Crystal form of fluoro-substituted isoindoline compound, preparation method therefor and use thereof

Abstract

Disclosed in the present invention are a crystal form of a fluoro-substituted isoindoline compound, a preparation method therefor and the use thereof. Specifically, disclosed in the present invention is a crystal form of a compound of formula (I), which is crystal form A, crystal form B, or crystal form C of the compound of formula (I). The crystal form of the compound of formula (I) provided in the present invention has high stability and wide pharmaceutical application prospects.

Description

Crystal form of fluorine-substituted isoindoline compound, preparation method and application thereof

[0001] This application claims priority to Chinese patent application 2024110413790 with the filing date of July 30, 2024. This application incorporates the entirety of the aforementioned Chinese patent application. TECHNICAL FIELD

[0002] The present application relates to a crystal form of a fluorine-substituted isoindoline compound, a preparation method of the crystal form, a composition comprising the crystal form and applications thereof. BACKGROUND

[0003] Tumor necrosis factor (TNF-a) is a pro-inflammatory cytokine, one of the main mediators of inflammation, and plays an important role in immune homeostasis, inflammation and host defense. TNF-a can also be produced by tumors and can play a role in promoting tumor formation and can also cause programmed death of tumor cells. Unregulated TNF-a activity or overproduction of TNF-a is associated with the pathology of a variety of diseases, including but not limited to cancer, for example, colon, rectal, prostate, breast, brain and intestinal cancer; and inflammatory diseases, particularly inflammation associated with cancer. Abnormal regulation of TNF-a can also cause autoimmune diseases, toxic shock syndrome, cachexia, arthritis, psoriasis, HIV infection and AIDS, nervous system diseases and central nervous system diseases, sepsis, congestive heart failure, transplant rejection, and viral infection. Therefore, reducing TNF-a levels, or modulating TNF-a activity is a very promising strategy for the treatment of many immunological, inflammatory and malignant diseases, such as cancer and inflammation.

[0004] Lenalidomide is a small molecule immunomodulator that has been shown to inhibit the secretion of TNF-a and other pro-inflammatory cytokines and increase the secretion of anti-inflammatory cytokines. Lenalidomide is approved for the treatment of multiple myeloma (2006), myelodysplastic syndrome (2005) and mantle cell lymphoma (2013). WO2016065980 discloses a class of lenalidomide derivatives, which specifically discloses a compound of formula (I), a preparation method thereof and applications thereof, but does not disclose specific crystal forms of the compound.

[0005] It is worth noting that it is not possible to predict in advance whether certain crystalline forms of a compound exist, let alone how to successfully make them, e.g., see Braga and Grepioni, 2005, "Making crystals from crystals: a green route to crystal engineering and polymorphism", Chem. Commun.: 3635-3645, which states that with respect to crystal engineering, the results can not be predictable if the instructions are not precise and / or if other external factors affect the process; Jones et al., 2006, Pharmaceutical Cocrystals: An Emerging Approach to Physical Property Enhancement", MRS Bulletin 31 : 875-879, which states that currently, it is not generally possible to predict by calculation the number of polymorphs that can be observed even for the simplest molecules; Price, 2004, "The computational prediction of pharmaceutical crystal structures and polymorphism", Advanced Drug Delivery Reviews 56: 301-319 ("Price"); and Bernstein, 2004, "Crystal Structure Prediction and Polymorphism", ACA Transactions 39: 14-23, which states that much work remains to be learned and done before one can have sufficient confidence in the ability to predict crystal structures, let alone polymorphism.

[0006] In addition, different solid forms of the same pharmaceutical compound can differ significantly in stability and bioavailability, among other things, and thus affect the efficacy of the drug. The identification and selection of solid forms of a pharmaceutical compound is complex because variations in solid forms can affect a variety of physical and chemical properties, which can result in benefits or drawbacks in processing, formulation, stability, bioavailability, storage, handling (e.g., shipping), and other important pharmaceutical characteristics.

[0007] Accordingly, it is of great importance and a pressing need in the drug development process to discover and obtain new solid forms of a compound that make it more amenable to drug processing and use in pharmaceutical compositions, and that provide more qualitative and quantitative information for the efficacy study of the solid drug. SUMMARY

[0008] The application provides a crystal form of a fluorine-substituted isoindoline compound, a preparation method and application thereof.

[0009] The application provides a solid form of a compound of formula (I), a method of making the solid form, compositions comprising the solid form, and uses thereof.

[0010] The compound of formula (I) has the chemical name (S)-3-(4-amino-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione-3-d.

[0011] In one embodiment, the solid form is a free base of the compound of formula (I). In one embodiment, the solid form is a solvate of a free base of the compound of formula (I). In one embodiment, the solid form is a hydrate of a free base of the compound of formula (I). In one embodiment, the solid form is an anhydrous form (anhydrate) of a free base of the compound of formula (I).

[0012] The application provides a crystal form A of a compound of formula (I) having an X-ray powder diffraction pattern, expressed in terms of 2 theta (2θ) angles using Cu-Kα radiation, with diffraction peaks at 7.95±0.2°, 11.71±0.2° and 17.66±0.2°;

[0013] In one embodiment, the crystal form A of the compound of formula (I) has an X-ray powder diffraction pattern, expressed in terms of 2 theta (2θ) angles using Cu-Kα radiation, with diffraction peaks at one or more of 17.21±0.2°, 18.11±0.2°, 18.58±0.2°, 19.25±0.2°, 20.97±0.2°, 24.09±0.2°, 24.43±0.2°, 25.41±0.2° and 26.96±0.2°.

[0014] In one embodiment, the crystal form A of the compound of formula (I) has an X-ray powder diffraction pattern, expressed in terms of 2 theta (2θ) angles using Cu-Kα radiation, with diffraction peaks at 7.95±0.2°, 11.71±0.2°, 17.21±0.2°, 17.66±0.2°, 24.43±0.2° and 26.96±0.2°.

[0015] In one embodiment, the crystalline Form A of the compound of formula (I) has an X- ray powder diffraction pattern, expressed in angles 2Q, using Cu-Ka radiation, with diffraction peaks at 7.95 ± 0.2°, 11.71 ± 0.2°, 17.21 ± 0.2°, 17.66 ± 0.2°, 18.11 ± 0.2°, 24.09 ± 0.2°, 24.43 ± 0.2°, 25.41 ± 0.2° and 26.96 ± 0.2°.

[0016] In one embodiment, the crystalline Form A of the compound of formula (I) has an X- ray powder diffraction pattern, expressed in angles 2Q, using Cu-Ka radiation, with diffraction peaks at 7.95 ± 0.2°, 11.71 ± 0.2°, 17.21 ± 0.2°, 17.66 ± 0.2°, 18.11 ± 0.2°, 18.58 ± 0.2°, 19.25 ± 0.2°, 20.97 ± 0.2°, 24.09 ± 0.2°, 24.43 ± 0.2°, 25.41 ± 0.2° and 26.96 ± 0.2°.

[0017] In one embodiment, the crystalline Form A of the compound of formula (I) has an X- ray powder diffraction pattern, expressed in angles 2Q, using Cu-Ka radiation, with diffraction peaks at 7.95 ± 0.2°, 9.44 ± 0.2°, 11.71 ± 0.2°, 14.72 ± 0.2°, 15.91 ± 0.2°, 17.21 ± 0.2°, 17.66 ± 0.2°, 18.11 ± 0.2°, 18.58 ± 0.2°, 19.25 ± 0.2°, 20.97 ± 0.2°, 22.31 ± 0.2°, 23.52 ± 0.2°, 24.09 ± 0.2°, 24.43 ± 0.2°, 25.41 ± 0.2°, 26.43 ± 0.2°, 26.96 ± 0.2°, 29.00 ± 0.2°, 29.36 ± 0.2°, 31.04 ± 0.2°, 31.47 ± 0.2°, 32.08 ± 0.2°, 32.91 ± 0.2°, 34.04 ± 0.2° and 35.02 ± 0.2°.

[0018] In one embodiment, the crystalline Form A of the compound of formula (I) has an X- ray powder diffraction pattern, expressed in angles 2Q, using Cu-Ka radiation, with diffraction peaks at 7.95 ± 0.2°, 11.71 ± 0.2° and 17.66 ± 0.2°; preferably, the intensity of at least two of the diffraction peaks at 7.95 ± 0.2°, 11.71 ± 0.2° and 17.66 ± 0.2° is more than 20%; more preferably, the intensity of at least two of the diffraction peaks at 7.95 ± 0.2°, 11.71 ± 0.2° and 17.66 ± 0.2° is more than 30%.

[0019] In one embodiment, the crystalline Form A of the compound of formula (I) has an X- ray powder diffraction pattern, expressed in angles 2Q, using Cu-Ka radiation, with diffraction peaks as shown in Table 1:

[0020] Table 1

[0021] In one embodiment, the crystalline Form A of the compound of formula (I) has an X- ray powder diffraction pattern substantially as shown in Figure 1 using Cu-Ka radiation.

[0022] In one embodiment, the crystalline Form A of the compound of formula (I) has an X- ray powder diffraction pattern, expressed in terms of 2 theta (2Q) angles, comprising 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more (e.g. 26) of the following diffraction peaks selected from the group consisting of: 7.95±0.2°, 9.44±0.2°, 11.71±0.2°, 14.72±0.2°, 15.91±0.2°, 17.21±0.2°, 17.66±0.2°, 18.11±0.2°, 18.58±0.2°, 19.25±0.2°, 20.97±0.2°, 22.31±0.2°, 23.52±0.2°, 24.09±0.2°, 24.43±0.2°, 25.41±0.2°, 26.43±0.2°, 26.96±0.2°, 29.00±0.2°, 29.36±0.2°, 31.04±0.2°, 31.47±0.2°, 32.08±0.2°, 32.91±0.2°, 34.04±0.2° and 35.02±0.2°.

[0023] In one embodiment, the crystalline Form A of the compound of formula (I) has an X- ray powder diffraction pattern, expressed in terms of 2 theta (2Q) angles, comprising 3 of the following diffraction peaks.

[0024] In one embodiment, the crystalline Form A of the compound of formula (I) has an X- ray powder diffraction pattern, expressed in terms of 2 theta (2Q) angles, comprising 6 of the following diffraction peaks.

[0025] In one embodiment, the crystalline Form A of the compound of formula (I) has an X- ray powder diffraction pattern, expressed in terms of 2 theta (2Q) angles, comprising 9 of the following diffraction peaks.

[0026] In one embodiment, the crystalline Form A of the compound of formula (I) has an X- ray powder diffraction pattern, expressed in terms of 2 theta (2Q) angles, comprising 12 of the following diffraction peaks.

[0027] In one embodiment, the crystalline Form A of the compound of formula (I) has an X- ray powder diffraction pattern, expressed in terms of 2 theta (2Q) angles, comprising 26 of the following diffraction peaks.

[0028] In one embodiment, the crystalline Form A of the compound of formula (I) has a differential scanning calorimetry (DSC) curve with an endothermic peak at a peak temperature of about 256.1 °C and 298.3 °C, and an exothermic peak at a peak temperature of about 257.8 °C.

[0029] In one embodiment, the crystalline Form A of the compound of formula (I) has a differential scanning calorimetry (DSC) curve substantially as shown in Figure 3.

