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

Abstract

Disclosed in the present invention are a salt form of a complement factor B inhibitor, a preparation method therefor, and use thereof. The present invention specifically relates to a salt form of the following compound of formula I, the salt form of the compound of formula I being a salt formed by the compound of formula I and an acid or a base. The salt form of the complement factor B inhibitor of the present invention has good stability and / or pharmacokinetic properties.

Description

Salt forms of complement factor B inhibitors, their preparation methods and applications

[0001] This application claims priority to Chinese patent application 2025101141503, filed on January 24, 2025. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of medicine, specifically relating to the salt form of complement factor B inhibitors, their preparation methods, and applications. Background Technology

[0003] Complement is a class of soluble pattern recognition molecules in the immune system that perform a variety of effector functions. Under natural conditions, complement components exist in inactive zymogen form. Various specific and non-specific immunological mechanisms break down these inactive zymogens, producing active large and small fragments. The large fragments typically remain on the surface of pathogens or cells, causing their lysis or accelerating their clearance; the small fragments leave the cell surface and mediate various inflammatory responses. Complement activation consists of two closely related processes, forming a cascade of complement activation. Currently known complement activation pathways mainly include three: the classical pathway, the lectin pathway, and the alternative pathway. Although the initiation mechanisms and activation sequences of these three complement activation pathways differ, they share a common terminal pathway. The activation of the alternative pathway is independent of the antigen-antibody complex. Typically, C3b deposited on the cell surface binds to factor B, becoming readily broken down by factor D in serum. During this process, factor B is broken down into Ba and Bb. C3b and Bb then form a complex, becoming the C3 convertase C3bBb in the alternative pathway. In this process, complement factor B plays an early and central role in the activation of the alternative pathway within the complement cascade. Here, C3b is both a product of C3 convertase breakdown and a component of the alternative pathway C3 convertase, thus forming a feedback amplification mechanism where the classical and alternative pathways influence each other. Current research has found a correlation between various diseases, including hematologic, autoimmune, inflammatory, and neurodegenerative diseases, and complement system dysfunction.

[0004] Currently, the publicly disclosed patents for complement factor B inhibitors include WO2013164802, WO2013192345, WO2014143638, WO2015009616, WO2015066241, WO2019043609A1 and WO2022028527A1. Summary of the Invention

[0005] This invention provides a polymorph of compound I, 4-[(2S,4S)-4-(2,2-difluorovinyl)-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]hexahydropyridin-2-yl]benzoic acid, with the structure of the compound I as follows.

[0006] In another aspect, the present invention provides a salt form of the compound of formula I, wherein the salt form is a salt formed by the compound of formula I with an acid or a base;

[0007] The acid is selected from hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthylcarboxylic acid, nicotinic acid, pyruvic acid, pectinic acid, persulfate, 3-phenylpropionic acid, picric acid, tervamolonic acid, 2-hydroxyethanesulfonic acid, itaconic acid, aminosulfonic acid, trifluoromethanesulfonic acid, dodecyl sulfuric acid, ethanesulfonic acid, benzenesulfonic acid, and p- The following are selected from the following: toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, L-tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucohepanoic acid, glycerophosphate, aspartic acid, sulfosalicylic acid, hemisulfonic acid, or thiocyanate; preferably selected from the following: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, citric acid, L-tartaric acid, oxalic acid, formic acid, acetic acid, trifluoroacetic acid, lauric acid, benzoic acid, and benzenesulfonic acid.

[0008] The alkali is selected from alkali metal hydroxides or alkaline earth metal hydroxides, preferably from sodium hydroxide or potassium hydroxide.

[0009] In some embodiments of the present invention, the salt form of the compound of Formula I is selected from one of its hydrochloride, sulfate, phosphate, methanesulfonate, p-toluenesulfonate, fumarate, maleate, citrate, L-tartrate, and oxalate.

[0010] In some embodiments of the present invention, the salt form of the compound of formula I is a hydrochloride or a methanesulfonate.

[0011] In some embodiments of the present invention, the salt form of the compound of formula I is its hydrochloride salt.

[0012] In another aspect, the present invention provides a method for preparing a salt form of the compound of formula I, characterized in that the preparation method comprises reacting the compound of formula I with the acid or base to prepare a salt form of the compound of formula I; preferably, the preparation method comprises reacting the compound of formula I with the acid or base in a solvent to prepare a salt form of the compound of formula I; preferably, the solvent is selected from two or more combinations of alcohols, ketones, esters, ethers, and nitrile solvents, or mixtures of the above solvents or combinations with water; the acid or base is independently defined herein.

[0013] According to embodiments of the present invention, in the salt form of the compound of formula I, the molar ratio of the compound of formula I to the acid or base can be independently selected from 1:1, 2:1, or 3:1, provided that the ions of the compound of formula I in the salt are in charge balance with the ions of the acid or base. For example, when the acid (such as hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid) has 1 ionizable hydrogen atom, the molar ratio of the compound of formula I to the acid is 1:1; when the acid (such as sulfuric acid, fumaric acid, maleic acid, citric acid, L-tartaric acid, oxalic acid) has 2 ionizable hydrogen atoms, the molar ratio of the compound of formula I to the acid can be 1:1 or 2:1; when the acid (such as phosphoric acid) has 3 ionizable hydrogen atoms, the molar ratio of the compound of formula I to the acid is 1:1, 2:1, or 3:1.

[0014] According to embodiments of the present invention, the alcohols may be selected from alcohols having 1-8 carbon atoms, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, neopentyl alcohol, or combinations thereof; the ketones may be selected from ketones having 3-10 carbon atoms, such as acetone, butanone, pentanone, methyl ethyl ketone, 4-methyl-2-pentanone, or combinations thereof; the esters may be selected from organic carboxylic acid esters, such as methyl formate, ethyl acetate, isobutyl formate, isopropyl acetate, or combinations thereof; and the ethers may be straight-chain or branched alkyl ethers or cyclic ether compounds, such as methyl tert-butyl ether, tetrahydrofuran, 2-methyl-tetrahydrofuran, or combinations thereof.

[0015] The nitrile solvent can be selected from nitrile solvents having 2-5 carbon atoms, such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile, and valerate.

[0016] According to an embodiment of the present invention, the molar ratio of the compound of formula I to the acid or base can be 1:0.8 to 1:1.5, preferably 1:0.9 to 1:1.3, and more preferably 1:1.0 to 1:1.1.

[0017] According to an embodiment of the present invention, in the preparation method, the reaction temperature can be selected within a wide range, for example, 10℃ to 50℃, preferably 20℃ to 40℃.

[0018] According to an embodiment of the present invention, the preparation method further includes a step of filtration and / or drying after the reaction is completed, in order to prepare the salt form of the compound of formula I.

[0019] In some embodiments of the present invention, the salt form of the compound of formula I is the compound of formula I-1.

