Crystal of bridged heterocycle substituted benzoic acid derivative or salt thereof and preparation method thereof

Abstract

The invention discloses a crystal of a bridged heterocycle substituted benzoic acid derivative or a salt thereof and a preparation method of the crystal, and particularly discloses a crystal of a compound as shown in a formula (II), hydrochloride of the compound as shown in the formula (II), a crystal of the hydrochloride and a preparation method of the hydrochloride. # imgabs0 #

Description

Crystallization of a bridged heterocycle-substituted benzoic acid derivative or its salt and preparation method thereof

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority and benefits of Chinese invention patent application No. 202210861774.8 filed with the State Intellectual Property Office of China on July 20, 2022, and all the contents disclosed in the application are incorporated herein by reference in their entirety. Technical Field

[0003] The present invention belongs to the field of pharmaceutical technology and relates to a crystal of a bridged heterocycle-substituted benzoic acid derivative or a salt thereof and a preparation method thereof, and specifically relates to a crystal of a compound of formula (II), a hydrochloride of the compound of formula (II) and a crystal thereof, and a preparation method thereof. Background Art

[0004] The complement system is a crucial component of the human body's innate immune system, defending against infections by foreign pathogens, bacteria, and parasites. It also plays a crucial role in connecting innate and adaptive immunity. Complement is composed of plasma proteins, including soluble proteins, membrane-bound proteins, and complement receptors. Complement is primarily produced by membrane proteins expressed in the liver or on the cell surface, and exerts its effects in plasma, tissues, or cells. The complement system is activated primarily through three pathways: the classical pathway (CP), the lectin pathway (LP), and the alternative pathway (AP).

[0005] Under normal physiological conditions in healthy individuals, the AP pathway maintains a low level of activation to monitor the invasion of foreign pathogens. Complement proteins are distributed on the surface of apoptotic cells, and complement activation is strictly regulated, serving only to clear apoptotic cells without further activating other innate or adaptive immune responses. In the event of infection by foreign pathogens, the complement system is fully activated, generating inflammatory responses, opsonization, or phagocytosis, destroying the pathogens and ultimately activating the adaptive immune response. Both inefficient and overstimulated complement can be harmful to the human body and are associated with increased susceptibility to infections and non-infectious diseases, such as autoimmune diseases, chronic inflammation, thrombotic microangiopathy, transplant rejection, and tumors.

[0006] Complement factor B (Factor B) acts on the AP pathway. Inhibiting Factor B activity can prevent activation of the API pathway without interfering with the CP and LP pathways, thus avoiding the increased risk of infection due to complement system inhibition. Currently, there are no small molecule Factor B inhibitors on the market. Novartis' Factor B inhibitor LNP023 is in Phase III clinical trials for the treatment of diseases such as PNH, IgAN, and C3G. Therefore, it is necessary to develop new small molecule inhibitors of the complement system Factor B, increase clinical research and verification, and use them for the treatment of various diseases caused by complement abnormalities, providing new treatment options for unmet clinical needs.

[0007] Summary of the Invention

[0008] In one aspect, the present invention provides a crystal of a compound of formula (II),

[0009] The crystals of the compound of formula (II) of the present invention may be in the form of a non-solvate or a solvate, such as a hydrate.

[0010] In one embodiment of the present invention, the crystal of the compound of formula (II) is crystal form A, and the X-ray powder diffraction pattern of the crystal form A using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 7.15±0.20°, 9.28±0.20° and 14.31±0.20°.

[0011] In one embodiment of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A using Cu Kα radiation has at least 3 or 4 characteristic diffraction peaks at the following 2θ angles: 7.15±0.20°, 9.28±0.20°, 14.31±0.20°, 19.52±0.20° and 21.77±0.20°.

[0012] In one embodiment of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 7.15±0.20°, 9.28±0.20°, 14.31±0.20°, 19.52±0.20° and 21.77±0.20°.

[0013] In one embodiment of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 7.15°, 9.28°, 14.31°, 19.52° and 21.77°.

[0014] In some embodiments of the present invention, the XRPD pattern of the above-mentioned crystal form A under Cu Kα radiation is shown in FIG1 .

[0015] In some embodiments of the present invention, the peak positions and relative intensities of the diffraction peaks in the Cu Kα radiation XRPD pattern of the above-mentioned crystal form A are shown in Table 1-1:

[0016] Table 1-1 XRPD diffraction data of the crystal form of compound A of formula (II)

[0017] In some embodiments of the present invention, the peak positions and relative intensities of the diffraction peaks in the Cu Kα radiation XRPD pattern of the above-mentioned crystal form A are shown in Table 1:

[0018] Table 1 XRPD diffraction data of the crystal form of compound A of formula (II)

[0019] On the other hand, the present invention also provides the hydrochloride salt of the compound of formula (II),

[0020] In another aspect, the present invention provides a crystalline hydrochloride salt of the compound of formula (II).

[0021] The crystals of the hydrochloride of the compound of formula (II) of the present invention may be in the form of a non-solvate or a solvate, such as a hydrate.

[0022] In another aspect, the present invention provides a compound of formula (II-1),

[0023] in,

[0024] m is selected from 0 to 2.5;

[0025] n is selected from 0 to 2.5.

[0026] In some embodiments of the present invention, m is selected from 0, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3 or 2.0.

[0027] In some embodiments of the present invention, the above m is selected from 1.0 or 2.0.

[0028] In some embodiments of the present invention, the above m is selected from 1.0.

[0029] In some embodiments of the present invention, n is selected from 0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4 or 2.5.

[0030] In some embodiments of the present invention, the above n is selected from 0, 1.0 or 2.0.

[0031] In some embodiments of the present invention, the above n is selected from 0.

[0032] In some embodiments of the present invention, the compound of formula (II-1) is selected from the compound of formula (I),

[0033] On the other hand, the present invention also provides a crystal of the compound of formula (I),

[0034] The crystals of the compound of formula (I) of the present invention may be in the form of a non-solvate or a solvate, such as a hydrate.

[0035] In one embodiment of the present invention, the crystal of the compound of formula (I) is crystal form B, and the X-ray powder diffraction pattern of the crystal form B using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 6.16±0.20°, 8.96±0.20° and 10.53±0.20°.

[0036] In one embodiment of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 6.16±0.20°, 8.96±0.20°, 10.53±0.20°, 18.55±0.20° and 24.62±0.20°.

[0037] In one embodiment of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form with Cu Kα radiation has at least 6 or 7 characteristic diffraction peaks at the following 2θ angles: 6.16±0.20°, 8.96±0.20°, 10.53±0.20°, 12.30±0.20°, 16.74±0.20°, 18.55±0.20°, 19.95±0.20° and 24.62±0.20°.

[0038] In one embodiment of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form with Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 6.16±0.20°, 8.96±0.20°, 10.53±0.20°, 12.30±0.20°, 16.74±0.20°, 18.55±0.20°, 19.95±0.20° and 24.62±0.20°.

[0039] In one embodiment of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form with Cu Kα radiation has at least 9, 10 or 11 characteristic diffraction peaks at the following 2θ angles: 6.16±0.20°, 8.96±0.20°, 10.53±0.20°, 12.30±0.20°, 16.74±0.20°, 17.39±0.20°, 18.55±0.20°, 19.49±0.20°, 19.95±0.20°, 22.17±0.20°, 22.75±0.20° and 24.62±0.20°.

[0040] In one embodiment of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form with Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 6.16±0.20°, 8.96±0.20°, 10.53±0.20°, 12.30±0.20°, 16.74±0.20°, 17.39±0.20°, 18.55±0.20°, 19.49±0.20°, 19.95±0.20°, 22.17±0.20°, 22.75±0.20° and 24.62±0.20°.

[0041] In one embodiment of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form with Cu Kα radiation has at least 11, 12, 13, 14 or 15 characteristic diffraction peaks at the following 2θ angles: 6.16±0.20°, 8.96±0.20°, 10.53±0.20°, 12.30±0.20°, 13.19±0.20°, 14.74±0.20°, 16.74±0.20°, 17.39±0.20°, 17.90±0.20°, 18.55±0.20°, 19.49±0.20°, 19.95±0.20°, 21.55±0.20°, 22.17±0.20°, 22.75±0.20° and 24.62±0.20°.

[0042] In one embodiment of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form with Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 6.16±0.20°, 8.96±0.20°, 10.53±0.20°, 12.30±0.20°, 13.19±0.20°, 14.74±0.20°, 16.74±0.20°, 17.39±0.20°, 17.90±0.20°, 18.55±0.20°, 19.49±0.20°, 19.95±0.20°, 21.55±0.20°, 22.17±0.20°, 22.75±0.20° and 24.62±0.20°.