[0030] In one embodiment, the crystalline Form A of the compound of formula (I) has a thermogravimetric analysis curve (TGA) with a weight loss of about 1.12% in the temperature range of about 20.2 °C to about 150 °C.

[0031] In one embodiment, the crystalline Form A of the compound of formula (I) has a thermogravimetric analysis curve (TGA) substantially as shown in Figure 2.

[0032] In one embodiment, the crystalline Form A of the compound of formula (I) is free of solvent, such as water.

[0033] In one embodiment, the crystalline Form A of the compound of formula (I) has a dynamic vapor sorption analysis (DVS) with a weight gain of 0.2% to 2% under 25 °C / 80% RH conditions, for example, a weight gain of about 0.97%.

[0034] In one embodiment, the crystalline Form A of the compound of formula (I) has a dynamic vapor sorption analysis (DVS) substantially as shown in Figure 4.

[0035] The present application provides a single crystal of a compound of formula (I) having the following unit cell parameters: orthorhombic, space group P 212121; α = 90°, β = 90°, γ = 90°, the number of asymmetric units in the unit cell Z = 4, and a crystal density of 1.537 mg / m 3 .

[0036] The present application provides a crystalline Form B of a compound of formula (I) having an X-ray powder diffraction pattern with Cu-Ka radiation, in terms of 2θ angles, having peaks at 5.78 ± 0.2°, 10.38 ± 0.2° and 19.46 ± 0.2°;

[0037] In one embodiment, the crystalline Form B of the compound of formula (I) has an X- ray powder diffraction pattern, using Cu-Ka radiation, expressed in angles of 2 theta, further having a diffraction peak at one or more of the following: 14.45+0.2°, 16.65+0.2°, 17.42+0.2°, 17.85+0.2°, 18.23+0.2°, 18.78+0.2°, 19.86+0.2°, 23.29+0.2°, 24.08+0.2°, 24.62+0.2°, 24.89+0.2°, 27.09+0.2°, and 36.34+0.2°.

[0038] In one embodiment, the crystalline Form B of the compound of formula (I) has an X- ray powder diffraction pattern, using Cu-Ka radiation, expressed in angles of 2 theta, having a diffraction peak at 5.78+0.2°, 10.38+0.2°, 16.65+0.2°, 19.46+0.2°, 19.86+0.2°, and 24.89+0.2°.

[0039] In one embodiment, the crystalline Form B of the compound of formula (I) has an X- ray powder diffraction pattern, using Cu-Ka radiation, expressed in angles of 2 theta, having a diffraction peak at 5.78+0.2°, 10.38+0.2°, 16.65+0.2°, 18.23+0.2°, 19.46+0.2°, 19.86+0.2°, 24.08+0.2°, 24.89+0.2°, and 27.09+0.2°.

[0040] In one embodiment, the crystalline Form B of the compound of formula (I) has an X- ray powder diffraction pattern, using Cu-Ka radiation, expressed in angles of 2 theta, having a diffraction peak at 5.78+0.2°, 10.38+0.2°, 14.45+0.2°, 16.65+0.2°, 17.42+0.2°, 17.85+0.2°, 18.23+0.2°, 18.78+0.2°, 19.46+0.2°, 19.86+0.2°, 23.29+0.2°, 24.08+0.2°, 24.62+0.2°, 24.89+0.2°, 27.09+0.2°, and 36.34+0.2°.

[0041] In one embodiment, Form B of the compound of formula (I) has an X-ray powder diffraction pattern, using Cu-Ka radiation, expressed in angles of 2 theta, with diffraction peaks at 5.78 ± 0.2°, 10.38 ± 0.2°, 14.45 ± 0.2°, 16.65 ± 0.2°, 17.42 ± 0.2°, 17.85 ± 0.2°, 18.23 ± 0.2°, 18.78 ± 0.2°, 19.46 ± 0.2°, 19.86 ± 0.2°, 20.83 ± 0.2°, 21.76 ± 0.2°, 22.47 ± 0.2°, 23.29 ± 0.2°, 23.70 ± 0.2°, 24.08 ± 0.2°, 24.62 ± 0.2°, 24.89 ± 0.2°, 27.09 ± 0.2°, 28.60 ± 0.2°, 34.41 ± 0.2°, 35.25 ± 0.2°, and 36.34 ± 0.2°.

[0042] In one embodiment, Form B of the compound of formula (I) has an X-ray powder diffraction pattern, using Cu-Ka radiation, expressed in angles of 2 theta, with the following diffraction peaks as shown in Table 2:

[0043] Table 2

[0044] In one embodiment, Form B of the compound of formula (I) has an X-ray powder diffraction pattern, using Cu-Ka radiation, substantially as shown in Figure 9.

[0045] In one embodiment, Form B of the compound of formula (I) has an X-ray powder diffraction pattern, using Cu-Ka radiation, expressed in angles of 2 theta, with a diffraction pattern comprising 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or more (e.g., 23) of the following peaks expressed in degrees of 2 theta: 5.78 ± 0.2°, 10.38 ± 0.2°, 14.45 ± 0.2°, 16.64 ± 0.2°, 17.42 ± 0.2°, 17.85 ± 0.2°, 18.23 ± 0.2°, 18.78 ± 0.2°, 19.46 ± 0.2°, 19.86 ± 0.2°, 20.83 ± 0.2°, 21.76 ± 0.2°, 22.46 ± 0.2°, 23.29 ± 0.2°, 23.70 ± 0.2°, 24.08 ± 0.2°, 24.62 ± 0.2°, 24.89 ± 0.2°, 27.09 ± 0.2°, 28.60 ± 0.2°, 34.41 ± 0.2°, 35.25 ± 0.2°, 36.34 ± 0.2°.

[0046] In one embodiment, Form B of the compound of formula (I) has an X-ray powder diffraction pattern, using Cu-Ka radiation, expressed in angles of 2 theta, with a diffraction pattern comprising 3 of the following peaks expressed in degrees of 2 theta: 5.78 ± 0.2°, 10.38 ± 0.2°, 14.45 ± 0.2°, 16.64 ± 0.2°, 17.42 ± 0.2°, 17.85 ± 0.2°, 18.23 ± 0.2°, 18.78 ± 0.2°, 19.46 ± 0.2°, 19.86 ± 0.2°, 20.83 ± 0.2°, 21.76 ± 0.2°, 22.46 ± 0.2°, 23.29 ± 0.2°, 23.70 ± 0.2°, 24.08 ± 0.2°, 24.62 ± 0.2°, 24.89 ± 0.2°, 27.09 ± 0.2°, 28.60 ± 0.2°, 34.41 ± 0.2°, 35.25 ± 0.2°, 36.34 ± 0.2°.

[0047] In one embodiment, the crystalline Form B of the compound of formula (I) has an X- ray powder diffraction pattern, expressed in terms of 2 theta (θ) angles using Cu-Ka radiation, comprising 6 of said peaks.

[0048] In one embodiment, the crystalline Form B of the compound of formula (I) has an X- ray powder diffraction pattern, expressed in terms of 2 theta (θ) angles using Cu-Ka radiation, comprising 9 of said peaks.

[0049] In one embodiment, the crystalline Form B of the compound of formula (I) has an X- ray powder diffraction pattern, expressed in terms of 2 theta (θ) angles using Cu-Ka radiation, comprising 16 of said peaks.

[0050] In one embodiment, the crystalline Form B of the compound of formula (I) has an X- ray powder diffraction pattern, expressed in terms of 2 theta (θ) angles using Cu-Ka radiation, comprising 23 of said peaks.

[0051] In one embodiment, the differential scanning calorimetry (DSC) curve of the crystalline Form B of the compound of formula (I) has an endothermic peak with an onset at about 126.0 °C, and / or the differential scanning calorimetry (DSC) curve of the crystalline Form B of the compound of formula (I) has endothermic peaks with peak temperatures at about 127.7 °C and 272.7 °C.

[0052] In one embodiment, the differential scanning calorimetry (DSC) curve of the crystalline Form B of the compound of formula (I) is substantially as shown in Figure 10.

[0053] In one embodiment, the thermogravimetric analysis curve (TGA) of the crystalline Form B of the compound of formula (I) has a weight loss of about 9.72% in the temperature range of about 18.9 °C to about 100 °C, and a weight loss of about 16.74% in the temperature range of about 100 °C to about 130 °C.

[0054] In one embodiment, the thermogravimetric analysis curve (TGA) of the crystalline Form B of the compound of formula (I) is substantially as shown in Figure 10.

[0055] In one embodiment, the crystalline Form B of the compound of formula (I) contains a solvent, for example DMSO, for example the crystalline Form B of the compound of formula (I) is a crystalline form of the DMSO solvate of the compound of formula (I) wherein the molar ratio of the compound of formula (I) to DMSO is preferably 1 : (0.01-1.5), more preferably 1 : (0.5-1.5), for example 1 : 0.07, 1 : 0.3, 1 : 0.67, 1 : 0.7, 1 : 0.9 or 1 : 1.

[0056] In one embodiment, the nuclear magnetic resonance hydrogen spectrum (1H-NMR) of the crystalline Form B of the compound of formula (I) is substantially as shown in Figure 11. 1 H-NMR).

[0057] The present application provides a crystalline form C of a compound of formula (I) having an X-ray powder diffraction pattern expressed in terms of 2 theta angle using Cu-Ka radiation with diffraction peaks at 7.93±0.2°, 8.54±0.2° and 9.38±0.2°;

[0058] In one embodiment, the crystalline form C of the compound of formula (I) has an X-ray powder diffraction pattern expressed in terms of 2 theta angle using Cu-Ka radiation with diffraction peaks at one or more of: 14.29±0.2°, 15.05±0.2°, 15.90±0.2°, 17.13±0.2°, 18.50±0.2°, 20.13±0.2°, 23.94±0.2°, 26.91±0.2° and 37.31±0.2°.

[0059] In one embodiment, the crystalline form C of the compound of formula (I) has an X-ray powder diffraction pattern expressed in terms of 2 theta angle using Cu-Ka radiation with diffraction peaks at 7.93±0.2°, 8.54±0.2°, 9.38±0.2°, 14.29±0.2°, 20.13±0.2° and 23.94±0.2°.

[0060] In one embodiment, the crystalline form C of the compound of formula (I) has an X-ray powder diffraction pattern expressed in terms of 2 theta angle using Cu-Ka radiation with diffraction peaks at 7.93±0.2°, 8.54±0.2°, 9.38±0.2°, 14.29±0.2°, 15.90±0.2°, 17.13±0.2°, 18.50±0.2°, 20.13±0.2° and 23.94±0.2°.

[0061] In one embodiment, the crystalline form C of the compound of formula (I) has an X-ray powder diffraction pattern expressed in terms of 2 theta angle using Cu-Ka radiation with diffraction peaks at 7.93±0.2°, 8.54±0.2°, 9.38±0.2°, 14.29±0.2°, 15.05±0.2°, 15.90±0.2°, 17.13±0.2°, 18.50±0.2°, 20.13±0.2°, 23.94±0.2°, 26.91±0.2° and 37.31±0.2°.

