A salt form of a biphenyl compound as an immunomodulator, a crystal form thereof, and a method for preparing the same

Abstract

The application discloses a salt type and crystal form of a biphenyl compound (I) as an immunomodulator, a preparation method of the salt type and the crystal form, and application of the salt type and the crystal form in preparation of related drugs of the immunomodulator.

Description

[0001] This application is a divisional application filed on April 25, 2023, with application number CN202310472954.1, entitled "A salt form, crystal form and preparation method of a biphenyl compound as an immunomodulator". Technical Field

[0002] This invention belongs to the field of medicinal chemistry, specifically relating to the salt form and crystal form of a biphenyl compound as an immunomodulator, and its preparation method, as well as the application of the salt form and crystal form in the preparation of drugs for treating immunomodulatory related diseases. Background Technology

[0003] Tumor immunotherapy is a novel treatment method that stimulates the body's immune system, enhancing its own anti-tumor immunity to inhibit or kill tumor cells. This method has achieved groundbreaking progress after more than a century of research. In 2013, *Science* magazine listed tumor immunotherapy as the top scientific breakthrough of the year (Couzin-Frankel J., 2013, *Science*, 342: 1432-1433), making it one of the most promising fields of anti-tumor treatment.

[0004] Compared to normal cells, tumor cells have a variety of 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 T cells are activated by antigen recognition signals mediated by T cell receptors (TCRs), they comprehensively regulate T cell effects through co-stimulatory and co-inhibitory signals. These include inhibitory receptors such as the V-domain immunoglobulinsuppressor of T-cell activation (VISTA), T cell immunoglobulin and mucin domain-containing-3 (TIM3), and lymphocyte activation gene 3 (LAG3), as well as inhibitory receptors such as CD28, CD134 (OX40), and glucocorticoid-induced TNFR-related protein. Immune checkpoints are activating receptors for stimulatory signals such as GITR, CD137, CD27, and HVEM (Mellman I., Coukos G., Dranoff G., 2011, Nature, 480: 480-489). Under normal physiological conditions, immune checkpoints participate in maintaining immune tolerance to self-antigens to avoid autoimmune diseases, and also prevent excessive activation of the immune response leading to tissue damage. However, in tumor cells, they can evade immune killing by inhibiting T cell activation through immune checkpoints. Therefore, it is necessary to reactivate T cells to attack tumor cells by activating co-stimulatory signals (stepping on the "accelerator") and inhibiting co-inhibitory signals (releasing the "brake"), thereby achieving tumor immunotherapy.

[0005] PD-1 is expressed on activated T cells, B cells, and bone marrow cells. Belonging to the CD28 family, it is a type 1 transmembrane glycoprotein on T cells, composed of 288 amino acids. The molecular structure of PD-1 consists of an extracellular region resembling immunoglobulin IgV (amino acids 35-145), a transmembrane region, and a cytoplasmic tail region that connects to a signal peptide. The extracellular region binds to ligands and plays an important role (Cheng X., Veverka V., Radhakrishnan A., et al. 2013, J. Biol.Chem., 288: 11771-11785). Programmed death protein ligand 1 (PD-L1) is one of the ligands of PD-1, belonging to the B7 family. It is continuously expressed on various tumor cells, T cells, antigen-presenting cells (APCs), and various non-hematopoietic cells. It is also a type 1 transmembrane glycoprotein, composed of 290 amino acids. The interaction between PD-1 and PD-L1 inhibits T cell activation, which is crucial for maintaining immune tolerance in normal organisms. However, in tumor cells and during viral infection, PD-1 is induced to be highly expressed on T cells, and PD-L1 expression is upregulated, leading to sustained activation of the PD-1 signaling pathway and inhibition of T cell proliferation, resulting in immune escape by tumor cells and pathogens (Fuller MJ, Callendret B., Zhu B., et al. 2013, Proc. Natl. Acad. Sci. USA., 110: 15001-15006; Dolan D.E., 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 numerous PD-1 and PD-L1 antibody drugs that have been launched in recent years have fully demonstrated that blocking the PD-1 / PD-L1 interaction is a very effective treatment in the immunotherapy of tumors and many other immune-related diseases.

[0006] Studies have found that PD-L1 can interact with CD80 and inhibit the binding of PD-L1 and PD-1, as well as the ability to suppress T cell activation. Therefore, blocking the immune activation caused by the CD80 / PD-L1 interaction may also promote enhanced T cell activity, thus providing new therapeutic opportunities for immune-related diseases (Sugiura D., Maruhashi T., Okazakill-mi, et al. 2019, Science, 364: 558-566).