[0043] In one embodiment of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 3.16±0.20°, 6.16±0.20°, 8.96±0.20°, 10.53±0.20°, 12.30±0.20°, 13.19±0.20°, 14.74±0.20°, 16.74±0.20°, 17.39±0.20°, 17.90±0.20°, 18 There are characteristic diffraction peaks at .55±0.20°, 19.49±0.20°, 19.95±0.20°, 21.55±0.20°, 22.17±0.20°, 22.75±0.20°, 24.62±0.20°, 27.29±0.20°, 28.05±0.20°, 29.03±0.20°, 32.55±0.20° and 34.15±0.20°.

[0044] In one embodiment of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form with Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 6.16±0.20°, 8.96±0.20°, 10.53±0.20°, and / or 3.16±0.20°, and / or 10.79±0.20°, and / or 12.30±0.20°, and / or 13.19±0.20°, and / or 14.74±0.20°, and / or 16.74±0.20°, and / or 17.39±0.20°, and / or 17.90±0.20°, and / or Or there are characteristic diffraction peaks at 18.55±0.20°, and / or 19.49±0.20°, and / or 19.95±0.20°, and / or 21.55±0.20°, and / or 22.17±0.20°, and / or 22.75±0.20°, and / or 24.62±0.20°, and / or 27.29±0.20°, and / or 28.05±0.20°, and / or 29.03±0.20°, and / or 32.55±0.20°, and / or 34.15±0.20°.

[0045] In one embodiment of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form with Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 3.16°, 6.16°, 8.96°, 10.53°, 10.79°, 12.30°, 13.19°, 14.74°, 16.74°, 17.39°, 17.90°, 18.55°, 19.49°, 19.95°, 21.55°, 22.17°, 22.75°, 24.62°, 27.29°, 28.05°, 29.03°, 32.55° and 34.15°.

[0046] In one embodiment of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form with Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 6.16°, 8.96°, 10.53°, 10.79°, 12.30°, 13.19°, 14.74°, 16.74°, 17.39°, 17.90°, 18.55°, 19.49°, 19.95°, 21.55°, 22.17°, 22.75°, 24.62°, 27.29°, 28.05° and 29.03°.

[0047] In one embodiment of the present invention, the XRPD pattern of the above-mentioned Form B under Cu Kα radiation is shown in FIG2 .

[0048] In one embodiment of the present invention, the peak positions and relative intensities of the diffraction peaks in the Cu Kα radiation XRPD pattern of the above-mentioned Form B are shown in Table 2-1:

[0049] Table 2-1 XRPD diffraction data of the crystal form B of compound of formula (I)

[0050] In one embodiment of the present invention, in the XRPD pattern of the above-mentioned Form B under Cu Kα radiation, the peak positions and relative intensities of the diffraction peaks are shown in Table 2:

[0051] Table 2 XRPD diffraction data of the crystal form B of compound of formula (I)

[0052] In one embodiment of the present invention, the differential scanning calorimetry (DSC) curve of the above-mentioned Form B shows an exothermic peak at 221.2°C±3°C.

[0053] In one embodiment of the present invention, the DSC spectrum of the above-mentioned Form B is shown in FIG3 .

[0054] In one embodiment of the present invention, the thermogravimetric analysis (TGA) curve of the above-mentioned Form B shows a weight loss of 3.85% at 150°C±3°C.

[0055] In one embodiment of the present invention, the TGA spectrum of the above-mentioned Form B is shown in FIG4 .

[0056] On the other hand, the present invention also provides a method for preparing the crystalline form B of the compound of formula (I), comprising mixing the hydrochloride of the compound of formula (II) in solvents S1, S2 and S3, and then separating the solid.

[0057] In one embodiment of the present invention, the hydrochloride salt of the compound of formula (II) is amorphous. In one embodiment of the present invention, the hydrochloride salt of the compound of formula (II) is a compound of formula (I).

[0058] In one embodiment of the present invention, the method for preparing the crystalline form of compound (I) B comprises first mixing the hydrochloride of the compound of formula (II) in solvents S1 and S2, and then adding solvent S3.

[0059] On the other hand, the present invention also provides a method for preparing the crystal form B of compound of formula (I),

[0060] The preparation method of the B crystal form comprises the following steps:

[0061] (a) adding the amorphous hydrochloride of the compound of formula (II) to solvent S1 and solvent S2 at 15°C to 70°C;

[0062] (b) stirring for 0.05 to 2 hours;

[0063] (c) adding solvent S3 at 15°C to 35°C;

[0064] (d) stirring for 1 to 16 hours to precipitate a solid;

[0065] (e) Filter and dry the filter cake in vacuum.

[0066] In one embodiment of the present invention, the solvent S1 is selected from acetonitrile or acetone, or a mixture of the two solvents.

[0067] In one embodiment of the present invention, the solvent S2 is selected from water.

[0068] In one embodiment of the present invention, the solvent S3 is selected from a mixed solvent of acetone and ethyl acetate, acetonitrile or 1,4-dioxane.

[0069] In one embodiment of the present invention, the volume ratio of the solvent S1 to the solvent S2 is 5:1 to 1:5.

[0070] On the other hand, the present invention also provides a method for preparing the crystal form B of compound of formula (I),

[0071] The preparation method of the B crystal form comprises the following steps:

[0072] (a) adding the amorphous hydrochloride of the compound of formula (II) to solvent S1 and solvent S2 at 15°C to 70°C;

[0073] (b) stirring for 0.05 to 2 hours;

[0074] (c) adding solvent S3 at 15°C to 35°C;

[0075] (d) stirring for 1 to 16 hours to precipitate a solid;

[0076] (e) filtering, and vacuum drying the filter cake;

[0077] in,

[0078] Solvent S1 is selected from one or a mixture of acetonitrile and acetone;

[0079] Solvent S2 is selected from water;

[0080] Solvent S3 is selected from a mixed solvent of acetone and ethyl acetate, acetonitrile or 1,4-dioxane;

[0081] The volume ratio of solvent S1 to solvent S2 is 5:1 to 1:5.

[0082] In some embodiments of the present invention, the volume ratio of the above-mentioned solvent S1 and solvent S2 is 5:1 to 1:1; preferably, the volume ratio of solvent S1 and solvent S2 is 5:1, 4:1, 3:1, 2:1 or 1:1; further preferably, the volume ratio of solvent S1 and solvent S2 is 5:1.

[0083] In some embodiments of the present invention, the solvent S1 is selected from acetone, and the solvent S2 is selected from water, and the volume ratio of acetone to water is 5:1, 4:1, 3:1, 2:1 or 1:1; preferably, the volume ratio of acetone to water is 5:1.

[0084] In some embodiments of the present invention, the solvent S3 is selected from a mixed solvent of acetone and ethyl acetate, and the volume ratio of acetone to ethyl acetate is 1:1 to 1:3; preferably, the volume ratio of acetone to ethyl acetate is 1:1, 1:1.5, 1:2 or 1:3; further preferably, the volume ratio of acetone to ethyl acetate is 1:1.5.

[0085] In some embodiments of the present invention, the above-mentioned solvent S1 is selected from acetone, the solvent S2 is selected from water, and the solvent S3 is selected from a mixed solvent of acetone and ethyl acetate; the volume ratios of the mixed solvents of acetone: water: acetone and ethyl acetate are 1-5:1:5-15 respectively; preferably, the volume ratios of the mixed solvents of acetone: water: acetone and ethyl acetate are 5:1:5, 5:1:10, 5:1:15, 1:1:15, 2:1:15, 3:1:15, 4:1:15, 1:1:5, 2:1:5, 3:1:5, 4:1:5, 1:1:10, 2:1:10, 3:1:10 or 4:1:10; further preferably, the volume ratios of the mixed solvents of acetone and ethyl acetate are 5:1:5, 5:1:10 or 5:1:15 respectively; further preferably, the volume ratios of the mixed solvents of acetone and ethyl acetate are 5:1:15 respectively.

[0086] In some embodiments of the present invention, the mass volume ratio of the hydrochloride salt of the compound of formula (II) to the solvent S1 is 100 mg:0.5-1 mL; preferably, the mass volume ratio of the hydrochloride salt of the compound of formula (II) to the solvent S1 is 100 mg:0.5 mL, 100 mg:0.6 mL, 100 mg:0.7 mL, 100 mg:0.8 mL, 100 mg:0.9 mL or 100 mg:1 mL; further preferably, the mass volume ratio of the hydrochloride salt of the compound of formula (II) to the solvent S1 is 100 mg:0.6 mL.

[0087] In some embodiments of the present invention, the stirring temperature of step (b) is 15°C to 35°C; the stirring time is 5 minutes to 1 hour; preferably, the stirring temperature of step (b) is 15°C to 25°C; the stirring time is 5 to 10 minutes; further preferably, the stirring temperature of step (b) is 15°C to 25°C; the stirring time is 5 minutes.

[0088] In some embodiments of the present invention, the stirring temperature of step (d) is 15°C to 35°C; the stirring time is 5 to 15 hours; preferably, the stirring temperature of step (d) is 15°C to 25°C; the stirring time is 12 hours.