[0062] In one embodiment, the crystalline Form C of the compound of formula (I) has an X- ray powder diffraction pattern, using Cu-Ka radiation, expressed in terms of 2 theta (2Q) angles, with diffraction peaks at 7.93 ± 0.2°, 8.54 ± 0.2°, 9.38 ± 0.2°, 14.29 ± 0.2°, 15.05 ± 0.2°, 15.90 ± 0.2°, 17.13 ± 0.2°, 17.64 ± 0.2°, 18.07 ± 0.2°, 18.50 ± 0.2°, 19.20 ± 0.2°, 20.13 ± 0.2°, 22.03 ± 0.2°, 23.94 ± 0.2°, 24.36 ± 0.2°, 25.34 ± 0.2°, 26.91 ± 0.2°, 29.33 ± 0.2°, 32.09 ± 0.2°, 33.29 ± 0.2°, and 37.31 ± 0.2°.

[0063] In one embodiment, the crystalline Form C of the compound of formula (I) has an X- ray powder diffraction pattern, using Cu-Ka radiation, expressed in terms of 2 theta (2Q) angles, with diffraction peaks as shown in Table 3:

[0064] Table 3

[0065] In one embodiment, the crystalline Form C of the compound of formula (I) has an X- ray powder diffraction pattern, using Cu-Ka radiation, expressed in terms of 2 theta (2Q) angles, with diffraction peaks as shown in Table 3:

[0066] In one embodiment, the crystalline Form C of the compound of formula (I) has an X- ray powder diffraction pattern, using Cu-Ka radiation, expressed in terms of 2 theta (2Q) angles, with diffraction peaks as shown in Table 3:

[0067] In one embodiment, the crystalline Form C of the compound of formula (I) has an X- ray powder diffraction pattern, using Cu-Ka radiation, expressed in terms of 2 theta (2Q) angles, with diffraction peaks as shown in Table 3:

[0068] In one embodiment, the crystalline Form C of the compound of formula (I) has an X- ray powder diffraction pattern, expressed in angles 2Q, using Cu-Ka radiation, comprising at least 6 of said peaks.

[0069] In one embodiment, the crystalline Form C of the compound of formula (I) has an X- ray powder diffraction pattern, expressed in angles 2Q, using Cu-Ka radiation, comprising at least 9 of said peaks.

[0070] In one embodiment, the crystalline Form C of the compound of formula (I) has an X- ray powder diffraction pattern, expressed in angles 2Q, using Cu-Ka radiation, comprising at least 12 of said peaks.

[0071] In one embodiment, the crystalline Form C of the compound of formula (I) has an X- ray powder diffraction pattern, expressed in angles 2Q, using Cu-Ka radiation, comprising at least 21 of said peaks.

[0072] In one embodiment, the differential scanning calorimetry (DSC) curve of the crystalline Form C of the compound of formula (I) has an endothermic peak at a peak temperature of about 87.2 °C and 258.4 °C, and an exothermic peak at a peak temperature of about 263.4 °C;

[0073] Preferably, the differential scanning calorimetry (DSC) curve of the crystalline Form C of the compound of formula (I) has an endothermic peak at a peak temperature of about 87.2 °C.

[0074] In one embodiment, the differential scanning calorimetry (DSC) curve of the crystalline Form C of the compound of formula (I) is substantially as shown in Figure 17.

[0075] In one embodiment, the thermogravimetric analysis curve (TGA) of the crystalline Form C of the compound of formula (I) has a weight loss of about 5.30% in the temperature range of about 17.1 °C to about 150 °C.

[0076] In one embodiment, the thermogravimetric analysis curve (TGA) of the crystalline Form C of the compound of formula (I) is substantially as shown in Figure 16.

[0077] In one embodiment, the crystalline Form C of the compound of formula (I) contains a solvent, for example water, for example the crystalline Form C of the compound of formula (I) is a crystalline form of a hydrate of the compound of formula (I), wherein the molar ratio of the compound of formula (I) to water is preferably 1 : (0.01-1.5), more preferably 1 : (0.5-1.2), for example 1 :0.3, 1 :0.5, 1 :0.6, 1 :0.63, 1 :0.7, 1 :0.8, 1 :0.86, 1 :0.9 or 1 :1.

[0078] In one embodiment, the crystalline Form C of the compound of formula (I) has a nuclear magnetic resonance hydrogen spectrum (1H NMR) substantially as shown in Figure 18. 1H-NMR) substantially as shown in FIG. 18.

[0079] In one embodiment, the crystalline Form C of the compound of formula (I) has a dynamic vapor sorption analysis (DVS) of a weight gain of 2% to 15% under 25°C / 80%RH conditions, for example, a weight gain of about 3.81%.

[0080] In one embodiment, the crystalline Form C of the compound of formula (I) has a dynamic vapor sorption analysis (DVS) of a weight loss of about 3.32% under desorption curve with humidity less than 30%RH.

[0081] In one embodiment, the dynamic vapor sorption analysis (DVS) of the crystalline Form C of the compound of formula (I) is substantially as shown in FIG. 19.

[0082] The present application provides a pharmaceutical composition comprising the crystalline Form A, the crystalline Form B and / or the crystalline Form C of the compound of formula (I) of the present application, and one or more pharmaceutically acceptable excipients. In the above pharmaceutical composition, the crystalline Form A, the crystalline Form B and / or the crystalline Form C of the compound of formula (I) of the present application is included as an effective ingredient.

[0083] The present application provides use of the crystalline Form A, the crystalline Form B, the crystalline Form C of the compound of formula (I) and / or the above pharmaceutical composition in the preparation of a medicament for preventing or treating a disease, disorder or condition associated with TNF-α production or abnormal modulation of TNF-α activity.

[0084] The present application also provides a method for preventing or treating a disease, disorder or condition associated with TNF-α production or abnormal modulation of TNF-α activity, the method comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of the crystalline Form A, the crystalline Form B, the crystalline Form C of the compound of formula (I) and / or the above pharmaceutical composition.

[0085] Preferably, the disease, disorder or condition is cancer. More preferably, the disease, disorder or condition is selected from myelodysplastic syndrome, multiple myeloma, mantle cell lymphoma, non-Hodgkin's lymphoma, papillary and follicular thyroid cancer, breast cancer, prostate cancer, chronic lymphocytic leukemia, amyloidosis, complex regional pain syndrome type I, malignant melanoma, radiculopathy, myelofibrosis, glioblastoma, gliosarcoma, malignant glioma, refractory plasmacytomas, chronic myelomonocytic leukemia, follicular lymphoma, ciliary and chronic melanoma, iris melanoma, recurrent binocular melanoma, extraocular extension melanoma, solid tumors, T-cell lymphoma, erythroid lymphoma, monoblastic and monocytic leukemia, myeloid leukemia, central nervous system lymphoma, brain tumor, meningioma, spinal cord tumor, thyroid cancer, non-small cell lung cancer, ovarian cancer, skin cancer, renal cell carcinoma, bone marrow fibrosis, Burkitt's lymphoma, Hodgkin's lymphoma, large cell lymphoma, diffuse large B-cell lymphoma, astrocytoma, hepatocellular carcinoma or primary macroglobulinemia. Most preferably, the disease, disorder or condition is selected from prostate cancer or myelodysplastic syndrome.

[0086] The present application also provides a method for preparing the crystalline Form A of the compound of formula (I) above, said method being an anti-solvent addition method.

[0087] In one embodiment, the anti-solvent addition method comprises the step of adding a solvent B to a mixture of the compound of formula (I) and a solvent A, to obtain the crystalline Form A of the compound of formula (I).

[0088] In one embodiment, in the method for preparing the crystalline Form A of the compound of formula (I), the compound of formula (I) is amorphous of the compound of formula (I).

[0089] In one embodiment, in the method for preparing the crystalline Form A of the compound of formula (I), the solvent A is selected from one or more of N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide and N-methylpyrrolidone.

[0090] In one embodiment, in the method for preparing the crystalline Form A of the compound of formula (I), the solvent B is selected from one or more of 2-methyltetrahydrofuran, ethanol, methyl isobutyl ketone, isopropyl acetate, isopropyl alcohol, tetrahydrofuran, acetone, acetonitrile, water and dichloromethane.

[0091] Preferably, when the solvent A is N,N-dimethylacetamide, the solvent B is selected from one or more of ethanol, methyl isobutyl ketone and isopropyl acetate. Preferably, when the solvent A is N,N-dimethylformamide, the solvent B is selected from one or more of methyl isobutyl ketone, isopropyl acetate, acetone and water. Preferably, when the solvent A is dimethyl sulfoxide, the solvent B is selected from one or more of 2-methyltetrahydrofuran, isopropyl alcohol, tetrahydrofuran, acetone, acetonitrile and water. Preferably, when the solvent A is N-methyl pyrrolidone, the solvent B is water and / or dichloromethane. For example, the solvent A is dimethyl sulfoxide and the solvent B is water or 2-methyltetrahydrofuran.

[0092] In one embodiment, in the preparation method of the crystalline form A of the compound of formula (I), the volume ratio of the solvent A and the solvent B is a conventional volume ratio in the art, for example, 1:(1-20), for example, 1:10, 1:5 or 1:4.

[0093] In one embodiment, the preparation method of the crystalline form A of the compound of formula (I) comprises the following steps:

[0094] The compound of formula (I) is mixed and dissolved with the solvent A at 10-40°C to obtain a mixture of the compound of formula (I) and the solvent A, the solvent B is added, and the crystallization is performed at -20°C to room temperature (for example, 5-10°C) (for example, the crystallization is stirring) to obtain the crystalline form A of the compound of formula (I).

[0095] In one embodiment, in the preparation method of the crystalline form A of the compound of formula (I), the amount of the solvent A is a conventional amount in the art, for example, the amount of the solvent A is such that the compound of formula (I) is dissolved (completely dissolved).

[0096] In one embodiment, the crystalline form A of the compound of formula (I) is prepared by the anti-solvent addition method, and the method comprises the following steps: the compound of formula (I) is mixed and dissolved with DMSO at 10-40°C, water is added, and the crystallization is performed at room temperature (for example, 5-10°C) (for example, the crystallization is stirring when the water is added), and then separated to obtain the crystalline form A of the compound of formula (I).

[0097] In one embodiment, the crystalline form A of the compound of formula (I) is prepared by the anti-solvent addition method, and the method comprises the following steps: the compound of formula (I) is mixed and dissolved with DMSO at 10-40°C, 5 times the volume (i.e., the volume ratio of 2-methyltetrahydrofuran to DMSO is 5) of 2-methyltetrahydrofuran is added, and the crystallization is performed at -5°C to 10°C (for example, the crystallization is stirring when the 2-methyltetrahydrofuran is added), and then separated to obtain the crystalline form A of the compound of formula (I).

[0098] The present application also provides a preparation method of the single crystal of the compound of formula (I), which comprises the following step: drying (e.g. volatilizing) the mixture (e.g. mixed solution) of the crystal form A of the compound of formula (I) and the "mixed solution of acetone and water in a volume ratio of 10:1" to obtain the single crystal of the compound of formula (I).

[0099] The present application also provides a preparation method of the crystal form B of the compound of formula (I), which is an anti-solvent addition method.

[0100] In one embodiment, the anti-solvent addition method comprises the following step: adding solvent D to the mixture of the compound of formula (I) and solvent C to obtain the crystal form B of the compound of formula (I).

[0101] In one embodiment, in the preparation method of the crystal form B of the compound of formula (I), the solvent C is dimethyl sulfoxide.

