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

Abstract

The present invention belongs to the technical field of biology. Disclosed are a crystal form of a complement factor B inhibitor, a preparation method therefor and the use thereof. Specifically, the present invention provides a crystal form of a compound represented by formula I, a preparation method therefor and the use thereof. The crystal form prepared by the present invention has good stability, for example, crystal form stability and thermal stability.

Description

Crystalline form 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. CN202410909721.8, 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 a crystalline form 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 functions 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 to produce 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 associated with 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 the activation of AP, inhibiting FB activity can prevent the activation of AP pathway, and does not interfere with CP and LP pathways, which can avoid the risk of increased infection due to complement system inhibition. PCT / CN2024 / 071419 provides a class of complement factor B inhibitors. 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 may also be produced. Therefore, it is of great significance to develop a drug suitable for industrial production and with good biological activity to further study the polymorphism of the compound and obtain a crystal form with stable chemical properties. 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 crystal form of a compound represented by formula I, a preparation method and uses thereof.

[0009] In one aspect, the present application provides a crystal form of a compound represented by formula I, wherein the structure of formula I is as follows:

[0010] The chemical name of the compound represented by formula I is 4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid.

[0011] In some embodiments, there is provided a crystalline Form B of the compound of Formula I having an X-ray powder diffraction pattern with peaks at 9.5° ± 0.2°, 15.1° ± 0.2°, 20.5° ± 0.2° and 22.3° ± 0.2° in terms of 2Θ.

[0012] Preferably, the crystalline Form B has an X-ray powder diffraction pattern with peaks at 9.5° ± 0.2°, 13.0° ± 0.2°, 15.1° ± 0.2°, 17.8° ± 0.2°, 20.5° ± 0.2° and 22.3° ± 0.2° in terms of 2Θ.

[0013] More preferably, the crystalline Form B has an X-ray powder diffraction pattern with peaks at 9.5° ± 0.2°, 10.2° ± 0.2°, 13.0° ± 0.2°, 15.1° ± 0.2°, 17.8° ± 0.2°, 20.5° ± 0.2°, 22.3° ± 0.2° and 24.1° ± 0.2° in terms of 2Θ.

[0014] Further preferably, the crystalline Form B has an X-ray powder diffraction pattern with peaks at 9.5° ± 0.2°, 10.2° ± 0.2°, 13.0° ± 0.2°, 15.1° ± 0.2°, 16.9° ± 0.2°, 17.8° ± 0.2°, 18.5° ± 0.2°, 20.5° ± 0.2°, 22.3° ± 0.2° and 24.1° ± 0.2° in terms of 2Θ.

[0015] Still further preferably, the crystalline Form B has an X-ray powder diffraction pattern with peaks at 9.5° ± 0.2°, 10.2° ± 0.2°, 13.0° ± 0.2°, 15.1° ± 0.2°, 16.9° ± 0.2°, 17.8° ± 0.2°, 18.5° ± 0.2°, 20.5° ± 0.2°, 22.3° ± 0.2°, 23.3° ± 0.2°, 23.5° ± 0.2° and 24.1° ± 0.2° in terms of 2Θ.

[0016] In some embodiments, the crystalline Form B has an X-ray powder diffraction pattern with peaks at 2Θ angles as shown in Table 1 below.

[0017] Table 1: X-ray powder diffraction pattern data of Form B

[0018] In some embodiments, the crystalline Form B has an X-ray powder diffraction with an XRPD pattern as shown in Figure 2.

[0019] In some embodiments, the crystalline Form B has an endothermic peak at a starting temperature of 180 °C to 190 °C in a thermogram measured by differential scanning calorimetry (DSC).

[0020] In some embodiments, the Form B has an endothermic peak at an onset temperature of 183-188 °C in a thermogram measured by differential scanning calorimetry (DSC).

[0021] In some embodiments, the Form B has an endothermic peak at an onset temperature of 186 °C in a thermogram measured by differential scanning calorimetry (DSC).

[0022] In some embodiments, the Form B has no weight loss before 150 °C in a TGA plot.

[0023] In some embodiments, the Form B has a DSC profile as shown in Figure 3.

[0024] In some embodiments, the Form B has a TGA profile as shown in Figure 4.

[0025] In some embodiments, there is provided a crystalline Form A of the compound of Formula I, which has an X-ray powder diffraction pattern having peaks at 8.8°±0.2°, 9.5°±0.2°, 14.9°±0.2° and 20.5°±0.2° in terms of 2Θ.

[0026] Preferably, the Form A has an X-ray powder diffraction pattern having peaks at 8.8°±0.2°, 9.5°±0.2°, 14.9°±0.2°, 20.5°±0.2°, 21.7°±0.2° and 24.3°±0.2° in terms of 2Θ.

[0027] More preferably, the Form A has an X-ray powder diffraction pattern having peaks at 8.8°±0.2°, 9.1°±0.2°, 9.5°±0.2°, 14.9°±0.2°, 20.5°±0.2°, 21.7°±0.2°, 24.0°±0.2° and 24.3°±0.2° in terms of 2Θ.

[0028] Further preferably, the Form A has an X-ray powder diffraction pattern having peaks at 8.8°±0.2°, 9.1°±0.2°, 9.5°±0.2°, 14.9°±0.2°, 15.6°±0.2°, 17.7°±0.2°, 20.5°±0.2°, 21.7°±0.2°, 24.0°±0.2° and 24.3°±0.2° in terms of 2Θ.

[0029] More preferably, the Form A has an X-ray powder diffraction pattern with diffraction peaks at 8.8°±0.2°, 9.1°±0.2°, 9.5°±0.2°, 12.1°±0.2°, 14.9°±0.2°, 15.6°±0.2°, 17.4°±0.2°, 17.7°±0.2°, 20.5°±0.2°, 21.7°±0.2°, 24.0°±0.2° and 24.3°±0.2° in terms of 2Θ.