[0020] In another aspect of the invention, a hydrochloride crystal form A1 of the compound of formula I (i.e., crystal form A1 of the compound of formula I-1) is provided, wherein the hydrochloride crystal form A1 has characteristic peaks at 12.66±0.20°, 22.45±0.20° and 28.76±0.20° when X-ray powder diffraction is performed using Cu-Kα radiation in 2θ angles.

[0021] In some embodiments of the invention, the crystal form Al is irradiated with Cu-Kα radiation, and X-ray powder diffraction in 2θ angles has characteristic peaks at 11.10±0.20°, 12.66±0.20°, 22.45±0.20°, 25.33±0.20° and 28.76±0.20°.

[0022] In some embodiments of the present invention, the crystal form Al is subjected to Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angles, exhibits characteristic peaks as shown in Table 1, wherein the error range of the 2θ angles is ±0.20°.

[0023] Table 1

[0024] In some embodiments of the present invention, the crystal form A1 is an anhydrous form of the monohydrochloride salt of compound I;

[0025] In another aspect, the present invention provides a single crystal of the hydrochloride Al of the compound of formula I (i.e., a single crystal of the crystal form Al of the compound of formula I-1), characterized in that the cell parameters of the single crystal are as follows:

[0026] Monoclinic crystal system, space group P21;

[0027] α = γ = 90°;

[0028] β=94.999(2)°;

[0029] Z = 2.

[0030] In another aspect of the invention, a hydrochloride crystal form A2 of the compound of formula I is provided, wherein the hydrochloride crystal form A2 exhibits characteristic peaks at 3.79±0.20°, 11.38±0.20°, 15.66±0.20° and 21.98±0.20° when X-ray powder diffraction is performed using Cu-Kα radiation in 2θ angles.

[0031] In some embodiments of the present invention, the hydrochloride crystal form A2, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction, expressed in 2θ angles, as shown in Table 2, wherein the error range of the 2θ angles is ±0.20°.

[0032] Table 2

[0033] In another aspect, the present invention provides a hydrochloride crystal form B of the compound of formula I, wherein the hydrochloride crystal form B exhibits characteristic peaks at 11.71±0.20°, 16.84±0.20°, 18.28±0.20°, 22.53±0.20°, and 25.59±0.20° when X-ray powder diffracted using Cu-Kα radiation in 2θ angles.

[0034] In some embodiments of the present invention, the hydrochloride crystal form B is subjected to Cu-Kα radiation, and X-ray powder diffraction in 2θ angles further shows characteristic peaks at 13.78±0.20°, 16.5±0.20°, 17.37±0.20°, 19.27±0.20°, 22.04±0.20°, 24.93±0.20°, 26.08±0.20°, 27.24±0.20°, and 28.08±0.20°.

[0035] In some embodiments of the present invention, the hydrochloride crystal form B, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction, expressed in 2θ angles, as shown in Table 3, wherein the error range of the 2θ angles is ±0.20°.

[0036] Table 3

[0037] In some embodiments of the present invention, the hydrochloride crystal form B is subjected to Cu-Kα radiation, and the X-ray powder diffraction pattern expressed in 2θ angle is shown in Figure 1.

[0038] In some embodiments of the present invention, the thermogravimetric analysis of the hydrochloride crystal form B shows a weight loss of 2.29% when heated to 160°C.

[0039] In some embodiments of the present invention, the thermogravimetric analysis diagram of the hydrochloride crystal form B is shown in Figure 2.

[0040] In some embodiments of the present invention, the differential scanning calorimetry (DSC) of the hydrochloride crystal form B has two endothermic peaks at 183.1 and 260.6 °C (peak temperatures) and one exothermic peak at 214.9 °C (peak temperature).

[0041] In some embodiments of the present invention, the differential scanning calorimetry (DSC) of the hydrochloride crystal form B is shown in Figure 2.

[0042] In another aspect, the present invention provides a method for preparing the hydrochloride crystal form B of the compound of formula I, comprising the following steps: reacting the compound of formula I and an aqueous solution of the hydrochloride in a solvent to obtain the hydrochloride crystal form B of the compound of formula I.

[0043] In some embodiments of the present invention, in the method for preparing hydrochloride crystal form B, the solvent is a nitrile solvent, preferably acetonitrile, propionitrile, butyronitrile, isobutyronitrile, valerate, or adiponitrile, for example, acetonitrile.

[0044] In some embodiments of the present invention, in the method for preparing the hydrochloride crystal form B, the mass-to-volume ratio of the compound of formula I to the solvent is 50-70 mg / mL; preferably 60 mg / mL.

[0045] In some embodiments of the present invention, in the method for preparing hydrochloride crystal form B, the concentration of the aqueous solution of the hydrochloride is 10-14 mol / L; preferably 12 mol / L.

[0046] In some embodiments of the present invention, in the method for preparing the hydrochloride crystal form B, the mass ratio of the compound of formula I to the aqueous solution of the hydrochloride is 3:1-5:1; preferably 4.3:1.

[0047] In some embodiments of the present invention, in the method for preparing hydrochloride crystal form B, the reaction temperature is room temperature, preferably 15-30°C; for example, 20°C or 25°C.

[0048] In some embodiments of the present invention, the reaction time in the method for preparing hydrochloride crystal form B is not specifically limited, but is related to the reaction scale. Generally, the reaction endpoint is taken as the point at which the raw materials no longer disappear or the products no longer increase. For example, the reaction time is 10-48 hours, preferably 24 hours.

[0049] In some embodiments of the present invention, the method for preparing hydrochloride crystal form B further includes a post-processing step: after the reaction, the solid is separated and dried.

[0050] In another aspect, the present invention provides a sulfate crystal form A of the compound of Formula I, wherein the sulfate crystal form A exhibits characteristic peaks at 9.74±0.20°, 14.12±0.20°, 15.17±0.20°, 22.17±0.20°, and 22.59±0.20° when X-ray powder diffracted using Cu-Kα radiation in 2θ angles.

[0051] In some embodiments of the present invention, the sulfate crystal form A is subjected to Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angles, exhibits characteristic peaks as shown in Table 4, wherein the error range of the 2θ angles is ±0.20°.

[0052] Table 4

[0053] In another aspect of the invention, a maleate crystal form A of the compound of Formula I is provided, wherein the maleate crystal form A exhibits characteristic peaks at 8.63±0.20°, 8.96±0.20°, 14.42±0.20°, 15.81±0.20°, and 17.54±0.20° when X-ray powder diffracted using Cu-Kα radiation in 2θ angles.

[0054] In some embodiments of the present invention, the maleate crystal form A, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction, expressed in 2θ angles, as shown in Table 5, wherein the error range of the 2θ angles is ±0.20°.

[0055] Table 5

[0056] In another aspect of the invention, maleate crystal form B of the compound of formula I is provided, wherein the maleate crystal form B exhibits characteristic peaks at 9.09±0.20°, 9.61±0.20°, 14.23±0.20°, 15.70±0.20°, 17.47±0.20°, 24.08±0.20°, and 24.46±0.20° when X-ray powder diffracted using Cu-Kα radiation in 2θ angles.

