Crystal form of biphenyl compound serving as immunomodulator and preparation method of crystal form

Abstract

The invention relates to a crystal form of a biphenyl compound (I) serving as an immunomodulator and a preparation method of the crystal form, and further discloses application of the crystal form in preparation of related drugs of the immunomodulator. # imgabs0 #

Description

A crystal form of a biphenyl compound as an immunomodulator and a preparation method thereof Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and specifically relates to a crystal form of a biphenyl compound used as an immunomodulator and a preparation method thereof, and also includes the use of the crystal form in the preparation of drugs for treating immunomodulation-related diseases. Background Art

[0002] Tumor immunotherapy is a new treatment approach that stimulates the body's immune system, enhancing its anti-tumor immunity and thereby inhibiting or killing tumor cells. This approach has achieved breakthroughs after over a century of research. In 2013, Science magazine listed tumor immunotherapy as one of the top ten scientific breakthroughs of the year (Couzin-Frankel J., 2013, Science, 342:1432-1433), making it one of the most promising areas of anti-tumor treatment.

[0003] Compared with normal cells, tumor cells have multiple genetic and epigenetic changes. The immune system can use the surface antigens produced by tumor cells to distinguish between the two, thereby triggering an anti-tumor immune response. In the process of T cell anti-tumor immunity, after being activated by antigen recognition signals mediated by the T cell receptor (TCR), T cell effects are comprehensively regulated by costimulatory and costimulatory signals, including inhibitory receptors such as cytotoxic T-lymphocyte associated antigen 4 (CTLA4), programmed death protein 1 (PD-1), V-domain immunoglobulin suppressor of T-cell activation (VISTA), T cell immunoglobulin and mucin domain–containing-3 (TIM3), and lymphocyte activation gene 3 (LAG3), and activating receptors such as CD28, CD134 (OX40), glucocorticoid-induced TNFR-related protein (GITR), CD137, CD27, and HVEM (Mellman et al., 2012). I., Coukos G., Dranoff G., 2011, Nature, 480:480-489). Under normal physiological conditions, immune checkpoints play a role in maintaining immune tolerance to autoantigens, preventing autoimmune diseases, and in preventing excessive immune responses that can lead to tissue damage. However, in tumor cells, immune checkpoints can inhibit T cell activation and evade immune killing. Therefore, tumor immunotherapy requires reactivating T cells to attack tumor cells by activating co-stimulatory signals (pressing the "accelerator") and inhibiting co-inhibitory signals (releasing the "brakes").

[0004] PD-1 is expressed on activated T cells, B cells, and bone marrow cells. It belongs to the CD28 family and is a type 1 transmembrane glycoprotein on T cells, consisting of 288 amino acids. The molecular structure of PD-1 consists of an extracellular domain resembling an immunoglobulin V (IgV) (amino acids 35-145), a transmembrane region, and a cytoplasmic tail that functions as a linker to a signal peptide. The extracellular domain plays a crucial role in ligand binding (Cheng X., Veverka V., Radhakrishnan A., et al. 2013, J. Biol. Chem., 288:11771-11785). Programmed death protein ligand 1 (PD-L1), a ligand for PD-1, belongs to the B7 family and is persistently expressed on various tumor cells, T cells, antigen-presenting cells (APCs), and various non-hematopoietic cells. It is also a type 1 transmembrane glycoprotein consisting of 290 amino acids. The interaction between PD-1 and PD-L1 inhibits T cell activation, which is crucial for maintaining normal immune tolerance. In tumor cells and viral infections, PD-1 on T cells is induced to be highly expressed, and PD-L1 expression is upregulated, leading to the continuous activation of the PD-1 signaling pathway and the inhibition of T cell proliferation, causing the immune escape of tumor cells and pathogens (Fuller MJ, Callendret B., Zhu B., et al. 2013, Proc. Natl. Acad. Sci. USA., 110: 15001-15006; Dolan DE, Gupta S., 2014, Cancer Control, 21: 231-237; Chen L., Han X., 2015, J. Clin. Invest., 125: 3384-3391; Postow MA, Callahan MK, Wolchok JD, 2015, J. Clin. Oncol., 33:1974-1982). The recent launch of multiple PD-1 and PD-L1 antibody drugs has fully demonstrated that blocking the PD-1 / PD-L1 interaction is a very effective treatment in tumor immunotherapy and various other immune-related diseases.

[0005] Studies have found that PD-L1 can interact with CD80 and inhibit the binding of PD-L1 to PD-1, as well as the ability to inhibit T cell activation. Therefore, blocking the immune activation caused by the CD80 / PD-L1 interaction may also promote the enhancement of T cell activity, thereby providing new treatment opportunities for immune-related diseases (Sugiura D., Maruhashi T., Okazaki ll-mi, et al. 2019, Science, 364:558-566).

[0006] To date, significant progress has been made in the development of antibody drugs targeting PD-1 / PD-L1. However, all antibody drugs require injection, are subject to multiple ADMET issues, and present serious immune system-related side effects. Small molecule immunomodulators offer advantages over antibody drugs, including oral administration, improved tissue penetration, and the ability to minimize side effects through pharmacological adjustments. Furthermore, small molecule inhibitors offer the potential for lower prices.

[0007] Clinical studies on PD-1 / PD-L1 antibody drugs have shown that nivolumab T 1 / 2 The duration of treatment is 25.2 days, and the frequency of administration is once every two weeks; 1 / 2 The duration of treatment is 25 days, with a dosing frequency of once every three weeks; Atezolizumab T 1 / 2 The dosing frequency of the above-mentioned drugs is shorter than their half-lives, indicating that sustained in vivo exposure of these target drugs is key to achieving optimal clinical efficacy. However, the in vivo exposure of previously published small molecule immunomodulators is relatively low, and the duration of sustained exposure is relatively short, which will affect clinical efficacy.

[0008] Summary of the Invention

[0009] The present invention provides a crystalline form of a compound represented by formula (I) or a solvate thereof, wherein the crystalline form is selected from the group consisting of Form A, Form B, Form C, Form D, Form E, Form F, and Form G.

[0010] The X-ray powder diffraction pattern of the Form A crystal form has characteristic diffraction peaks at the following 2θ angles: 6.39±0.2°, 13.85±0.2°;

[0011] The X-ray powder diffraction pattern of the Form B crystal form has characteristic diffraction peaks at the following 2θ angles: 5.70±0.2°, 9.54±0.2°, and 13.90±0.2°;

[0012] The X-ray powder diffraction pattern of the Form C crystal form has characteristic diffraction peaks at the following 2θ angles: 6.10±0.2°, 12.30±0.2°;

[0013] The X-ray powder diffraction pattern of the Form D crystal form has characteristic diffraction peaks at the following 2θ angles: 6.45±0.2°, 12.95±0.2°, and 13.65±0.2°;

[0014] The X-ray powder diffraction pattern of the Form E crystal form has characteristic diffraction peaks at the following 2θ angles: 6.81±0.2°, 13.73±0.2°, and 15.89±0.2°;

[0015] The X-ray powder diffraction pattern of the Form F crystal form has characteristic diffraction peaks at the following 2θ angles: 6.73±0.2°, 9.07±0.2°;

[0016] The X-ray powder diffraction pattern of the Form G crystal form has characteristic diffraction peaks at the following 2θ angles: 14.75±0.2° and 17.72±0.2°. The compound represented by formula (I) is described in patent CN202180004723.7, the entire content of which is incorporated herein by reference.

[0017] The present invention provides a Form A crystal form of a compound represented by formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.39±0.2° and 13.85±0.2°.

[0018] In some embodiments of the present invention, the compound represented by formula (I) in Form A has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 6.39±0.2°, 13.85±0.2°, and 17.25±0.2°.

[0019] In some embodiments of the present invention, the compound represented by formula (I) in Form A has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 6.39±0.2°, 12.70±0.2°, 13.85±0.2°, 15.30±0.2°, 17.25±0.2°, and 25.06±0.2°.

[0020] In some embodiments of the present invention, the compound represented by formula (I) in Form A has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 6.39±0.2°, 9.28±0.2°, 10.75±0.2°, 11.46±0.2°, 12.70±0.2°, 12.93±0.2°, 13.85±0.2°, 14.55±0.2°, 15.30±0.2°, 16.30±0.2°, 16.83±0.2°, 17.25±0.2°, 18. 52±0.2°, 18.94±0.2°, 20.37±0.2°, 20.83±0.2°, 21.65±0.2°, 22.97±0.2°, 24.18±0.2°, 25.06±0.2°, 25.94±0.2°, 27.40±0.2°, 28.96±0.2°, 29.88±0.2°, 30.78±0.2°, 32.50±0.2°, 33.16±0.2°.