[0030] In some embodiments, the Form A has an X-ray powder diffraction pattern as shown in Table 2:

[0031] Table 2: X-ray powder diffraction pattern data of Form A

[0032] In some embodiments, the Form A has an X-ray powder diffraction pattern as shown in Figure 7.

[0033] In another aspect, the present application also provides a method for preparing the compound of Formula I in a crystal form, including but 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.

[0034] In some embodiments, the method for preparing the compound of Formula I in a crystal form comprises the following steps: weighing a proper amount of the compound, dissolving in a corresponding positive solvent, adding anti-solvent to the solution after optionally adding seed crystal, stirring, and cooling crystallization.

[0035] In some embodiments, the method for preparing the compound of Formula I in a crystal form comprises the following steps: weighing a proper amount of the compound, dissolving in a corresponding positive solvent, adding anti-solvent to the solution, stirring, and cooling crystallization.

[0036] In the present application, the positive solvent includes one or more of methanol, ethanol, acetone, 2-butanone, ethyl acetate, isopropyl acetate, acetonitrile, chloroform, benzene, propyl alcohol, N,N-dimethylformamide and ethyl formate; preferably one or more of methanol, ethanol, acetone, 2-butanone, ethyl acetate, isopropyl acetate and acetonitrile.

[0037] In the present application, the anti-solvent includes one or more of n-hexane, n-heptane, water, cyclohexane, methyl tert-butyl ether and isopropyl ether; preferably one or both of n-heptane and water.

[0038] In some embodiments, the method for preparing the compound of Formula I in a crystal form B comprises the following steps: weighing a proper amount of the compound, dissolving in a corresponding positive solvent, adding anti-solvent to the solution after optionally adding seed crystal, stirring, and cooling crystallization.

[0039] In some embodiments, the method for preparing the compound of formula I, crystal form B, comprises the following steps: weighing a proper amount of the compound, dissolving in a corresponding positive solvent, dissolving completely by heating, adding anti-solvent to the solution, stirring, and crystallizing by cooling.

[0040] Preferably, in the method for preparing the compound of formula I, crystal form B, the positive solvent is one or more of ethanol, acetone, ethyl acetate or isopropyl acetate.

[0041] Preferably, in the method for preparing the compound of formula I, crystal form B, the anti-solvent is selected from n-heptane or water.

[0042] In some embodiments, the method for preparing the compound of formula I, crystal form A, comprises the following steps: weighing a proper amount of the compound, crystal form B, dissolving in a corresponding positive solvent, adding anti-solvent to the solution, stirring, and crystallizing by cooling.

[0043] In another aspect, the present application provides a crystal form composition of crystal form B, wherein the weight of the crystal form B accounts for more than 50% of the weight of the crystal form composition; preferably more than 80%; further preferably more than 90%; more further preferably more than 95%; most preferably more than 98%.

[0044] In another aspect, the present application also provides a pharmaceutical composition containing a therapeutically effective amount of the crystal form of the compound of formula I.

[0045] In some embodiments, the pharmaceutical composition contains a therapeutically effective amount of the crystal form B of the compound of formula I.

[0046] In some embodiments, the pharmaceutical composition contains a therapeutically effective amount of the crystal form A of the compound of formula I.

[0047] In another aspect, the present application also provides a pharmaceutical composition containing a therapeutically effective amount of the crystal form of the compound of formula I and a pharmaceutically acceptable carrier.

[0048] In some embodiments, the pharmaceutical composition contains a therapeutically effective amount of the crystal form B of the compound of formula I and a pharmaceutically acceptable carrier.

[0049] In some embodiments, the pharmaceutical composition contains a therapeutically effective amount of the crystal form A of the compound of formula I and a pharmaceutically acceptable carrier.

[0050] In the present application, the pharmaceutical composition can be administered by any applicable route or method, for example, by oral or parenteral (e.g., intravenous) administration. The therapeutically effective amount of the aforementioned compound crystal form is from about 1 mg to 1 g / Kg body weight / day.

[0051] In another aspect, the present application also provides use of the crystalline form of the aforementioned compound or the pharmaceutical composition thereof in the manufacture of a medicament for preventing and / or treating a complement factor B mediated disease or condition.

[0052] 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 crystalline form of the aforementioned compound or the pharmaceutical composition thereof.

[0053] In another aspect, the present application also provides the crystalline form of the aforementioned compound of the present application or the pharmaceutical composition of the present application for use in preventing and / or treating a complement factor B mediated disease or condition.

[0054] In another aspect, the present application also provides the crystalline form as previously described or the crystalline form prepared as previously described or the composition as previously described for use in therapy.

[0055] In another aspect, the present application also provides the crystalline form as previously described or the crystalline form prepared as previously described or the composition as previously described for use in preventing and / or treating a complement factor B mediated disease or condition.

[0056] 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.

[0057] In some specific embodiments, the complement factor B mediated disease or condition is arthritis.

[0058] The advantages of the present application are as follows:

[0059] The crystalline form, especially the crystalline form B, prepared in the present application has good stability, for example, crystalline form stability and thermal stability.

[0060] Related definitions

[0061] Unless otherwise defined, the following terms used in the specification and claims have the following meanings:

[0062] The term "optionally" or "optionally" means that the subsequently described event or circumstance can or can not occur, and the description includes the occurrence of the event or circumstance and the non-occurrence of the event or circumstance.

[0063] The "X-ray powder diffraction pattern" in the present application is measured using Cu-Ka radiation. It should be noted that in X-ray powder diffraction spectra (XRPD), the diffraction pattern obtained from a crystalline compound is often characteristic of a 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. Thus, 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 known in the art of crystallography. For example, due to changes in temperature during sample analysis, sample movement, or calibration of the instrument, the positions of the peaks can shift, and the measurement error in the 2-theta values is sometimes about ±0.5°, and sometimes about ±0.2°. Therefore, when determining each crystalline structure, this error should be taken into account, and when the critical characteristic peak shifts by about ±0.5°, especially by about ±0.2°, it can be determined that the crystal forms are the same.