[0057] In some embodiments of the present invention, the maleate crystal form B, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction, expressed in 2θ angles, as shown in Table 6, wherein the error range of the 2θ angles is ±0.20°.

[0058] Table 6

[0059] In another aspect, the present invention provides a phosphate crystal form A of the compound of Formula I, wherein the phosphate crystal form A exhibits characteristic peaks at 7.11±0.20°, 7.71±0.20°, 9.57±0.20°, 11.05±0.20°, 11.99±0.20°, and 19.12±0.20° when X-ray powder diffracted using Cu-Kα radiation in 2θ angles.

[0060] In some embodiments of the present invention, the phosphate crystal form A is subjected to Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angles, exhibits characteristic peaks as shown in Table 7, wherein the error range of the 2θ angles is ±0.20°.

[0061] Table 7

[0062] In another aspect of the invention, a phosphate crystal form B of the compound of formula I is provided, wherein the phosphate crystal form B has characteristic peaks at 9.74±0.20°, 12.02±0.20°, 20.12±0.20° and 24.21±0.20° when X-ray powder diffraction is performed using Cu-Kα radiation and expressed in 2θ angles.

[0063] In some embodiments of the present invention, the phosphate crystal form B is subjected to Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angles, exhibits characteristic peaks as shown in Table 8, wherein the error range of the 2θ angles is ±0.20°.

[0064] Table 8

[0065] In another aspect of the invention, a fumarate crystal form A of the compound of Formula I is provided, wherein the fumarate crystal form A exhibits characteristic peaks at 9.50±0.20°, 9.98±0.20°, 11.46±0.20°, 16.94±0.20°, 18.92±0.20°, and 25.11±0.20° when X-ray powder diffracted using Cu-Kα radiation in 2θ angles.

[0066] In some embodiments of the present invention, the fumarate crystal form A, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction, expressed in 2θ angles, as shown in Table 9, wherein the error range of the 2θ angles is ±0.20°.

[0067] Table 9

[0068] In another aspect of the invention, a hippurate crystal form A of the compound of Formula I is provided, wherein the hippurate crystal form A has characteristic peaks at 9.62±0.20°, 10.82±0.20°, 17.19±0.20° and 19.78±0.20° when X-ray powder diffraction is performed using Cu-Kα radiation and expressed in 2θ angles.

[0069] In some embodiments of the present invention, the hippurate crystal form A, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction, expressed in 2θ angles, as shown in Table 10, wherein the error range of the 2θ angles is ±0.20°.

[0070] Table 10

[0071] In another aspect, the present invention provides a hippurate crystal form B of the compound of formula I, wherein the hippurate crystal form B has characteristic peaks at 7.86±0.20°, 11.4182±0.20°, 12.0201±0.20° and 14.2898±0.20° when X-ray powder diffraction is performed using Cu-Kα radiation in 2θ angles.

[0072] In some embodiments of the present invention, the hippurate crystal form B, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction, expressed in 2θ angles, as shown in Table 11, wherein the error range of the 2θ angles is ±0.20°.

[0073] Table 11

[0074] In another aspect, the present invention provides adipate crystal form A of the compound of Formula I, wherein adipate crystal form A has characteristic peaks at 9.04±0.20°, 9.88±0.20°, 18.44±0.20°, 19.49±0.20° and 24.01±0.20° when X-ray powder diffracted using Cu-Kα radiation in 2θ angles.

[0075] In some embodiments of the present invention, the adipate crystal form A, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction, expressed in 2θ angles, as shown in Table 12, wherein the error range of the 2θ angles is ±0.20°.

[0076] Table 12

[0077] In another aspect, the present invention provides a p-toluenesulfonate crystal form A of the compound of Formula I, wherein the p-toluenesulfonate crystal form A exhibits characteristic peaks at 9.74±0.20°, 11.45±0.20°, 12.02±0.20°, 19.78±0.20°, and 20.16±0.20° when X-ray powder diffracted using Cu-Kα radiation in 2θ angles.

[0078] In some embodiments of the present invention, the p-toluenesulfonate crystal form A is subjected to Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angles, exhibits characteristic peaks as shown in Table 13, wherein the error range of the 2θ angles is ±0.20°.

[0079] Table 13

[0080] In another aspect of the invention, a methanesulfonate crystal form A of the compound of formula I is provided, wherein the methanesulfonate crystal form A has characteristic peaks at 11.26±0.20°, 11.41±0.20°, 14.53±0.20° and 18.74±0.20° when X-ray powder diffraction is performed using Cu-Kα radiation in 2θ angles.

[0081] In some embodiments of the present invention, the methanesulfonate crystal form A is subjected to Cu-Kα radiation, and X-ray powder diffraction in 2θ angles further shows characteristic peaks at 12.79±0.20°, 16.34±0.20°, 16.63±0.20°, 20.41±0.20° and 23.19±0.20°.

[0082] In some embodiments of the present invention, the methanesulfonate crystal form A, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction, expressed in 2θ angles, as shown in Table 14, wherein the error range of the 2θ angles is ±0.20°.

[0083] Table 14

[0084] In some embodiments of the present invention, the methanesulfonate crystal form A is subjected to Cu-Kα radiation, and the X-ray powder diffraction pattern expressed in 2θ angle is shown in Figure 3.

[0085] In some embodiments of the present invention, the thermogravimetric analysis of the methanesulfonate crystal form A shows a weight loss of 1.09% when heated to 160°C.

[0086] In some embodiments of the present invention, the thermogravimetric analysis diagram of the methanesulfonate crystal form A is shown in Figure 4.

[0087] In some embodiments of the present invention, the differential scanning calorimetry (DSC) of the methanesulfonate crystal form A has an endothermic peak at 193.2°C (peak temperature) and an exothermic peak at 195.8°C (peak temperature).

[0088] In some embodiments of the present invention, the differential scanning calorimetry (DSC) of the methanesulfonate crystal form A is shown in Figure 4.

[0089] In another aspect, the present invention provides a method for preparing the methanesulfonate crystal form A of the compound of formula I, comprising the following steps: reacting the compound of formula I with methanesulfonic acid in a solvent to obtain the methanesulfonate crystal form A of the compound of formula I.

[0090] In some embodiments of the present invention, in the method for preparing methanesulfonate crystal form A, the solvent is a nitrile solvent, preferably acetonitrile, propionitrile, butyronitrile, isobutyronitrile, valerate, or adiponitrile, for example, acetonitrile.

[0091] In some embodiments of the present invention, in the method for preparing the methanesulfonate crystal form A, the mass-to-volume ratio of the compound of formula I to the solvent is 50-70 mg / mL; preferably 60.5 mg / mL.

[0092] In some embodiments of the present invention, in the method for preparing the methanesulfonate crystal form A, the molar ratio of the compound of formula I to the methanesulfonic acid is 1:0.8-1:1.2; preferably 1:1.