[0021] In some embodiments of the present invention, the compound represented by formula (I) is in crystal form Form A, and its XPRD spectrum is shown in FIG1 .

[0022] In some embodiments of the present invention, the XPRD spectrum analysis data of the Form A crystal form of the compound represented by formula (I) is shown in Table 1.

[0023] Table 1 Analysis of the XPRD spectrum of the Form A crystal form of the compound represented by formula (I)

[0024] In some embodiments of the present invention, the differential scanning calorimetry curve of the Form A crystal form of the compound represented by formula (I) has an endothermic signal at 40°C.

[0025] In some embodiments of the present invention, the differential scanning calorimetry curve of the Form A crystal form of the compound represented by formula (I) has a melting endothermic peak at 162°C.

[0026] In some embodiments of the present invention, the compound represented by formula (I) is in crystal form Form A, and its DSC spectrum is shown in FIG2 .

[0027] In some embodiments of the present invention, the thermogravimetric analysis curve of the Form A crystal form of the compound represented by formula (I) shows a weight loss of 0.9% during heating to 100°C.

[0028] In some embodiments of the present invention, the compound represented by formula (I) is in crystal form Form A, and its TGA spectrum is shown in FIG3 .

[0029] The present invention also provides a Form B crystal form of the compound represented by formula (I), whose X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2θ angle: 5.70±0.2°.

[0030] In some embodiments of the present invention, the Form B crystalline form of the compound represented by formula (I) has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 5.70±0.2°, 9.54±0.2°, and 13.90±0.2°.

[0031] In some embodiments of the present invention, the Form B crystalline form of the compound represented by formula (I) has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 5.70±0.2°, 9.54±0.2°, 13.90±0.2°, and 17.48±0.2°.

[0032] In some embodiments of the present invention, the Form B crystalline form of the compound represented by formula (I) has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 5.70±0.2°, 9.54±0.2°, 13.90±0.2°, 16.93±0.2°, 17.48±0.2°, and 17.72±0.2°.

[0033] In some embodiments of the present invention, the compound represented by formula (I) in Form B has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 4.40±0.2°, 5.70±0.2°, 6.52±0.2°, 7.78±0.2°, 8.11±0.2°, 8.74±0.2°, 9.54±0.2°, 11.46±0.2°, 12.66±0.2°, 12.94±0.2°, 13.35±0.2°, 13.90 ±0.2°, 14.83±0.2°, 15.33±0.2°, 15.80±0.2°, 16.93±0.2°, 17.48±0.2°, 17.72±0.2°, 18.47±0.2°, 18.66±0.2°, 19.11±0.2°, 19.61±0.2°, 20.24±0.2°, 20.77±0.2°, 21.45±0.2°, 22.07±0.2°, 22.91±0.2°, 23.55±0.2°, 24.28±0.2°, 25.09±0.2°, 25.41±0.2°, 25.91±0.2°, 26.16±0.2°, 27.19±0.2°, 27.99±0.2°, 28.58±0.2°, 29.38±0.2°, 29.97±0.2°, 31.30 ±0.2°, 32.04±0.2°, 32.95±0.2°, 33.23±0.2°, 33.91±0.2°, 34.25±0.2°, 34.88±0.2°, 35.35±0.2°, 36.06±0.2°, 37.34±0.2°, 38.19±0.2°, 39.46±0.2°, 42.23±0.2°, 44.02±0.2°.

[0034] In some embodiments of the present invention, the compound represented by formula (I) is in Form B, and its XPRD spectrum is shown in FIG4 .

[0035] In some embodiments of the present invention, the XPRD spectrum analysis data of the Form B crystal form of the compound represented by formula (I) is shown in Table 2.

[0036] Table 2 Analysis of the XPRD spectrum of the Form B crystal form of the compound represented by formula (I)

[0037] In some embodiments of the present invention, the differential scanning calorimetry curve of the Form B crystal form of the compound represented by formula (I) has an endothermic signal at 31°C.

[0038] In some embodiments of the present invention, the differential scanning calorimetry curve of the Form B crystalline form of the compound represented by formula (I) has a melting endothermic peak at 188°C.

[0039] In some embodiments of the present invention, the compound represented by formula (I) is in Form B, and its DSC spectrum is shown in FIG5 .

[0040] In some embodiments of the present invention, the thermogravimetric analysis curve of the Form B crystalline form of the compound represented by formula (I) shows a weight loss of 1.0% during heating to 150°C.

[0041] In some embodiments of the present invention, the compound represented by formula (I) is in Form B, and its TGA spectrum is shown in FIG6 .

[0042] The present invention also provides a Form C crystalline form of the compound represented by formula (I), whose X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2θ angle: 6.10±0.2°.

[0043] In some embodiments of the present invention, the compound represented by formula (I) in Form C has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 6.10±0.2° and 12.30±0.2°.

[0044] In some embodiments of the present invention, the Form C crystalline form of the compound represented by formula (I) has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 6.10±0.2°, 12.30±0.2°, 13.22±0.2°, and 15.00±0.2°.

[0045] In some embodiments of the present invention, the compound represented by formula (I) in Form C has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 6.10±0.2°, 9.89±0.2°, 10.68±0.2°, 12.30±0.2°, 13.22±0.2°, 13.90±0.2°, 15.00±0.2°, 15.82±0.2°, 16.63±0.2°, 17.86±0.2°, 18.13±0.2°, 18.68±0.2°, 19.98±0. 2°, 20.41±0.2°, 21.84±0.2°, 22.77±0.2°, 23.79±0.2°, 24.14±0.2°, 24.53±0.2°, 26.10±0.2°, 26.52±0.2°, 26.91±0.2°, 27.50±0.2°, 28.21±0.2°, 30.06±0.2°, 31.18±0.2°, 32.28±0.2°, and 33.12±0.2°.

[0046] In some embodiments of the present invention, the compound represented by formula (I) is in crystal form Form C, and its XPRD spectrum is shown in FIG7 .

[0047] In some embodiments of the present invention, the XPRD spectrum analysis data of the Form C crystal form of the compound represented by formula (I) is shown in Table 3.

[0048] Table 3 XPRD spectrum analysis of Form C crystal form of compound represented by formula (I)

[0049] In some embodiments of the present invention, the differential scanning calorimetry curve of the Form C crystalline form of the compound represented by formula (I) has endothermic signals at 33°C, 158°C, and 213°C.

[0050] In some embodiments of the present invention, the compound represented by formula (I) is in Form C, and its DSC spectrum is shown in FIG8 .

[0051] In some embodiments of the present invention, the thermogravimetric analysis curve of the Form C crystalline form of the compound represented by formula (I) shows a weight loss of 9.8% during heating to 250°C.

[0052] In some embodiments of the present invention, the compound represented by formula (I) is in Form C, and its TGA spectrum is shown in FIG9 .

[0053] The present invention also provides a Form D crystal form of the compound represented by formula (I), whose X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2θ angle: 6.45±0.2°.

[0054] In some embodiments of the present invention, the compound represented by formula (I) in Form D has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 6.45±0.2°, 12.95±0.2°, and 13.65±0.2°.

[0055] In some embodiments of the present invention, the Form D crystalline form of the compound represented by formula (I) has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 6.45±0.2°, 10.98±0.2°, 12.95±0.2°, 13.41±0.2°, 13.65±0.2°, and 16.30±0.2°.

[0056] In some embodiments of the present invention, the compound represented by formula (I) is The X-ray powder diffraction pattern of form D has characteristic diffraction peaks at the following 2θ angles: 6.45±0.2°, 9.41±0.2°, 10.13±0.2°, 10.98±0.2°, 11.59±0.2°, 12.95±0.2°, 13.41±0.2°, 13.65±0.2°, 14.42±0.2°, 15.55±0.2°, 15.79±0.2°, 16.30±0.2°, 16.89±0.2°, 17.50±0.2°, 17.97±0.2°, 18.26±0.2°, 18.81±0.2°, 19.49±0.2°, 19.73±0.2°, 20.02±0.2°, 20. 35±0.2°, 20.66±0.2°, 21.38±0.2°, 21.67±0.2°, 22.07±0.2°, 22.75±0.2°, 23.82±0.2°, 24.66±0.2°, 25.87±0.2°, 26.52±0.2°, 26.84±0.2°, 27.50±0 .2°, 28.76±0.2°, 29.35±0.2°, 29.71±0.2°, 31.40±0.2°, 31.95±0.2°, 32.81±0.2°, 33.29±0.2°, 34.17±0.2°, 36.99±0.2°, 38.16±0.2°, 39.46±0.2°.

[0057] In some embodiments of the present invention, the compound represented by formula (I) is in Form D, and its XPRD spectrum is shown in FIG10 .

[0058] In some embodiments of the present invention, the XPRD spectrum analysis data of the Form D crystal form of the compound represented by formula (I) is shown in Table 4.