[0102] In one embodiment, in the preparation method of the crystal form B of the compound of formula (I), the solvent D is ethyl acetate or toluene.

[0103] Preferably, when the solvent C is dimethyl sulfoxide, the solvent D is toluene.

[0104] In one embodiment, in the preparation method of the crystal form B of the compound of formula (I), the volume ratio of the solvent C and solvent D is a conventional volume ratio in the art, for example 1:(5-20), preferably 1:(8-15), and for example 1:10 or 1:12.

[0105] In one embodiment, the crystal form B of the compound of formula (I) is prepared by the anti-solvent addition method, which comprises the following steps: mixing and dissolving the compound of formula (I) with solvent C at 10-40°C to obtain a mixture of the compound of formula (I) and solvent C, adding solvent D, and separating the crystal form B of the compound of formula (I) by crystallization (e.g. stirring crystallization or vacuum drying crystallization) at -20°C-5°C.

[0106] In one embodiment, in the preparation method of the crystal form B of the compound of formula (I), the compound of formula (I) is in the form of amorphous solid of the compound of formula (I).

[0107] In one embodiment, in the preparation method of the crystal form B of the compound of formula (I), the amount of the solvent C is a conventional amount in the art, for example the amount of the solvent C is such that the compound of formula (I) is dissolved (completely dissolved).

[0108] In one embodiment, the crystalline Form B of the compound of Formula (I) is prepared by an anti-solvent addition method, which comprises the following steps: dissolving the compound of Formula (I) in DMSO at 10-40 °C, adding 5-20 times (i.e. the volume ratio of toluene to DMSO is 5-20) volume of toluene, crystallizing at 0-5 °C (e.g. crystallizing under stirring), and isolating to obtain the crystalline Form B of the compound of Formula (I).

[0109] The present application also provides a preparation method of the crystalline Form C of the compound of Formula (I), which is a stirring-suspension recrystallization method.

[0110] In one embodiment, the stirring-suspension recrystallization method comprises the following steps: crystallizing the mixture of the compound of Formula (I) and water to obtain the crystalline Form C of the compound of Formula (I).

[0111] In one embodiment, in the preparation method of the crystalline Form C of the compound of Formula (I), the compound of Formula (I) is in the form of amorphous solid of the compound of Formula (I).

[0112] In one embodiment, the crystallization is stirring (e.g. stirring-suspension).

[0113] Terminology:

[0114] As used herein and unless otherwise indicated, the terms "crystalline" and related terms used herein, when used to describe a substance, modification, material, component, or product, mean that the substance, modification, material, component, or product is substantially crystalline as determined by X-ray diffraction. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed., Lippincott, Williams and Wilkins, Baltimore, MD (2005); The United States Pharmacopeia, 23rd ed., 1843-1844 (1995).

[0115] As used herein and unless otherwise indicated, the term "solvate" refers to a crystalline form of a substance that contains solvent in the crystal structure. The term "hydrate" refers to a solvate in which the solvent is water.

[0116] Techniques for characterizing crystalline forms include, but are not limited to, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), single crystal X-ray diffraction, vibrational spectroscopies such as infrared (IR) and Raman spectroscopy, solid and solution nuclear magnetic resonance (NMR) spectroscopy, optical microscopy, hot-stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility measurements, dissolution measurements, elemental analysis, and Karl Fischer analysis. One or more of the following techniques can be employed to determine characteristic unit cell parameters, such as, but not limited to, X-ray diffraction and neutron diffraction, including single crystal diffraction and powder diffraction. Techniques that can be used to analyze powder diffraction data include profile refinement, such as Rietveld refinement, which can be used to analyze diffraction peaks associated with, for example, a single phase in a sample that includes more than one solid phase. Other methods that can be used to analyze powder diffraction data include unit cell indexing, which can be used by one skilled in the art to determine unit cell parameters from a sample comprising crystalline powder.

[0117] As used herein and unless otherwise indicated, the terms "about" and "approximately," when used in connection with a numerical value or a range of values below to characterize a particular solid form, indicate that the value or range of values can vary to a degree a person skilled in the art would consider reasonable (e.g., taking into account error) while still describing the particular solid form: for example, a specific temperature or range of temperatures to describe a melting, dehydration, desolvation, or glass transition temperature; a change in mass, for example, as a function of temperature or humidity; a solvent content or water content in units of, for example, mass or percentage; or a peak position in, for example, analysis by IR or Raman spectroscopy or XRPD. For example, in particular embodiments, the terms "about" and "approximately," when used in this context, indicate that the numerical value or range of values can vary within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the stated value or range of values. The tilde symbol (i.e., "~") used before a numerical value or range of values herein indicates "about" or "approximately."

[0118] It should be noted that in X-ray powder diffraction patterns, the position of the diffraction peaks or the relative intensities of the diffraction peaks can vary depending on the measuring instrument, the measuring method / conditions, and the like. For any particular crystalline form, there can be an error in the position of the peaks, for example, ±0.2° in the 2-theta value. Therefore, in determining each crystalline form, this error should be taken into account, and within the error, it is also within the scope of the present application.

[0119] It should be noted that the position of thermal events (e.g., endothermic peaks, exothermic peaks, etc.) can vary for the same crystalline form due to factors such as the instrument of measurement, the method / conditions of measurement, etc. For any particular crystalline form, the position of an endothermic peak can be in error by ± 10 °C, by ± 8 °C, by ± 5 °C, by ± 3 °C, or by ± 2 °C. Thus, in determining each crystalline form, this error should be taken into account, and within the error, it is also within the scope of the present application.

[0120] It should be noted that the position of weight loss temperatures can vary for the same crystalline form due to factors such as the instrument of measurement, the method / conditions of measurement, etc. For any particular crystalline form, the position of a weight loss temperature can be in error by ± 10 °C, by ± 8 °C, by ± 5 °C, by ± 3 °C, or by ± 2 °C. Thus, in determining each crystalline form, this error should be taken into account, and within the error, it is also within the scope of the present application.

[0121] As used herein, when referring to a "pharmaceutically acceptable" salt, composition, or excipient, etc., means that the salt, composition, or excipient, etc. is generally non-toxic, safe, and suitable for use with a subject, preferably a mammalian subject, more preferably a human subject.

[0122] As used herein and unless otherwise indicated, the term "excipient" refers to those excipients that are employed in the pharmaceutical arts. Excipients are used primarily to provide a safe, stable, and functional pharmaceutical composition, and can also provide a means to allow the active ingredient to be released at a desired rate after administration to a subject, or to facilitate the active ingredient being effectively absorbed after administration of the composition to a subject. An excipient can be an inert filler, or provide some function, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredient of the composition.

[0123] As used herein, the term "subject" refers to any animal that is or will be the recipient of the compound or composition. Mammals are preferred, with humans being most preferred. As used herein, the term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, and the like, with humans being most preferred. The terms "subject" and "patient" are used interchangeably herein.

[0124] In one embodiment, "treatment" refers to the improvement, prevention or reversal of a disease or disorder or at least one discernible symptom thereof, e.g., by reducing or stabilizing symptoms of a cancer or disorder, treating a cancer. In another embodiment, "treatment" refers to the improvement, prevention or reversal of at least one measurable physical parameter of a disease or disorder being treated, which can not be discernible by the subject. In yet another embodiment, "treatment" refers to the slowing of progression of a disease or disorder, or the stabilization of physical, e.g., discernible symptoms, or physiological, e.g., measurable parameters, or both. In another embodiment, "treatment" refers to the delay of the onset of a disease or disorder.

[0125] In certain embodiments, the compounds of interest are administered as a prophylactic measure. As used herein, "prevention" refers to reducing the risk of acquiring a given disease or disorder. In a preferred mode of the embodiments, the specified compound is administered to a subject as a prophylactic measure, e.g., a subject with a family history or predisposition to a cancer or autoimmune disease.

[0126] As used herein, the term "therapeutically effective amount" refers to the amount of a compound or composition that elicits the biological or medical response that is being sought in a tissue system, animal or human, which can include alleviation of the symptoms of the disease or disorder being treated. In a preferred embodiment, a therapeutically effective amount is an amount that is effective to treat, ameliorate the treatment of, or prevent disorders, diseases and conditions associated with TNF-α production or dysregulation.

[0127] As used herein, the term "prophylactically effective amount" refers to the amount of an active compound or pharmaceutical agent that is effective in inhibiting the onset of a disorder in a subject that is being sought by a researcher, veterinarian, medical doctor or other clinician. A prophylactically effective amount of a compound refers to the amount of a therapeutic agent that, when used alone or in conjunction with other therapeutically active compounds, provides a therapeutic benefit in the treatment or prevention of a disease, disorder or condition.

[0128] As used herein, the term "room temperature" refers to 5°C to 28°C, unless otherwise specified.

[0129] As used herein, the term "stirring" refers to the use of conventional methods of agitation in the art, e.g., magnetic or mechanical stirring, at a speed of 50 to 1800 rpm, wherein magnetic stirring is at a speed of 200 to 1500 rpm, preferably 300 to 1000 rpm, and mechanical stirring is at a speed of 100 to 300 rpm.

[0130] The terms "a," "an," and "the" as used herein mean one or more, unless otherwise specified.

[0131] The above-mentioned preferred conditions described in the specification of the present application can be combined arbitrarily, i.e. to obtain the preferred embodiments of the present application, without violating the common knowledge in the art. The upper limit value and the lower limit value of the numerical range described in the specification of the present application can be combined arbitrarily.

[0132] The reagents used in the present application are commercially available.

[0133] The positive progress effect of the present application is that, compared with the prior art, the crystal form A, the crystal form B and the crystal form C of the compound of formula (I) provided by the present application have advantages in at least one or more of solubility, melting point, stability, dissolution, hygroscopicity, and processing performance, purification effect, preparation of preparations, safety, etc., which provides a new and better choice for the preparation of pharmaceutical preparations containing the compound of formula (I), and has very important significance for drug development. BRIEF DESCRIPTION OF DRAWINGS

[0134] Figure 1 is an XRPD spectrum of the crystal form A of the compound of formula (I).

[0135] Figure 2 is a TGA spectrum of the crystal form A of the compound of formula (I).

[0136] Figure 3 is a DSC spectrum of the crystal form A of the compound of formula (I).

[0137] Figure 4 is a DVS curve of the crystal form A of the compound of formula (I).

[0138] Figure 5 is a polarizing microscope (PLM) spectrum of the crystal form A of the compound of formula (I).

[0139] Figure 6 is an XRPD superimposition of the crystal form A of the compound of formula (I) before and after DVS test.

[0140] Figure 7 is a single crystal structure diagram of the compound of formula (I).

[0141] Figure 8 is a superimposition of the single crystal fitted XRPD and the actually measured XRPD of the single crystal sample of the compound of formula (I).

[0142] Figure 9 is an XRPD spectrum of the crystal form B of the compound of formula (I).

[0143] Figure 10 is a TGA / DSC superimposition of the crystal form B of the compound of formula (I).

[0144] Figure 11 is a 1 H NMR spectrum of the crystal form B of the compound of formula (I).

[0145] Figure 12 is an XRPD superimposition of the crystal form B of the compound of formula (I) before and after heating of the sample.

[0146] Figure 13 is a 1H NMR spectrum.