[0093] In some embodiments of the present invention, in the method for preparing methanesulfonate crystal form A, the reaction temperature is room temperature, preferably 15-30°C; for example, 20°C or 25°C.

[0094] In some embodiments of the present invention, the reaction time in the method for preparing methanesulfonate crystal form A is not specifically limited, but is related to the scale of the reaction. Generally, the reaction endpoint is taken as the point at which the raw materials no longer disappear or the products no longer increase. For example, the reaction time is 10-48 hours, preferably 24 hours.

[0095] In some embodiments of the present invention, the method for preparing methanesulfonate crystal form A further includes a post-processing step: after the reaction, the solid is separated and dried.

[0096] In another aspect of the invention, a hydrobromide crystal form B of the compound of formula I is provided, wherein the hydrobromide crystal form B has characteristic peaks at 8.79±0.20°, 11.28±0.20°, 15.57±0.20° and 16.20±0.20° when X-ray powder diffraction is performed using Cu-Kα radiation and expressed in 2θ angles.

[0097] In some embodiments of the present invention, the hydrobromide crystal form B, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction, expressed in 2θ angles, as shown in Table 15, wherein the error range of the 2θ angles is ±0.20°.

[0098] Table 15

[0099] In another aspect, the present invention provides a hydrobromide crystal form C of the compound of Formula I, wherein the hydrobromide crystal form C exhibits characteristic peaks at 8.78±0.20°, 11.60±0.20°, 16.57±0.20°, 18.10±0.20°, 22.20±0.20°, 24.91±0.20°, 25.43±0.20°, 25.80±0.20°, and 27.1847±0.20° when X-ray powder diffracted using Cu-Kα radiation in 2θ angles.

[0100] In some embodiments of the present invention, the hydrobromide crystal form C, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at a 2θ angle, as shown in Table 16, wherein the error range of the 2θ angle is ±0.20°.

[0101] Table 16

[0102] In another aspect, the present invention provides a hydrobromide crystal form D of the compound of formula I, wherein the hydrobromide crystal form D exhibits characteristic peaks at 8.75±0.20°, 15.21±0.20°, 18.97±0.20°, 22.11±0.20°, 26.87±0.20°, and 28.20±0.20° when X-ray powder diffracted using Cu-Kα radiation in 2θ angles.

[0103] In some embodiments of the present invention, the hydrobromide crystal form D is subjected to Cu-Kα radiation, and X-ray powder diffraction, expressed in 2θ angles, exhibits characteristic peaks as shown in Table 17, wherein the error range of the 2θ angles is ±0.20°.

[0104] Table 17

[0105] In another aspect of the invention, a D-camphor sulfonate crystal form A of the compound of Formula I is provided, wherein the D-camphor sulfonate crystal form A exhibits characteristic peaks at 9.97±0.20°, 10.49±0.20°, 12.10±0.20°, and 15.98±0.20° when X-ray powder diffraction is performed using Cu-Kα radiation and expressed in 2θ angles.

[0106] In some embodiments of the present invention, the D-camphor sulfonate crystal form A, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at a 2θ angle, as shown in Table 18, wherein the error range of the 2θ angle is ±0.20°.

[0107] Table 18

[0108] In another aspect of the present invention, D-camphor sulfonate crystal form A of the compound of formula I is provided, wherein D-camphor sulfonate crystal form A shows a weight loss of 1.69% when the sample is heated to 150°C and has an endothermic peak at 202.6°C (peak temperature).

[0109] In another aspect, the present invention provides a sodium salt crystal form B of the compound of formula I, wherein the sodium salt crystal form B exhibits characteristic peaks at 3.62±0.20°, 15.40±0.20°, 16.54±0.20°, 16.92±0.20°, 32.29±0.20°, and 33.58±0.20° when X-ray powder diffracted using Cu-Kα radiation in 2θ angles.

[0110] In some embodiments of the present invention, the sodium salt crystal form B is subjected to Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angles, exhibits characteristic peaks as shown in Table 19, wherein the error range of the 2θ angles is ±0.20°.

[0111] Table 19

[0112] In another aspect of the present invention, a pharmaceutical composition is provided comprising the above-described salt form (e.g., hydrochloride crystal form B or mesylate crystal form A) and one or more pharmaceutically acceptable excipients;

[0113] Preferably, the pharmaceutical composition is in the form of a pharmaceutical preparation.

[0114] In another aspect of the invention, the use of a salt form of a compound of formula I (e.g., hydrochloride crystal form B or mesylate crystal form A) or a pharmaceutical composition thereof in the preparation of a medicament for the prevention and / or treatment of complement factor B-mediated diseases or conditions is provided.

[0115] In some embodiments of the present invention, the complement factor B-mediated disease or condition is selected from at least one of the following: paroxysmal nocturnal hemoglobinuria (PNH), primary glomerulonephritis (IgAN), membranous nephropathy (MN), diabetic nephropathy (DKD), C3 glomerulonephritis (C3G), lupus nephritis (LN), proliferative nephritis, systemic lupus erythematosus (SLE), age-related macular degeneration (AMD), geographic atrophy (GA), atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome (HUS), diabetic retinopathy (DR), hemodialysis complications, hemolytic anemia or hemodialysis, neuromyelitis (N... MO), arthritis, rheumatoid arthritis, psoriatic arthritis, liver inflammation, dermatomyositis and amyotrophic lateral sclerosis, myasthenia gravis (MG), Guillain-Barré syndrome (GBS), neuromyelitis optica spectrum disorder (NMOSD), uveitis, retinitis pigmentosa, macular edema, Behçet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, avian retinal choroiditis, sympathetic ophthalmia, ocular pemphigoid, ocular pemphigoid, non-arterial ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, Doyne's honeycomb retinal dystrophy / Malattia Leventinese, Sorsby retinal dystrophy, late-onset macular dystrophy, North Carolina macular dystrophy, Stargardt disease, keratitis, antineutrophil cytoplasmic antibody-associated vasculitis (ANCA-AAV), Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemia-reperfusion syndrome, myocardial infarction, balloon angioplasty, post-pump syndrome of cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, acute kidney injury, and mesenteric artery reperfusion after aortic reconstruction.

[0116] In the context of this specification, "above," "below," and "within" should be understood to include the stated number. As an example, "at least one" should be understood as "one, two, or more kinds." Similarly, "two or more kinds" should be understood as "two or more kinds," such as "two, three, four, or more kinds."

[0117] The positive and progressive effects of the present invention are as follows: the salt form of the compound of formula I of the present invention has one or more of the following advantages: (1) it has a good inhibitory effect on the human serum complement system bypass pathway; (2) it has good safety; (3) it has good pharmacokinetic properties (e.g., high peak blood drug concentration); (4) it has good hygroscopicity; (5) it has good stability; (6) it has good solubility. Attached Figure Description

[0118] Figure 1 is an XRPD diagram of the hydrochloride crystal form B of compound I in Example 1.