[0089] In one embodiment of the present invention, the crystal of the compound of formula (I) is crystal form C, and the X-ray powder diffraction pattern of the crystal form C with Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 7.72±0.20°, 15.31±0.20° and 19.53±0.20°.

[0090] In one embodiment of the present invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form with Cu Kα radiation has at least 6 or 7 characteristic diffraction peaks at the following 2θ angles: 7.72±0.20°, 14.67±0.20°, 15.31±0.20°, 16.66±0.20°, 18.76±0.20°, 19.53±0.20°, 22.67±0.20° and 24.28±0.20°.

[0091] In one embodiment of the present invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form with Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 7.72±0.20°, 14.67±0.20°, 15.31±0.20°, 16.66±0.20°, 18.76±0.20°, 19.53±0.20°, 22.67±0.20° and 24.28±0.20°.

[0092] In one embodiment of the present invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form with Cu Kα radiation has at least 9, 10 or 11 characteristic diffraction peaks at the following 2θ angles: 7.72±0.20°, 10.75±0.20°, 13.80±0.20°, 14.67±0.20°, 15.31±0.20°, 16.66±0.20°, 18.76±0.20°, 19.53±0.20°, 22.67±0.20°, 24.28±0.20°, 25.95±0.20° and 26.65±0.20°.

[0093] In one embodiment of the present invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form with Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 7.72±0.20°, 10.75±0.20°, 13.80±0.20°, 14.67±0.20°, 15.31±0.20°, 16.66±0.20°, 18.76±0.20°, 19.53±0.20°, 22.67±0.20°, 24.28±0.20°, 25.95±0.20° and 26.65±0.20°.

[0094] In one embodiment of the present invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form with Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 7.72±0.20°, 15.31±0.20°, 19.53±0.20°, and / or 10.75±0.20°, and / or 13.80±0.20°, and / or 14.67±0.20°, and / or 16.66±0.20°, and / or 18.76±0.20°, and / or 22.67±0.20°, and / or 24.28±0.20°, and / or 25.95±0.20°, and / or 26.65±0.20°.

[0095] In one embodiment of the present invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form with Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 7.72°, 10.75°, 13.80°, 14.67°, 15.31°, 16.66°, 18.76°, 19.53°, 22.67°, 24.28°, 25.95° and 26.65°.

[0096] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form using Cu Kα radiation is shown in Figure 5.

[0097] In some embodiments of the present invention, the peak positions and relative intensities of the diffraction peaks in the Cu Kα radiation XRPD pattern of the above-mentioned C crystal form are shown in Table 3-1:

[0098] Table 3-1 XRPD diffraction data of the crystal form C of compound of formula (I)

[0099] In some embodiments of the present invention, the peak positions and relative intensities of the diffraction peaks in the Cu Kα radiation XRPD pattern of the above-mentioned C crystal form are shown in Table 3:

[0100] Table 3 XRPD diffraction data of the crystal form C of compound of formula (I)

[0101] In some embodiments of the present invention, the differential scanning calorimetry (DSC) curve of the above-mentioned crystal form C shows an exothermic peak at 227.5°C±3°C.

[0102] In some embodiments of the present invention, the DSC spectrum of the above-mentioned crystal form C is shown in Figure 6.

[0103] In some embodiments of the present invention, the thermogravimetric analysis (TGA) curve of the above-mentioned crystal form C shows a weight loss of 2.88% at 150.0°C±3°C.

[0104] In some embodiments of the present invention, the TGA spectrum of the above-mentioned C crystal form is shown in Figure 7.

[0105] In one embodiment of the present invention, the crystal of the compound of formula (I) is D crystal form, and the X-ray powder diffraction pattern of the D crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 5.93±0.20° and 11.82±0.20°.

[0106] In one embodiment of the present invention, the X-ray powder diffraction pattern of the above-mentioned D crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 5.93° and 11.82°.

[0107] In some embodiments of the present invention, the XRPD pattern of the above-mentioned D crystal form is shown in Figure 8.

[0108] In some embodiments of the present invention, the peak positions and relative intensities of the diffraction peaks in the Cu Kα radiation XRPD pattern of the above-mentioned D crystal form are shown in Table 4-1:

[0109] Table 4-1 XRPD diffraction data of Form D of the compound of formula (I)

[0110] In some embodiments of the present invention, the peak positions and relative intensities of the diffraction peaks in the Cu Kα radiation XRPD pattern of the above-mentioned D crystal form are shown in Table 4:

[0111] Table 4 XRPD diffraction data of Form D of the compound of formula (I)

[0112] In one embodiment of the present invention, the crystal of the compound of formula (I) is E crystal form, and the X-ray powder diffraction pattern of the E crystal form with Cu Kα radiation has at least three characteristic diffraction peaks at the following 2θ angles: 5.98±0.20°, 7.83±0.20°, 8.87±0.20° and 10.76±0.20°.

[0113] In one embodiment of the present invention, the crystalline form E of the compound of formula (I) is in the form of a hydrate.

[0114] In one embodiment of the present invention, the crystal of the compound of formula (I) is in the form of a hydrate, and the hydrate is crystal form E, and the X-ray powder diffraction pattern of the crystal form E with Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 5.98±0.20°, 7.83±0.20°, 8.87±0.20° and 10.76±0.20°.

[0115] In one embodiment of the present invention, the X-ray powder diffraction pattern of the above-mentioned E crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 5.98°, 7.83°, 8.87° and 10.76°.

[0116] In one embodiment of the present invention, the X-ray powder diffraction pattern of the above-mentioned E crystal form is shown in Figure 9.

[0117] In one embodiment of the present invention, the peak positions and relative intensities of the diffraction peaks in the Cu Kα radiation XRPD pattern of the above-mentioned E crystal form are shown in Table 5-1:

[0118] Table 5-1 XRPD diffraction data of the E-form of the hydrate of the compound of formula (I)

[0119] In one embodiment of the present invention, in the XRPD pattern of Cu Kα radiation of the above-mentioned E crystal form, the peak positions and relative intensities of the diffraction peaks are shown in Table 5:

[0120] Table 5 XRPD diffraction data of the hydrated form E of the compound of formula (I)

[0121] In one embodiment of the present invention, the crystal of the compound of formula (I) is F crystal form, and the X-ray powder diffraction pattern of the F crystal form with Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 5.96±0.20°, 8.86±0.20°, 17.40±0.20°, 19.52±0.20° and 24.04±0.20°.

[0122] In one embodiment of the present invention, the X-ray powder diffraction pattern of the above-mentioned F crystal form using Cu Kα radiation has at least 6 or 7 characteristic diffraction peaks at the following 2θ angles: 5.96±0.20°, 8.86±0.20°, 10.82±0.20°, 13.32±0.20°, 17.40±0.20°, 19.52±0.20°, 24.04±0.20° and 24.74±0.20°.

[0123] In one embodiment of the present invention, the X-ray powder diffraction pattern of the above-mentioned F crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 5.96±0.20°, 8.86±0.20°, 10.82±0.20°, 13.32±0.20°, 17.40±0.20°, 19.52±0.20°, 24.04±0.20° and 24.74±0.20°.

[0124] In one embodiment of the present invention, the X-ray powder diffraction pattern of the above-mentioned F crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 5.96±0.20°, 8.86±0.20°, 10.66±0.20°, 10.82±0.20°, 11.94±0.20°, 13.32±0.20°, 14.86±0.20°, 17.40±0.20°, 17.96±0.20°, 18.72±0.20°, 19.52±0.20°, 21.66±0.20°, 24.04±0.20°, 24.74±0.20° and 26.56±0.20°.

[0125] In one embodiment of the present invention, the X-ray powder diffraction pattern of the above-mentioned F crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 5.96±0.20°, 8.86±0.20°, 17.40±0.20°, 19.52±0.20°, 24.04±0.20°, and / or 10.66±0.20°, and / or 10.82±0.20°, and / or 11.06±0.20°, and / or 11.54±0.20°, and / or 11.94 ±0.20°, and / or 13.32±0.20°, and / or 14.86±0.20°, and / or 17.96±0.20°, and / or 18.72±0.20°, and / or 21.66±0.20°, and / or 23.68±0.20°, and / or 24.74±0.20°, and / or 26.56±0.20°, and / or 27.42±0.20° and / or 30.78±0.20°.

[0126] In one embodiment of the present invention, the X-ray powder diffraction pattern of the above-mentioned F crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 5.96°, 8.86°, 10.66°, 10.82°, 11.06°, 11.54°, 11.94°, 13.32°, 14.86°, 17.40°, 17.96°, 18.72°, 19.52°, 21.66°, 23.68°, 24.04°, 24.74°, 26.56°, 27.42° and 30.78°.

[0127] In one embodiment of the present invention, the XRPD pattern of the above-mentioned F crystal form under Cu Kα radiation is shown in FIG11 .