[0059] Table 4 XPRD spectrum analysis of Form D crystal form of the compound represented by formula (I)

[0060] In some embodiments of the present invention, the differential scanning calorimetry curve of the Form D crystal form of the compound represented by formula (I) has endothermic signals at 70°C and 199°C.

[0061] In some embodiments of the present invention, the compound represented by formula (I) is in crystal form Form D, and its DSC spectrum is shown in FIG11 .

[0062] In some embodiments of the present invention, the thermogravimetric analysis curve of the Form D crystal form of the compound represented by formula (I) shows a weight loss of 2.5% during heating to 150°C.

[0063] In some embodiments of the present invention, the compound represented by formula (I) is in crystal form Form D, and its TGA spectrum is shown in FIG12 .

[0064] The present invention also provides a Form E crystal form of the compound represented by formula (I), whose X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2θ angle: 13.73±0.2°.

[0065] In some embodiments of the present invention, the compound represented by formula (I) in Form E crystal form has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 6.81±0.2°, 13.73±0.2°, and 15.89±0.2°.

[0066] In some embodiments of the present invention, the Form E crystalline form of the compound represented by formula (I) has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 6.81±0.2°, 13.11±0.2°, 13.73±0.2°, 15.49±0.2°, 15.89±0.2°, and 19.37±0.2°.

[0067] In some embodiments of the present invention, the compound represented by formula (I) in Form E has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 6.81±0.2°, 9.93±0.2°, 10.59±0.2°, 11.59±0.2°, 13.11±0.2°, 13.73±0.2°, 15.49±0.2°, 15.89±0.2°, 16.58±0.2°, 17.15±0.2°, 17.69±0.2°, 18.19±0.2°, 19.12±0.2°, 19.37±0.2°, 20. 91±0.2°, 21.40±0.2°, 22.16±0.2°, 23.97±0.2°, 25.32±0.2°, 25.94±0.2°, 26.67±0.2°, 27.50±0.2°, 29.00±0.2°, 30.13±0.2°, 31.07±0.2°, 32.57±0.2°, 33.65±0.2°, 35.92±0.2°, 37.48±0.2°, 39.50±0.2°, 42.10±0.2°.

[0068] In some embodiments of the present invention, the compound represented by formula (I) is in Form E, and its XPRD spectrum is shown in FIG13 .

[0069] In some embodiments of the present invention, the XPRD spectrum analysis data of the Form E crystal form of the compound represented by formula (I) is shown in Table 5.

[0070] Table 5 XPRD spectrum analysis of Form E crystal form of the compound represented by formula (I)

[0071] In some embodiments of the present invention, the differential scanning calorimetry curve of the Form E crystal form of the compound represented by formula (I) has endothermic signals at 40°C, 151°C, 174°C, and 191°C.

[0072] In some embodiments of the present invention, the compound represented by formula (I) is in Form E, and its DSC spectrum is shown in FIG14 .

[0073] In some embodiments of the present invention, the thermogravimetric analysis curve of the Form E crystal form of the compound represented by formula (I) shows a weight loss of 2.7% during heating to 150°C.

[0074] In some embodiments of the present invention, the compound represented by formula (I) is in Form E, and its TGA spectrum is shown in FIG15 .

[0075] The present invention also provides a Form F crystalline form of the compound represented by formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.73±0.2° and 9.07±0.2°.

[0076] In some embodiments of the present invention, the Form F crystalline form of the compound represented by formula (I) has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 6.73±0.2°, 9.07±0.2°, 13.33±0.2°, 18.17±0.2°, and 19.20±0.2°.

[0077] In some embodiments of the present invention, the Form F crystalline form of the compound represented by formula (I) has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 6.32±0.2°, 6.73±0.2°, 9.07±0.2°, 13.33±0.2°, 17.04±0.2°, 17.81±0.2°, 18.17±0.2°, 19.20±0.2°, 21.08±0.2°, and 21.30±0.2°.

[0078] In some embodiments of the present invention, the compound represented by formula (I) in Form F has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 4.56±0.2°, 6.32±0.2°, 6.73±0.2°, 7.82±0.2°, 9.07±0.2°, 10.41±0.2°, 11.65±0.2°, 12.66±0.2°, 13.33±0.2°, 13.62± 0.2°, 14.63±0.2°, 15.00±0.2°, 15.24±0.2°, 15.58±0.2°, 16.08±0.2°, 16.47±0.2°, 17.04±0.2°, 17.81±0.2°, 18.17±0.2°, 18.68±0.2°, 19.20±0.2°, 19.9 8±0.2°, 20.45±0.2°, 21.08±0.2°, 21.30±0.2°, 21.97±0.2°, 22.62±0.2°, 22.80±0.2°, 23.50±0.2°, 23.85±0.2°, 24.09±0.2°, 24.39±0.2°, 24.77±0.2°, 25 .72±0.2°, 26.29±0.2°, 26.83±0.2°, 27.44±0.2°, 28.12±0.2°, 28.89±0.2°, 29.16±0.2°, 29.51±0.2°, 30.46±0.2°, 31.47±0.2°, 32.06±0.2°, 32.81±0.2°.

[0079] In some embodiments of the present invention, the compound represented by formula (I) is in crystal form Form F, and its XPRD spectrum is shown in FIG16 .

[0080] In some embodiments of the present invention, the XPRD spectrum analysis data of the Form F crystal form of the compound represented by formula (I) is shown in Table 6.

[0081] Table 6 Analysis of the XPRD spectrum of the Form F crystal form of the compound represented by formula (I)

[0082] In some embodiments of the present invention, the differential scanning calorimetry curve of the Form F crystalline form of the compound represented by formula (I) has endothermic signals at 102°C, 151°C, and 174°C.

[0083] In some embodiments of the present invention, the compound represented by formula (I) is in crystal form Form F, and its DSC spectrum is shown in FIG17 .

[0084] In some embodiments of the present invention, the thermogravimetric analysis curve of the Form F crystalline form of the compound represented by formula (I) shows a weight loss of 7.8% during heating to 100°C.

[0085] In some embodiments of the present invention, the compound represented by formula (I) is in crystal form Form F, and its TGA spectrum is shown in FIG18 .

[0086] The present invention also provides a Form G crystalline form of the compound represented by formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 14.75±0.2° and 17.72±0.2°.

[0087] In some embodiments of the present invention, the Form G crystalline form of the compound represented by formula (I) has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 14.75±0.2°, 17.72±0.2°, 18.47±0.2°, and 19.22±0.2°.

[0088] In some embodiments of the present invention, the Form G crystalline form of the compound represented by formula (I) has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 7.03±0.2°, 14.10±0.2°, 14.75±0.2°, 15.49±0.2°, 17.06±0.2°, 17.72±0.2°, 18.47±0.2°, 19.22±0.2°, and 24.61±0.2°.

[0089] In some embodiments of the present invention, the compound represented by formula (I) in Form F has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 7.03±0.2°, 8.02±0.2°, 8.21±0.2°, 8.50±0.2°, 8.97±0.2°, 9.49±0.2°, 9.99±0.2°, 10.67±0.2°, 11.04±0.2°, 11.69±0.2°, 12.78 ±0.2°, 13.64±0.2°, 14.10±0.2°, 14.75±0.2°, 15.49±0.2°, 16.08±0.2°, 16.50±0.2°, 17.06±0.2°, 17.72±0.2°, 18.47±0.2°, 18.86±0.2°, 19.22±0.2°, 19.73±0.2°, 20.20±0.2°, 20.94±0.2°, 21.29±0.2°, 21.53±0.2°, 22.83±0.2°, 23.46±0.2°, 24.24±0.2°, 24.61±0.2°, 24.99±0.2°, 25.73±0.2°, 26.58±0.2°, 27.50±0.2°, 28.54 ±0.2°, 29.13±0.2°, 29.77±0.2°, 30.43±0.2°, 31.14±0.2°, 31.95±0.2°, 32.57±0.2°, 33.55±0.2°, 35.05±0.2°, 36.42±0.2°, 36.80±0.2°, 38.82±0.2°, 40.87±0.2°.

[0090] In some embodiments of the present invention, the compound represented by formula (I) is in Form G, and its XPRD spectrum is shown in FIG19 .

[0091] In some embodiments of the present invention, the XPRD spectrum analysis data of the Form G crystal form of the compound represented by formula (I) is shown in Table 7.

[0092] Table 7 XPRD spectrum analysis of the Form G crystal form of the compound represented by formula (I)

[0093] In some embodiments of the present invention, the differential scanning calorimetry curve of the Form G crystal form of the compound represented by formula (I) has endothermic signals at 152°C and 175°C.