[0119] Figure 2 is a TGA / DSC diagram of the hydrochloride crystal form B of compound I in Example 1.

[0120] Figure 3 is an XRPD diagram of the methanesulfonate crystal form A of compound I in Example 2.

[0121] Figure 4 is a TGA / DSC diagram of the methanesulfonate crystal form A of compound I in Example 2.

[0122] Figure 5 is an XRPD diagram of D-camphor sulfonate crystal form A of compound I in Example 3. Detailed Implementation

[0123] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0124] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0125] Experimental instrument parameters

[0126] X-ray powder diffraction (XRPD)

[0127] The device used was a Bruker D8 Advance diffractometer. The sample was scanned using the following parameters:

[0128] The radiation source is a Cu-Kα target.

[0129] The minimum operating voltage and current of the fluorescent tube are 40kV and 40mA, respectively.

[0130] Detection conditions: Scan range 2θ value from 3° to 40°; step size: 0.02°; speed: 0.1 seconds / step.

[0131] Thermogravimetric analysis (TGA)

[0132] Thermogravimetric analysis (TGA) data were acquired from a METTLER TOLEDO TGA2 instrument, and the instrument control and analysis software was STARe software. Typically, 1–10 mg of sample was placed in an alumina crucible (with the lid off), and the sample was heated from 30 °C to 350 °C at a heating rate of 10 °C / min under the protection of dry nitrogen at a rate of 50 mL / min.

[0133] Differential Scanning Calorimeter (DSC)

[0134] Differential thermal analysis (DSC) data were acquired from a METTLER TOLEDO DSC3 instrument, and the instrument control and analysis software was STARe software. Typically, 0.5–5 mg of sample was placed in an aluminum crucible (with a perforated lid), and the sample was heated from 30 °C to 300 °C at a heating rate of 10 °C / min under the protection of dry nitrogen at a rate of 50 mL / min.

[0135] Dynamic water vapor adsorption (DVS)

[0136] Under a relative humidity (RH) cycle of 0%–90%–0%, approximately 10 mg of sample was weighed and subjected to a moisture absorption / desorption characteristic test at 25°C. The parameters are as follows:

[0137] Table 20

[0138] Hygroscopicity classification:

[0139] Table 21

[0140] * indicates that the product is stored at 25±1℃ and 80±2%RH (2020 edition of the Chinese Pharmacopoeia).

[0141] "W": Weight gain due to moisture absorption at 80% RH.

[0142] Single crystal testing instruments and conditions

[0143] Instrument Model: D8 Venture

[0144] Instrument parameters:

[0145] Explanation of Abbreviations

[0146] 60℃ / 30%RH refers to the conditions at 60℃ and 30% humidity.

[0147] 25℃ / 90%RH refers to conditions at 25℃ and 90% humidity.

[0148] 25℃ / 60%RH refers to conditions at 25℃ and 60% humidity.

[0149] 40℃ / 75%RH refers to the conditions at 40℃ and 75% humidity.

[0150] Preparation Example 1: Preparation of Compound I

[0151] Step 1: Synthesis of compound 1b

[0152] Under nitrogen protection, potassium tert-butoxide solution (6.54 mL, 6.54 mmol) was slowly added to a mixture of trimethyl sulfoxide (1.44 g, 6.54 mmol) in THF and DMSO (10 mL / 10 mL). The mixture was stirred at room temperature for 0.5 hours, then compound 1a (CAS: 2408761-20-4) (2 g, 5.45 mmol) in DMSO (10 mL) was added. The reaction mixture was stirred at 30 °C for 16 hours. After the reaction was complete, the reaction solution was poured into ice water and extracted with ethyl acetate (50 mL × 3). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 5 / 1 to 2 / 1) to give compound 1b (1.81 g). MS m / z (ESI): 382.4 [M+1] + .

[0153] Step 2: Synthesis of compound 1c

[0154] At room temperature, tris(pentafluorophenyl)borane (1.34 g, 2.62 mmol) was added to a toluene (20 mL) solution of compound 1b (1 g, 2.62 mmol), and the reaction mixture was stirred at 30 °C for 16 hours. After the reaction was complete, the reaction solution was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (50 mL × 3), the combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 5 / 1 to 2 / 1) to give compound 1c (0.81 g). MS m / z (ESI): 382.2 [M+1] + .

[0155] Step 3: Synthesis of compound 1d

[0156] At room temperature, 1.50 g (4.20 mmol) of (triphenylphosphonium)difluoroacetic acid inner salt was added to a 15 mL NMP solution of compound 1c (800 mg, 2.10 mmol). The reaction mixture was stirred at 40 °C for 4 hours. After the reaction was complete, the reaction solution was diluted with 100 mL of aqueous solution, extracted with ethyl acetate (100 mL × 3), and the combined organic phases were washed with saturated brine (50 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 40 / 1 to 5 / 1) to give compound 1d (570 mg). MS m / z (ESI): 416.4 [M+1] + .

[0157] Step 4: Synthesis of compound 1e

[0158] At room temperature, TMSI (1.30 g, 6.51 mmol) was added to a DCM (10 mL) solution of compound 1d (540 mg, 1.30 mmol), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the pH of the reaction solution was adjusted to >7 with saturated sodium bicarbonate solution, and extracted with DCM (30 mL × 3). The crude product was purified by silica gel column chromatography (DCM / MeOH = 50 / 1 to 10 / 1) to give compound 1e (340 mg). MS m / z (ESI): 282.2 [M+1] + .

[0159] Step 5: Synthesis of compound 1f

[0160] Sodium borohydride acetate (905 mg, 4.27 mmol) was added to a 5 mL THF solution of compound 1e (300 mg, 1.07 mmol) and compound 2a (463 mg, 1.60 mmol, synthesized according to the method of intermediate 2 in Example 2, pages 49-50 of the specification in CN114057758A). The reaction mixture was stirred at 40 °C for 16 hours. After the reaction was complete, the reaction solution was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (30 mL × 3). The crude product was purified by silica gel column chromatography (PE / EA = 20 / 1 to 5 / 1) to give compound 1f (440 mg). MS m / z (ESI): 555.5 [M+1] + .

[0161] Step 6: Synthesis of Compound I

[0162] NaOH (289 mg, 7.22 mmol) was added to a methanol / tetrahydrofuran / water mixture (4 mL / 4 mL / 4 mL) containing 400 mg, 0.72 mmol of compound 1f. The reaction mixture was stirred at 40 °C for 16 hours. After the reaction was complete, the pH of the reaction solution was adjusted to 5 with glacial acetic acid, and the solution was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Xbridge-C18; 19 × 150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 20-70%; column temperature: 25 °C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound I (211.3 mg). The obtained compound I was found to be amorphous, and the XRPD chromatogram of the amorphous compound is shown in Figure 1. MS m / z (ESI): 441.1 [M+1] + . 1H NMR(400MHz,DMSO-d6):d 10.81(s,1H),7.95(d,J=8.4Hz,2H),7.65(d,J=8.0Hz,2H),7.27-7.23(m,1H),6.65(s,1H),6.51-6.47(m,1H),5.03-4.90(m,1H),3.71 (s,3H),3.61-3.48(m,3H),2.69-2.53(m,2H),2.42(s,3H),2.35-2.20(m,1H),1.89-1.81(m,1H),1.70-1.58(m,2H),1.46-1.41(m,1H).