[0064] Differential scanning calorimetry (DSC) measures the transition temperature when a crystal absorbs or releases heat due to a change in its crystal structure or melting of the crystal. For the same crystalline form of the same compound, the thermal transition temperature and melting point error in successive analyses are typically within about 5°C, and usually within about 3°C. When a compound is described as having a given DSC peak or melting point, it means the DSC peak or melting point ± 5°C. DSC provides an auxiliary method for distinguishing different crystal forms. Different crystal forms can be identified according to their different transition temperature characteristics. It should be noted that for mixtures, the DSC peak or melting point can fluctuate within a larger range. In addition, since decomposition occurs during the melting of a substance, the melting temperature is related to the heating rate.

[0065] Thermogravimetric analysis (TGA) refers to a thermal analysis technique for measuring the relationship between the mass of the sample to be tested and the change in temperature under program-controlled temperature. When the measured substance sublimates or vaporizes during heating, it decomposes gas or loses crystalline water, causing the measured mass to change. At this time, the thermogravimetric curve is not a straight line but has a decline. By analyzing the thermogravimetric curve, it can be known at what temperature the measured substance changes, and according to the weight lost, it can be calculated how much mass is lost.

[0066] Dynamic vapor sorption (DVS) method refers to a method for determining 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 millionth), which is often used to detect the hygroscopicity of drugs.

[0067] 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 a person skilled in the art.

[0068] "Subject" as described herein 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. In this document, the terms "subject" and "patient" are used interchangeably, for example, to refer to a mammal or a human.

[0069] The term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is nontoxic but is effective for the intended purpose.

[0070] The term "pharmaceutically acceptable carrier" refers to those carriers that have no significant stimulating effect on the body and do not impair the biological activity and performance 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.

[0071] DMSO: dimethyl sulfoxide.

[0072] DMSO-d6: deuterated dimethyl sulfoxide.

[0073] 1 H NMR: nuclear magnetic resonance hydrogen spectrum.

[0074] HPLC: high performance liquid chromatography.

[0075] m / z: mass-to-charge ratio.

[0076] SFC: supercritical fluid chromatography.

[0077] V / V: volume / volume.

[0078] Tris: tris(hydroxymethyl)aminomethane.

[0079] Tris buffer salt: tris(hydroxymethyl)aminomethane buffer salt.

[0080] MgCl2: magnesium chloride.

[0081] Chaps: 3-[3-(cholamidopropyl)dimethylammonio]propanesulfonate inner salt.

[0082] PBS: phosphate buffer.

[0083] w / v: mass concentration.

[0084] Bid: twice a day. BRIEF DESCRIPTION OF DRAWINGS

[0085] FIG. 1 is a crystal structure of compound 1a-2 in Experimental Example 1;

[0086] FIG. 2 is an X-ray powder diffraction pattern of the crystal form B of the compound of Formula I;

[0087] FIG. 3 is a differential scanning calorimetry pattern of the crystal form B of the compound of Formula I;

[0088] FIG. 4 is a thermogravimetric analysis pattern of the crystal form B of the compound of Formula I;

[0089] FIG. 5 is a dynamic moisture sorption pattern of the crystal form B of the compound of Formula I;

[0090] FIG. 6 is an overlay of X-ray powder diffraction patterns of the crystal form B of the compound of Formula I before and after DVS characterization;

[0091] FIG. 7 is an X-ray powder diffraction pattern of the crystal form A of the compound of Formula I. DETAILED DESCRIPTION

[0092] 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.

[0093] 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, and such combinations can be easily performed by those skilled in the art.

[0094] The raw materials and equipment used in the detailed description of the present application are known products, and can be obtained by purchasing commercially available products, unless otherwise specified.

[0095] 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

[0096] a) Preparation of (±) tert-butyl 3-(4-(methoxycarbonyl)phenyl)-4-oxopiperidine-1- carboxylate

[0097] tert-Butyl 3-bromo-4-oxopiperidine-1-carboxylate (50 g), (4-(methoxycarbonyl)phenyl)boronic acid (48.52 g), nickel(II) trifluoromethanesulfonate (3.21 g), 1,10- phenanthroline (1.62 g), potassium carbonate (49.62 g), 1,4-dioxane (500 mL) were added into a reaction flask, which was protected by nitrogen, stirred at 80 °C for 16 h, the reaction solution was diluted with water (500 mL), extracted with ethyl acetate (3 x 500 mL), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a sand, which was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to give the title compound 32 g.

[0098] b) Preparation of (±)-rel-(3S,4R)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1- carboxylate and (±)-rel-(3S,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1- carboxylate

[0099] (±) tert-Butyl 3-(4-(methoxycarbonyl)phenyl)-4-oxopiperidine-1-carboxylate (30 g) was added into a reaction flask, methanol (300 mL) was added, sodium borohydride (10.21 g) was added portionwise at 0 °C under nitrogen protection, stirred at room temperature for 1 h, the reaction was quenched by the addition of water (500 mL) in an ice bath, extracted with ethyl acetate (3 x 500 mL), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a sand, which was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 3 / 1 (V / V)) to give the title compounds 8.9 g and 21.3 g, respectively, according to the corresponding elution gradient.

[0100] (±)-rel-(3S,4R)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1 - carboxylic acid tert-butyl ester

[0101] 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).

[0102] (±)-rel-(3S,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1 - carboxylic acid tert-butyl ester

[0103] 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).

[0104] 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

[0105] a) Preparation of (±)-rel-(3S,4S)-4-((1-(tert-butoxycarbonyl)-3-(4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-methoxy-7-methyl-1H-indole-1- carboxylic acid tert-butyl ester

[0106] (±)-rel-(3S,4S)-4-((l-(tert-butoxycarbonyl)-3-(4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-methoxy-7-methyl- lH-indole- 1 - carboxylate (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 was concentrated under reduced pressure to give the title compound 16 g as a residue.