[0007] Significant progress has been made in targeting PD-1 / PD-L1 antibody drugs to date. However, due to their large molecular weight, antibody drugs have relatively weak tissue penetration, potentially affecting their effectiveness in treating solid tumors. Secondly, antibody drugs are highly immunogenic, potentially causing serious immune system-related side effects. Furthermore, antibody drugs require injection, leading to issues with medication adherence. Compared to antibody drugs, small-molecule immunomodulators offer several advantages, including differences in molecular mechanisms, greater tissue penetration, oral administration, and the ability to minimize side effects through pharmacological modifications. Additionally, small-molecule inhibitors will have a lower price advantage. Summary of the Invention

[0008] This invention provides pharmaceutically acceptable salts of the compounds represented by formula (I) or solvates of said pharmaceutically acceptable salts.

[0009] .

[0010] The compound shown in formula (I) is described in patent CN202180004723.7, the entire contents of which are incorporated herein by reference.

[0011] The pharmaceutically acceptable salt of the compound shown in formula (I) of the present invention is prepared by reacting the compound shown in formula (I) with a basic compound, wherein the basic compound includes an inorganic base or an organic base.

[0012] In some embodiments of the present invention, the inorganic base is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, lithium hydroxide, sodium carbonate, and sodium bicarbonate.

[0013] In some embodiments of the present invention, the inorganic base is preferably sodium hydroxide or potassium hydroxide.

[0014] In some embodiments of the present invention, sodium hydroxide is most preferably used as the inorganic base.

[0015] In some embodiments of the present invention, the organic base is selected from meglumine, ethanolamine, diethanolamine, triethanolamine, tert-butylamine, basic amino acids, diethylamine, triethylamine, cyclohexylamine, dicyclohexylamine, benzylamine, dibenzylamine, and N-methylbenzylamine.

[0016] In some embodiments of the present invention, the organic base is preferably meglumine.

[0017] In some embodiments of the present invention, the salt-forming ratio of the compound shown in formula (I) to the basic compound is 1:2 to 2:1, preferably 1:1.

[0018] The pharmaceutically acceptable salt of the compound shown in formula (I) of the present invention is also prepared by reacting the compound shown in formula (I) with an acidic compound, wherein the acidic compound is an inorganic acid or an organic acid.

[0019] In some embodiments of the present invention, the inorganic acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, and nitric acid.

[0020] In some embodiments of the present invention, the inorganic acid is preferably hydrochloric acid, sulfuric acid, or phosphoric acid.

[0021] In some embodiments of the present invention, the inorganic acid is preferably hydrochloric acid or sulfuric acid.

[0022] In some embodiments of the present invention, the inorganic acid is most preferably hydrochloric acid.

[0023] In some embodiments of the present invention, the organic acid is selected from methanesulfonic acid, p-toluenesulfonic acid, L-camphorsulfonic acid, oxalic acid, maleic acid, fumaric acid, L-tartaric acid, citric acid, L-malic acid, acidic amino acids, benzenesulfonic acid, benzoic acid, succinic acid, and glycolic acid.

[0024] In some embodiments of the present invention, the organic acid is preferably methanesulfonic acid, p-toluenesulfonic acid, L-camphorsulfonic acid, oxalic acid, maleic acid, fumaric acid, L-tartaric acid, citric acid, or L-malic acid.

[0025] In some embodiments of the present invention, the organic acid is more preferably methanesulfonic acid, oxalic acid, maleic acid, fumaric acid, or citric acid.

[0026] In some embodiments of the present invention, the organic acid is most preferably maleic acid.

[0027] In some embodiments of the present invention, the salt formation ratio of the compound shown in formula (I) to the acidic compound is 1:2 to 2:1, preferably 1:2.

[0028] The present invention further provides the compound (sodium salt) of formula (II) in crystal form Type A, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angles: 8.11 ± 0.2. ° 9.39±0.2 ° 11.88±0.2 ° ,

[0029] .

[0030] In some embodiments of the present invention, the X-ray powder diffraction pattern of the Type A crystal form of the compound (sodium salt) shown in formula (II) above exhibits a characteristic diffraction peak at the following 2θ angle: 5.78 ± 0.2. ° 8.11±0.2 ° 9.39±0.2 ° 11.30±0.2 ° 11.88±0.2 ° 12.43±0.2 ° 13.35±0.2 ° 16.31±0.2 ° 18.36±0.2 ° 18.85±0.2 ° 20.33±0.2 ° .

