate, a p-toluenesulfonate, a maleate, a tartrate or a citrate; preferably a hydrochloride, a phosphate or a sulfate; Alternatively, the base salt is selected from a sodium salt, a potassium salt, a calcium salt, a choline sulfate salt or a diethylamine salt; preferably a sodium salt or a calcium salt; Preferably, the salt is selected from a sodium salt, a calcium salt, a hydrochloride, a phosphate or a sulfate.

3. The salt of claim 2, characterized in that, The salt is a calcium salt; Preferably, the salt is a calcium salt, and n is 2; Preferably, the salt is a calcium salt, having the following structure: Preferably, the salt is a crystalline form of a calcium salt of the compound of Formula II; Preferably, the crystalline form of the calcium salt has an X-ray powder diffraction pattern with peaks at 2-theta of 3.8°±0.2°, 5.2°±0.2°, 10.6°±0.2° and 11.3°±0.2°; More preferably, the crystalline form of the calcium salt has an X-ray powder diffraction pattern with peaks at 2-theta of 3.8°±0.2°, 5.2°±0.2°, 7.5°±0.2°, 9.7°±0.2°, 10.6°±0.2° and 11.3°±0.2°; Further preferably, the crystalline form of the calcium salt has an X-ray powder diffraction pattern with peaks at 2-theta of 3.8°±0.2°, 5.2°±0.2°, 7.5°±0.2°, 9.7°±0.2°, 10.6°±0.2°, 11.3°±0.2° and 12.4°±0.2°; More further preferably, the crystalline form of the calcium salt has an X-ray powder diffraction pattern with peaks at 2-theta as shown in Figure 5.

4. The salt of claim 2, wherein The salt is a phosphate salt; Preferably, the salt is a phosphate salt, and n is 1; Preferably, the salt is a phosphate salt, having the following structure: Preferably, the salt is a crystalline form of a phosphate salt of the compound of Formula III; Preferably, the crystalline form of the phosphate salt has an X-ray powder diffraction pattern with peaks at 2-theta of 9.0°±0.2°, 9.8°±0.2°, 16.0°±0.2° and 18.0°±0.2°; More preferably, the crystalline form of the phosphate salt has an X-ray powder diffraction pattern with peaks at 2-theta of 9.0°±0.2°, 9.8°±0.2°, 16.0°±0.2°, 18.0°±0.2°, 23.1°±0.2° and 23.5°±0.2°; More preferably, the crystalline form of the phosphate salt has an X-ray powder diffraction pattern with peaks at 2-theta of 9.0°±0.2°, 9.8°±0.2°, 15.3°±0.2°, 16.0°±0.2°, 18.0°±0.2°, 23.1°±0.2°, 23.5°±0.2° and 24.2°±0.2°; Further preferably, the crystalline form of the phosphate salt has an X-ray powder diffraction pattern with diffraction peaks at 2-theta = 9.0°±0.2°, 9.8°±0.2°, 13.1°±0.2°, 15.3°±0.2°, 16.0°±0.2°, 18.0°±0.2°, 21.0°±0.2°, 23.1°±0.2°, 23.5°±0.2° and 24.2°±0.2°; More preferably, the crystalline form of the phosphate salt has an X-ray powder diffraction pattern with diffraction peaks at 2-theta = 9.0°±0.2°, 9.8°±0.2°, 13.1°±0.2°, 15.3°±0.2°, 16.0°±0.2°, 16.7°±0.2°, 18.0°±0.2°, 21.0°±0.2°, 23.1°±0.2°, 23.5°±0.2°, 24.2°±0.2° and 27.0°±0.2°; Most preferably, the crystalline form of the phosphate salt has an X-ray powder diffraction pattern with the pattern as shown in Figure 6.

5. The salt of claim 2, wherein The salt is a hydrochloride salt; Preferably, the salt is a hydrochloride salt and n is 1 ; Preferably, the salt is a hydrochloride salt, having the following structure: Preferably, the salt is a crystalline form of a hydrochloride salt of the compound of Formula IV. Preferably, the crystalline form of the hydrochloride salt has an X-ray powder diffraction pattern with diffraction peaks at 2-theta = 7.6°±0.2°, 8.6°±0.2°, 11.4°±0.2° and 17.4°±0.2°; Preferably, the crystalline form of the hydrochloride salt has an X-ray powder diffraction pattern with diffraction peaks at 2-theta = 7.6°±0.2°, 8.6°±0.2°, 11.4°±0.2°, 17.4°±0.2°, 19.6°±0.2° and 23.1°±0.2°; More preferably, the crystalline form of the hydrochloride salt has an X-ray powder diffraction pattern with diffraction peaks at 2-theta = 7.6°±0.2°, 8.6°±0.2°, 11.4°±0.2°, 15.7°±0.2°, 17.4°±0.2°, 19.6°±0.2°, 22.8°±0.2° and 23.1°±0.2°; Further preferably, the crystalline form of the hydrochloride salt has an X-ray powder diffraction pattern with diffraction peaks at 2-theta = 7.6°±0.2°, 8.6°±0.2°, 11.2°±0.2°, 11.4°±0.2°, 15.7°±0.2°, 17.4°±0.2°, 19.6°±0.2°, 22.8°±0.2°, 23.1°±0.2° and 24.0°±0.2°; More preferably, the crystalline form of the hydrochloride salt has an X-ray powder diffraction pattern with diffraction peaks at 2-theta = 7.6°±0.2°, 8.6°±0.2°, 11.2°±0.2°, 11.4°±0.2°, 15.1°±0.2°, 15.7°±0.2°, 17.4°±0.2°, 19.6°±0.2°, 22.8°±0.2°, 23.1°±0.2°, 24.0°±0.2° and 24.4°±0.2°; Most preferably, the hydrochloride salt crystalline form has an X-ray powder diffraction pattern with peaks at 2-theta angles as shown in Figure 7.