[0107] b) Preparation of (±)-rel-(3S,4S)-5-methoxy-4-((3-(4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-lH-indole-l- carboxylate

[0108] (±)-rel-(3S,4S)-4-((l-(tert-butoxycarbonyl)-3-(4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-methoxy-7-methyl- lH-indole- 1 - carboxylate (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 was concentrated under reduced pressure to give the title compound 16 g as a residue.

[0109] LCMS m / z = 495.4 [M + 1] + .

[0110] c) Preparation of (±)-rel-(3S,4S)-5-methoxy-4-((3-(4- (methoxycarbonyl)phenyl)-l-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)-7-methyl- lH-indole-l-carboxylate

[0111] (±)-rel-(3S,4S)-4-((l-(tert-butoxycarbonyl)-3-(4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-methoxy-7-methyl- lH-indole- 1 - carboxylate (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 was concentrated under reduced pressure to give the title compound 16 g as a residue.

[0112] LCMS m / z = 577.1 [M+H] + .

[0113] 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

[0114] (±)-rel-(3S,4S)-5-methoxy-4-((3-(4-(methyloxy)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 (3 M), diluted with water (100 mL) and extracted with ethyl acetate (3 x 500 mL), the organic phase was separated, combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to sand, purified by column chromatography (mobile phase: dichloromethane methanol 5 / 1 (V / V)) to give the title compound enantiomer 1.7 g.

[0115] (±)-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 configuration of 1a-2 was confirmed by X-ray single crystal diffraction experiment of experimental example 1, which was 4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2- trifluoroethyl)piperidin-3-yl)benzoic acid. (Resolution method: chromatographic column: 250*25 mm, 10 μm; mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonium methanol); A:B:75:25, flow rate: 100 mL / min; detection wavelength: 214 nm)

[0116] 1a-1, t r = 1.87 min

[0117] 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), 2.47 - 2.41 (m, 1H), 2.34 (d, J = 11.4 Hz, 3H), 1.70 (d, J = 3.6 Hz, 2H).

[0118] LCMS m / z = 463.1 [M+H] + .

[0119] 1a-2, t r = 2.73 min

[0120] 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), 3.12 - 3.05 (m, 1H), 2.89 (d, J = 13.0 Hz, 2H), 2.64 (t, J = 11.3 Hz, 1H), 2.42 (s, 1H), 2.32 (s, 3H), 1.67 (d, J = 3.5 Hz, 2H).

[0121] LCMS m / z = 463.1 [M+H] + .

[0122] 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

[0123] 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).

[0124] (±)-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® IC (250*20 mm, 10 μm); Mobile phase A: Supercritical CO2; Mobile phase B: Methanol (+0.1% 7.0 mol / L ammonium hydroxide); A:B: 75:25; Flow rate: 100 mL / min; Detection wavelength: 214 nm) 250*20 mm, 10 μm; Mobile phase A: Supercritical CO2; Mobile phase B: Methanol (+0.1% 7.0 mol / L ammonium hydroxide); A:B: 75:25; Flow rate: 100 mL / min; Detection wavelength: 214 nm)

[0125] 1b-1, t r = 1.06 min

[0126] 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).

[0127] LCMS m / z = 463.1 [M+H] + .

[0128] 1b-2, t r = 2.37 min

[0129] 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).

[0130] LCMS m / z = 463.1 [M+H] + .

[0131] Experimental Example 1: X-ray single crystal diffraction experiment

[0132] 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 get transparent single crystal after one day.

[0133] After integrating and reducing the diffraction data using the SAINT program, the data was empirically corrected for absorption using the SADABS program; the single crystal structure was solved by direct method using SHELXT2014, and the structure was refined by least squares method, the hydrogen atom refinement process was obtained by isotropic calculation, the hydrogen atom on C-H was obtained by calculation and hydrogenation, and was refined by riding model. The Flack constant is: 0.09(10), the chirality of C11 and C17 is R configuration. Figure 1 and Table 3 below are the single crystal results of the acetonitrile solvate of compound 1a-2.

[0134] Structure description: single crystal X-ray diffraction and structure analysis show that the prepared single crystal is 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 acetonitrile solvate, and the structure is as follows:

[0135] Table 3: Single crystal diffraction data

[0136] Experimental Example 2: Human complement factor B TR-FRET assay

[0137] Competitive binding assays were performed using Cy5-labeled small molecule inhibitors (+) or (-)-2-((1E,3E,5E)-5-(1-(6-((2-(3-(4-((R)-3-amino-3-phenylpropionyl)-1-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazin-2-yl)phenoxy)ethyl)amino)-6-oxohexyl)-3,3-dimethyl-5-sulfodihydroindole-2-yl)pent-1,3-dien-1-yl)-1-ethyl-3,3-dimethyl-5-sulfo-3H-indole-1-onium (prepared according to Example 2 of Biological Studies, CN201480050471.1) as probes to test the inhibitory activity of the compounds against complement factor B. Complement factor B (ComplementTech, A135) and EZ-Link TM Sulfo-NHS-LC-LC-Biotin (Thermo, 21338) was incubated on ice at a 1:20 ratio for 2 hours, followed by termination with 1M Tris (pH 7.5). Then, 2 mL of Zeba was added. TM Biotin-labeled complement factor B was obtained by purification twice using a desalt spin column (Thermo, 89890). In the experiment, biotin-labeled complement factor B at a final concentration of 25 nM was incubated with different concentrations of the compound in buffer (PBS containing 10 mM MgCl2 and 0.05% Chaps) at 4°C for 30 minutes. Cy5 fluorescently labeled probes and europium chelate-labeled streptavidin (PerkinElmer, AD0060) at final concentrations of 75 nM and 0.225 nM were added, and the reaction was carried out at 4°C for 2 hours. After the reaction, time-dependent fluorescence energy transfer (TR-FRET) data were read using a microplate reader (Tecan, SPARK; excitation light 337 nm, 615 nm, and 665 nm) to determine the IC50. 50 The test results are shown in Table 4 below.