[0128] In one embodiment of the present invention, in the XRPD pattern of Cu Kα radiation of the above-mentioned F crystal form, the peak positions and relative intensities of the diffraction peaks are shown in Table 16-1:

[0129] Table 16-1 XRPD simulated diffraction data of the crystal form F of the compound of formula (I)

[0130] In one embodiment of the present invention, the peak positions and relative intensities of the diffraction peaks in the Cu Kα radiation XRPD pattern of the above-mentioned F crystal form are shown in Table 16.

[0131] In another aspect, the present invention provides a crystalline composition comprising crystals of the compound of formula (II), wherein the crystals of the compound of formula (II) constitute at least 50% by weight of the crystalline composition, preferably at least 75%, more preferably at least 90%, and most preferably at least 95%. Each of the crystalline compositions may also contain a small amount of other crystalline or non-crystalline forms of the compound of formula (II).

[0132] In another aspect, the present invention provides a crystalline composition comprising crystals of the compound of formula (I), wherein the crystals of the compound of formula (I) constitute at least 50% by weight of the crystalline composition, preferably at least 75%, more preferably at least 90%, and most preferably at least 95%. Each of the crystalline compositions may also contain a small amount of other crystalline or non-crystalline forms of the compound of formula (I).

[0133] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (II) or a crystal thereof, or a crystalline composition thereof; the pharmaceutical composition may comprise at least one pharmaceutically acceptable carrier or other excipient. In addition, the pharmaceutical composition of the present application may further include one or more other therapeutic agents.

[0134] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) above, or a crystal thereof, or a crystalline composition thereof; the pharmaceutical composition may comprise at least one pharmaceutically acceptable carrier or other excipient. In addition, the pharmaceutical composition of the present application may further include one or more other therapeutic agents.

[0135] On the other hand, the present invention provides the use of the above-mentioned compound of formula (II) or its crystal, the above-mentioned compound of formula (I) or its crystal, the above-mentioned crystalline composition, or the above-mentioned pharmaceutical composition in the preparation of drugs for treating or preventing diseases related to complement factor B.

[0136] On the other hand, the present invention provides the use of the compound of formula (II) or its crystal, the compound of formula (I) or its crystal, the crystalline composition, or the pharmaceutical composition for treating or preventing diseases related to complement factor B.

[0137] On the other hand, the present invention provides a method for treating or preventing diseases related to complement factor B, which comprises administering a therapeutically effective amount of the above-mentioned compound of formula (II) or its crystal, the above-mentioned compound of formula (I) or its crystal, the above-mentioned crystalline composition, or the above-mentioned pharmaceutical composition to a mammal in need thereof.

[0138] In another aspect, the present invention provides the compound of formula (II) or its crystal, the compound of formula (I) or its crystal, the crystalline composition, or the pharmaceutical composition for treating or preventing diseases associated with complement factor B.

[0139] In some embodiments of the invention, the mammal is a human.

[0140] In some embodiments of the present invention, the complement factor B-related disease is selected from inflammatory disorders and autoimmune diseases.

[0141] Technical Effects

[0142] The compounds of the present invention have significant inhibitory activity against activation of the human serum bypass pathway and also have significant binding activity against human complement factor B protein. The crystal and salt forms of the compounds of the present invention have simple preparation processes, stable physical and chemical properties, good hygroscopicity, and good pharmacokinetic properties (e.g., AUC, C max 、T 1 / 2 ), which is convenient for preparation and has broad application prospects in the prevention and / or treatment of complement factor B-related drugs.

[0143] Definition and Description

[0144] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term should not be construed as ambiguous or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears herein, it is intended to refer to the corresponding commercial product or its active ingredient.

[0145] The intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0146] The chemical reactions of the present invention are carried out in suitable solvents that are compatible with the chemical transformations of the present invention and the reagents and materials required. To obtain the compounds of the present invention, it may sometimes be necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0147] Unless otherwise indicated, in the differential scanning calorimetry curves of the compounds of the present invention, upward direction indicates exothermic heat (Exo Up).

[0148] Unless otherwise specified, room temperature in the present invention means 15°C to 35°C.

[0149] "Mammal" includes humans and domestic animals such as laboratory mammals and household pets (e.g., cats, dogs, pigs, sheep, cattle, goats, horses, rabbits), and non-domesticated mammals, such as wild mammals.

[0150] The term "pharmaceutical composition" refers to a formulation of a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal, such as a human. The medium includes all pharmaceutically acceptable carriers for use therein. A pharmaceutical composition facilitates administration of the compound to an organism.

[0151] The term "therapeutically effective amount" refers to a non-toxic amount of a drug or pharmaceutical agent sufficient to achieve the desired effect. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0152] The term "treatment" means administering the compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0153] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0154] (ii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0155] The term "prevention" means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, and includes preventing the occurrence of a disease or disease state in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0156] As used herein, "pharmaceutically acceptable carrier" refers to a carrier that is administered with the active ingredient, has no significant irritating effect on the organism, and does not impair the biological activity and properties of the active compound. For additional information on carriers, see Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0157] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0158] The present invention will be described in detail below through examples, which are not intended to limit the present invention in any way.

[0159] The structures of the compounds of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compounds, the absolute configuration can be confirmed by conventional techniques in the art. For example, single crystal X-ray diffraction (SXRD) is used to collect diffraction intensity data on the cultured single crystal using a Bruker D8 venture diffractometer, using CuKα radiation as the light source and scanning mode: After scanning and collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0160] The following abbreviations are used in this disclosure: ACN stands for acetonitrile; DMSO stands for dimethyl sulfoxide; N2: nitrogen; RH: relative humidity; mL: milliliter; L: liter; min: minute; °C: degrees Celsius; μm: micrometer; mm: millimeter; μL: microliter; moL / L: mole per liter; mg: milligram; s: second; nm: nanometer; MPa: megapascal; lux: lux; μw / cm 2: microwatt per square centimeter; h: hour; Kg: kilogram; nM: nanomole, rpm: rotational speed; XRPD stands for X-ray powder diffraction; DSC stands for differential scanning calorimetry; TGA stands for thermogravimetric analysis; 1 H NMR stands for proton nuclear magnetic resonance.

[0161] The compounds of the present invention are named according to the conventional nomenclature in the art or using Software naming, commercially available compounds use supplier catalog names, and all solvents used in the present invention are commercially available.

[0162] Instrument and analysis method of the present invention

[0163] (1) X-ray powder diffractometer (XRPD) method of the present invention

[0164] Instrument model: PANalytical X'Pert 3 Type X-ray diffractometer.

[0165] Test method: Approximately 10 mg of sample was used for XRPD analysis.

[0166] The detailed XRPD parameters are as follows:

[0167] X-ray type: Cu, Kα.

[0168] 1.540598; 1.544426.

[0169] Kα2 / Kα1 intensity ratio: 0.50.

[0170] Voltage: 45 kilovolts (kV).

[0171] Current: 40 milliamperes (mA).

[0172] Divergence slit: 1 / 8 degree.

[0173] Scan mode: Continuous.

[0174] Scanning range: from 3.0 to 40.0 degrees.

[0175] Scan time per step: 46.7 seconds.

[0176] Step size: 0.0263 degrees.

[0177] (2) Differential Scanning Calorimeter (DSC) and Thermogravimetric Analyzer (TGA) methods of the present invention

[0178] The instrument models and parameters are shown in Table 6.

[0179] Table 6 DSC and TGA test parameters

[0180] (3) High Performance Liquid Chromatography / Ion Chromatography (HPLC / IC) Instruments

[0181] The acid-base molar ratio test in the experiment was conducted by combining an Agilent H-Class high performance liquid chromatograph and an ion chromatograph. The analysis conditions are shown in Tables 7 and 8.

[0182] Table 7 HPLC test conditions

[0183] Table 8 Ion chromatography test conditions

[0184] (4) Dynamic Vapor Sorption (DVS) method

[0185] Weigh approximately 10 mg of sample and use the SMS DVS intrinsic plus moisture adsorption instrument for testing. Detailed instrument information and parameters are as follows:

[0186] Temperature: 25℃;

[0187] Sample size 10-20 mg;

[0188] Protective gas / flow rate: nitrogen, 200 mL / min;

[0189] dm / dt: 0.002% / min;

[0190] Minimum dm / dt balance time: 10min;

[0191] Maximum equilibration time: 180 min;

[0192] RH range: 0%RH-95%RH;

[0193] RH gradient: 10% (0% RH-90% RH, 90% RH-0% RH); 5% (90% RH-95% RH, 95% RH-90% RH).