[0147] Figure 14 is a TGA pattern of the crystal form B of the compound of formula (I) after heating the sample to 130°C. 1 H NMR spectrum.

[0148] Figure 15 is an XRPD pattern of the crystal form C of the compound of formula (I).

[0149] Figure 16 is a TGA pattern of the crystal form C of the compound of formula (I).

[0150] Figure 17 is a DSC pattern of the crystal form C of the compound of formula (I).

[0151] Figure 18 is a DVS curve of the crystal form C of the compound of formula (I). 1 H NMR spectrum.

[0152] Figure 19 is a DVS curve of the crystal form C of the compound of formula (I).

[0153] Figure 20 is an XRPD pattern of the amorphous form of the compound of formula (I). DETAILED DESCRIPTION

[0154] The present application is further illustrated by the following examples without limiting the present application to the examples. The experimental methods in the following examples, if not specified, are selected according to the conventional methods and conditions, or according to the product instructions.

[0155] The X-ray powder diffraction (XRPD) and X-ray diffraction involved in the present application are collected by using the Empyrean and X'Pert Pro X-ray powder diffraction analyzers produced by PANalytical Company, wherein the method parameters are as follows: 3

[0156] The thermogravimetric analysis curve (TGA) involved in the present application is collected by using the Discovery TGA5500 thermogravimetric analyzer produced by TA Company, and the differential scanning calorimetric curve (DSC) involved in the present application is collected by using the Discovery DSC 2500 differential scanning calorimeter produced by TA Company, wherein the method parameters are as follows:

[0157] The dynamic water vapor adsorption (DVS) curve involved in the present application is collected by using the Intrinsic dynamic water vapor adsorption instrument produced by SMS (Surface Measurement Systems) Company, and the relative humidity at 25°C is corrected by using the deliquescence points of LiCl, Mg(NO3)2 and KCl, wherein the method parameters are as follows: ​

[0158] The hygroscopicity characteristics described in the present application refer to the definition of hygroscopic weight gain (Guidelines for Hygroscopicity Test of Drugs in Chinese Pharmacopoeia 2020 Edition Volume 4):

[0159] Deliquescence: Absorbing sufficient moisture to form a liquid;

[0160] Highly hygroscopic: hygroscopic weight gain is not less than 15%;

[0161] Hygroscopic: hygroscopic weight gain is less than 15% but not less than 2%;

[0162] Slightly hygroscopic: hygroscopic weight gain is less than 2% but not less than 0.2%;

[0163] Non-hygroscopic or almost non-hygroscopic: hygroscopic weight gain is less than 0.2%.

[0164] The nuclear magnetic resonance spectrum (NMR) involved in the present application is collected using a Bruker 400M nuclear magnetic resonance instrument, and DMSO-d6 is used as the nuclear magnetic test solvent.

[0165] The polarized light microscope (PLM) spectrum involved in the present application is collected using Axio Scope.A1 of Germany Carl Zeiss.

[0166] The purity, solubility and chiral purity of the sample involved in the present application are collected by high performance liquid chromatography on Agilent 1290 / 1260. The specific instruments and test parameters are as follows:

[0167] The liquid chromatography-mass spectrometry involved in the present application is collected on Agilent 1290 UPLC equipped with MS detector (single quadrupole). The specific instruments and test parameters are as follows:

[0168] The English / abbreviation-Chinese correspondence table of the solvent involved in the present application is as follows:

[0169] Example 1. Preparation method of compound of formula (1)

[0170] Step 1 : To a solution of L-glutamic acid-5-benzyl ester (50.0 g, 211 mmol) in deuterated acetic acid AcOD (150 mL) was added benzaldehyde (1.34 g, 12.6 mmol) and heated to 65 °C with stirring for 18 h. The solvent was removed by concentration under reduced pressure. To the remaining solid was added methanol (25 mL), acetonitrile (50 mL) and methyl tert-butyl ether (200 mL), and stirred for half an hour before filtration. The filter cake was rinsed with methyl tert-butyl ether (200 mL). The solid was dried under reduced pressure and reprocessed in the same manner once to give I-31A (32.5 g, 65% yield). 1 H NMR [(CD3OD + D2O), 300 MHz]: δ 7.33-7.42 (m, 5H), 5.14 (s, 2H), 3.70 (t, <0.05H), 2.58-2.63 (m, 2H), 2.13-2.17 (m, 2H).

[0171] Step 2: Compound I-31A (32.5 g, 137 mmol) was dissolved in a mixture of THF (600 ml) and water (600 ml) and NaHC03(12.6 g, 150 mmol) was added under ice bath. After 10 min, (Boc)20 (32.7 g, 150 mmol) was slowly added to the reaction system. After natural warming to room temperature, the stirring was continued for 4 h. The remaining material was added to a suitable amount of saturated NaHC03solution to dissolve it. Extraction was performed with methyl tert-butyl ether (200 ml x 2), and the aqueous phase was cooled in an ice bath and acidified with 3N HC1 solution to pH ~ 1. Extraction was performed with EtOAc (300 ml x 2), and the product was dried over anhydrous Na2S04, filtered, and concentrated to give white solid intermediate I-31B (46.5 g, yield: 100%). The product was used directly in the next step without further purification. 1 H NMR (CD3OD, 300 MHz): δ 7.29-7.35 (m, 5H), 5.12 (s, 2H), 4.13 (br s, 0.05H), 2.45-2.50 (m, 2H), 2.12-2.21 (m, 1H), 1.85-1.94 (m, 1H), 1.42 (s, 9H).

[0172] Step 3: Compound I-31B (46.5 g, 137 mmol) was dissolved in THF (300 mL), the reaction solution was cooled to 5 °C, then methylmorpholine (NMM, 16.5 g, 164 mmol) and ethyl chloroformate (17.8 g, 164 mmol) were added, stirred at 0-5 °C for one hour, then saturated ammonia water (150 ml) was added to the reaction solution, stirred vigorously at room temperature for 2 hours. Extracted with ethyl acetate (200 mL) and separated, the aqueous phase was extracted with ethyl acetate (200 mL) again. The organic phase was combined, washed with saturated sodium bicarbonate solution (200 mL x 2) and saturated brine (200 ml) respectively, dried over anhydrous sodium sulfate, filtered and concentrated to give white solid product I-31C (41 g, yield: 90%). 1 H NMR (DMSO-d6, 400 MHz): δ 8.37 (br s, 3H), 8.04 (s, 1H), 7.56 (m, 1H), 7.33-7.38 (m, 5H), 5.10 (s, 2H), 3.77 (t, <0.05H), 2.48-2.52 (m, 2H), 2.01-2.05 (m, 2H).

[0173] Step 4: Compound I-31C (41.0 g, 121 mmol) was dissolved in 1,4-dioxane (200 mL), 6N HCl / dioxane solution (300 mL) was added, stirred at room temperature for 2 hours. The reaction solution was concentrated and evaporated to dryness, then 200 mL methyl tert-butyl ether was added to make a slurry, filtered and dried to give white solid I-31D (31.3 g, yield: 95%). 1 H NMR (DMSO-d6, 400 MHz): δ 8.37 (br s, 3H), 8.04 (s, 1H), 7.56 (m, 1H), 7.33-7.38 (m, 5H), 5.10 (s, 2H), 3.77 (t, <0.05H), 2.48-2.52 (m, 2H), 2.01-2.05 (m, 2H).

[0174] Step 5: Methyl 2-bromomethyl-5-fluoro-3-nitrobenzoate (31.8 g, 109 mmol) and compound I-31D (29.7 g, 109 mmol) were dissolved in acetonitrile (550 mL), TEA (22.1 g, 218 mmol) was added with stirring. The temperature was raised to 75 °C and reacted overnight. Concentrated to dryness under reduced pressure, the residue was added to CH3CN (100 mL) to make a slurry to give light yellow solid compound I-31E (34.5 g, yield: 76.2%). 1 H NMR (DMSO-d 6，300 MHz): δ 8.33 (dd, J = 8.7, 2.4 Hz, 1H), 8.04 (dd, J = 6.9, 2.4 Hz, 1H), 7.66 (s, 1H), 7.26-7.36 (m, 6H), 4.82-5.05 (m, 4H), 2.20-2.39 (m, 3H), 2.06-2.15 (m, 1H).

[0175] Step 6: Compound I-31E was separated by HPLC chiral resolution (column: DAICEL CHIRALPAK IA, 10 pm, 25 x 250 mm; mobile phase MeOH / DCM 80 / 20 (v / v); flow rate 30 mL / min; temperature 35 °C; detection wave band 254 nM) to give I-31F1 1 H NMR (DMSO-d 6， 300 MHz): δ 8.31-8.35 (m, 1H), 8.03 (dd, J = 7.2, 2.1 Hz, 1H), 7.66 (s, 1H), 7.29-7.35 (m, 6H), 4.83-5.04 (m, 4H), 2.22-2.40 (m, 3H), 2.06-2.16 (m, 1H)].

[0176] Compound of formula (I): Compound I-31F1 (2.5 g, 6.0 mmol) and Pd / C (10%, 250 mg, 50% water) were added to anhydrous methanol (30 mL) and reacted at room temperature under 50 Psi hydrogen pressure for 4 h. The reaction solution was suction filtered, and the filtrate was concentrated to dryness. The remaining solid was added to DCE (15 mL) and stirred for 5 min, and then concentrated to dryness under reduced pressure. A white-like crude product (1.6 g) was obtained. 1.5 g (5.1 mmol) of the crude product was dissolved in a mixture of dry THF (10 mL) and DCE (40 mL), and SOCl2(1.52 g, 12.8 mmol) was slowly added dropwise at -30 °C. After the addition was completed, the reaction was stirred for 2 h, pyridine (1.01 g, 12.8 mmol) was added dropwise, and the temperature was maintained at -30 °C for 40 min. TEA (1.30 g, 12.8 mmol) was added, and the reaction was continued for 2 h. About 0.2 mL of water was added, and the reaction mixture was concentrated to dryness under reduced pressure. Water (5 mL) was added, and the mixture was extracted with EtOAc (70 mL x 5), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by Pre-HPLC (mobile phase acetonitrile-water system), and the sample was freeze-dried to obtain the compound of formula (I) (0.58 g, yield: 41%; 99% ee). 1 H NMR (DMSO-d 6，400 MHz), 10.99 (s, 1H), 6.52-6.61 (m, 2H), 5.71 (br s, 2H), 5.08 (dd, J = 18.0, 7.2 Hz, 0.04H), 4.17 (d, J = 17.4 Hz, 1H), 4.06 (d, J = 17.4 Hz, 1H), 2.83-2.96 (m, 1H), 2.56-2.62 (m, 1H), 2.21-2.32 (m, 1H), 1.98-2.05 (m, 1H). LCMS: 279.1 ([M+1] + The XRPD pattern of the obtained solid compound of formula (I) is shown in Figure 20, which has no obvious sharp diffraction peak and is amorphous. The obtained solid compound of formula (I) is detected for chiral purity by HPLC (the detection parameters are shown in the aforementioned table of "HPLC parameters for chiral purity test"), and the chiral purity is 99.95%, and the retention time is 7.500 min.