[0138] Reference standard LNP023: synthesized according to Example 26 of CN201480050471.1, with the following structure:

[0139] Table 4: Inhibitory activity of compounds against complement factor B

[0140] Experimental Example 3: Serum Alternate Pathway Complement Deposition Experiment

[0141] use Complement System Bypass Pathway Kit 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 5 below.

[0142] Table 5: Serum alternative pathway complement deposition results

[0143] Experimental Example 4: Mouse pharmacokinetic study test

[0144] 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.

[0145] Experimental animals: male ICR (CD-1) mice, body weight 32-35 g; supplier: Vivotek Laboratory Animal Technology Co., Ltd.

[0146] 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))).

[0147] Sample collection: 40 μL of whole blood sample was collected from the experimental animals at each set time point via the orbit, 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.

[0148] 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.

[0149] Table 6: Pharmacokinetic study results

[0150] Example 5: Efficacy study of test substance in CAIA mouse model

[0151] Objective: To evaluate the efficacy of the test substance on collagen antibody and lipopolysaccharide-induced arthritis (CAIA) in BALB / c mice.

[0152] Experimental animals: BALB / c mice, male, 6-8 weeks, 18-20 grams; supplier: Shanghai Jihui Experimental Animal Breeding Co., Ltd.

[0153] Experimental procedure:

[0154] 1. Induction of mouse CAIA model: On day 0, all mice were injected with 0.15 mL of 5 clone mixture type II collagen antibody (10 mg / mL, Chondrex); on day 3, mice were injected with 0.2 mL of LPS (E. coli 0111: B4 lipopolysaccharide, 0.5 mg / mL; Chondrex) intraperitoneally.

[0155] 2. Drug administration:

[0156] Table 7: Drug administration groups and administration scheme

[0157] a: 0.5% methyl cellulose (w / v), 0.5% Tween 80 (v / v) aqueous solution

[0158] 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.

[0159] Arthritis score: From the day of modeling, the incidence of arthritis in the limbs of animals in each group was observed three times a week until the end of the experiment. According to the different degrees (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.

[0160] Score AUC: After the end of the experiment, the mean arthritis score of each group of animals was analyzed at each time point using GraphPad Prism 8.4.3 software, and the Area under curve of XY analyses was selected to calculate the arthritis score AUC of each group of animals. The greater the AUC, the greater the severity of arthritis. The AUC experimental results are shown in Table 8.

[0161] Table 8: Arthritis score AUC

[0162] Experimental conclusion: According to the score results, compared with the model group, the compound of the application can significantly improve the degree of arthritis in the model animals, and the score AUC is significantly lower than that of LNP023.

[0163] Experimental example 6: Polymorph research

[0164] 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 crystal form often has the same pharmacological and pharmacodynamic activity. On this basis, the inventors further studied the physicochemical properties of the corresponding compound crystal form, but the preparation and characterization of the following specific crystal forms do not represent a limitation on the scope of protection of the application. Those skilled in the art can obtain more crystals of the compound of the application based on the application, and these crystals are all protected by the application. The specific crystal forms are as follows:

[0165] 1. Instrument test information

[0166] 1) X-ray powder diffraction (XRPD) parameters

[0167] Table 9: X-ray powder diffraction (XRPD) parameters

[0168] 2) Thermogravimetric analyzer parameters

[0169] Table 10: Thermogravimetric analyzer parameters

[0170] 3) Differential scanning calorimeter parameters

[0171] Table 11: Differential scanning calorimeter parameters

[0172] 4) Dynamic water vapor sorption (DVS) parameters

[0173] Table 12: Dynamic water vapor sorption (DVS) parameters

[0174] 5) Analysis conditions for HPLC

[0175] Table 13: Analysis conditions for HPLC

[0176] 6) Accelerated and long-term test impurity detection conditions

[0177] Determined according to the high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Volume IV General Rules 0512).

[0178] Solvent: acetonitrile-water (60:40, v / v).

[0179] Test solution: accurately weigh an appropriate amount of Compound of Formula I Form B, dissolve and dilute to prepare a solution containing about 0.5 mg per 1 ml.

[0180] Control solution: accurately measure an appropriate amount of test solution, dilute with solvent to prepare a solution containing about 0.5 μg per 1 ml.

[0181] Chromatographic conditions: octadecylsilane-bonded silica gel as the filler (Inertsil ODS-3V 4.6 mm x 250 mm, 5 μm or a chromatographic column with equivalent performance); 0.1% phosphoric acid solution as mobile phase A, acetonitrile as mobile phase B, gradient elution according to the following table; flow rate of 1.0 ml per minute; column temperature of 40°C; detection wavelength of 236 nm; injection volume of 10 μl.

[0182] The gradient conditions are shown in Table 14.

[0183] Table 14: Gradient conditions

[0184] 2. Preparation of the crystal form

[0185] 2.1 Solvent screening purification experiment of Compound of Formula I

[0186] Into 5 5 mL glass vials, 0.2 g of Compound of Formula I was added, the corresponding solvent was added, and after warming to 45°C and dissolving, the temperature was lowered to room temperature to crystallize, and the crystal form and purity of the sample were detected by XRPD and HPLC, and the analysis method of HPLC is shown in Table 13.

[0187] Table 15

[0188] 2. Preparation of Form B

[0189] 1. Into a 5-mL glass vial, 0.2 g of the compound of Formula I and 0.4 mL of acetone were added, warmed to 50 °C, after dissolution, cooled to room temperature and stirred for 0.5 h, then 1.2 mL of n-heptane was added and stirred for 1 h, cooled to 4±5 °C and stirred for 2-4 h, suction filtered, and the wet filter cake was placed at 40±5 °C and dried under reduced pressure for 15-16 h. The product was collected, the yield was 85.5%, and the XRPD results of Form B were shown in Figure 2; the DSC results were shown in Figure 3; the TGA results were shown in Figure 4; the DVS results were shown in Figure 5; and the XRPD superimposition before and after DVS characterization was shown in Figure 6.