[0094] In some embodiments of the present invention, the differential scanning calorimetry curve of the Form G crystal form of the compound represented by formula (I) has a melting endothermic peak at 210°C.

[0095] In some embodiments of the present invention, the compound represented by formula (I) is in Form G, and its DSC spectrum is shown in FIG20 .

[0096] In some embodiments of the present invention, the thermogravimetric analysis curve of the Form G crystal form of the compound represented by formula (I) shows a weight loss of 0.6% during heating to 150°C.

[0097] In some embodiments of the present invention, the compound represented by formula (I) is in Form G, and its TGA spectrum is shown in FIG21 .

[0098] The present invention also provides the use of the pharmaceutically acceptable crystal form of the compound represented by the above formula (I) in drugs related to small molecule immunomodulators.

[0099] The present invention also provides different crystalline forms of the compound represented by formula (I) prepared by solvent evaporation method, suspension method, dissolution crystallization method, cooling method, vapor diffusion method, and thermal crystallization method, which are further described as follows:

[0100] Solvent evaporation method: Weigh an appropriate amount of sample and dissolve it in a selected single solvent or binary solvent. The resulting clear solution is left open at room temperature until the solvent is completely evaporated to obtain a solid.

[0101] Suspension method: 1) Suspension at room temperature: weigh an appropriate amount of sample of different crystal forms, add a certain amount of sample to the selected single solvent or binary solvent until a suspension is formed, suspend and stir at room temperature for a certain period of time, centrifuge the suspension, and vacuum dry the solid at room temperature. 2) Suspension at 50°C: weigh an appropriate amount of sample of different crystal forms, add a certain amount of sample to the selected solvent until a suspension is formed, suspend and stir at 50°C for 24 hours, centrifuge the suspension, and vacuum dry the solid at room temperature;

[0102] Dissolution crystallization method: 1) Binary solvent forward drop method, that is, weigh a certain amount of sample, add an appropriate amount of good solvent at room temperature to completely dissolve the sample; take a certain amount of solution respectively, and add the solution to 10 times or 20 times the volume of poor solvent. After stirring for 1 hour, the system with solid precipitation is centrifuged and the solid is vacuum dried at room temperature; the clarified solution is stirred for 24 hours. The system with no solid precipitation is placed in a 4°C refrigerator for 3 days. The system with solid precipitation is centrifuged and the solid is vacuum dried at room temperature. If there is still no solid precipitation, the solution is left to stand at room temperature in an open air until the solvent is completely evaporated to obtain a solid. 2) Binary solvent back drop method, that is, weigh a certain amount of sample, add an appropriate amount of good solvent at room temperature to completely dissolve the sample; take a certain amount of solution respectively, and add poor solvent until solid precipitation occurs. After stirring at room temperature for 1 hour, the system with solid precipitation was centrifuged and the solid was vacuum dried at room temperature. The clear solution was stirred for 24 hours. If there was still no solid precipitation, the system was placed in a 4°C refrigerator for 3 days. The system with solid precipitation was centrifuged and the solid was vacuum dried at room temperature. If there was still no solid precipitation, the solution was left open at room temperature until the solvent was completely evaporated to obtain a solid.

[0103] Cooling method: 1) Single solvent cooling method, that is, weigh an appropriate amount of sample, add the preheated selected solvent at 50°C until the solid is just completely dissolved. Quickly transfer the solution to room temperature to cool. Let it stand at room temperature for more than 2 hours. If not enough solid is precipitated, place the solution at room temperature and stir for 1 day. If there is still no solid precipitation, place it at 4°C to cool for 1 day. For systems with sufficient solid precipitation, centrifuge and dry the solid in vacuum at room temperature. 2) Binary solvent cooling method, that is, weigh an appropriate amount of sample, mix it with a certain amount of poor solvent at 50°C to form a suspension. Gradually add the preheated good solvent until the solid is just completely dissolved, and transfer the solution to room temperature to cool. Let it stand at room temperature for more than 2 hours. If not enough solid is precipitated, place the solution at 4°C to cool for another day. For systems with sufficient solid precipitation, centrifuge and dry the solid in vacuum at room temperature;

[0104] Vapor Diffusion Method: Weigh a certain amount of sample and add an appropriate amount of good solvent at room temperature to completely dissolve the sample. Take a certain amount of solution separately and place the clear solution in a poor solvent atmosphere at room temperature until solid precipitates. Remove the solution from the system with solid precipitate with a syringe and perform XRPD analysis on the wet sample.

[0105] Thermal crystallization method: Using an Instec HCS424GXY hot stage (Instec Inc., US), 6-8 mg of sample was placed on a glass slide and placed on the hot stage. The sample was heated to 120°C at a rate of 20°C / min and kept at this temperature for 20 min. The sample was then cooled naturally to room temperature to obtain a solid.

[0106] The solvent of the aforementioned method is selected from methanol, ethanol, n-propanol, isopropanol, acetone, 4-methyl-2-pentanone, ethyl acetate, isopropyl acetate, ethyl formate, butyl formate, n-heptane, cyclohexane, 1,4-dioxane, ether, methyl tert-butyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, water, acetonitrile, toluene, N,N′-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, tetrahydrofuran, N-methylpyrrolidone, trifluoroethanol, or a mixed solvent of two or more of these solvents.Preferred include but are not limited to methanol, ethanol, n-propanol, isopropanol, acetone, tetrahydrofuran, ethyl acetate, methyl tert-butyl ether, N,N'-dimethylformamide, dichloromethane, chloroform, 4-methyl-2-pentanone, isopropyl acetate, ethyl formate, cyclohexane, ethyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, water, acetonitrile, toluene, dimethyl sulfoxide, dichloromethane and chloroform, dichloromethane and tetrahydrofuran, dichloromethane and methanol, dichloromethane and acetone, dichloromethane and acetone, dichloromethane and ethyl acetate, dichloromethane and cyclohexane, dichloromethane and n-heptane, dichloromethane and methyl tert-butyl ether, dichloromethane and toluene, dichloromethane and butyl formate, chloroform and Butyl formate, chloroform and ethanol, chloroform and tetrahydrofuran, chloroform and acetone, chloroform and 4-methyl-2-pentanone, chloroform and isopropyl acetate, chloroform and n-heptane, chloroform and acetonitrile, chloroform and 1,4-dioxane, chloroform and toluene, tetrahydrofuran and isopropanol, tetrahydrofuran and 4-methyl-2-pentanone, tetrahydrofuran and ethyl acetate, tetrahydrofuran and toluene, tetrahydrofuran and butyl formate, tetrahydrofuran and n-heptane, tetrahydrofuran and cyclohexane, tetrahydrofuran and ethylene glycol dimethyl ether, tetrahydrofuran and methyl tert-butyl ether, tetrahydrofuran and water, methanol and acetone, ethanol and ethyl acetate, n-propanol and n-heptane, isopropanol and cyclohexane, methanol and 1,4-dioxane, n-Propanol and methyl tert-butyl ether, ethanol and water, isopropanol and toluene, acetone and ethyl acetate, acetone and cyclohexane, acetone and ethyl ether, 4-methyl-2-pentanone and n-heptane, 4-methyl-2-pentanone and methanol, 4-methyl-2-pentanone and methyl tert-butyl ether, 4-methyl-2-pentanone and acetonitrile, ethyl acetate and cyclohexane, isopropyl acetate and ethylene glycol methyl ether, isopropyl acetate and toluene, butyl formate and acetonitrile, methyl tert-butyl ether and acetonitrile, ethylene glycol dimethyl ether and toluene, water and acetonitrile, acetonitrile and toluene, N,N'-dimethylformamide and ethylene glycol methyl ether, N,N'-dimethylformamide and butyl formate, N,N'-dimethylformamide and 4-methyl -2-pentanone, N,N′-dimethylformamide and toluene, N,N′-dimethylformamide and methanol, N,N′-dimethylformamide and n-propanol, N,N′-dimethylformamide and isopropanol, N,N′-dimethylformamide and water, N,N′-dimethylformamide and acetonitrile, dimethyl sulfoxide and methyl tert-butyl ether, dimethyl sulfoxide and water, dimethyl sulfoxide and toluene, methyl sulfoxide and acetonitrile, dimethyl sulfoxide and methanol, dimethyl sulfoxide and ethanol, dimethyl sulfoxide and n-propanol, dimethyl sulfoxide and acetone, ethanol and isopropyl acetate, ethanol and acetonitrile, ethylene glycol dimethyl ether and acetonitrile, alcohol and water, n-propanol and cyclohexane, 1,4-dioxane and water.

[0107] Unless otherwise specified, all of the following terms and phrases in the present invention are intended to have the following meanings. A particular phrase or term not specifically defined should not be considered ambiguous or unclear, but should be understood according to its ordinary meaning.