[0163] Unless otherwise stated, all compounds of formula I mentioned below are prepared by the methods described above or by repeating the methods described above.

[0164] Example 1: Hydrochloride crystal form B of compound I

[0165] 70.0 mg of 12 M hydrochloric acid aqueous solution was weighed into a glass bottle, and 5 mL of ACN and 301.9 mg of compound I were added. The mixture was suspended and stirred at room temperature for 1 day. After centrifugation, the solid was vacuum dried at room temperature for about 3 days. The obtained product was characterized by XRPD. The results showed that it was the hydrochloride crystal form B of compound I. The positions and intensities of the characteristic XRPD peaks are shown in Table 22 and Figure 1. The TGA / DSC spectrum is shown in Figure 2.

[0166] Table 22 List of XRPD diffraction peaks for hydrochloride crystal form B

[0167] Example 2: Methanesulfonate crystal form A of compound I

[0168] Weigh 67.0 mg of methanesulfonic acid into a glass bottle, add 5 mL of ACN and 302.5 mg of compound I into the bottle. Suspend and stir at room temperature for 1 day. After centrifugation, the solid was vacuum dried at room temperature for approximately 3 days. XRPD characterization of the obtained product showed that it was the methanesulfonate crystal form A of compound I. The positions and intensities of the characteristic XRPD peaks are shown in Table 23 and Figure 3, and the TGA / DSC spectrum is shown in Figure 4.

[0169] Table 23 List of XRPD diffraction peaks for methanesulfonate crystal form A

[0170] Example 3: D-camphor sulfonate crystal form A of compound I

[0171] Weigh 160.1 mg of D-camphor sulfonic acid and 298.0 mg of compound I into a glass bottle, and add 4 mL of IPAc to the bottle. Suspend and stir at room temperature for 1 day. After centrifugation, the solid was vacuum dried at room temperature for approximately 3 days. XRPD characterization of the obtained product showed that it was the methanesulfonate form A of compound I. The positions and intensities of the characteristic XRPD peaks are shown in Table 24 and Figure 5.

[0172] Table 24 List of XRPD diffraction peaks for D-camphor sulfonate crystal form A

[0173] Biological test cases

[0174] Test Example 1. Complement Hemolytic Activity Detection

[0175] The hemolysis assay was performed according to Xuan Yuan et al., Haematologica. (2017) 102:466-475. Prior to the experiment, the optimal concentration of normal human serum (NHS) required to achieve 100% lysis of rabbit erythrocytes (REs) was obtained by titration. In this experiment, NHS (derived from healthy volunteers) was dissolved in GVB containing 10 mM Mg-EGTA. 0 Diluted in buffer (0.1% gelatin, 5 mM Veronal, 145 mM NaCl, 0.025% NaN3, pH 7.3, Complement technology) and incubated with test compounds at 37°C for 15 min at various concentration gradients. Freshly suspended in GVB containing 10 mM Mg-EGTA. 0 The RE (derived from healthy Japanese white rabbits) added to the buffer solution reached 1×10⁻⁶. 8 The final concentration was determined by cells / ml and incubation at 37°C for 30 minutes. The positive control group (100% lysed) consisted of GVB containing 10 mM Mg-EGTA with NHS and RE but without the tested compounds. 0 Buffer composition; negative control (0% lysis) consisted of GVB containing 10 mM Mg-EGTA with inactivated NHS (heated at 56°C for 30 min or 65°C for 5 min) and RE but without the tested compound. 0 Buffer composition. Samples were centrifuged at 2000g for 5 minutes, and the supernatant was collected. Absorbance at 415 nm (A415) was measured using a microplate reader (Molecular Devices, SpectraMax i3X). IC 50 The values ​​were calculated from the percentage of hemolysis as a function of the concentration of the test compound using nonlinear regression. The test results are shown in Table 25.

[0176] Table 25

[0177] Test Example 2. Evaluation Experiment of the Inhibitory Effect of the Test Substance on the Human Serum Complement System Bypass Pathway

[0178] The test compound was initially tested at a concentration of 10 μM, diluted 3-fold, with 8 concentration points, and the final concentration of DMSO was 0.1%, with replicates. A Human Serum (Complement Technology, NHS) vial was removed from a -80°C cryogenic freezer and, after complete thawing on ice, gently mixed by pipetting. The mixture was then tested using Diluent AP (…). The compound system alternating pathway (AP330RUO) was diluted to a 1.25x Human Serum working solution. Simultaneously, an appropriate amount of Human Serum was inactivated by heating in a 56°C water bath for 30 min, and also diluted to a 1.25x inactivated working solution as the NC control. In a 96-well plate, 25 μL of the compound working solution, 100 μL of the 1.25x Human Serum working solution, and 25 μL of 5‰ DMSO and 100 μL of the 1.25x Human Serum working solution were added sequentially. For the PC control wells, 25 μL of 5‰ DMSO and 100 μL of the 1.25x Human Serum working solution were added. For the negative control wells, 25 μL of 5‰ DMSO and 100 μL of the 1.25x Human Serum inactivated working solution were added. The mixture was gently mixed on a microplate shaker and incubated at room temperature for 15 min. Then, 100 μL of the mixture was gently transferred to the pre-coated (containing LPS) wells provided with the kit. In the COMPLEMENT SYSTEM ALTERNATIVE PATHWAY (provided by AP330RUO), take 100 μL of Diluent AP as a blank control, avoid air bubbles, and incubate at 37℃ for 65 min. Pour out the liquid in the wells, add 300 μL of 1X wash buffer per well, repeat 4 times, and pat the liquid in the plate as dry as possible on the last wash. Add 100 μL of conjugate to each well, incubate at room temperature (20-25℃) for 30 min, and repeat the washing operation. Add 100 μL of substrate solution per well, protect from light, incubate at room temperature (20-25℃) for 30 min, and immediately read the OD405 value, or add 5 mM EDTA to stop the reaction and read the OD405 value within 60 min. Calculate complement activity according to the formula %complement activity = (Sample-NC) / (PC-NC)*100, and analyze the data. The test results are shown in Table 26.