[0190] 2. Into a 20-L reaction kettle, 1228 g of the compound of Formula I and 12280 mL of absolute ethanol were added, the temperature in the container was controlled at 50±5 °C, and stirred until dissolution. Filtration was followed by distillation under reduced pressure at a temperature of 50±5 °C until the remaining volume was one-fifth of the original volume. After distillation, the temperature was cooled to 40±5 °C, 1% of seed crystals (Form B) were added and stirred for 1 h, 6140 mL of n-heptane was added, and stirred for 1 h. After completion of the incubation, 6140 mL of n-heptane was continuously added and stirred for 1 h. After completion of the incubation, the temperature was cooled to 4±5 °C and stirred for 3 h. Suction filtration was performed, and the filter cake was placed at 50±5 °C and dried under reduced pressure for 10-11 h. The product was collected, the yield was 90.2%, and the XRPD detection results were consistent with those of Form B in Figure 2.

[0191] 3. Into a 5-mL glass vial, 0.2 g of the compound of Formula I and 0.8 mL of ethyl acetate were added, warmed to 50 °C, after dissolution, cooled to room temperature and stirred for 0.5 h, then 2.4 mL of n-heptane was added and stirred for 1 h, cooled to 4±5 °C and stirred for 2-4 h, suction filtered, and the wet filter cake was placed at 40±5 °C and dried under reduced pressure for 15-16 h. The product was collected, the yield was 84.0%, and the XRPD detection results were consistent with those of Form B in Figure 2.

[0192] 4. Into a 5-mL glass vial, 0.2 g of the compound of Formula I and 0.8 mL of absolute ethanol were added, warmed to 50 °C, after dissolution, cooled to room temperature and stirred for 0.5 h, then 2.4 mL of n-heptane was added and stirred for 1 h, cooled to 4±5 °C and stirred for 2-4 h, suction filtered, and the wet filter cake was placed at 40±5 °C and dried under reduced pressure for 15-16 h. The product was collected, the yield was 85.2%, and the XRPD detection results were consistent with those of Form B in Figure 2.

[0193] 5. Into a 5-mL glass vial, 0.2 g of the compound of Formula I and 0.8 mL of isopropyl acetate were added, warmed to 50 °C, after dissolution, cooled to room temperature and stirred for 0.5 h, then 3.0 mL of n-heptane was added and stirred for 1 h, cooled to 4±5 °C and stirred for 2-4 h, suction filtered, and the wet filter cake was placed at 40±5 °C and dried under reduced pressure for 15-16 h. The product was collected, the yield was 85.5%, and the XRPD detection results were consistent with those of Form B in Figure 2.

[0194] 6. Into a 20-mL glass vial, add 1 g of the compound of Formula I and 2 mL of absolute ethanol, heat to 50 °C until dissolved, then cool to room temperature and stir. Then add seed crystals and stir for 1-2 h, add 2 mL of water and stir for 1 h. Continue to add 2 mL of water and stir for 1 h. Cool to 4±5 °C and stir for 2-4 h. Filter under suction, dry the wet cake at 40±5 °C under reduced pressure for 10-12 h. Collect the material, yield 86.5%, and the XRPD results are consistent with Form B of Figure 2.

[0195] 2. Preparation of Form A

[0196] 1. Into a 3-L reactor, add 160 g of the compound of Formula I, Form B, 160 mL of acetonitrile, and 64 mL of water. Dissolve the mixture, then cool to an internal temperature of 4±5 °C and agitate for 2 h. Filter under suction to obtain Form A. The XRRD results are shown in Figure 7.

[0197] 2. Into a 5-mL glass vial, add 0.2 g of the compound of Formula I, Form B, and 1 mL of methanol, heat to 50 °C until dissolved, then cool to room temperature and stir for 0.5 h. Then add 3 mL of water, cool to 4±5 °C and stir for 2-4 h. Filter under suction, dry the wet cake at 40±5 °C under reduced pressure for 15-16 h. Collect the material, yield 87.5%, and the XRPD results are consistent with Form A of Figure 7.

[0198] 3. Into a 3-mL glass vial, add 0.18 g of the compound of Formula I, Form B, and 0.2 mL of 98% acetonitrile / water, cool to 4±5 °C and stir for 2-4 h. Filter under suction, dry the filter cake at 40±5 °C under reduced pressure for 2 h. Collect the material, yield 85.2%, and the XRPD results are consistent with Form A of Figure 7.

[0199] 3. Stability study experiment

[0200] (1) Influence factor experiment

[0201] The compound of Formula I, Form B, was placed under the conditions of 60 °C, 40 °C / 75% RH, light, and 92.5% RH for 30 days. The physical and chemical stability of the samples were detected by XRPD and HPLC. The analysis method of HPLC is shown in Table 13.

[0202] Table 16: Stability experiment results

[0203] The results of the influencing factor test showed that: crystal form B was placed at high temperature (40℃) and relative humidity (75%) for 30 days, and all indicators met the requirements and had no significant changes compared with before placement. Crystal form B was placed at high temperature (60℃) for 30 days, and all indicators met the requirements and had no significant changes compared with before placement. Crystal form B was placed under light for 30 days, and all indicators met the requirements and had no significant changes compared with before placement. Crystal form B was placed at relative humidity (92.5%) for 30 days, and all indicators met the requirements and had no significant changes compared with before placement.

[0204] (2) Accelerated test

[0205] The accelerated test was carried out according to (Guidelines for Stability Test of Raw Materials and Preparations, Chinese Pharmacopoeia 2020 Edition, Part IV, Chapter 9001).

[0206] Investigation conditions: 40℃±2℃, 75%RH±5%RH;

[0207] The packaging conditions were: inner packaging (pharmaceutical low-density polyethylene bag); outer packaging (polyester / aluminum / polyethylene pharmaceutical composite bag + paper barrel).

[0208] An appropriate amount of three batches of crystal form B of the compound of formula I was placed at a temperature of 40℃±2℃ and a relative humidity of 75%RH±5%RH for 6 months according to the above packaging conditions, and samples were taken once at the end of the 1st month, 2nd month, 3rd month and 6th month for detection according to the key investigation items of stability.