[0108] When the structural formula of the compound described in the present invention is inconsistent with the Chinese name, the chemical structural formula shall prevail.

[0109] When the peak shape in the XPRD spectrum is not a very sharp diffraction peak, the peak values ​​calculated by different software may be different, which is within the scope of the present invention.

[0110] In the present invention, the temperatures are all allowed to have a certain error. Unless otherwise specified, the error is preferably ±5°C, more preferably ±3°C, even more preferably ±2°C, and most preferably ±1°C. For example, "the differential scanning calorimetry curve of the Form A crystal form has an endothermic signal at 40°C" preferably means "the differential scanning calorimetry curve of the Form A crystal form has an endothermic signal at 40±5°C", more preferably "the differential scanning calorimetry curve of the Form A crystal form has an endothermic signal at 40±3°C", even more preferably "the differential scanning calorimetry curve of the Form A crystal form has an endothermic signal at 40±2°C", and most preferably "the differential scanning calorimetry curve of the Form A crystal form has an endothermic signal at 40±1°C". BRIEF DESCRIPTION OF THE DRAWINGS

[0111] Figure 1 is an XPRD spectrum of the Form A crystal form of the compound represented by formula (I).

[0112] FIG2 is a DSC spectrum of the Form A crystal form of the compound represented by formula (I).

[0113] FIG3 is a TGA spectrum of the Form A crystal form of the compound represented by formula (I).

[0114] Figure 4 is an XPRD spectrum of the Form B crystalline form of the compound represented by formula (I).

[0115] Figure 5 is a DSC spectrum of the Form B crystal form of the compound represented by formula (I). Figure 6 is a TGA spectrum of the Form B crystal form of the compound represented by formula (I).

[0116] Figure 7 is an XPRD spectrum of the Form C crystalline form of the compound represented by formula (I).

[0117] FIG8 is a DSC spectrum of the Form C crystalline form of the compound represented by formula (I).

[0118] Figure 9 is a TGA spectrum of the Form C crystalline form of the compound represented by formula (I).

[0119] Figure 10 is an XPRD spectrum of the Form D crystalline form of the compound represented by formula (I).

[0120] Figure 11 is a DSC spectrum of the Form D crystal form of the compound represented by formula (I).

[0121] Figure 12 is a TGA spectrum of the Form D crystal form of the compound represented by formula (I).

[0122] Figure 13 is an XPRD spectrum of the Form E crystalline form of the compound represented by formula (I).

[0123] FIG14 is a DSC spectrum of the Form E crystalline form of the compound represented by formula (I).

[0124] FIG15 is a TGA spectrum of the Form E crystalline form of the compound represented by formula (I).

[0125] Figure 16 is an XPRD spectrum of the Form F crystalline form of the compound represented by formula (I).

[0126] FIG17 is a DSC spectrum of the Form F crystalline form of the compound represented by formula (I).

[0127] FIG18 is a TGA spectrum of the Form F crystalline form of the compound represented by formula (I).

[0128] Figure 19 is an XPRD spectrum of the Form G crystalline form of the compound represented by formula (I).

[0129] Figure 20 is a DSC spectrum of the Form G crystalline form of the compound represented by formula (I).

[0130] Figure 21 is a TGA spectrum of the Form G crystalline form of the compound represented by formula (I).

[0131] Figure 22 is a DVS spectrum of the Form B crystalline form of the compound represented by formula (I).

[0132] FIG23 is a superimposed spectrum of XPRD data of Form B of the compound represented by Formula (I) before and after DVS testing.

[0133] FIG24 is a superimposed XRPD data spectrum of the stability study of Form B crystalline form of the compound represented by formula (I). DETAILED DESCRIPTION

[0134] The present invention is further illustrated below with reference to examples, but the scope of protection of the present invention is not limited to these examples. The percentages described in the present invention are all weight percentages unless otherwise specified. The numerical ranges described in the specification, such as units of measurement, reaction conditions, physical states of compounds, or percentages, are all intended to provide unambiguous written references. When practicing this patent, those skilled in the art may use temperatures, concentrations, amounts, carbon number, etc. outside of these ranges or different from single numerical values ​​and still obtain the expected results.

[0135] All compounds and intermediates described herein can be purified by common separation methods, such as extraction, recrystallization, silica gel column chromatography, and preparative TLC separation. The 200-300 mesh silica gel and thin-layer chromatography silica gel plates used were produced by Qingdao Ocean Chemical Plant. Solvents and chemical reagents used were commercially available products of analytical or chemical grade and were used without further purification.

[0136] X-ray powder diffraction (XRPD) analysis method of the present invention:

[0137] The solid samples were analyzed using an Empyrean X-ray powder diffractometer (Panalytical, NL). The 2θ scan angle ranged from 3° to 45°, with a scan step size of 0.013°, and the total measurement time was 4 minutes. The tube voltage and current were 45 kV and 40 mA, respectively, and the sample pan was set to a zero-background sample pan.

[0138] Online variable temperature XRPD (XRPD) measurements were performed using a Malvern Panalytical Aeris X-ray powder diffractometer (Malvern Panalytical, UK). The 2θ scan angle ranged from 8° to 40°, with a scan step size of 0.02°, and the measurement time was 15 min. The tube voltage and current were 40 kV and 7.5 mA, respectively, and the sample pan was a zero-background sample pan. The samples were placed on a BTS500 hot stage (Anton Paar, AT) for XRPD measurements at room temperature. The samples were then heated at 20°C / min to 120°C or 150°C, held at that temperature for 20 min, and then subjected to XRPD measurements at the same temperature.

[0139] Differential Scanning Calorimetry (DSC) method of the present invention:

[0140] The differential scanning calorimeter was a TA Discovery 2500 (TA, US). 1-2 mg of sample was accurately weighed and placed in a perforated DSC Tzero sample pan. The sample was heated to the final temperature at a rate of 10°C / min, with nitrogen purge rate of 50 mL / min.

[0141] Thermogravimetric analysis (TGA) method of the present invention:

[0142] The thermogravimetric analyzer (TA Discovery 550, US) was used. A 2-5 mg sample was placed in a equilibrated open aluminum sample pan and automatically weighed in the TGA furnace. The sample was heated to the final temperature at a rate of 10°C / min. A nitrogen purge rate of 60 mL / min was maintained at the sample and 40 mL / min at the balance.

[0143] Dynamic water vapor adsorption and desorption analysis (DVS) method of the present invention:

[0144] Dynamic water vapor adsorption / desorption analysis was performed using a DVS Intrinsic (SMS, UK). The test used a gradient mode with humidity changes from 50% to 95% to 0% to 50%, with each humidity change of 10% within the 0% to 90% range. The gradient endpoint was determined using the dm / dt method, with a dm / dt of less than 0.002% maintained for 10 minutes. After completion of the test, the samples were analyzed by XRPD to confirm any changes in the solid form.

[0145] The hygroscopicity classification evaluation is as follows: Note: ΔW% indicates the weight gain of the test sample at 25±1℃ and 80±2%RH

[0146] The present invention nuclear magnetic ( 1 H-NMR) analysis method:

[0147] 1 H-NMR measurements were performed at room temperature on a BRUKER AVANCE-400 MHz NMR spectrometer in deuterated dimethyl sulfoxide (DMSO-d6) or deuterated chloroform (CDCl3) with tetramethylsilane (TMS) as the internal standard. Signal peaks are represented as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and dd (doublet of doublets). Coupling constants (J) are reported in Hertz (Hz).

[0148] Example 1 Preparation of the compound of formula (I)

[0149] first step

[0150] 1a (530.00 mg, 1.13 mmol, 1.0 eq, synthesis reference CN202111092852.4) was dissolved in 1,4-dioxane (10 mL), trifluoroacetic acid (5 mL) was added, and the mixture was stirred at ambient temperature for 1 h. The reaction solution was concentrated, and the residue was dissolved in 1,4-dioxane (10 mL). 1b (583.08 mg, 1.13 mmol, 1.0 eq, synthesis reference CN202111092852.4), 1,1'-bis(dicyclohexylphosphino)ferrocenepalladium dichloride (83.05 mg, 0.11 mmol, 0.1 eq), anhydrous sodium carbonate (359.34 mg, 3.39 mmol, 3.0 eq), and water (5 mL) were added. The resulting mixture was heated to 110°C using a microwave for 1 h and then cooled to ambient temperature. The reaction mixture was concentrated, and the crude product was separated by silica gel column chromatography (dichloromethane / methanol (v / v) = 40 / 1 to 20 / 1) to obtain solid 1c (363.00 mg, yield 47.3%). LC-MS MS-ESI (m / z) 679.6 [M+H] + .