[0179] Table 26

[0180] Test Example 3. Single-dose gavage administration pharmacokinetic experiment in rats

[0181] Experimental methods:

[0182] Six- to nine-week-old male SD rats (Shanghai Bikai Keji Biotechnology Co., Ltd.) were used. After overnight fasting, three rats per group were administered the test compound via gavage. Blood was collected via the jugular vein at a volume of 10 mL / kg, with 0.2 mL administered at each time point. The blood was anticoagulated with EDTA-K2 and immediately centrifuged at 4000 rpm for 5 min at 4°C. The supernatant was collected. Blood collection time points were: 15 min, 30 min, 1 h, 2 h, 4 h, 7 h, and 24 h. Animals were monitored closely after administration. After blood collection at all time points, the animals were euthanized. Plasma samples were analyzed using LC-MS / MS, and kinetic parameters were calculated using WinNonlin software. Results are shown in Table 27.

[0183] Table 27

[0184] Test Example 4. Hygroscopicity Assessment

[0185] The hygroscopicity of the free amorphous form, hydrochloride form B, methanesulfonate form A, and D-camphorsulfonate form A of compound I was evaluated using a dynamic moisture adsorption analyzer (DVS). Starting at room humidity (50% RH or 60% RH), the percentage change in sample mass was collected under a constant temperature of 25°C as humidity varied (room humidity - 95% RH - 0% RH - 95% RH). The results showed that the moisture adsorption of the free amorphous form, hydrochloride form B, methanesulfonate form A, and D-camphorsulfonate form A at 25°C / 80% RH was 7.434%, 0.6468%, 1.436%, and 1.047%, respectively. All samples maintained their crystal form after DVS testing.

[0186] Table 28 Hygroscopicity Assessment Results

[0187] As shown in Table 28, the free amorphous form has the worst hygroscopicity, while the remaining hydrochloride crystal form B, methanesulfonate crystal form A, and D-camphorsulfonate crystal form A all have good hygroscopicity.

[0188] Test Example 5. Solid-state stability assessment

[0189] The solid-state stability of free amorphous, hydrochloride crystal form B, methanesulfonate crystal form A, and D-camphorsulfonate crystal form A was evaluated at 25℃ / 60%RH and 40℃ / 75%RH. Physical and chemical stability were tested by XRPD and HPLC, respectively. No significant changes in purity or crystal form were observed in any of the samples after the stability evaluation.

[0190] Table 29 Summary of Solid Stability Assessment

[0191] Test Example 6. Dynamic Solubility Investigation

[0192] The dynamic solubility of hydrochloride crystal form B, methanesulfonate crystal form, and D-camphorsulfonate crystal form A prepared in Examples 1-3 was evaluated in 99.5% MC (0.5%):0.5% Tween 80 (v / v), pure water, and three biosolvents. The dynamic solubility of each sample in 99.5% MC (0.5%):0.5% Tween 80, pure water, SGF, FaSSIF, and FeSSIF was determined at 37°C using a rotary mixing method at feed concentrations of 2–5 mg / mL (calculated in free state). After centrifugation and filtration (using a 0.22 μm PTFE filter), the concentration, purity, and pH of the filtrate were measured at each time point.

[0193] Table 30 Solvent Preparation Method

[0194] Table 31 Summary of Dynamic Solubility Assessment

[0195] Table 32 Summary of Dynamic Solubility Assessment

[0196] in conclusion:

[0197] Dynamic solubility results showed that the solubility of methanesulfonate crystal form A and hydrochloride crystal form B in 99.5% MC (0.5%): 0.5% Tween 80 (v / v) solvent and pure water was higher than that of other salt forms; in SGF, the solubility of methanesulfonate crystal form A was higher than that of other salt forms; in FaSSIF, all salt forms were completely dissolved after 24 hours (all solubility was higher than 2 mg / mL, of which the solubility of methanesulfonate crystal form A was higher than 5 mg / mL); in FeSSIF, the solubility of hydrochloride crystal form B and methanesulfonate crystal form A was higher than that of D-camphor sulfonate crystal form A.

Claims

1. A salt form of a compound of formula I, wherein the salt form of the compound of formula I is a salt formed by the compound of formula I with an acid or a base; in, The acid is selected from hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthylcarboxylic acid, nicotinic acid, pyruvic acid, pectinic acid, persulfate, 3-phenylpropionic acid, picric acid, tervamolonic acid, 2-hydroxyethanesulfonic acid, itaconic acid, aminosulfonic acid, trifluoromethanesulfonic acid, dodecyl sulfuric acid, ethanesulfonic acid, benzenesulfonic acid, and p- The following are selected from the following: toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, L-tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucohepanoic acid, glycerophosphate, aspartic acid, sulfosalicylic acid, hemisulfonic acid, or thiocyanate; preferably selected from the following: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, citric acid, L-tartaric acid, oxalic acid, formic acid, acetic acid, trifluoroacetic acid, lauric acid, benzoic acid, and benzenesulfonic acid. The alkali is selected from alkali metal hydroxides and alkaline earth metal hydroxides, preferably from sodium hydroxide and potassium hydroxide; Preferably, the salt form of the compound of formula I is selected from one of its hydrochloride, sulfate, phosphate, methanesulfonate, camphorsulfonic acid, p-toluenesulfonate, fumarate, maleate, citrate, L-tartrate and oxalate; more preferably, the salt form of the compound of formula I is hydrochloride or methanesulfonate.

2. The salt form of the compound of formula I as described in claim 1, characterized in that, The hydrochloride salt of the compound of formula I is the hydrochloride salt crystal form B of the compound of formula I; The hydrochloride crystal form B, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 11.71±0.20°, 16.84±0.20°, 18.28±0.20°, 22.53±0.20°, and 25.59±0.20° in 2θ angles. Alternatively, the methanesulfonate of the compound of formula I is the methanesulfonate crystal form A of the compound of formula I; The methanesulfonate crystal form A, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 11.26±0.20°, 11.41±0.20°, 14.53±0.20°, and 18.74±0.20° when expressed in 2θ angles.

3. The salt form of the compound of formula I as described in claim 2, characterized in that, The hydrochloride crystal form B satisfies one or more of the following conditions: (1) The hydrochloride crystal form B, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 13.78±0.20°, 16.5±0.20°, 17.37±0.20°, 19.27±0.20°, 22.04±0.20°, 24.93±0.20°, 26.08±0.20°, 27.24±0.20°, and 28.08±0.20° in terms of 2θ angle. (2) The thermogravimetric analysis of the hydrochloride crystal form B shows a weight loss of 2.29% when heated to 160°C; (3) The differential scanning calorimetry of the hydrochloride crystal form B has two endothermic peaks at 183.1 and 260.6 °C and one exothermic peak at 214.9 °C. Alternatively, the methanesulfonate crystal form A may satisfy one or more of the following conditions: (1) The methanesulfonate crystal form A was subjected to Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angles, further showed characteristic peaks at 12.79±0.20°, 16.34±0.20°, 16.63±0.20°, 20.41±0.20° and 23.19±0.20°. (2) The thermogravimetric analysis of the methanesulfonate crystal form A showed a weight loss of 1.09% when heated to 160°C; (3) The differential scanning calorimetry of the methanesulfonate crystal form A has an endothermic peak at 193.2℃ and an exothermic peak at 195.8℃.