[0177] Example 2. Preparation and characterization of the compound of formula (1) in crystalline form A

[0178] Preparation method 1: about 15-20 mg of the raw sample of the compound of formula (I) (i.e. the amorphous solid of the compound of formula (I)) obtained in Example 1 is dissolved in an appropriate amount of DMSO to obtain a clear solution, water (about 10 times the volume of DMSO) is added to the solution, and stirring is performed while adding to precipitate solid, and the solid is collected to obtain crystalline form A. The XRPD pattern of the obtained crystalline form A is shown in Figure 1, and the XRPD pattern does not change after the sample is dried at room temperature in an open sample chamber for 4 days. The XRPD diffraction peak data of crystalline form A are shown in Table 1. The obtained sample of crystalline form A is detected for chiral purity by HPLC (the detection parameters are shown in the aforementioned table of "HPLC parameters for chiral purity test"), and the chiral purity is 99.96%, and the retention time is 7.498 min.

[0179] The TGA pattern of crystalline form A is shown in Figure 2, and the weight loss of the sample is 1.12% when heated from 20.2°C to 150°C. The DSC pattern of crystalline form A is shown in Figure 3, and two endothermic peaks and one exothermic peak are observed at 256.1°C, 257.8°C and 298.3°C (peak temperature) in the DSC curve. It is considered that crystalline form A is an anhydrous crystalline form in combination with the small TGA weight loss of the sample and the absence of obvious thermal signals in the DSC before 150°C.

[0180] The DVS curve of crystalline form A is shown in Figure 4, and the hygroscopic weight gain of the sample of crystalline form A under the condition of 25°C / 80% RH is 0.968% in the adsorption curve of cycle 1, indicating that the sample has slight hygroscopicity. The XRPD comparison results show that the sample does not change in crystalline form before and after the DVS test (as shown in Figure 6).

[0181] The PLM spectrum of crystalline form A is shown in Figure 5, which shows that crystalline form A is mainly composed of needle-shaped crystals.

[0182] Preparation of single crystal: A sample of Form A was dissolved in solvent acetone / H20 (10 / 1, v / v) to give a clear solution, and single crystal was prepared by solvent evaporation and single crystal structure was solved. The obtained single crystal structure is shown in Figure 7. The molecule of the single crystal contains one chiral carbon with "S" configuration. Figure 8 is the overlay of simulated XRPD of single crystal structure and measured XRPD of single crystal sample (in the figure, A represents simulated XRPD of single crystal structure, and B represents measured XRPD of single crystal sample), which shows that the simulated XRPD of single crystal structure is consistent with the measured XRPD of single crystal sample, and the diffraction peaks are consistent with the XRPD of Form A, confirming that the obtained single crystal is the single crystal of Form A. The main crystal parameter data are as follows:

[0183] Preparation method 2: A sample of about 15-20 mg of the starting material of the compound of formula (I) was dissolved in about 0.5 ml of DMSO to give a clear solution, 2-MeTHF (about 4 times the volume of DMSO) was added to the solution, and stirring was performed while adding, and then the solution was transferred to stirring at -5-10°C to precipitate a solid, and the solid was collected to obtain Form A. The obtained XRPD pattern of Form A is consistent with Figure 1.

[0184] Example 3. Preparation and characterization of Form B

[0185] Preparation method: After adding anti-solvent toluene to the DMSO solution of the starting material of the compound of formula (1) obtained in Example 1, no solid was precipitated in the solution, and the obtained solution was further transferred to stirring at 5°C for about 20 minutes to precipitate a solid, to obtain Form B of the compound of formula (1). The XRPD pattern of the obtained Form B is shown in Figure 9, and no crystal form change occurred in the XRPD after the sample was dried at room temperature for 4 days. The XRPD diffraction peak data of Form B of the compound of formula (1) are shown in Table 2.

[0186] The TGA / DSC overlay of Form B is shown in Figure 10, and the sample lost 9.72% from 18.9°C to 100°C, and lost 16.74% from 100°C to 130°C, and two endothermic peaks were observed at 127.7°C and 272.7°C (peak temperature) in the DSC curve. Form B has an onset point of endothermic peak at 126.0°C, a peak temperature at 127.7°C, and an enthalpy of 41.4 J / g.

[0187] Form B of the compound of formula (1) 1H NMR results (as shown in Figure 11) indicated that DMSO (1.0 mole, ~21.9%) was detected in the sample, and it was speculated that the TGA step weight loss of the sample was mainly due to the removal of DMSO, and it was speculated that Form B might be a DMSO solvate, which was further identified by heating experiment. Form B was heated to 100°C and 130°C and then decreased to room temperature, and was exposed to air. The XRPD overlay of Form B sample before and after heating is shown in Figure 12 (in Figure 12, A represents the XRPD of the sample before heating, B represents the XRPD of the sample heated to 100°C, C represents the XRPD of the sample heated to 130°C, and D represents the reference XRPD of Form A), and in the figure, the XRPD (B) heated to 100°C is consistent with the XRPD (A) before heating, indicating that the crystal form of the sample after heating to 100°C does not change significantly; while the XRPD (C) after heating to 130°C is consistent with the reference XRPD (D) of Form A, indicating that the sample is converted from Form B to Form A.

[0188] The XRPD of the sample obtained after heating Form B to 100°C 1 H NMR results (as shown in Figure 13) showed that there was still significant DMSO (0.67 mole, ~15.8%) detected in the sample, which was only reduced by 6.1% compared with before heating; after further heating to 130°C, the DMSO in the sample was further reduced to 0.07 mole, ~1.9%. 1 H NMR results (as shown in Figure 14) showed that the residual DMSO (0.07 mole, ~1.9%) in the sample was significantly reduced. Combined with the XRPD change results, it was confirmed that Form B was a DMSO solvate.

[0189] Example 4. Preparation and characterization of Form C

[0190] Preparation method: the amorphous sample of the compound of formula (1) obtained in Example 1 was stirred in water for about 2 hours, and then the solid was separated and dried at room temperature for about 1 day to obtain Form C of the compound of formula (1). The XRPD spectrum of the obtained Form C is shown in Figure 15. The XRPD diffraction peak data of Form C is shown in Table 3.

[0191] The TGA spectrum of Form C is shown in Figure 16, and the sample lost 5.30% (equivalent to 0.86 mole of water) from 17.1°C to 150°C. The DSC spectrum of Form C is shown in Figure 17, and two endothermic peaks and one exothermic peak were observed at 87.2°C, 258.4°C and 263.4°C (peak temperature) in the DSC curve.

[0192] The XRPD of Form C 1 H NMR results (as shown in Figure 18) showed that there was no significant solvent residue detected in the sample.

[0193] To further identify, heating experiment was carried out on Form C. Form C sample was heated to 100°C and exposed to air, the heated sample was converted to Form A. Based on the characterization data, it was considered that the TGA weight loss and DSC thermal signal at 87.2°C of Form C sample were related to the removal of crystallization water, therefore Form C was a hydrate. The water content was 0.86 mol (i.e. the molar ratio of the compound of Formula (I) and water was 1:0.86) according to the TGA weight loss of 5.30%.

[0194] The DVS curve of Form C is shown in Figure 19. In cycle 1 sorption curve (Sorp), the hygroscopic weight gain of the sample under 25°C / 80% RH condition was 3.806%, indicating that the sample had hygroscopicity. In cycle 1 desorption curve (Desorp), the desorption of water changed relatively gently before the relative humidity decreased to 30%, but there was a significant desorption of water (3.315%) during the relative humidity decreased from 30% to 0%, which was related to the removal of crystallization water of the sample under low humidity condition. The sample obtained from cycle 1 desorption was subjected to sorption test at 25°C, and in cycle 2 sorption curve, the hygroscopic weight gain of the sample under 25°C / 80% RH condition was 1.124%. Cycle 2 sorption curve was significantly different from cycle 1 sorption curve, which was related to the change of crystal form. The XRPD results showed that the crystallization water of Form C sample was removed and converted to anhydrous Form A after DVS test.

[0195] Example 5. Suspension stirring (room temperature / 50°C) test

[0196] Different temperatures and solvents were used to set up suspension stirring test. About 15-20 mg of Form A sample of the compound of Formula (1) was weighed into an HPLC vial, 0.5 mL of the solvent listed in Table 4 was added respectively, and the obtained suspension was stirred at the corresponding temperature (room temperature / 50°C), the solid was collected by centrifugation and subjected to XRPD test. The test results are shown in Table 8. Form A did not change in crystal form in various solvent systems in the suspension stirring test, which indicated that Form A had good stability to various solvent systems.

[0197] Table 4 Summary of suspension stirring (room temperature / 50°C) test

[0198] Example 6. Grinding test

[0199] Three grinding tests were performed using different solvents. About 15 mg of sample of crystalline Form A of the compound of formula (1) was taken in a mortar, and an appropriate amount of the corresponding solvent was added to the mortar and the solid was ground by hand (for about 3 minutes). After grinding, the solid sample obtained was tested by XRPD. The results of the tests are shown in Table 5, which show that the solid obtained after grinding is still crystalline Form A, which indicates that crystalline Form A has good grinding stability.

[0200] Table 5. Summary of grinding tests Note: NA: no solvent was added.

[0201] Example 7. Screening of the preparation method of Form A / B / C samples

[0202] To prepare Form A / B / C samples, the preparation method thereof was screened. The preparation method and the results are shown in Table 6, wherein the raw material sample is the solid compound of formula (I) obtained in Example 1.

[0203] Table 6. Screening of the preparation method of Form A / B / C samples and the results

[0204] Example 8. Suspension competition test of Form A and Form C

[0205] Suspension competition of Form A and Form C was performed at room temperature and at 50°C under different water activity conditions. In the suspension competition test, a sample of Form A of the compound of formula (1) was put into 0.7 mL of the corresponding solvent to prepare a suspension, and was stirred magnetically at room temperature and at 50°C. The clear saturated solution was obtained by filtration. The samples of Form A and Form C were added to the saturated solution of the corresponding system, and the solid was separated after stirring at room temperature for a period of time at a rotation speed of 1000 rpm, and was tested by XRPD. The results of the suspension competition are shown in Table 7.

[0206] Table 7. Results of the suspension competition Note: a w The ratio of acetone to water (Acetone / H2O) is by volume.

[0207] The results show that at 50°C, the mixture of Form A and Form C was suspended and stirred in acetone, acetone / H2O (a w = 0.2, 0.4, 0.6, 0.8) and H2O for 2 days, and anhydrous Form A was obtained.

[0208] Example 9. Solid state stability evaluation of Form A and amorphous

[0209] To compare the stability of Form A and amorphous, Form A and amorphous samples of the compound of formula (1) were prepared according to the preparation method described above, and appropriate amounts of samples were placed at 60 °C and 25 °C / 4500 lux under sealed conditions, and at 25 °C / 92.5% RH and 40 °C / 75% RH under open conditions for 7-15 days. The samples after storage were characterized by XRPD, TGA, LC-MS and HPLC to detect changes in solid state properties and chemical purity. The relevant results are summarized in Table 8.

[0210] Table 8 Summary of stability evaluation results of Form A and amorphous samples Note: The actual sampling time of the amorphous sample was 7 days and 14 days; Yes: the crystal form of the sample changed; No: the crystal form of the sample did not change.