[0151] Step 2

[0152] Intermediate 1c (363.00 mg, 0.53 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), and triethylamine (1 mL) and 1d (143.78 mg, 0.79 mmol, 1.5 eq, synthesis reference CN202111092852.4) were added. The resulting mixture was stirred at ambient temperature for 1 h. Then, sodium acetate borohydride (674.16 mg, 3.18 mmol, 6.0 eq) was added and stirred for a further 16 h. The reaction mixture was quenched with saturated sodium bicarbonate solution and extracted three times with dichloromethane / methanol (10 / 1, 100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by preparative TLC (dichloromethane / methanol (v / v) = 8 / 1) to yield 1e as a solid (363.00 mg, 47.3% yield). LC-MS MS-ESI(m / z)845.9[M+H]+.

[0153] Step 3

[0154] Intermediate 1e (338.00 mg, 0.40 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (10 mL) was added. The resulting solution was stirred at ambient temperature for 1 h. The reaction mixture was concentrated, and the residue was dissolved in dichloromethane (10 mL) and concentrated again. The resulting trifluoroacetate salt was used directly in the next stage. The trifluoroacetate salt was dissolved in dichloromethane (10 mL), and triethylamine (1 mL) and commercially available 1f (117.6 mg, 0.60 mmol, 1.5 eq) were added. The resulting mixture was stirred at ambient temperature for 1 h, and then sodium acetate borohydride (508.80 mg, 2.40 mmol, 6.0 eq) was added and stirring continued for 16 h. The reaction mixture was quenched with saturated sodium bicarbonate solution and extracted three times with dichloromethane / methanol (10 / 1, 100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by preparative TLC (dichloromethane / methanol (v / v) = 6 / 1) to obtain 1 g (307.00 mg, yield 82.9%). LC-MS MS-ESI (m / z) 926.0 [M+H] + .

[0155] Step 4

[0156] Intermediate 1g (307.00 mg, 0.33 mmol, 1.0 eq) was dissolved in tetrahydrofuran (10 mL), and water (10 mL) and lithium hydroxide monohydrate (277.20 mg, 6.60 mmol, 20.0 eq) were added. The resulting solution was stirred at ambient temperature for 16 h. The tetrahydrofuran was removed by concentration, and the pH was adjusted to 5-6 with 1M hydrochloric acid. The solid was collected by filtration and dried to obtain an off-white solid I (84.00 mg, 27.9% yield). LC-MS MS-ESI (m / z) 912.0 [M+H] + . 1 H-NMR (400MHz, DMSO-d6) δppm 9.89 (s, 2H), 8.38 (d, J = 8.4Hz, 2H), 7.49 (t, J = 8.0Hz, 2H), 7.14 (d, J = 7.4Hz, 2H), 3.90 (s, 6H), 3.48-3.41 (m, 4H),3.33(s,2H),3.24(s,3H),2.78-2.70(m,4H),2.69-2.62(m,4H),2.56-2.51 (m,4H),1.89-1.83(m,2H),1.75-1.69(m,4H),1.58-1.22(m,16H),1.12(s,2H).

[0157] Example 2 Preparation of different crystal forms of the compound represented by formula (I)

[0158] 2.1 Volatilization method

[0159] 1) Single solvent evaporation method

[0160] Appropriate amounts of Formula (I) samples were dissolved in various solvents, and the resulting clear solutions were allowed to stand at room temperature in an open atmosphere until the solvent evaporated completely to yield a solid. The resulting wet samples were then directly subjected to XRPD analysis. The results are shown in Table 8.

[0161] Table 8 Single solvent evaporation crystallization results

[0162] 2) Binary solvent evaporation method

[0163] Approximately 20 mg of a sample of Formula (I) was dissolved in a certain volume of a mixed solvent. After filtration, the filtrate was left unopened at room temperature until the solvent completely evaporated to obtain a solid. The resulting wet sample was directly subjected to XRPD analysis. The results are shown in Table 9.

[0164] Table 9 Binary solvent evaporation crystallization results

[0165] 2.2 Suspension method

[0166] Using different crystalline forms of the sample of formula (I) as raw materials, suspension experiments were carried out at room temperature (-25°C) and 50°C using different solvents.

[0167] 1) Room temperature suspension of Form A sample of formula (I)

[0168] A certain amount of Form A sample of formula (I) was weighed and suspended in the selected single and binary solvents at room temperature for 7 days. The results are shown in Table 10.

[0169] Table 10 Form A room temperature suspension crystallization results

[0170] 2) Form A sample of formula (I) was suspended at 50°C

[0171] A certain amount of Form A sample of formula (I) was weighed and suspended in different solvents at 50° C. for 24 h. The results are shown in Table 11.

[0172] Table 11 Form A suspension crystallization results at 50°C

[0173] 3) Room temperature suspension of Form B sample of formula (I)

[0174] A certain amount of Form B sample of formula (I) was weighed and suspended in a selected single solvent at room temperature for 1 day. The results are shown in Table 12.

[0175] Table 12 Room temperature suspension crystallization results of Form A

[0176] 4) Room temperature suspension of Form C sample of formula (I)

[0177] A certain amount of Form C sample of formula (I) was weighed and suspended in a selected single solvent at room temperature for 1 day. The results are shown in Table 13.

[0178] Table 13 Room temperature suspension crystallization results of Form C

[0179] 5) Room temperature suspension of Form A and Form D samples of formula (I)

[0180] A certain amount of Form A and Form D samples of formula (I) were weighed, suspended in a selected single solvent at room temperature for 1 day, and then the solid and liquid were separated by centrifugation and dried in vacuo at 40°C for 1 day. The results are shown in Table 14.

[0181] Table 14 Room temperature suspension crystallization results of Form A and Form D

[0182] 2.3 Dissolution crystallization method

[0183] 1) Binary solvent back titration method

[0184] A certain amount of sample of formula (I) was weighed, and N,N′-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, or tetrahydrofuran was selected as a good solvent, and combined with various poor solvents to conduct binary solvent dissolution crystallization experiments using the back titration method. The results are shown in Table 15.

[0185] Table 15 Crystallization results of binary solvent back-titration method of dissolution crystallization

[0186] 2) Binary solvent positive drop method

[0187] A certain amount of sample of formula (I) was weighed, and N,N′-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, or tetrahydrofuran was selected as a good solvent, and combined with various poor solvents to conduct binary solvent dissolution crystallization experiments using the positive drop method. The results are shown in Table 16.

[0188] Table 16 Binary solvent positive drop method crystallization results of dissolution crystallization method

[0189] 2.4 Cooling method

[0190] 1) Single solvent cooling method

[0191] A certain amount of sample of formula (I) was weighed and a single solvent cooling crystallization experiment was carried out using dioxane. The results are shown in Table 17.

[0192] Table 17 Single solvent cooling crystallization results

[0193] 1) Binary solvent cooling method

[0194] A certain amount of sample of formula (I) was weighed, and a binary solvent cooling crystallization experiment was carried out at 50°C using N,N′-dimethylformamide or dimethyl sulfoxide as a good solvent in combination with various anti-solvents. The results are shown in Table 18.

[0195] Table 18 Single binary solvent cooling crystallization results

[0196] 2.5 Gas Diffusion Method

[0197] A certain amount of Formula (I) sample was weighed and an appropriate amount of a good solvent was added dropwise at room temperature to completely dissolve the sample. Separately, a solution containing approximately 20 mg of the sample after filtration was placed in a poor solvent atmosphere and allowed to stand at room temperature until solid precipitated. The solution containing the precipitated solid was removed using a syringe, and the wet sample was subjected to XRPD analysis. The results are shown in Table 19.

[0198] Table 19 Vapor diffusion crystallization results

[0199] 2.6 Thermal Transformation Method

[0200] 1) Online temperature change

[0201] Using different crystal forms as raw materials, online variable temperature XRPD was used to heat to the target temperature and maintain the temperature for 20 minutes. Then, online XRPD testing was performed at this temperature. The results are shown in Table 20.

[0202] Table 20 Online variable temperature XPRD thermal crystallization method crystallization results

[0203] 2) Hot plate thermal transfer

[0204] 6-8 mg of Form F was placed on a glass slide on a hot plate and heated to 120°C at a rate of 20°C / min. The temperature was maintained constant for 20 min. The solid was then cooled naturally to room temperature and subjected to XRPD analysis. The results are shown in Table 21.

[0205] Table 21 Hot stage thermal transfer crystallization results

[0206] Example 3 Study on the Hygroscopicity of the Compound of Formula (I) Form B

[0207] The present invention evaluated the hygroscopicity of Form B using the aforementioned dynamic vapor sorption / desorption (DVS) method. After the test, the sample was subjected to XRPD analysis to confirm whether the solid form had changed. The results are shown in Table 22.