[0194] Hygroscopicity evaluation classification: Absorbs sufficient water to form a liquid: Deliquescence; ΔW% ≥ 15%: Extremely hygroscopic; 15% > ΔW% ≥ 2%: Somewhat hygroscopic; 2% > ΔW% ≥ 0.2%: Slightly hygroscopic; ΔW% < 0.2%: No or almost no hygroscopicity. ΔW% represents the weight gain of the test sample based on moisture absorption at 25 ± 1°C and 80 ± 2% relative humidity. BRIEF DESCRIPTION OF THE DRAWINGS

[0195] Figure 1 is the XRPD pattern of the crystalline form A of compound of formula (II).

[0196] Figure 2 is the XRPD pattern of the crystalline form B of compound of formula (I).

[0197] FIG3 is a DSC spectrum of the crystalline form B of compound of formula (I).

[0198] FIG4 is a TGA spectrum of the crystalline form B of compound of formula (I).

[0199] Figure 5 is the XRPD pattern of the crystalline form C of compound of formula (I).

[0200] FIG6 is a DSC spectrum of the crystalline form C of compound of formula (I).

[0201] FIG7 is a TGA spectrum of the crystalline form C of compound of formula (I).

[0202] FIG8 is an XRPD pattern of the crystalline form D of the compound of formula (I).

[0203] FIG9 is an XRPD pattern of the hydrate E crystal form of the compound of formula (I).

[0204] FIG10 is an ellipsoid diagram of the three-dimensional structure of a single crystal of the compound of formula (I).

[0205] FIG11 is an XRPD simulation diagram of a single crystal of the compound of formula (I). DETAILED DESCRIPTION

[0206] The present invention is described in detail below by way of examples, but is not intended to limit the present invention in any way. While the present invention has been described in detail herein, and specific embodiments thereof have been disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0207] Example 1: Preparation of the hydrochloride salt of the compound of formula (II)

[0208] first step

[0209] To a solution of compound 2 (0.5 g) in tetrahydrofuran (5 mL) at 15°C, di-tert-butyl dicarbonate (812.33 mg) and N,N-diisopropylethylamine (37.89 mg) were added. The reaction solution was stirred at 15°C for 1 hour. The reaction solution was added to water (15 mL) and stirred for 5 minutes. The liquid was separated, and the aqueous phase was extracted with ethyl acetate (20 mL*3). The combined organic layer was washed with saturated brine (20 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0:1 to 1:10) to obtain compound 3.

[0210] 1 H NMR (400MHz, CDCl3) δppm 7.54-7.48(m,1H),6.90-6.84(m,1H),6.77-6.70(m,1H),6.50-6.43(m,1H),3.9 0-3.77(m,3H),2.70-2.55(m,3H),1.66-1.61(m,9H); LC-MS: m / z=206.1[M-56+H] + .

[0211] Step 2

[0212] At 15°C, oxalyl chloride (431.90 mg) was slowly added dropwise to a solution of N-methyl-N-formylaniline (459.93 mg) in dichloromethane (2.7 mL) under nitrogen protection. After the addition was complete, the reaction solution was stirred at 15°C for 12 hours, and then added dropwise to a solution of compound 3 (0.684 g) in dichloromethane (2.8 mL) at -14°C. After the addition was complete, the reaction solution was stirred at -15°C for 1.5 hours. The reaction solution was poured into ice water (20 mL) and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (20 mL*3), and the combined organic phases were washed with saturated brine (20 mL*3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0:1 to 1:10) to obtain compound 4.

[0213] 1 H NMR(400MHz,DMSO-d6)δppm 10.61-10.41(m,1H),7.91-7.71(m,1H),7.38-7.21(m,1H),7.07-6.97(m,1H),3 .97-3.93(m,3H),2.63-2.59(m,3H),1.60-1.58(m,9H); LC-MS: m / z=290.1[M+H] + .

[0214] Step 3

[0215] At 0°C, sodium borohydride (1.71g) was slowly added to a solution of compound 4 (5.24g) in tetrahydrofuran (20mL) and methanol (20mL) under nitrogen protection. After the addition, the reaction solution was stirred at 15°C for 0.5 hours, and then dilute hydrochloric acid (0.5M, 20mL) was slowly added. After the addition, the reaction solution was stirred for 20 minutes. The mixture was extracted with ethyl acetate (60mL*3), and the combined organic phases were washed with saturated brine (60mL*2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:10 to 1:3) to obtain compound 5.

[0216] 1 H NMR (400MHz, CDCl3) δppm 7.59-7.50(m,1H),6.80-6.70(m,1H),6.66-6.60(m,1H),4.97-4.85(m,2H),3.96-3.86(m,3H),2.68-2.58(m,3H),1.65-1.63(m,9H).

[0217] Step 4

[0218] To a nitrogen-protected solution of compound 5 (0.3 g) in dichloromethane (6.87 mL) at 15°C was added (chloromethylene)dimethylammonium chloride (197.71 mg). After the addition, the reaction mixture was stirred at 15°C for 1 hour. The reaction mixture was cooled to 0°C, and aqueous sodium bicarbonate (5%, 30 mL) was added. The mixture was then extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to yield compound 6.

[0219] 1 H NMR(400MHz,DMSO-d6)δppm 7.73-7.61(m,1H),6.91-6.86(m,1H),6.82-6.75(m,1H),4.99-4.91(m,2H),3.89-3.82(m,3H),2.56-2.54(m,3H),1.60-1.57(m,9H).

[0220] Step 5

[0221] At 30 ° C, under nitrogen protection, magnesium chips (402.78 g) were added to tetrahydrofuran (3000 mL), compound 19 (60 g) was slowly added, and then iodine (3.0 g) was added to initiate the reaction. The reaction solution was stirred for 0.5 hours at 30 ° C under nitrogen protection. The remaining compound 19 (540.0 g) was then added dropwise to the reaction solution, and the addition process lasted for about 2 hours. After the addition was completed, the reaction solution was stirred at 30 ° C under a nitrogen atmosphere for 0.5 hours to obtain a tetrahydrofuran solution of compound 8 (concentration measured by iodine titration: 0.66 M), which was directly used in the next step reaction.

[0222] Step 6

[0223] At -70 ° C, a tetrahydrofuran solution of compound 8 (0.66M, 2.01L) was added dropwise to a toluene (1000mL) solution containing compound 7 (200g) and cuprous bromide (17.30g). The reaction was carried out under nitrogen protection and the addition time was 3 hours. After the addition was completed, it was stirred at -70 ° C for 0.5 hours. The reaction solution was poured into ice water (2000mL), the pH was adjusted to 7 with dilute hydrochloric acid (1M), and then extracted with ethyl acetate (2000mL*2). The organic phases were combined and washed with saturated potassium carbonate aqueous solution (500mL), saturated ammonium chloride (500mL) and saturated sodium chloride (500mL) in sequence. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was then stirred in n-heptane (1000mL) at 10-15 ° C for 30 minutes, filtered, and the filter cake was collected to obtain compound 9. 1 H NMR (400MHz, CDCl3) δppm 8.07-7.94(m,2H),7.80-7.65(m,2H),4.93(t,J=4.1Hz,1H),3.96-3.76(m,4H),3.05(t,J=7.3Hz,2H),2.10(dt,J=4.1,7.3Hz,2H).

[0224] Step 7

[0225] Compound 9 (264 g) was dissolved in a mixed solvent of water (150 mL) and formic acid (1500 mL). The reaction mixture was heated to 40°C and stirred at this temperature for 2 hours. After cooling to room temperature, the reaction mixture was slowly added to 15% aqueous potassium carbonate solution (8 L). Solids precipitated and were collected by filtration. The filter cake was washed with water (500 mL) and dried to obtain compound 10. 1 H NMR (400MHz, CDCl3) δppm 9.92 (s, 1H), 8.20-8.03 (m, 2H), 7.95-7.68 (m, 2H), 3.51-3.22 (m, 2H), 3.09-2.88 (m, 2H).

[0226] Step 8

[0227] Benzylamine (194.62 g) was slowly added to acetic acid (103.88 mL) in water (850 mL). The reaction system was cooled to 0-10°C, and 1,3-acetonedicarboxylic acid (265.36 g) was slowly added in portions. The reaction solution was allowed to react at 0°C for 0.5 hours. A solution of compound 10 (170 g) in dioxane (850 mL) was slowly added to the reaction system. The reaction solution was slowly allowed to return to room temperature and then allowed to react at 45°C for 12 hours. The reaction solution was cooled to room temperature and then extracted with ethyl acetate (500 mL x 2). The organic phases were combined and washed sequentially with saturated sodium bicarbonate (500 mL) and saturated sodium chloride (500 mL). After drying over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was stirred in a mixture of n-heptane and methyl tert-butyl ether (1:1, 500 mL) for 0.5 hours. The solid was then filtered and collected to obtain compound 11. LC-MS: m / z=317.1[M+H] + .