[0031] In some embodiments of the present invention, the X-ray powder diffraction pattern of the Type A crystal form of the compound (sodium salt) shown in formula (II) above exhibits a characteristic diffraction peak at the following 2θ angle: 5.78 ± 0.2. ° 8.11±0.2 ° 9.39±0.2 ° 11.30±0.2 ° 11.88±0.2 ° 12.43±0.2 ° 13.01±0.2 ° 13.35±0.2 ° 15.29±0.2 ° 16.31±0.2 ° 16.66±0.2 ° 18.07±0.2 ° 18.36±0.2 ° 18.85±0.2 ° 20.33±0.2 ° .

[0032] In some embodiments of the present invention, the X-ray powder diffraction pattern of the Type A crystal form of the compound (sodium salt) shown in formula (II) above exhibits a characteristic diffraction peak at the following 2θ angle: 5.78 ± 0.2. ° 8.11±0.2 ° 9.39±0.2 ° 11.30±0.2 ° 11.88±0.2 ° 12.43±0.2 ° 13.01±0.2 °13.35±0.2 ° 15.29±0.2 ° 16.31±0.2 ° 16.66±0.2 ° 17.23±0.2 ° 18.07±0.2 ° 18.36±0.2 ° 18.85±0.2 ° 20.33±0.2 ° 21.36±0.2 ° 22.70±0.2 ° 23.65±0.2 ° 24.56±0.2 ° 24.78±0.2 ° 25.83±0.2 ° 26.62±0.2 ° 27.29±0.2 ° 27.65±0.2 ° 28.34±0.2 ° 29.41±0.2 ° 32.32±0.2 ° 33.13±0.2 ° 34.60±0.2 ° .

[0033] In some embodiments of the present invention, the compound (sodium salt) of formula (II) above, in crystal form Type A, has the following XPRD spectrum: Figure 1 As shown.

[0034] In some embodiments of the present invention, the XPRD spectrum analysis data of the Type A crystal form of the compound (sodium salt) shown in formula (II) above are shown in Table 1.

[0035]

[0036] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (sodium salt) of the above formula (II) Type A crystal form has a relatively wide endothermic signal corresponding to TGA weight loss at around 25ºC-130ºC.

[0037] In some embodiments of the present invention, the differential scanning calorimetry curves of the compound (sodium salt) of the above formula (II) Type A crystal form have endothermic peaks at 187±3ºC and 283±3ºC.

[0038] In some embodiments of the present invention, the compound (sodium salt) of formula (II) above, in crystal form Type A, has the following DSC spectrum: Figure 2 As shown.

[0039] In some embodiments of the present invention, the thermogravimetric analysis curve of the Type A crystal form of the compound (sodium salt) shown in formula (II) above shows a weight loss of 9.6% during heating to 150ºC.

[0040] In some embodiments of the present invention, the compound (sodium salt) of formula (II) above, in crystal form Type A, has the following TGA spectrum: Figure 3 As shown.

[0041] The present invention further provides the compound (potassium salt) of formula (Ⅲ) in crystal form Type A, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angles: 8.08 ± 0.2. ° 9.42±0.2 ° 11.94±0.2 ° ,

[0042] .

[0043] In some embodiments of the present invention, the X-ray powder diffraction pattern of the compound (potassium salt) of type A crystal form shown in formula (Ⅲ) above exhibits characteristic diffraction peaks at the following 2θ angle: 8.08 ± 0.2 ° 9.42±0.2 ° 11.94±0.2 ° 16.27±0.2 ° .

[0044] In some embodiments of the present invention, the X-ray powder diffraction pattern of the compound (potassium salt) of formula (Ⅲ) above, type A, exhibits a characteristic diffraction peak at the following 2θ angle: 5.81 ± 0.2. ° 8.08±0.2 ° 8.53±0.2 ° 9.42±0.2 ° 11.15±0.2 ° 11.94±0.2 ° 12.34±0.2 ° 13.08±0.2 ° 16.27±0.2 ° 18.26±0.2 ° 18.78±0.2 ° 20.08±0.2 ° 24.94±0.2 ° .