6. The salt of claim 2, wherein The salt is a sodium salt; Preferably, the salt is a sodium salt, and n is 1. Preferably, the salt is a sodium salt, having the following structure: Preferably, the salt is a sodium salt, and the sodium salt form is amorphous. Preferably, the amorphous sodium salt has an X-ray powder diffraction pattern with peaks at 2-theta angles as shown in Figure 8. Alternatively, preferably, the salt is a sodium salt, and the sodium salt form is a crystalline form. Preferably, the crystalline form of the sodium salt has an X-ray powder diffraction pattern with peaks at 2-theta angles of 5.2°±0.2°, 10.4°±0.2°, 20.8°±0.2° and 26.1°±0.2°. Preferably, the crystalline form of the sodium salt has an X-ray powder diffraction pattern with peaks at 2-theta angles of 5.2°±0.2°, 9.0±0.2°, 10.4°±0.2°, 15.6°±0.2°, 20.8°±0.2° and 26.1°±0.2°. More preferably, the crystalline form of the sodium salt has an X-ray powder diffraction pattern with peaks at 2-theta angles of 5.2°±0.2°, 9.0±0.2°, 10.4°±0.2°, 15.6°±0.2°, 20.8°±0.2°, 22.8°±0.2°, 26.1°±0.2° and 39.9°±0.2°. Further preferably, the crystalline form of the sodium salt has an X-ray powder diffraction pattern with peaks at 2-theta angles of 5.2°±0.2°, 9.0±0.2°, 10.4°±0.2°, 15.6°±0.2°, 18.8°±0.2°, 20.8°±0.2°, 22.8°±0.2°, 26.1°±0.2°, 29.1°±0.2° and 39.9°±0.2°. More further preferably, the crystalline form of the sodium salt has an X-ray powder diffraction pattern with peaks at 2-theta angles of 5.2°±0.2°, 9.0±0.2°, 10.4°±0.2°, 15.6°±0.2°, 18.5°±0.2°, 18.8°±0.2°, 20.8°±0.2°, 22.8°±0.2°, 26.1°±0.2°, 29.1°±0.2°, 38.0°±0.2° and 39.9°±0.2°. Most preferably, the crystalline form of the sodium salt has an X-ray powder diffraction pattern with peaks at 2-theta angles as shown in Figure 9.

7. The salt of claim 2, wherein The salt is a sulfate salt; Preferably, the salt is a sulfate salt, and n is 1-2. Preferably, the salt is a sulfate salt, having the structure of VI, n is 1 to 2, Preferably, the sulfate salt form is amorphous or a crystalline form.

8. A method for preparing the salt of any one of claims 1-7, comprising the step of salifying the compound of Formula A with an acid or a base. Preferably, the method comprises the steps of weighing an appropriate amount of the compound of Formula A, dissolving in a corresponding solvent, and salifying with an acid or a base. The solvent comprises one or more of methanol, ethanol, acetone, ethyl acetate, isopropyl acetate, acetonitrile, chloroform, benzene, propyl alcohol, N,N-dimethylformamide, ethyl formate, n-heptane, and water; preferably one or more of ethanol, acetonitrile, and water; 9. A pharmaceutical composition comprising a therapeutically effective amount of the salt of any one of claims 1-7. Preferably, the pharmaceutical composition comprises a therapeutically effective amount of the crystalline form of the salt of any one of claims 1-7. Preferably, the pharmaceutical composition comprises a therapeutically effective amount of the salt of any one of claims 1-7 and a pharmaceutically acceptable carrier. Preferably, it contains a therapeutically effective amount of the crystalline form of the salt according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier; More preferably, the salt is selected from a sodium salt, a calcium salt, a hydrochloride salt, a phosphate salt or a sulphate salt.

10. Use of the salt according to any one of claims 1 to 7, the crystalline form of the salt or the pharmaceutical composition according to claim 9 for the manufacture 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 renal system, a disease of the respiratory system, a cardiovascular disease; more preferably, the complement factor B mediated disease or condition is arthritis.

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