[0228] Step 9

[0229] Compound 11 (220 g, 1 eq) was dissolved in acetonitrile (1700 mL), then heated to 70°C and stirred for 2 hours. L-dibenzoyltartaric acid (200 g, 0.8 eq) was slowly added with stirring. The reaction mixture was stirred at 70°C for another 2 hours, then slowly returned to 25°C and stirred for 12 hours. The solid was collected by filtration, and the filter cake was washed with acetonitrile (400 mL x 2). The filtered solid was added to 1000 mL of water, and the pH was adjusted to 8 with 1 M NaOH aqueous solution. The mixture was then extracted with ethyl acetate (2000 mL x 2). The organic phases were combined and washed with saturated brine (2000 mL x 2). The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield compound 12 (retention time: 2.175 min, ee = 99.1%). LC-MS: m / z = 317.1 [M+H] + SFC analysis method: chromatographic column: Chiralpak AD 50×4.6 mm ID, 3 μm, mobile phase: A: CO2, B: methanol (0.05% diethylamine), gradient B%: 5%-40%.

[0230] Step 10

[0231] Compound 12 (94 g) was dissolved in tetrahydrofuran (750 mL), followed by the addition of water (10.71 mL), nitrogen replacement three times, and the temperature was lowered to -40°C. At this temperature, lithium tri-sec-butylborohydride (1 M) was slowly added dropwise. After the addition was complete, stirring was continued at this temperature for 30 minutes. Hydrogen peroxide (102.77 mL, 30% purity) was slowly added dropwise to the reaction solution, controlling the temperature below 0°C. A solution of sodium sulfite (135 g) in water (1000 mL) was then slowly added, and extraction was performed with methyl tert-butyl ether (500 mL*2). The organic phase was washed with saturated brine (1000 mL*2), dried, filtered, and concentrated under reduced pressure to give compound 13 (retention time: 1.197 min, ee=96.9%). LC-MS: m / z=319.1 [M+H] + SFC analysis method: Column: Chiralcel OJ 50×4.6 mm ID, 3 μm, Mobile phase: A: CO2, B: methanol (0.05% diethylamine), Gradient B%: 5%-40%.

[0232] Step 11

[0233] Compound 13 (7 g) was dissolved in N,N-dimethylformamide (35 mL), replaced with nitrogen three times, cooled to 0°C, and then sodium tert-butoxide (6.34 g) was added and stirred for 30 min. The temperature was lowered to -10°C and diethyl sulfate (6.78 g) was slowly added dropwise at this temperature. After the addition was complete, stirring was continued at this temperature for 2 hours. The reaction solution was added to water (160 mL), the pH was adjusted to 5-6 with solid citric acid, and ethyl acetate (100 mL) was added for extraction. The organic phase was washed with saturated sodium carbonate aqueous solution (50 mL) and brine (100 mL) in sequence, dried and filtered, and the filtrate was concentrated under reduced pressure to obtain compound 14. LC-MS: m / z=347.2[M+H] + .

[0234] Step 12

[0235] Potassium carbonate (3.51 g) was added to a solution of compound 14 (8 g) in dimethyl sulfoxide (40 mL) at 20°C, followed by the slow dropwise addition of hydrogen peroxide (3.93 g, 30% purity). After the addition was complete, the reaction mixture was heated to 40°C and stirred for 16 hours. After cooling to room temperature, the reaction mixture was slowly added to ice water (150 mL) and stirred at 0°C for 1 hour. The precipitated solid was filtered and the filter cake dried to obtain compound 15. LC-MS: m / z = 365.2 [M+H] + .

[0236] Step 13

[0237] At room temperature, N,N-dimethylformamide dimethyl acetal (59.81 g) was added to a solution of compound 15 (99 g) in methanol (1000 mL). The reaction solution was heated to 40°C and stirred for 16 hours. The reaction solution was directly concentrated under reduced pressure to obtain a residue. Ethyl acetate (1000 mL) was added to the residue, followed by washing with water (500 mL) and saturated brine (500 mL), drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate to obtain compound 16, which was used directly in the next step. LC-MS: m / z = 380.2 [M+H] + .

[0238] Step 14

[0239] To a solution of compound 16 (4 g) in methanol (40 mL) at 20°C under a nitrogen atmosphere, concentrated hydrochloric acid (1.18 g, 36% purity) and wet palladium on carbon (1 g, 10% content) were added sequentially. The atmosphere was replaced with hydrogen three times, and the reaction mixture was stirred at 50°C for 1.5 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain crude compound 17, which was used directly in the next step. LC-MS: m / z = 290.1 ​​[M+H] + .

[0240] Step 15

[0241] Cesium carbonate (16.2 g) and potassium iodide (4.13 g) were added to a mixed solution of compound 17 (3.6 g) and compound 6 (4.05 g) in N,N-dimethylformamide (40 mL) at room temperature, and the reaction system was reacted at 15°C for 16 hours. The reaction solution was slowly added to 200 mL of ice water to quench. The aqueous phase was extracted with ethyl acetate (400 mL*2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 10:1) to give compound 18, LC-MS: m / z = 563.4 [M+H] + .

[0242] Step 16

[0243] To a mixed solution of compound 18 (5 g) in tetrahydrofuran (50 mL) and methanol (50 mL) at 15°C under nitrogen was added a 1.5 M aqueous solution of lithium hydroxide (50 mL). The reaction mixture was heated to 50°C and stirred for 16 hours. The reaction mixture was cooled to room temperature and the pH was adjusted to 6-7 with glacial acetic acid. The mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by high-performance liquid chromatography (column: Phenomenex luna C18Mltra 250*80 mm, 15 μm; mobile phase: A: water (0.05% hydrochloric acid), B: acetonitrile, step B: 20%-50%, 20 min) to obtain the amorphous hydrochloride salt of compound (II). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.23(brs,1H),11.26(s,1H),9.96(s,1H),8.24-7.96(m,4H),7.46(t,J=2.8 Hz,1H),6.86(s,1H),6.43(brs,1H),3.72(s,3H),3.70(brd,J=3.5Hz,2H),3. 18(brs,1H),3.06(brd,J=2.0Hz,2H),2.42(s,3H),2.25-2.15(m,1H),2.12-1 .86(m,6H),1.55-1.48(m,1H),1.11(t,J=6.8Hz,3H); LC-MS:m / z=449.3[M+H] + .

[0244] Example 2: Preparation of Crystalline Form A of Compound (II)

[0245] The amorphous hydrochloride of the compound of formula (II) prepared in Example 1 (0.4 g) was dissolved in a mixed solvent of deionized water (1 mL) and acetonitrile (3 mL). Saturated aqueous sodium bicarbonate (70 μL) was then slowly added to precipitate a solid. The reaction system was stirred at 20°C for 5 minutes. The solid was collected by filtration and dried to obtain the crystalline form A of the compound of formula (II). 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.81 (brs, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.4 Hz, 2H), 7.26 (t, J = 2.8 Hz, 1H), 6.66 (s, 1H), 6.53 (brs, 1H), 3.72 (s, 3H), 3.70 (brd, J = 3.5 Hz, 2H), 3.18 (brs, 1H), 3.06 (brd, J = 2.0 Hz, 2H), 2.42 (s, 3H), 2.25-2.15 (m, 1H), 2.12-1.86 (m, 6H), 1.55-1.48 (m, 1H), 1.11 (t, J = 6.8 Hz, 3H). The XRPD spectrum is shown in Figure 1.

[0246] Referring to the above preparation method, the amorphous form of the hydrochloride of the compound of formula (II) prepared in Example 1 is replaced with the crystalline form B of the compound of formula (I), the crystalline form C of the compound of formula (I), the crystalline form D of the compound of formula (I) or the crystalline form E of the compound of formula (I) to obtain the crystalline form A of the compound of formula (II).

[0247] Example 3: Preparation of Crystalline Form B of Compound (I)

[0248] Method 1: 100 mg of the amorphous hydrochloride of the compound of formula (II) prepared in Example 1 was dissolved in a mixed solution of acetone (0.5 mL) and water (0.1 mL) and stirred for 5 minutes. A mixed solution of acetone (0.6 mL) and ethyl acetate (0.9 mL) was added dropwise to the mixed solution. The reaction solution was stirred at room temperature for 12 hours. The precipitated solid was filtered, and the filter cake was dried to obtain the crystalline form B of the compound of formula (I). 1 H NMR(400MHz,DMSO-d6)δppm 13.36-13.07(m,1H),11.39-11.13(m,1H),10.22-9.95(m,1H),8.17-8.10(m,2H),8.03-7.96(m,1H),7.45-7.39(m,1H),6 .84-6.76(m,1H),6.48-6.43(m,1H),4.07-3.93(m,4H),3.89-3.83(m,3H),3.65-3.56(m,1H),3.43-3.37(m,2H),3.35(br s,2H),2.92-2.64(m,1H),2.49-2.30(m,3H),2.09-1.98(m,3H),1.13(t,J=6.8Hz,3H); LC-MS: m / z=449.3[M+H] + .