[0211] The results showed that:

[0212] (1) The chemical purity and chiral purity of the Form A sample did not change significantly (area percentage change < 0.5%) after stability evaluation. The XRPD results of the samples before and after stability evaluation showed that the crystal form of the samples did not change. The TGA results showed that the weight loss of the samples was 0.82%-2.91%, and no significant change was observed. This indicates that Form A has good physical and chemical stability under the current evaluation conditions.

[0213] (2) The chemical purity and chiral purity of the amorphous sample did not change significantly (area percentage change < 0.5%) after stability evaluation. The XRPD results showed that the amorphous sample was unstable under the conditions of 60 °C sealed (high temperature), 40 °C / 75% RH (high temperature and high humidity), and / or 25 °C / 92.5% RH (high humidity), and converted to other crystal forms, for example, the sample converted to Form C after being placed under open conditions at 25 °C / 92.5% RH (high humidity), but the sample remained amorphous after being placed under sealed conditions at 25 °C / 4500 lux. The TGA results showed that the weight loss of the amorphous sample before and after stability evaluation was 0.66%-3.48%, and the change in TGA weight loss may be related to the conversion of the crystal form of the sample.

[0214] Example 10. Solubility evaluation of Form A and amorphous

[0215] To compare the solubility of Form A and amorphous samples in biological media and water, dynamic solubility tests were carried out on Form A and amorphous samples of the compound of formula (1) in SGF (simulated gastric fluid), FaSSIF (fasted state simulated intestinal fluid), FeSSIF (fed state simulated intestinal fluid), and water at 37 °C.

[0216] In the test, the samples were mixed with the solvents in centrifuge tubes (10 mg / mL of initial loading) and rotated (25 rpm) for 0.5, 2 and 24 hours at 37°C. The turbid samples were centrifuged and separated by filtration (10000 rpm, 0.45 μm PTFE filter membrane), and the HPLC concentration and pH of the supernatant after filtration were determined, and the remaining solid was determined by XRPD to determine the crystal form. The results of the solubility test are shown in Table 9.

[0217] Table 9 Summary of the solubility results of Form A and amorphous in different media at 37°C

[0218] The results show that:

[0219] (1) The amorphous sample has higher solubility in water (1.7-1.8 mg / mL vs. 0.46-0.54 mg / mL), SGF (4.0-4.3 mg / mL vs. 0.53-0.63 mg / mL), FaSSIF (2.1-2.8 mg / mL vs. 0.42-0.46 mg / mL) and FeSSIF (2.9 mg / mL-3.5 mg / mL vs. 0.48-0.52 mg / mL) than Form A.

[0220] (2) The XRPD results show that the XRPD of the remaining solid of Form A did not change after 24 hours of equilibrium in each medium, while the remaining solid of the amorphous sample after equilibrium in each medium was converted to Form C.

[0221] Although the specific embodiments of the present application are described above, those skilled in the art should understand that these are only illustrative, and various changes or modifications can be made to these embodiments without departing from the principles and essence of the present application. Therefore, the scope of protection of the present application is defined by the appended claims.

Claims

1. A crystal form of a compound of formula (I), which is crystal form A, crystal form B or crystal form C of the compound of formula (I); in, The structure of the compound of formula (I) is as follows: The crystal form A of the compound of formula (I) has diffraction peaks at 7.95±0.2°, 11.71±0.2° and 17.66±0.2° in its X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation. The crystal form B of the compound of formula (I) has diffraction peaks at 5.78±0.2°, 10.38±0.2° and 19.46±0.2° in its X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation. The crystal form C of the compound of formula (I) has diffraction peaks at 7.93±0.2°, 8.54±0.2° and 9.38±0.2° in its X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angle.

2. The crystal form of the compound of formula (I) as described in claim 1, characterized in that, The crystal form of the compound of formula (I) satisfies one or more of the following conditions: (1) The crystal form A of the compound of formula (I) has a Cu-Kα radiation X-ray powder diffraction pattern expressed in 2θ angles with one or more of the following diffraction peaks: 17.21±0.2°, 18.11±0.2°, 18.58±0.2°, 19.25±0.2°, 20.97±0.2°, 24.09±0.2°, 24.43±0.2°, 25.41±0.2° and 26.96±0.2°; (2) The crystal form B of the compound of formula (I) has a diffraction peak at one or more of the following locations in its X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angle: 14.45±0.2°, 16.65±0.2°, 17.42±0.2°, 17.85±0.2°, 18.23±0.2°, 18.78±0.2°, 19.86±0.2°, 23.29±0.2°, 24.08±0.2°, 24.62±0.2°, 24.89±0.2°, 27.09±0.2° and 36.34±0.2°; The crystal form C of the compound of formula (I) described in (3) has a Cu-Kα radiation X-ray powder diffraction pattern expressed in 2θ angles with one or more of the following diffraction peaks: 14.29±0.2°, 15.05±0.2°, 15.90±0.2°, 17.13±0.2°, 18.50±0.2°, 20.13±0.2°, 23.94±0.2°, 26.91±0.2° and 37.31±0.2°.

3. The crystal form of the compound of formula (I) as described in claim 1, characterized in that, The crystal form of the compound of formula (I) satisfies one or more of the following conditions: (1) The crystal form A of the compound of formula (I) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 7.95±0.2°, 11.71±0.2°, 17.21±0.2°, 17.66±0.2°, 24.43±0.2° and 26.96±0.2°; For example, the crystal form A of the compound of formula (I) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 7.95±0.2°, 11.71±0.2°, 17.21±0.2°, 17.66±0.2°, 18.11±0.2°, 24.09±0.2°, 24.43±0.2°, 25.41±0.2° and 26.96±0.2°. For example, the crystal form A of the compound of formula (I) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, showing diffraction peaks at 7.95±0.2°, 11.71±0.2°, 17.21±0.2°, 17.66±0.2°, 18.11±0.2°, 18.58±0.2°, 19.25±0.2°, 20.97±0.2°, 24.09±0.2°, 24.43±0.2°, 25.41±0.2°, and 26.96±0.2°. Preferably, the crystal form A of the compound of formula (I) has an X-ray powder diffraction pattern expressed as 2θ angle using Cu-Kα radiation at 7.95±0.2°, 9.44±0.2°, 11.71±0.2°, 14.72±0.2°, 15.91±0.2°, 17.21±0.2°, 17.66±0.2°, 18.11±0.2°, 18.58±0.2°, 19.25±0.2°, 20.97±0.2°, and 22. Diffraction peaks are observed at 31±0.2°, 23.52±0.2°, 24.09±0.2°, 24.43±0.2°, 25.41±0.2°, 26.43±0.2°, 26.96±0.2°, 29.00±0.2°, 29.36±0.2°, 31.04±0.2°, 31.47±0.2°, 32.08±0.2°, 32.91±0.2°, 34.04±0.2°, and 35.02±0.2°. More preferably, in the crystal form A of the compound of formula (I), the intensity of at least two diffraction peaks at 7.95±0.2°, 11.71±0.2° and 17.66±0.2° in the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation exceeds 20%; more preferably, the intensity of at least two diffraction peaks at 7.95±0.2°, 11.71±0.2° and 17.66±0.2° exceeds 30%. (2) Crystal form A of the compound of formula (I) is solvent-free, and the solvent is, for example, water; (3) The crystal form B of the compound of formula (I) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 5.78±0.2°, 10.38±0.2°, 16.65±0.2°, 19.46±0.2°, 19.86±0.2° and 24.89±0.2°; For example, the crystal form B of the compound of formula (I) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 5.78±0.2°, 10.38±0.2°, 16.65±0.2°, 18.23±0.2°, 19.46±0.2°, 19.86±0.2°, 24.08±0.2°, 24.89±0.2°, and 27.09±0.2°. For example, the crystal form B of the compound of formula (I) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, showing diffraction peaks at 5.78±0.2°, 10.38±0.2°, 14.45±0.2°, 16.65±0.2°, 17.42±0.2°, 17.85±0.2°, 18.23±0.2°, 18.78±0.2°, 19.46±0.2°, 19.86±0.2°, 23.29±0.2°, 24.08±0.2°, 24.62±0.2°, 24.89±0.2°, 27.09±0.2°, and 36.34±0.2°. Preferably, the crystal form B of the compound of formula (I) has an X-ray powder diffraction pattern, expressed as a 2θ angle, using Cu-Kα radiation at 5.78±0.2°, 10.38±0.2°, 14.45±0.2°, 16.65±0.2°, 17.42±0.2°, 17.85±0.2°, 18.23±0.2°, 18.78±0.2°, 19.46±0.2°, and 19.86±0.2°. Diffraction peaks are observed at 2°, 20.83±0.2°, 21.76±0.2°, 22.47±0.2°, 23.29±0.2°, 23.70±0.2°, 24.08±0.2°, 24.62±0.2°, 24.89±0.2°, 27.09±0.2°, 28.60±0.2°, 34.41±0.2°, 35.25±0.2°, and 36.34±0.2°. (4) The crystal form B of the compound of formula (I) contains a solvent, such as DMSO. For example, the crystal form B of the compound of formula (I) is the crystal form of the dimethyl sulfoxide solvate of the compound of formula (I). The molar ratio of the compound of formula (I) to dimethyl sulfoxide is preferably 1:(0.01-1.5), more preferably 1:(0.5-1.5), such as 1:0.07, 1:0.3, 1:0.67, 1:0.7, 1:0.9 or 1:

1. (5) The crystal form C of the compound of formula (I) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 7.93±0.2°, 8.54±0.2°, 9.38±0.2°, 14.29±0.2°, 20.13±0.2° and 23.94±0.2°; For example, the crystal form C of the compound of formula (I) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 7.93±0.2°, 8.54±0.2°, 9.38±0.2°, 14.29±0.2°, 15.90±0.2°, 17.13±0.2°, 18.50±0.2°, 20.13±0.2° and 23.94±0.2°. For example, the crystal form C of the compound of formula (I) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, showing diffraction peaks at 7.93±0.2°, 8.54±0.2°, 9.38±0.2°, 14.29±0.2°, 15.05±0.2°, 15.90±0.2°, 17.13±0.2°, 18.50±0.2°, 20.13±0.2°, 23.94±0.2°, 26.91±0.2° and 37.31±0.2°. Preferably, the crystal form C of the compound of formula (I) has an X-ray powder diffraction pattern expressed as 2θ angle using Cu-Kα radiation at 7.93±0.2°, 8.54±0.2°, 9.38±0.2°, 14.29±0.2°, 15.05±0.2°, 15.90±0.2°, 17.13±0.2°, 17.64±0.2°, and 18.07±0.2°. Diffraction peaks are observed at 18.50±0.2°, 19.20±0.2°, 20.13±0.2°, 22.03±0.2°, 23.94±0.2°, 24.36±0.2°, 25.34±0.2°, 26.91±0.2°, 29.33±0.2°, 32.09±0.2°, 33.29±0.2°, and 37.31±0.2°. The crystal form C of the compound of formula (I) described in (6) contains a solvent, such as water. For example, the crystal form C of the compound of formula (I) is the crystal form of the hydrate of the compound of formula (I). The molar ratio of the compound of formula (I) to water is preferably 1:(0.01-1.5), more preferably 1:(0.5-1.2), such as 1:0.3, 1:0.5, 1:0.6, 1:0.63, 1:0.7, 1:0.8, 1:0.86, 1:0.9 or 1:

1.