[0208] Table 22 Hygroscopicity study results of the Form B crystal form of the compound of formula (I) Note: ΔW% indicates the weight gain of the test sample due to moisture absorption at 25±1℃ and 80±2%RH; a The DVS data are shown in Figure 22; b The XPRD data overlay comparison before and after the DVS test is shown in Figure 23.

[0209] Experimental conclusion: The Form B crystal form of the compound represented by formula (I) of the present invention is hygroscopic, and the crystal form before and after the DVS test remains consistent.

[0210] Example 4 Study on the solid stability of the Form B crystal form of the compound represented by formula (I)

[0211] Stability studies were conducted on Form B samples of the compound represented by Formula (I) under conditions of high temperature (60°C), high humidity (25°C / 92.5% RH), light (25°C / 4500 Lux), and accelerated (40°C / 75% RH). XRPD characterization was performed on samples taken at 17 and 22 days, respectively. The results are shown in Table 23.

[0212] Table 23 Form B stability study results a a The XPRD data overlay comparison is shown in Figure 24.

[0213] Experimental conclusion: XRPD results showed that Form B was stable under high temperature, high humidity, light, and accelerated conditions for 17 days and 22 days, and no crystal transformation occurred.

Claims

1. A crystalline form of the compound represented by formula (I), characterized in that Selected from Form A crystal form, Form B crystal form, Form C crystal form, Form D crystal form, Form E crystal form, Form F crystal form and Form G crystal form, The X-ray powder diffraction pattern of the Form A crystal form has characteristic diffraction peaks at the following 2θ angles: 6.39±0.2°, 13.85±0.2°; The X-ray powder diffraction pattern of the Form B crystal form has characteristic diffraction peaks at the following 2θ angles: 5.70±0.2°, 9.54±0.2°, and 13.90±0.2°; The X-ray powder diffraction pattern of the Form C crystal form has characteristic diffraction peaks at the following 2θ angles: 6.10±0.2°, 12.30±0.2°; The X-ray powder diffraction pattern of the Form D crystal form has characteristic diffraction peaks at the following 2θ angles: 6.45±0.2°, 12.95±0.2°, and 13.65±0.2°; The X-ray powder diffraction pattern of the Form E crystal form has characteristic diffraction peaks at the following 2θ angles: 6.81±0.2°, 13.73±0.2°, and 15.89±0.2°; The X-ray powder diffraction pattern of the Form F crystal form has characteristic diffraction peaks at the following 2θ angles: 6.73±0.2°, 9.07±0.2°; The X-ray powder diffraction pattern of the Form G crystal form has characteristic diffraction peaks at the following 2θ angles: 14.75±0.2° and 17.72±0.2°.

2. The crystal form according to claim 1, characterized in that The X-ray powder diffraction pattern of the Form A crystal form has characteristic diffraction peaks at the following 2θ angles: 6.39±0.2°, 13.85±0.2°, and 17.25±0.2°; preferably, the X-ray powder diffraction pattern of the Form A crystal form has characteristic diffraction peaks at the following 2θ angles: 6.39±0.2°, 12.70±0.2°, 13.85±0.2°, 15.30±0.2°, 17.25±0.2°, and 25.06±0.2°; more preferably, the X-ray powder diffraction pattern of the Form A crystal form has characteristic diffraction peaks at the following 2θ angles: 6.39±0.2°, 9.28±0.2°, 10.75±0.2°, 11.46±0.2°, 12.70±0.2°, 12.93±0.2°, 13.85±0.2°, 14.55±0.2°, 15.30±0.2°, 16.30±0.2°, 16.83±0.2°, 17.25±0.2°, 18.52±0.2°, 18.94±0.2°, 20.37±0.2°, 20.83±0.2°, 21.65±0.2°, 22.97±0.2°, 24.18±0.2°, 25.06±0.2°, 25.94±0.2°, 27.40±0.2°, 28.96±0.2°, 29.88±0.2°, 30.78±0.2°, 32.50±0.2°, 33.16±0.2°; Also preferably, the XPRD spectrum of the Form A crystal form is shown in Figure 1.

3. The crystal form according to any one of claims 1 to 2, characterized in that The Form A crystal form has one or both of the following characteristics: (1) The differential scanning calorimetry curve of Form A crystal form has an endothermic signal at 40°C; the DSC spectrum of the preferred Form A crystal form is shown in Figure 2; (2) The thermogravimetric analysis curve of Form A crystal form shows a weight loss of 0.9% during heating to 100°C; the TGA spectrum of the preferred Form A crystal form is shown in Figure 3.

4. The crystal form according to claim 1, characterized in that The X-ray powder diffraction pattern of the Form B crystal form has characteristic diffraction peaks at the following 2θ angles: 5.70±0.2°, 9.54±0.2°, 13.90±0.2°, and 17.48±0.2°; Preferably, the X-ray powder diffraction pattern of the Form B crystal form has characteristic diffraction peaks at the following 2θ angles: 5.70±0.2°, 9.54±0.2°, 13.90±0.2°, 16.93±0.2°, 17.48±0.2°, and 17.72±0.2°; More preferably, the X-ray powder diffraction pattern of the Form B crystal form has characteristic diffraction peaks at the following 2θ angles: 4.40±0.2°, 5.70±0.2°, 6.52±0.2°, 7.78±0.2°, 8.11±0.2°, 8.74±0.2°, 9.54±0.2°, 11.46±0.2°, 12.66±0.2°, 12.94±0.2°, 13.35±0.2°, 13.90±0.2°, 14. 0.2°, 14.83±0.2°, 15.33±0.2°, 15.80±0.2°, 16.93±0.2°, 17.48±0.2°, 17.72±0.2°, 18.47±0.2°, 18.66±0.2°, 19.11±0.2°, 19.61±0.2°, 20.24±0.2°, 20.77±0.2°, 21.45±0.2°, 22.07±0.2°, 22.91±0.2°, 23.55±0.2°, 24.28±0.2°, 25.09±0.2°, 25.41±0.2°, 25.91±0.2°, 26.16±0.2°, 27.19±0.2°, 27.99±0.2°, 28.58±0.2°, 29.38±0.2°, 29.97±0.2°, 31.30 ±0.2°, 32.04±0.2°, 32.95±0.2°, 33.23±0.2°, 33.91±0.2°, 34.25±0.2°, 34.88±0.2°, 35.35±0.2°, 36.06±0.2°, 37.34±0.2°, 38.19±0.2°, 39.46±0.2°, 42.23±0.2°, 44.02±0.2°; Also preferably, the XPRD spectrum of the Form B crystal form is shown in Figure 4.

5. The crystal form according to claim 1 or 4, characterized in that The Form B crystal form has one or both of the following characteristics: (1) The differential scanning calorimetry curve of Form B crystal form has an endothermic signal at 31°C; the DSC spectrum of the preferred Form B crystal form is shown in Figure 5; (2) Thermogravimetric analysis of Form B shows a 1.0% weight loss during heating to 150°C. The TGA spectrum of the preferred Form B is shown in FIG6 .

6. The crystal form according to claim 1, characterized in that The X-ray powder diffraction pattern of the Form C crystal form has characteristic diffraction peaks at the following 2θ angles: 6.10±0.2°, 12.30±0.2°, 13.22±0.2°, and 15.00±0.2°; Preferably, the X-ray powder diffraction pattern of the Form C crystal form has characteristic diffraction peaks at the following 2θ angles: 6.10±0.2°, 9.89±0.2°, 10.68±0.2°, 12.30±0.2°, 13.22±0.2°, 13.90±0.2°, 15.00±0.2°, 15.82±0.2°, 16.63±0.2°, 17.86±0.2°, 18.13±0.2°, 18.68±0.2°, 19.98±0.2° °, 20.41±0.2°, 21.84±0.2°, 22.77±0.2°, 23.79±0.2°, 24.14±0.2°, 24.53±0.2°, 26.10±0.2°, 26.52±0.2°, 26.91±0.2°, 27.50±0.2°, 28.21±0.2°, 30.06±0.2°, 31.18±0.2°, 32.28±0.2°, 33.12±0.2°; More preferably, the XPRD spectrum of the Form C crystal form is shown in Figure 7.

7. The crystal form according to any one of claims 1 or 6, characterized in that The Form C crystal form has one or both of the following characteristics: (1) The differential scanning calorimetry curve of Form C crystal form has endothermic signals at 33°C, 158°C, and 213°C; the DSC spectrum of the preferred Form C crystal form is shown in FIG8 ; (2) Thermogravimetric analysis of Form C shows a 9.8% weight loss during heating to 250°C. The TGA spectrum of the preferred Form C is shown in FIG9 .