4. The salt form of the compound of formula I as described in claim 3, characterized in that, The hydrochloride crystal form B satisfies one or more of the following conditions: (1) The hydrochloride crystal form B, when subjected to Cu-Kα radiation, exhibits the following diffraction peaks in X-ray powder diffraction, expressed in terms of 2θ angle, as shown in the table below: (2) The thermogravimetric analysis diagram of the hydrochloride crystal form B is shown in Figure 2; (3) The differential scanning calorimetry (DSC) of the hydrochloride crystal form B is shown in Figure 2; Alternatively, the methanesulfonate crystal form A may satisfy one or more of the following conditions: (1) The methanesulfonate crystal form A, when subjected to Cu-Kα radiation, exhibits the following diffraction peaks in X-ray powder diffraction, expressed in terms of 2θ angle, as shown in the table below: (2) The thermogravimetric analysis diagram of the methanesulfonate crystal form A is shown in Figure 4; (3) The differential scanning calorimetry (DSC) of the methanesulfonate crystal form A is shown in Figure 4.

5. The salt form of the compound of formula I as described in claim 4, characterized in that, The X-ray powder diffraction pattern of the hydrochloride crystal form B, expressed in 2θ angle using Cu-Kα radiation, is shown in Figure 1. Alternatively, the methanesulfonate crystal form A is shown in Figure 3 using Cu-Kα radiation and the X-ray powder diffraction pattern expressed at a 2θ angle.

6. A method for preparing the salt form of the compound of formula I as described in claim 2, characterized in that, The method for preparing the hydrochloride crystal form B of the compound of formula I includes the following steps: reacting the compound of formula I and an aqueous solution of the hydrochloride in a solvent to obtain the hydrochloride crystal form B of the compound of formula I. Alternatively, the method for preparing the methanesulfonate crystal form A of the compound of formula I includes the following steps: reacting the compound of formula I with methanesulfonic acid in a solvent to obtain the methanesulfonate crystal form A of the compound of formula I.

7. The method for preparing the salt form of the compound of formula I as described in claim 6, characterized in that, The method for preparing hydrochloride crystal form B satisfies one or more of the following conditions: (1) The solvent is a nitrile solvent; (2) The mass-to-volume ratio of the compound of Formula I to the solvent is 50-70 mg / mL; (3) The concentration of the aqueous solution of the hydrochloride is 10-14 mol / L; (4) The mass ratio of the compound of Formula I to the aqueous solution of the hydrochloride is 3:1-5:1; (5) The reaction was carried out at room temperature; (6) The method for preparing hydrochloride crystal form B further includes a post-processing step: after the reaction, the solid is separated and dried; Alternatively, the method for preparing methanesulfonate crystal form A satisfies one or more of the following conditions: (1) The solvent is a nitrile solvent; (2) The mass-to-volume ratio of the compound of Formula I to the solvent is 50-70 mg / mL; (3) The molar ratio of the compound of formula I to the methanesulfonic acid is 1:0.8-1:1.2; (4) The reaction was carried out at room temperature; (5) The method for preparing the methanesulfonate crystal form A further includes a post-processing step: after the reaction, the solid is separated and dried.

8. The method for preparing the salt form of the compound of formula I as described in claim 7, characterized in that, The method for preparing hydrochloride crystal form B satisfies one or more of the following conditions: (1) The nitrile solvent is acetonitrile, propionitrile, butyronitrile, isobutyronitrile, valerate or adiponitrile; (2) The mass-to-volume ratio of the compound of Formula I to the solvent is 60 mg / mL; (3) The concentration of the aqueous solution of the hydrochloride salt is 12 mol / L; (4) The mass ratio of the compound of formula I to the aqueous solution of the hydrochloride is 4.3:1; (5) The reaction temperature is 15-30℃; Alternatively, the method for preparing methanesulfonate crystal form A satisfies one or more of the following conditions: (1) The nitrile solvent is acetonitrile, propionitrile, butyronitrile, isobutyronitrile, valerate or adiponitrile; (2) The mass-to-volume ratio of the compound of formula I to the solvent is 60.5 mg / mL; (3) The molar ratio of the compound of formula I to the methanesulfonic acid is 1:1; (4) The reaction temperature is 15-30℃.

9. The method for preparing the salt form of the compound of formula I as described in claim 8, characterized in that, The method for preparing hydrochloride crystal form B satisfies one or more of the following conditions: (1) The nitrile solvent is acetonitrile; (2) The reaction temperature is 20℃ or 25℃; Alternatively, the method for preparing methanesulfonate crystal form A satisfies one or more of the following conditions: (1) The nitrile solvent is acetonitrile; (2) The reaction temperature is 20℃ or 25℃.

10. A pharmaceutical composition comprising a salt form of the compound of formula I according to any one of claims 1-5 (e.g., hydrochloride crystal form B or methanesulfonate crystal form A of the compound of formula I), and one or more pharmaceutically acceptable excipients; Preferably, the pharmaceutical composition is in the form of a pharmaceutical preparation.

11. Use of a salt form of the compound of formula I as claimed in any one of claims 1-5 (e.g., hydrochloride crystal form B or methanesulfonate crystal form A of the compound of formula I) or the pharmaceutical composition as claimed in claim 10 in the preparation of a medicament for the prevention and / or treatment of complement factor B-mediated diseases or conditions; Preferably, the complement factor B-mediated disease or condition is selected from at least one of the following: paroxysmal nocturnal hemoglobinuria (PNH), primary glomerulonephritis (IgAN), membranous nephropathy (MN), diabetic nephropathy (DKD), C3 glomerulonephritis (C3G), lupus nephritis (LN), proliferative nephritis, systemic lupus erythematosus (SLE), age-related macular degeneration (AMD), geographic atrophy (GA), atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome (HUS), diabetic retinopathy (DR), hemodialysis complications, hemolytic anemia or hemodialysis, neuromyelitis (NMO). Arthritis, rheumatoid arthritis, psoriatic arthritis, liver inflammation, dermatomyositis and amyotrophic lateral sclerosis, myasthenia gravis (MG), Guillain-Barré syndrome (GBS), neuromyelitis optica spectrum disorder (NMOSD), uveitis, retinitis pigmentosa, macular edema, Behçet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, snioplasmic retinopathy and choroiditis, sympathetic ophthalmia, ocular pemphigoid, ocular pemphigoid, non-arterial ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, Doyne's honeycomb retinal dystrophy / Malattia Leventinese, Sorsby retinal dystrophy, late-onset macular dystrophy, North Carolina macular dystrophy, Stargardt disease, keratitis, antineutrophil cytoplasmic antibody-associated vasculitis (ANCA-AAV), Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemia-reperfusion syndrome, myocardial infarction, balloon angioplasty, post-pump syndrome of cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, acute kidney injury, and mesenteric artery reperfusion after aortic reconstruction.

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