[0249] Method 2: Approximately 20 mg of the amorphous hydrochloride salt of the compound of formula (II) prepared in Example 1 was weighed and placed in a 20 mL glass vial. 1.0 mL of the corresponding solvent was added to completely dissolve the solid. The antisolvent was added dropwise to the clear solution with stirring until solid precipitated or the antisolvent volume reached 10 mL. The solution was centrifuged and the solid collected for XRPD analysis. The results are shown in Table 9.

[0250] Table 9 XRPD test results

[0251] HPLC / IC results showed that the crystalline form of compound B of formula (I) was a monohydrochloride salt. The XRPD spectrum is shown in FIG2 , the DSC spectrum is shown in FIG3 , and the TGA spectrum is shown in FIG4 .

[0252] Example 4: Preparation of Crystalline Form C of Compound of Formula (I)

[0253] Approximately 20 mg of crystalline Form B of Compound (I) was weighed, added to 0.5 mL of acetonitrile, and the mixture was suspended and stirred at room temperature for 3 days. The mixture was then centrifuged and the solid was collected to obtain crystalline Form C of Compound (I). HPLC / IC results showed that the sample was a monohydrochloride salt. The XRPD spectrum is shown in Figure 5 , the DSC spectrum is shown in Figure 6 , and the TGA spectrum is shown in Figure 7 .

[0254] Example 5: Preparation of Crystalline Form D of Compound of Formula (I)

[0255] Approximately 20 mg of crystalline Form B of Compound (I) was weighed, 0.5 mL of isopropanol was added, and the mixture was suspended and stirred at 50°C for 3 days. The mixture was centrifuged and the solid was collected to obtain crystalline Form D of Compound (I). HPLC / IC results showed that the sample was the monohydrochloride salt, and the XRPD spectrum is shown in Figure 8.

[0256] Example 6: Preparation of Hydrate Form E of the Compound of Formula (I)

[0257] Approximately 20 mg of Form B of Compound (I) was weighed, 0.5 mL of ethanol was added, and the mixture was suspended and stirred at room temperature for 3 days. The mixture was then stirred at 5°C for 1 day, then at -20°C for another day, and then allowed to evaporate slowly at room temperature. The solid was collected to obtain Form E of Compound (I). HPLC / IC results showed that the sample was a monohydrochloride salt, and the XRPD spectrum is shown in Figure 9.

[0258] Example 7: Single crystal X-ray diffraction analysis of the compound of formula (I)

[0259] The amorphous hydrochloride salt of the compound of formula (II) (10 mg) was dissolved in acetonitrile / methanol (0.6 mL, volume ratio 5:1). The sample solution was placed in a 4 mL semi-sealed sample vial and slowly evaporated at 4°C. The next day, colorless needle-shaped crystals were obtained, and the single crystal was Form F of the compound of formula (I). The crystals were collected and diffraction intensity data were collected using a Rigaku Oxford Diffraction XtaLAB Synergy four-circle diffractometer (HyPix-6000HE area detector). The single crystal data showed that the single crystal was the compound of formula (I), and the absolute configuration of the compound of formula (I) could be determined. The three-dimensional structure ellipsoid diagram of the single crystal of the compound of formula (I) is shown in Figure 10, and the XRPD simulation diagram is shown in Figure 11. The crystal structure data and parameters of the compound of formula (I) are shown in Tables 10 to 15, and the diffraction data of the XRPD simulation diagram is shown in Table 16.

[0260] Table 10 Single crystal structure data of compound of formula (I)

[0261] Table 11 Atomic coordinates of single crystal of compound of formula (I) (×10 4 ) and the equivalent isotropic shift parameter

[0262] Table 12 Bond lengths of single crystals of compound of formula (I)

[0263] Table 13 Bond angles of single crystals of compound of formula (I) (Angle / °)

[0264] Table 14 Twist angle of single crystal of compound of formula (I) (Angle / °)

[0265] Table 15 Hydrogen bonding of single crystal of compound of formula (I) Note 1: +X,1+Y,+Z; Note 2: +X,-1+Y,+Z.

[0266] Table 16 XRPD simulated diffraction data of single crystal of compound of formula (I)

[0267] Example 8: Solid Stability Test of Crystal Form B of Compound of Formula (I)

[0268] According to the "Guidelines for Stability Testing of APIs and Preparations" (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 9001), in order to evaluate the solid stability of the crystal form B of compound of formula (I), the stability of the crystal form B was investigated under the influencing factors (high temperature, high humidity and light), 40°C / 75%RH and 25°C / 60%RH conditions. The crystal form B was placed under high temperature (60°C, open) and high humidity (25°C / 92.5%RH, open) conditions for 30 days each, and the total illumination of visible light reached 1200000Lux·hrs and the total illumination of ultraviolet light reached 200W·hrs / m 2 The samples were then placed open to visible and UV light (a light-shielded control sample was placed simultaneously and wrapped in tin foil) at 40°C / 75% RH (open) for 1, 2, and 3 months, and at 25°C / 60% RH (open) for 3 months. XRPD analysis was performed on all stability samples to detect changes in their crystalline form.

[0269] Accurately weigh about 10 mg of the crystal form and place it in a dry and clean glass bottle, spread it into a thin layer, and place it open under the influencing factor test conditions and accelerated conditions. 2 ) conditions were placed in transparent glass bottles, completely exposed, and samples for XRPD detection were placed separately.

[0270] After the sample is taken out at the time point, the lid is covered, sealed with parafilm, and stored in a -20°C refrigerator. When preparing the sample, the sample is taken out of the refrigerator, returned to room temperature, and 25 mL of diluent (acetonitrile / water, 1:1, v / v) is added to dissolve the sample to obtain a solution with a concentration of approximately 0.5 mg / mL. The sample is analyzed by liquid chromatography, and the test results are compared with the initial test results on day 0 to test the chemical stability of the crystal form.

[0271] Conclusion: The crystal form B of compound of formula (I) is stable under all stability conditions (high temperature, high humidity, and light) and has good chemical stability.

[0272] Example 9: Hygroscopicity Study of Crystal Form B of Compound of Formula (I)

[0273] About 10 mg of the compound of formula (I) Form B was placed in a DVS sample tray for testing. The experimental results showed that the compound of formula (I) Form B was slightly hygroscopic at 25°C / 80% RH.

[0274] Biological test data

[0275] Experimental Example 1: Inhibition of Wieslab Complement Alternative Pathway Activation (Enzyme Activity Test)

[0276] Purpose of the experiment:

[0277] pass Complement System Alternative Pathway Kit is used to determine the inhibitory activity of test compounds against the complement alternative pathway in human serum. Experimental plan:

[0278] Dilute the serum with diluent (1:23). Add the drug to the diluted serum, with 8 concentration gradients, up to 10mM or 50mM, and 5-fold gradient dilution. Incubate at room temperature for 15 minutes. Add the compound and serum mixture to the 96-well plate provided by the kit (100μL / well) and activate at 37 degrees for 1 hour. Wash three times with wash buffer. Add the detection antibody provided by the kit (100μL) and incubate at room temperature for 30 minutes. Wash three times with wash buffer. Add the substrate (100μL) and incubate at room temperature for 30 minutes. Detect the absorbance at 405nM using an enzyme reader.

[0279] Experimental results:

[0280] The results of the inhibitory activity of the test compounds on the complement alternative pathway are shown in Table 17.

[0281] Table 17 Results of the inhibitory activity of the compounds of the present invention on the complement alternative pathway

[0282] Conclusion: The hydrochloride of the compound of formula (II) in Example 1 has significant inhibitory activity on the activation of the human serum bypass pathway.

[0283] Experimental Example 2: Complement Human Factor B Protein Binding Assay (TR-FRET Method)

[0284] Purpose of the experiment:

[0285] The TR-FRET method was used to determine the binding activity of test compounds to human complement factor B protein.

[0286] Experimental plan:

[0287] Drugs were added to phosphate-buffered saline (PBS) (pH 7.4) at a concentration of 10, starting at 10 μM and diluted fourfold to a total of 10 concentrations. Biotinylated Factor B (25 nM) was added to the sample in the absence or presence of varying concentrations of the test compound. Cy5-labeled probe (75 nM) and europium chelate-labeled streptavidin (Perkin Elmer #AD0060; 0.225 nM) were then incubated at room temperature for 2 hours. Time-resolved fluorescence energy transfer (TR-FRET) data were measured using an excitation wavelength of 330 nm and an emission wavelength of 665 nm.

[0288] Experimental results:

[0289] The binding activities of the test compounds to human complement Factor B protein are shown in Table 18.

[0290] Table 18 Test results of the compounds of the present invention binding to human complement Factor B protein

[0291] Conclusion: The hydrochloride of the compound of formula (II) in Example 1 has significant binding activity to human complement Factor B protein.