[0045] In some embodiments of the present invention, the X-ray powder diffraction pattern of the compound (potassium salt) of formula (Ⅲ) above, type A, exhibits a characteristic diffraction peak at the following 2θ angle: 5.81 ± 0.2. ° 8.08±0.2 ° 8.53±0.2 ° 9.42±0.2 ° 11.15±0.2 ° 11.94±0.2 ° 12.34±0.2 ° 13.08±0.2 ° 15.18±0.2 ° 15.45±0.2 ° 16.27±0.2 ° 16.66±0.2 ° 17.21±0.2 ° 17.47±0.2 ° 17.93±0.2 ° 18.26±0.2 ° 18.78±0.2 ° 20.08±0.2 ° 21.22±0.2 ° 22.38±0.2 ° 23.58±0.2 ° 24.24±0.2 ° 24.51±0.2 ° 24.94±0.2 ° 25.70±0.2 ° 26.56±0.2 ° 27.57±0.2 ° 29.71±0.2 ° 30.91±0.2 ° 32.23±0.2 ° 32.94±0.2 ° 34.21±0.2 ° .

[0046] In some embodiments of the present invention, the compound (potassium salt) of formula (Ⅲ) above, in crystal form Type A, has the following XPRD spectrum: Figure 4 As shown.

[0047] In some embodiments of the present invention, the XPRD spectrum analysis data of the compound (potassium salt) of the above formula (Ⅲ) in crystal form Type A are shown in Table 2.

[0048]

[0049] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (potassium salt) of the above formula (Ⅲ) Type A crystal form has a relatively wide endothermic signal corresponding to TGA weight loss at around 25ºC-115ºC.

[0050] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (potassium salt) of the above formula (Ⅲ) Type A crystal form has an endothermic peak at 191±3ºC.

[0051] In some embodiments of the present invention, the compound (potassium salt) of formula (Ⅲ) above, in crystal form Type A, has the following DSC spectrum: Figure 5 As shown.

[0052] In some embodiments of the present invention, the thermogravimetric analysis curve of the compound (potassium salt) of the above formula (Ⅲ) Type A crystal form shows an 11.1% weight loss during heating to 150ºC.

[0053] In some embodiments of the present invention, the compound (potassium salt) of formula (Ⅲ) above, in crystal form Type A, has the following TGA spectrum: Figure 6 As shown.

[0054] This invention further provides the compound (glucamine salt) of formula (Ⅳ) in crystal form Type A, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 4.98±0.2 ° ,

[0055] .

[0056] In some embodiments of the present invention, the X-ray powder diffraction pattern of the compound (glucamine salt) of formula (Ⅳ) above, type A, exhibits characteristic diffraction peaks at the following 2θ angle: 3.43 ± 0.2. ° 4.98±0.2 ° 6.43±0.2 ° .

[0057] In some embodiments of the present invention, the X-ray powder diffraction pattern of the compound (glucamine salt) of formula (Ⅳ) above, type A, exhibits characteristic diffraction peaks at the following 2θ angle: 3.43 ± 0.2. ° 4.98±0.2 ° 6.43±0.2 ° 8.41±0.2 ° 8.91±0.2 ° .

[0058] In some embodiments of the present invention, the X-ray powder diffraction pattern of the compound (glucamine salt) of formula (Ⅳ) above, type A, exhibits characteristic diffraction peaks at the following 2θ angle: 3.43 ± 0.2. ° 4.98±0.2 ° 6.43±0.2 ° 8.41±0.2 ° 8.91±0.2 ° 12.82±0.2 ° 16.72±0.2 ° 19.81±0.2 ° .

[0059] In some embodiments of the present invention, the compound (glucamine salt) of formula (Ⅳ) above, in crystal form Type A, has the following XPRD spectrum: Figure 7 As shown.

[0060] In some embodiments of the present invention, the XPRD spectral analysis data of the compound (glucamine salt) of the above formula (Ⅳ) in crystal form Type A are shown in Table 3.

[0061]

[0062] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (glucamine salt) of the above formula (Ⅳ) Type A crystal form has a relatively broad endothermic signal corresponding to TGA weight loss at around 60ºC.

[0063] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (glucamine salt) of the above formula (Ⅳ) Type A crystal form has an endothermic peak at 170±3ºC.

[0064] In some embodiments of the present invention, the compound (glucamine salt) of formula (Ⅳ) above, in crystal form Type A, has the following DSC spectrum: Figure 8 As shown.

[0065] In some embodiments of the present invention, the thermogravimetric analysis curve of the compound (glucamine salt) of the Type A crystal form shown in formula (Ⅳ) above shows an 8.0% weight loss during heating to 180ºC.

[0066] In some embodiments of the present invention, the compound (glucamine salt) of formula (Ⅳ) above, in crystal form Type A, has the following TGA spectrum: Figure 9 As shown.