8. The crystal form according to claim 1, characterized in that The X-ray powder diffraction pattern of the Form D crystal form has characteristic diffraction peaks at the following 2θ angles: 6.45±0.2°, 10.98±0.2°, 12.95±0.2°, 13.41±0.2°, 13.65±0.2°, and 16.30±0.2°; Preferably, the Form The X-ray powder diffraction pattern of Form D has characteristic diffraction peaks at the following 2θ angles: 6.45±0.2°, 9.41±0.2°, 10.13±0.2°, 10.98±0.2°, 11.59±0.2°, 12.95±0.2°, 13.41±0.2°, 13.65±0.2°, 14.42±0.2°, 15.55±0.2°, 15.79±0.2°, 16.30±0.2°, 16.89±0.2°, 17.50±0.2°, 17.97±0.2°, 18.26±0.2°, 18.81±0.2°, 19.49±0.2°, 19.73±0.2°, 20.02±0.2°, 20. 35±0.2°, 20.66±0.2°, 21.38±0.2°, 21.67±0.2°, 22.07±0.2°, 22.75±0.2°, 23.82±0.2°, 24.66±0.2°, 25.87±0.2°, 26.52±0.2°, 26.84±0.2°, 27.50±0 .2°, 28.76±0.2°, 29.35±0.2°, 29.71±0.2°, 31.40±0.2°, 31.95±0.2°, 32.81±0.2°, 33.29±0.2°, 34.17±0.2°, 36.99±0.2°, 38.16±0.2°, 39.46±0.2°; More preferably, the XPRD spectrum of the Form D crystal form is shown in Figure 10.

9. The crystal form according to claim 1 or 8, characterized in that The Form D crystal form has one or both of the following characteristics: (1) The differential scanning calorimetry curve of Form D crystal form has endothermic signals at 70°C and 199°C; the DSC spectrum of the preferred Form D crystal form is shown in FIG11 ; (2) Thermogravimetric analysis of Form D shows a 2.5% weight loss during heating to 150°C. The TGA spectrum of the preferred Form D is shown in FIG12 .

10. The crystal form according to claim 1, characterized in that The X-ray powder diffraction pattern of the Form E crystal form has characteristic diffraction peaks at the following 2θ angles: 6.81±0.2°, 13.11±0.2°, 13.73±0.2°, 15.49±0.2°, 15.89±0.2°, and 19.37±0.2°; Preferably, the X-ray powder diffraction pattern of the Form E crystal form has characteristic diffraction peaks at the following 2θ angles: 6.81±0.2°, 9.93±0.2°, 10.59±0.2°, 11.59±0.2°, 13.11±0.2°, 13.73±0.2°, 15.49±0.2°, 15.89±0.2°, 16.58±0.2°, 17.15±0.2°, 17.69±0.2°, 18.19±0.2°, 19.12±0.2°, 19.37±0.2°, 20. 91±0.2°, 21.40±0.2°, 22.16±0.2°, 23.97±0.2°, 25.32±0.2°, 25.94±0.2°, 26.67±0.2°, 27.50±0.2°, 29.00±0.2°, 30.13±0.2°, 31.07±0.2°, 32.57±0.2°, 33.65±0.2°, 35.92±0.2°, 37.48±0.2°, 39.50±0.2°, 42.10±0.2°; More preferably, the XPRD spectrum of the Form E crystal form is shown in Figure 13.

11. The crystal form according to claim 1 or 10, characterized in that The Form E crystal form has one or both of the following characteristics: (1) The differential scanning calorimetry curve of the Form E crystal form has endothermic signals at 40°C, 151°C, 174°C, and 191°C; the DSC spectrum of the preferred Form E crystal form is shown in FIG14 ; (2) Thermogravimetric analysis of the Form E crystal showed a 2.7% weight loss during heating to 150°C. The TGA spectrum of the preferred Form E crystal is shown in FIG15 .

12. The crystal form according to claim 1, characterized in that The X-ray powder diffraction pattern of the Form F crystal form has characteristic diffraction peaks at the following 2θ angles: 6.73±0.2°, 9.07±0.2°, 13.33±0.2°, 18.17±0.2°, and 19.20±0.2°; Preferably, the X-ray powder diffraction pattern of the Form F crystal form has characteristic diffraction peaks at the following 2θ angles: 6.32±0.2°, 6.73±0.2°, 9.07±0.2°, 13.33±0.2°, 17.04±0.2°, 17.81±0.2°, 18.17±0.2°, 19.20±0.2°, 21.08±0.2°, and 21.30±0.2°; More preferably, the X-ray powder diffraction pattern of the Form F crystal form has characteristic diffraction peaks at the following 2θ angles: 4.56±0.2°, 6.32±0.2°, 6.73±0.2°, 7.82±0.2°, 9.07±0.2°, 10.41±0.2°, 11.65±0.2°, 12.66±0.2°, 13.33±0.2°, 13.62±0 .2°, 14.63±0.2°, 15.00±0.2°, 15.24±0.2°, 15.58±0.2°, 16.08±0.2°, 16.47±0.2°, 17.04±0.2°, 17.81±0.2°, 18.17±0.2°, 18.68±0.2°, 19.20±0.2°, 19.98 ±0.2°, 20.45±0.2°, 21.08±0.2°, 21.30±0.2°, 21.97±0.2°, 22.62±0.2°, 22.80±0.2°, 23.50±0.2°, 23.85±0.2°, 24.09±0.2°, 24.39±0.2°, 24.77±0.2°, 25 .72±0.2°, 26.29±0.2°, 26.83±0.2°, 27.44±0.2°, 28.12±0.2°, 28.89±0.2°, 29.16±0.2°, 29.51±0.2°, 30.46±0.2°, 31.47±0.2°, 32.06±0.2°, 32.81±0.2°; More preferably, the XPRD spectrum of the Form F crystal form is shown in Figure 16.

13. The crystal form according to claim 1 or 12, characterized in that The Form F crystalline form has one or both of the following characteristics: (1) The differential scanning calorimetry curve of Form F crystal form has endothermic signals at 102°C, 151°C, and 174°C; the DSC spectrum of the preferred Form F crystal form is shown in FIG17 ; (2) Thermogravimetric analysis of Form F shows a 7.8% weight loss during heating to 100°C. The TGA spectrum of the preferred Form F is shown in FIG18 .

14. The crystal form according to claim 1, characterized in that The X-ray powder diffraction pattern of the Form G crystal form has characteristic diffraction peaks at the following 2θ angles: 14.75±0.2°, 17.72±0.2°, 18.47±0.2°, and 19.22±0.2°; Preferably, the X-ray powder diffraction pattern of the Form G crystal form has characteristic diffraction peaks at the following 2θ angles: 7.03±0.2°, 14.10±0.2°, 14.75±0.2°, 15.49±0.2°, 17.06±0.2°, 17.72±0.2°, 18.47±0.2°, 19.22±0.2°, and 24.61±0.2°; More preferably, the X-ray powder diffraction pattern of the Form G crystal form has characteristic diffraction peaks at the following 2θ angles: 7.03±0.2°, 8.02±0.2°, 8.21±0.2°, 8.50±0.2°, 8.97±0.2°, 9.49±0.2°, 9.99±0.2°, 10.67±0.2°, 11.04±0.2°, 11.69±0.2°, 12.78± 0.2°, 13.64±0.2°, 14.10±0.2°, 14.75±0.2°, 15.49±0.2°, 16.08±0.2°, 16.50±0.2°, 17.06±0.2°, 17.72±0.2°, 18.47±0.2°, 18.86±0.2°, 19.22±0.2°, 19.73±0.2°, 20.20±0.2°, 20.94±0.2°, 21.29±0.2°, 21.53±0.2°, 22.83±0.2°, 23.46±0.2°, 24.24±0.2°, 24.61±0.2°, 24.99±0.2°, 25.73±0.2°, 26.58±0.2°, 27.50±0.2°, 28.54 ±0.2°, 29.13±0.2°, 29.77±0.2°, 30.43±0.2°, 31.14±0.2°, 31.95±0.2°, 32.57±0.2°, 33.55±0.2°, 35.05±0.2°, 36.42±0.2°, 36.80±0.2°, 38.82±0.2°, 40.87±0.2°; Also preferably, the XPRD spectrum of the Form G crystal form is shown in Figure 19.

15. The crystal form according to any one of claims 1 or 14, characterized in that The Form G crystal form has one or both of the following characteristics: (1) The differential scanning calorimetry curve of the Form G crystal form has endothermic signals at 152°C and 175°C; the DSC spectrum of the preferred Form G crystal form is shown in FIG20 ; (2) Thermogravimetric analysis of the Form G crystal showed a weight loss of 0.6% during heating to 150°C. The TGA spectrum of the preferred Form G crystal is shown in FIG21 .

16. Use of the crystal form according to any one of claims 1 to 15 in preparing a medicament for treating immune regulation-related diseases.

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