[0292] Experimental Example 3: Pharmacokinetic Study in Rats

[0293] Purpose of the experiment:

[0294] Male SD rats were used as test animals, and the drug concentrations in the plasma of the rats at different time points after oral gavage of the compound of the present invention were determined by LC / MS / MS to study the pharmacokinetic behavior of the compound of the present invention in rats and evaluate its pharmacokinetic characteristics.

[0295] Test plan:

[0296] Healthy male rats weighing 200-300 g were used, with 2 rats in each group.

[0297] The compound of the present invention was prepared into a suspension using an aqueous solution of 0.5% MC (4000 cP) / 0.5% Tween 80. Rats were fasted overnight and orally administered by gavage at doses of 10 mpk, 30 mpk, and 50 mpk. Blood was collected before administration and 0.25, 0.5, 1, 2, 4, 7, and 24 hours after administration, placed in heparinized anticoagulant tubes, centrifuged at 7000 rpm (5204 g) at 4°C, and plasma was separated and stored at -80°C. Food was consumed 4 hours after administration. The content of the test compound in the plasma of rats after oral administration was determined by LC / MS / MS. Plasma samples were pretreated with precipitated proteins and analyzed. Conclusion: Both the compound of the present invention and the crystals have good oral exposure and long half-life, and have excellent pharmacokinetic properties.

Claims

1. Crystallization of the compound of formula (II), It is characterized in that The crystal is a crystal form A, and the X-ray powder diffraction pattern of the crystal form A using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 7.15±0.20°, 9.28±0.20° and 14.31±0.20°; Alternatively, the X-ray powder diffraction pattern of the A crystal form using Cu Kα radiation has at least 3 or 4 characteristic diffraction peaks at the following 2θ angles: 7.15±0.20°, 9.28±0.20°, 14.31±0.20°, 19.52±0.20° and 21.77±0.20°.

2. A hydrochloride of a compound of formula (II) or a crystal thereof, Alternatively, a compound of formula (II-1) or a crystal thereof, in, m is selected from 0 to 2.5; n is selected from 0 to 2.5; Alternatively, a compound of formula (I) or a crystal thereof, 3. The crystal of the compound of formula (I) according to claim 2 is a B crystal form, characterized in that: The X-ray powder diffraction pattern of the B crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 6.16±0.20°, 8.96±0.20° and 10.53±0.20°; Alternatively, the X-ray powder diffraction pattern of the B crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 6.16±0.20°, 8.96±0.20°, 10.53±0.20°, 18.55±0.20° and 24.62±0.20°; Alternatively, the X-ray powder diffraction pattern of the B crystal form using Cu Kα radiation has at least 6 or 7 characteristic diffraction peaks at the following 2θ angles: 6.16±0.20°, 8.96±0.20°, 10.53±0.20°, 12.30±0.20°, 16.74±0.20°, 18.55±0.20°, 19.95±0.20° and 24.62±0.20°; Alternatively, the X-ray powder diffraction pattern of the B crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 6.16±0.20°, 8.96±0.20°, 10.53±0.20°, 12.30±0.20°, 16.74±0.20°, 18.55±0.20°, 19.95±0.20° and 24.62±0.20°; Alternatively, the X-ray powder diffraction pattern of the crystalline form B using Cu Kα radiation has at least 9, 10 or 11 characteristic diffraction peaks at the following 2θ angles: 6.16±0.20°, 8.96±0.20°, 10.53±0.20°, 12.30±0.20°, 16.74±0.20°, 17.39±0.20°, 18.55±0.20°, 19.49±0.20°, 19.95±0.20°, 22.17±0.20°, 22.75±0.20° and 24.62±0.20°; Alternatively, the X-ray powder diffraction pattern of the B crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 6.16±0.20°, 8.96±0.20°, 10.53±0.20°, 12.30±0.20°, 16.74±0.20°, 17.39±0.20°, 18.55±0.20°, 19.49±0.20°, 19.95±0.20°, 22.17±0.20°, 22.75±0.20° and 24.62±0.20°; Alternatively, the X-ray powder diffraction pattern of the crystalline form B using Cu Kα radiation has at least 11, 12, 13, 14 or 15 characteristic diffraction peaks at the following 2θ angles: 6.16±0.20°, 8.96±0.20°, 10.53±0.20°, 12.30±0.20°, 13.19±0.20°, 14.74±0.20°, 16.74±0.20°, 17.39±0.20°, 17.90±0.20°, 18.55±0.20°, 19.49±0.20°, 19.95±0.20°, 21.55±0.20°, 22.17±0.20°, 22.75±0.20° and 24.62±0.20°; Alternatively, the X-ray powder diffraction pattern of the B crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 6.16±0.20°, 8.96±0.20°, 10.53±0.20°, and / or 3.16±0.20°, and / or 10.79±0.20°, and / or 12.30±0.20°, and / or 13.19±0.20°, and / or 14.74±0.20°, and / or 16.74±0.20°, and / or 17.39±0.20°, and / or 17.90±0.20°, and / or or 18.55±0.20°, and / or 19.49±0.20°, and / or 19.95±0.20°, and / or 21.55±0.20°, and / or 22.17±0.20°, and / or 22.75±0.20°, and / or 24.62±0.20°, and / or 27.29±0.20°, and / or 28.05±0.20°, and / or 29.03±0.20°, and / or 32.55±0.20°, and / or 34.15±0.20° have characteristic diffraction peaks; Alternatively, the XRPD pattern of the B crystal form under Cu Kα radiation is shown in FIG2 .

4. The crystal of the compound of formula (I) according to claim 2 is crystal form C, characterized in that: The X-ray powder diffraction pattern of the C crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 7.72±0.20°, 15.31±0.20° and 19.53±0.20°; Alternatively, the X-ray powder diffraction pattern of the C crystal form with Cu Kα radiation has at least 6 or 7 characteristic diffraction peaks at the following 2θ angles: 7.72±0.20°, 14.67±0.20°, 15.31±0.20°, 16.66±0.20°, 18.76±0.20°, 19.53±0.20°, 22.67±0.20° and 24.28±0.20°.

5. The crystal of the compound of formula (I) according to claim 2 is D crystal form, characterized in that: The X-ray powder diffraction pattern of the D crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 5.93° and 11.82°.

6. The crystal of the compound of formula (I) according to claim 2 is E crystal form, characterized in that: The X-ray powder diffraction pattern of the E crystal form using Cu Kα radiation has at least three characteristic diffraction peaks at the following 2θ angles: 5.98±0.20°, 7.83±0.20°, 8.87±0.20° and 10.76±0.20°.

7. The crystal of the compound of formula (I) according to claim 2 is F crystal form, characterized in that: The X-ray powder diffraction pattern of the F crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 5.96±0.20°, 8.86±0.20°, 17.40±0.20°, 19.52±0.20° and 24.04±0.20°; Alternatively, the X-ray powder diffraction pattern of the F crystalline form using Cu Kα radiation has at least 6 or 7 characteristic diffraction peaks at the following 2θ angles: 5.96±0.20°, 8.86±0.20°, 10.82±0.20°, 13.32±0.20°, 17.40±0.20°, 19.52±0.20°, 24.04±0.20° and 24.74±0.20°; Alternatively, the X-ray powder diffraction pattern of the F crystalline form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 5.96±0.20°, 8.86±0.20°, 17.40±0.20°, 19.52±0.20°, 24.04±0.20°, and / or 10.66±0.20°, and / or 10.82±0.20°, and / or 11.06±0.20°, and / or 11.54±0.20°, and / or 11.94 ±0.20°, and / or 13.32±0.20°, and / or 14.86±0.20°, and / or 17.96±0.20°, and / or 18.72±0.20°, and / or 21.66±0.20°, and / or 23.68±0.20°, and / or 24.74±0.20°, and / or 26.56±0.20°, and / or 27.42±0.20° and / or 30.78±0.20°.

8. A crystalline composition comprising a compound of formula (II), a compound of formula (II-1) or a compound of formula (I) according to any one of claims 1 to 7, wherein: The crystals of the compound of formula (II), the compound of formula (II-1) or the compound of formula (I) according to any one of claims 1 to 7 account for more than 50% by weight of the crystalline composition, preferably more than 80%, more preferably more than 90%, and most preferably more than 95%.

9. A pharmaceutical composition comprising a therapeutically effective amount of a crystal of a compound of formula (II) according to any one of claims 1 to 7, a compound of formula (II-1) or a crystal thereof, a compound of formula (I) or a crystal thereof, or a therapeutically effective amount of a crystalline composition according to claim 8.

10. Use of a crystal of a compound of formula (II) according to any one of claims 1 to 7, a compound of formula (II-1) or a crystal thereof, a compound of formula (I) or a crystal thereof, a crystalline composition according to claim 8, or a pharmaceutical composition according to claim 9 in preventing or treating a disease associated with complement factor B, optionally wherein the disease associated with complement factor B is selected from an inflammatory disorder and an autoimmune disease.

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