[0209] The results of the accelerated test are shown in Table 17.

[0210] Table 17: Results of accelerated test

[0211] The results of the accelerated test showed that: under the above packaging conditions, the three batches of crystal form B of the compound of formula I were placed at a temperature of 40℃±2℃ and a relative humidity of 75%±5% for 6 months, and all detection indicators had no significant changes and met the requirements.

[0212] (3) Long-term test

[0213] The long-term test of the product was carried out according to (Guidelines for Stability Test of Raw Materials and Preparations, Chinese Pharmacopoeia 2020 Edition, Part IV, Chapter 9001).

[0214] Investigation conditions: 30℃±2℃, 65%RH±5%RH;

[0215] Packaging conditions: inner packaging (pharmaceutical low-density polyethylene bag); outer packaging (polyester / aluminum / polyethylene pharmaceutical composite bag + paper barrel).

[0216] Take three batches of Form B of the compound of Formula I, and place them in the above packaging conditions at a temperature of 30°C ± 2°C and a relative humidity of 65% RH ± 5% RH for 12 months. At the end of the 3rd month, 6th month, 9th month and 12th month, respectively, take samples and test them according to the key stability test items.

[0217] The long-term test results are shown in Table 18.

[0218] Table 18: Long-term test results

[0219] The long-term test results show that Form B of the compound of Formula I, when placed in the above packaging conditions at a temperature of 30°C ± 2°C and a relative humidity of 65% RH ± 5% RH for 12 months, has no significant changes in the test indicators when the data from the 3rd month, 6th month, 9th month and 12th month are compared with the data from the 0th month. This indicates that Form B of the compound of Formula I is relatively stable under long-term test conditions.

[0220] In summary, Form B of the compound of Formula I has good stability under the influence factors, accelerated test conditions and long-term test conditions.

[0221] 4. Single crystal culture of Form B

[0222] Method: A saturated solution of the compound of Formula I at a temperature of about 50°C was prepared using ethanol / water (1:2, v / v) as the solvent, with a volume of 1 mL. Then it was transferred to room temperature and left to stand, and needle-shaped crystals were obtained after one day.

[0223] After the diffraction data were integrated and reduced, the data were empirically corrected for absorption using the SADABS program. The single crystal structure was solved by direct methods using SHELXT 2014, and the structure was refined by least squares. The hydrogen atoms were refined by isotropic calculation, and the hydrogen atoms on C-H were added by calculation and refined by riding model.

[0224] Table 19: Crystal parameters and structure data table

[0225] The foregoing description of specific exemplary embodiments of the application is intended to be illustrative only and is not intended to limit the application to the precise forms described. Many modifications and variations are possible in light of the above teachings without departing from the spirit or essential characteristics of the application. The exemplary embodiments were chosen and described in order to explain the principles of the application and its practical application to thereby enable others skilled in the art to best utilize the application and various embodiments with various modifications as are suited to the particular use contemplated. It is intended that the scope of the application be defined by the claims and their equivalents.

Claims

1. A crystalline form of a compound of Formula I, wherein the structure of Formula I is: ###00001### Formula I ​ 2. The morphic form of claim 1, characterized by, Form B of the compound of Formula I, which has an X-ray powder diffraction pattern with peaks at 9.5°±0.2°, 15.1°±0.2°, 20.5°±0.2° and 22.3°±0.2° in terms of 2Θ; preferably, the Form B, which has an X-ray powder diffraction pattern with peaks at 9.5°±0.2°, 13.0°±0.2°, 15.1°±0.2°, 17.8°±0.2°, 20.5°±0.2° and 22.3°±0.2° in terms of 2Θ; more preferably, the Form B, which has an X-ray powder diffraction pattern with peaks at 9.5°±0.2°, 10.2°±0.2°, 13.0°±0.2°, 15.1°±0.2°, 17.8°±0.2°, 20.5°±0.2°, 22.3°±0.2° and 24.1°±0.2° in terms of 2Θ; further preferably, the Form B, which has an X-ray powder diffraction pattern with peaks at 9.5°±0.2°, 10.2°±0.2°, 13.0°±0.2°, 15.1°±0.2°, 16.9°±0.2°, 17.8°±0.2°, 18.5°±0.2°, 20.5°±0.2°, 22.3°±0.2° and 24.1°±0.2° in terms of 2Θ; more further preferably, the Form B, which has an X-ray powder diffraction pattern with peaks at 9.5°±0.2°, 10.2°±0.2°, 13.0°±0.2°, 15.1°±0.2°, 16.9°±0.2°, 17.8°±0.2°, 18.5°±0.2°, 20.5°±0.2°, 22.3°±0.2°, 23.3°±0.2°, 23.5°±0.2° and 24.1°±0.2° in terms of 2Θ; still further preferably, the Form B has an X-ray powder diffraction pattern with the XRPD pattern as shown in Figure 2 in terms of 2Θ angle; Alternatively, the Form B has an endothermic peak at an onset temperature of 180-190 °C in a thermal analysis pattern measured by differential scanning calorimetry; preferably, the Form B has an endothermic peak at an onset temperature of 183-188 °C in a thermal analysis pattern measured by differential scanning calorimetry; more preferably, the Form B has an endothermic peak at an onset temperature of 186 °C in a thermal analysis pattern measured by differential scanning calorimetry; further preferably, the Form B has a DSC pattern as shown in Figure 3; Alternatively, the Form B has no weight loss before 150 °C in a TGA pattern measured; preferably, the Form B has a TGA pattern as shown in Figure 4.