4. The crystal form of the compound of formula (I) as described in claim 1, characterized in that, The crystal form of the compound of formula (I) satisfies one or more of the following conditions: (1) The crystal form A of the compound of formula (I) has the diffraction peaks shown in Table 1 in the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation. Preferably, the crystal form A of the compound of formula (I) is given by Cu-Kα radiation, and its X-ray powder diffraction pattern is basically as shown in Figure 1. (2) The differential scanning calorimetry curve of crystal form A of the compound of formula (I) has endothermic peaks at peak temperatures of approximately 256.1℃ and 298.3℃, and exothermic peaks at peak temperatures of approximately 257.8℃. Preferably, the differential scanning calorimetry curve of crystal form A of the compound of formula (I) is basically as shown in Figure 3; (3) The thermogravimetric analysis curve of crystal form A of the compound of formula (I) shows a weight loss of about 1.12% in the temperature range of about 20.2 °C to about 150 °C; Preferably, the thermogravimetric analysis curve of crystal form A of the compound of formula (I) is basically as shown in Figure 2; (4) The crystal form A of the compound of formula (I) under dynamic gas adsorption analysis showed a moisture absorption weight gain of 0.2% to 2% at 25°C / 80%RH, for example, a moisture absorption weight gain of about 0.97%. Preferably, the dynamic gas adsorption analysis of crystal form A of the compound of formula (I) is basically as shown in Figure 4; (5) The crystal form B of the compound of formula (I) has the diffraction peaks shown in Table 2 in the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation. Preferably, the crystal form B of the compound of formula (I) has an X-ray powder diffraction pattern as shown in Figure 9 when subjected to Cu-Kα radiation. (6) The differential scanning calorimetry curve of crystal form B of the compound of formula (I) has an endothermic peak at about 126.0 °C, and / or the differential scanning calorimetry curve of crystal form B of the compound of formula (I) has endothermic peaks at peak temperatures of about 127.7 °C and 272.7 °C. Preferably, the differential scanning calorimetry curve of crystal form B of the compound of formula (I) is basically as shown in Figure 10; (7) The thermogravimetric analysis curve of crystal form B of the compound of formula (I) shows a weight loss of about 9.72% in the temperature range of about 18.9°C to about 100°C and a weight loss of about 16.74% in the temperature range of about 100°C to about 130°C. Preferably, the thermogravimetric analysis curve of crystal form B of the compound of formula (I) is basically as shown in Figure 10; (8) The nuclear magnetic resonance hydrogen spectrum of crystal form B of the compound of formula (I) is basically as shown in Figure 11; (9) The crystal form C of the compound of formula (I) has the diffraction peaks shown in Table 3 in the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation. Preferably, the crystal form C of the compound of formula (I) has an X-ray powder diffraction pattern as shown in Figure 15 when irradiated with Cu-Kα. (10) The differential scanning calorimetry curve of crystal form C of the compound of formula (I) has endothermic peaks at peak temperatures of approximately 87.2 °C and 258.4 °C, and exothermic peaks at peak temperatures of approximately 263.4 °C. For example, the differential scanning calorimetry curve of crystal form C of the compound of formula (I) has an endothermic peak at a peak temperature of about 87.2 °C; Preferably, the differential scanning calorimetry curve of crystal form C of the compound of formula (I) is basically as shown in Figure 17; (11) The thermogravimetric analysis curve of crystal form C of the compound of formula (I) shows a weight loss of about 5.30% in the temperature range of about 17.1 °C to about 150 °C; Preferably, the thermogravimetric analysis curve of crystal form C of the compound of formula (I) is basically as shown in Figure 16; (12) The nuclear magnetic resonance hydrogen spectrum of crystal form C of the compound of formula (I) is basically as shown in Figure 18; Dynamic gas adsorption analysis of the crystal form C of the compound of formula (I) described in (13) showed a moisture absorption weight gain of 2% to 15% under 25°C / 80%RH conditions, for example, its moisture absorption weight gain was about 3.81%; And / or, in the dynamic gas adsorption analysis desorption curve of the crystal form C of the compound of formula (I), the weight loss is about 3.32% under the condition of humidity less than 30% RH; Preferably, the dynamic gas adsorption analysis of crystal form C of the compound of formula (I) is basically as shown in Figure 19.

5. A single crystal of a compound of formula (I) having the following unit cell parameters: orthorhombic crystal system, space group P 212121; α = 90° β = 90° γ = 90° The number of asymmetric units within the unit cell is Z = 4, and the crystal density is 1.537 mg / m³. 3 ; 6. A method for preparing the crystal form of the compound of formula (I) as described in any one of claims 1-4, characterized in that, It is a method for preparing crystal form A of the compound of formula (I), a method for preparing crystal form B of the compound of formula (I), or a method for preparing crystal form C of the compound of formula (I); The method for preparing crystal form A of the compound of formula (I) is the antisolvent addition method; Preferably, the method for preparing crystal form A of the compound of formula (I) includes the following steps: adding solvent B to a mixture of the compound of formula (I) and solvent A to obtain crystal form A of the compound of formula (I); Solvent A is selected from one or more of N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone; solvent B is selected from one or more of 2-methyltetrahydrofuran, ethanol, methyl isobutyl ketone, isopropyl acetate, isopropanol, tetrahydrofuran, acetone, acetonitrile, water, and dichloromethane. The method for preparing crystal form B of the compound of formula (I) is the antisolvent addition method; Preferably, the method for preparing crystal form B of the compound of formula (I) includes the following steps: adding solvent D to a mixture of the compound of formula (I) and solvent C to obtain crystal form B of the compound of formula (I); Solvent C is dimethyl sulfoxide, and solvent D is ethyl acetate or toluene; The method for preparing crystal form C of the compound of formula (I) is the suspension stirring crystallization method; Preferably, the method for preparing crystal form C of the compound of formula (I) includes the following steps: crystallizing a mixture of the compound of formula (I) and water to obtain crystal form C of the compound of formula (I).

7. The method for preparing the crystal form of the compound of formula (I) as described in claim 6, characterized in that, The preparation method satisfies one or more of the following conditions: (1) In the method for preparing crystal form A of the compound of formula (I), the compound of formula (I) is an amorphous form of the compound of formula (I); (2) When solvent A is N,N-dimethylacetamide, solvent B is selected from one or more of ethanol, methyl isobutyl ketone and isopropyl acetate. Preferably, when solvent A is N,N-dimethylformamide, solvent B is selected from one or more of methyl isobutyl ketone, isopropyl acetate, acetone and water. More preferably, when solvent A is dimethyl sulfoxide, solvent B is selected from one or more of 2-methyltetrahydrofuran, isopropanol, tetrahydrofuran, acetone, acetonitrile and water. Further, when solvent A is N-methylpyrrolidone, solvent B is water and / or dichloromethane. For example, when solvent A is dimethyl sulfoxide, solvent B is water or 2-methyltetrahydrofuran. (3) In the method for preparing crystal form A of the compound of formula (I), the volume ratio of solvent A to solvent B is 1:(1-20), such as 1:10, 1:5 or 1:4; (4) In the method for preparing crystal form A of the compound of formula (I), the amount of solvent A is sufficient to dissolve the compound of formula (I); (5) The method for preparing crystal form A of the compound of formula (I) includes the following steps: at 10 to 40°C, the compound of formula (I) is mixed and dissolved with solvent A to obtain a mixture of the compound of formula (I) and solvent A, solvent B is added, and crystallization is carried out at -20°C to room temperature to obtain crystal form A of the compound of formula (I); Preferably, the method for preparing crystal form A of the compound of formula (I) comprises the following steps: dissolving the compound of formula (I) in DMSO at 10–40°C, adding water, crystallizing at room temperature, and separating to obtain crystal form A of the compound of formula (I); or, dissolving the compound of formula (I) in DMSO at 10–40°C, adding 5 times the volume of 2-methyltetrahydrofuran, crystallizing at -5°C to 10°C, and separating to obtain crystal form A of the compound of formula (I); (6) In the method for preparing crystal form B of the compound of formula (I), the compound of formula (I) is an amorphous form of the compound of formula (I); (7) When solvent C is dimethyl sulfoxide, solvent D is toluene; (8) In the method for preparing crystal form B of the compound of formula (I), the volume ratio of solvent C to solvent D is 1:(5-20), preferably 1:(8-15), or 1:10 or 1:

12. (9) In the method for preparing crystal form B of the compound of formula (I), the amount of solvent C used is sufficient to dissolve the compound of formula (I); (10) The method for preparing crystal form B of the compound of formula (I) includes the following steps: at 10 to 40°C, the compound of formula (I) is mixed and dissolved with solvent C to obtain a mixture of compound of formula (I) and solvent C, solvent D is added, and crystallization is performed at -20°C to 5°C to obtain crystal form B of the compound of formula (I). (11) In the method for preparing crystal form C of the compound of formula (I), the compound of formula (I) is an amorphous solid form of the compound of formula (I); In the method for preparing crystal form C of compound (I) described in (12), the crystallization is performed by stirring, such as suspension stirring.

8. A method for preparing a single crystal of the compound of formula (I) as described in claim 5, characterized in that, It includes the following steps: drying a mixture of crystal form A of the compound of formula (I) and a "mixed solution of acetone and water in a volume ratio of 10:1" to obtain a single crystal of the compound of formula (I), wherein the mixture is, for example, a mixed solution, and the drying is, for example, evaporation.

9. A pharmaceutical composition comprising crystal form A, crystal form B, crystal form C of the compound of formula (I) according to any one of claims 1-4 and / or a single crystal of the compound of formula (I) according to claim 5, and one or more pharmaceutically acceptable excipients.

10. Use of a crystal form A, crystal form B, crystal form C of a compound of formula (I) as claimed in any one of claims 1-4, a single crystal of a compound of formula (I) as claimed in claim 5, or a pharmaceutical composition as claimed in claim 9 in the preparation of a medicament for the prevention or treatment of diseases, symptoms, or conditions caused by or associated with abnormal regulation of TNF-α activity; Preferably, the disease, symptom, or condition is cancer; more preferably, the disease, symptom, or condition is selected from: myelodysplastic syndrome, multiple myeloma, mantle cell lymphoma, non-Hodgkin's lymphoma, papillary and follicular thyroid carcinoma, breast cancer, prostate cancer, chronic lymphocytic leukemia, amyloidosis, type I complex regional pain syndrome, malignant melanoma, radiculopathy, myelofibrosis, glioblastoma, glioma, malignant glioma, refractory plasmacytoma, chronic myelomonocytic leukemia, follicular lymphoma, ciliary body and chronic melanoma, iris melanoma. Tumors, recurrent interocular melanoma, extraocular melanoma, solid tumors, T-cell lymphoma, erythroid lymphoma, monocytic and monocytic leukemia, myeloid leukemia, central nervous system lymphoma, brain tumors, meningiomas, spinal cord tumors, thyroid cancer, non-small cell lung cancer, ovarian cancer, skin cancer, renal cell carcinoma, myelofibrosis, Burkitt lymphoma, Hodgkin lymphoma, large cell lymphoma, diffuse large B-cell lymphoma, astrocytoma, hepatocellular carcinoma, or primary macroglobulinemia; preferably, the diseases, symptoms, or conditions described are selected from prostate cancer or myelodysplastic syndromes.

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