3. The morphic form of claim 1, characterized by, Form A of the compound of Formula I, which has an X-ray powder diffraction pattern with diffraction peaks at 8.8°±0.2°, 9.5°±0.2°, 14.9°±0.2° and 20.5°±0.2° in terms of 2θ; preferably, the Form A of the compound of Formula I, which has an X-ray powder diffraction pattern with diffraction peaks at 8.8°±0.2°, 9.5°±0.2°, 14.9°±0.2°, 20.5°±0.2°, 21.7°±0.2° and 24.3°±0.2° in terms of 2θ; more preferably, the Form A of the compound of Formula I, which has an X-ray powder diffraction pattern with diffraction peaks at 8.8°±0.2°, 9.1°±0.2°, 9.5°±0.2°, 14.9°±0.2°, 20.5°±0.2°, 21.7°±0.2°, 24.0°±0.2° and 24.3°±0.2° in terms of 2θ; further preferably, the Form A of the compound of Formula I, which has an X-ray powder diffraction pattern with diffraction peaks at 8.8°±0.2°, 9.1°±0.2°, 9.5°±0.2°, 14.9°±0.2°, 15.6°±0.2°, 17.7°±0.2°, 20.5°±0.2°, 21.7°±0.2°, 24.0°±0.2° and 24.3°±0.2° in terms of 2θ; more further preferably, the Form A of the compound of Formula I, which has an X-ray powder diffraction pattern with diffraction peaks at 8.8°±0.2°, 9.1°±0.2°, 9.5°±0.2°, 12.1°±0.2°, 14.9°±0.2°, 15.6°±0.2°, 17.4°±0.2°, 17.7°±0.2°, 20.5°±0.2°, 21.7°±0.2°, 24.0°±0.2° and 24.3°±0.2° in terms of 2θ; still further preferably, the Form A of the compound of Formula I has an X-ray powder diffraction pattern with the pattern as shown in FIG. 7 in terms of 2θ angle.

4. A method for preparing the crystal form of the compound of Formula I according to claim 1, comprising anti-solvent addition method, anti-anti-solvent addition method, solvent evaporation method, gas-solid diffusion method, suspension stirring method and cooling crystallization method. Preferably, comprising the steps of: weighing a proper amount of the compound, adding a corresponding positive solvent to dissolve, adding an anti-solvent to the solution after optionally adding seed crystals, stirring, and cooling crystallization; preferably, comprising the steps of: weighing a proper amount of the compound, adding a corresponding positive solvent to dissolve, adding an anti-solvent to the solution, stirring, and cooling crystallization. The positive solvent comprises one or more of methanol, ethanol, acetone, 2-butanone, ethyl acetate, isopropyl acetate, acetonitrile, chloroform, benzene, propyl alcohol, N,N-dimethylformamide and ethyl formate; preferably one or more of methanol, ethanol, acetone, 2-butanone, ethyl acetate, isopropyl acetate and acetonitrile; The anti-solvent comprises one or more of n-hexane, n-heptane, water, cyclohexane, methyl tert-butyl ether and isopropyl ether; preferably one or both of n-heptane and water.

5. A method for preparing the crystal form B of the compound of formula I according to claim 2, comprising the steps of: weighing a proper amount of the compound, dissolving in a corresponding positive solvent, adding anti-solvent to the solution after optionally adding crystal seeds, stirring, and crystallizing by cooling. Preferably, comprising the steps of: weighing a proper amount of the compound, dissolving in a corresponding positive solvent, dissolving clear by warming, adding anti-solvent to the solution after optionally adding crystal seeds, stirring, and crystallizing by cooling. The positive solvent is one or more of ethanol, acetone, ethyl acetate or isopropyl acetate. The anti-solvent is selected from n-heptane or water.

6. A method for preparing the crystal form A of the compound of formula I according to claim 3, comprising the steps of: weighing a proper amount of the crystal form B of the compound, dissolving in a corresponding positive solvent, adding anti-solvent to the solution, stirring, and crystallizing by cooling.

7. A crystalline form composition of crystalline Form B, wherein, The weight of the crystal form B accounts for more than 50% of the weight of the crystal form composition; preferably more than 80%; further preferably more than 90%; more further preferably more than 95%; most preferably more than 98%.

8. A pharmaceutical composition comprising a therapeutically effective amount of the crystal form of the compound of formula I; preferably, it comprises a therapeutically effective amount of the crystal form of the compound of formula I and a pharmaceutically acceptable carrier. Preferably, it comprises a therapeutically effective amount of the crystal form B of the compound of formula I; preferably, it comprises a therapeutically effective amount of the crystal form B of the compound of formula I and a pharmaceutically acceptable carrier. Or, preferably, it comprises a therapeutically effective amount of the crystal form A of the compound of formula I; it comprises a therapeutically effective amount of the crystal form A of the compound of formula I and a pharmaceutically acceptable carrier.

9. Use of the crystal form according to any one of claims 1-3 or the crystal form prepared according to any one of claims 4-6 or the composition according to claim 7 or 8 in the preparation of a medicament for preventing and / or treating a complement factor B mediated disease or condition; preferably, the complement factor B mediated disease or condition is selected from one or more of ophthalmic diseases, autoimmune diseases, diseases related to the kidney system, diseases of the respiratory system, cardiovascular diseases; more preferably, the complement factor B mediated disease or condition is arthritis.

10. The crystal form according to any one of claims 1-3 or the crystal form prepared according to any one of claims 4-6 or the composition according to claim 7 or 8 for preventing and / or treating a complement factor B mediated disease or condition; preferably, the complement factor B mediated disease or condition is selected from one or more of ophthalmic diseases, autoimmune diseases, diseases related to the kidney system, diseases of the respiratory system, cardiovascular diseases; more preferably, the complement factor B mediated disease or condition is arthritis.

11. A method for preventing and / or treating a complement factor B mediated disease or condition, comprising the step of administering to a subject in need thereof an effective amount of the crystal form according to any one of claims 1-3 or the crystal form prepared according to any one of claims 4-6 or the composition according to claim 7 or 8. 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.

12. The crystalline form of any one of claims 1 to 3 or the crystalline form prepared by any one of claims 4 to 6 or the composition of claim 7 or 8 for use in therapy; Preferably, the crystalline form of any one of claims 1 to 3 or the crystalline form prepared by any one of claims 4 to 6 or the composition of claim 7 or 8 for use in 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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