[0067] This invention further provides the compound (sulfate) of formula (V) in crystal form Type A, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 5.31 ± 0.2. ° ,

[0068] .

[0069] In some embodiments of the present invention, the X-ray powder diffraction pattern of the compound (sulfate) of type A crystal form shown in formula (V) above exhibits a characteristic diffraction peak at the following 2θ angle: 5.31 ± 0.2. ° 15.83±0.2 ° .

[0070] In some embodiments of the present invention, the X-ray powder diffraction pattern of the compound (sulfate) of type A crystal form shown in formula (V) above exhibits a characteristic diffraction peak at the following 2θ angle: 5.31 ± 0.2. ° 7.94±0.2 ° 15.83±0.2 ° .

[0071] In some embodiments of the present invention, the X-ray powder diffraction pattern of the compound (sulfate) of type A crystal form shown in formula (V) above exhibits a characteristic diffraction peak at the following 2θ angle: 5.31 ± 0.2. ° 7.94±0.2 ° 10.65±0.2 ° 15.83±0.2 ° 17.26±0.2 ° 17.44±0.2 ° 18.45±0.2 ° 20.59±0.2 ° 21.88±0.2 ° 23.88±0.2 ° 26.75±0.2 ° 29.21±0.2 ° .

[0072] In some embodiments of the present invention, the compound (sulfate) shown in formula (V) above, in crystal form Type A, has the following XPRD spectrum: Figure 10 As shown.

[0073] In some embodiments of the present invention, the XPRD spectral analysis data of the compound (sulfate) of the Type A crystal form shown in formula (V) above are shown in Table 4.

[0074]

[0075] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (sulfate) of the Type A crystal form shown in formula (V) above has a relatively broad endothermic signal corresponding to TGA weight loss at around 62ºC.

[0076] In some embodiments of the present invention, the differential scanning calorimetry curve of the Type A crystal form of the compound (sulfate) shown in formula (V) above may have an endothermic signal after 240ºC.

[0077] In some embodiments of the present invention, the compound (sulfate) of formula (V) above, in crystal form Type A, has the following DSC spectrum: Figure 11 As shown.

[0078] In some embodiments of the present invention, the thermogravimetric analysis curve of the compound (sulfate) of the Type A crystal form shown in formula (V) above shows a weight loss of 4.8% during heating to 200ºC.

[0079] In some embodiments of the present invention, the compound (sulfate) shown in formula (V) above, in crystal form Type A, has the following TGA spectrum: Figure 12 As shown.

[0080] The present invention further provides the compound (methanesulfonate) of formula (VI) in crystal form Type A, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angles: 9.01 ± 0.2. ° 17.48±0.2 ° ,

[0081] .

[0082] In some embodiments of the present invention, the X-ray powder diffraction pattern of the compound (methanesulfonate) of formula (VI) above, type A, exhibits characteristic diffraction peaks at the following 2θ angle: 5.14 ± 0.2. ° 9.01±0.2 ° 15.71±0.2 ° 16.72±0.2 ° 17.48±0.2 ° .

[0083] In some embodiments of the present invention, the X-ray powder diffraction pattern of the compound (methanesulfonate) of formula (VI) above, type A, exhibits characteristic diffraction peaks at the following 2θ angle: 5.14 ± 0.2. ° 9.01±0.2 ° 13.15±0.2 ° 15.71±0.2 ° 16.72±0.2 ° 17.48±0.2 ° .

[0084] In some embodiments of the present invention, the X-ray powder diffraction pattern of the compound (methanesulfonate) of formula (VI) above, type A, exhibits characteristic diffraction peaks at the following 2θ angle: 5.14 ± 0.2. ° 9.01±0.2 ° 13.15±0.2 ° 14.07±0.2 ° 14.70±0.2 ° 15.08±0.2 ° 15.71±0.2 ° 16.72±0.2 ° 17.48±0.2 ° 22.67±0.2 ° 24.45±0.2 ° .

[0085] In some embodiments of the present invention, the compound (methanesulfonate) shown in formula (VI) above, in crystal form Type A, has the following XPRD spectrum: Figure 13 As shown.

[0086] In some embodiments of the present invention, the XPRD spectral analysis data of the compound (methanesulfonate) of the Type A crystal form shown in formula (VI) above are shown in Table 5.

[0087]

[0088] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (methanesulfonate) of the Type A crystal form shown in formula (VI) above has a relatively broad endothermic signal corresponding to TGA weight loss at around 60ºC.

[0089] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (methanesulfonate) of the Type A crystal form shown in formula (VI) above has an endothermic peak at 190±3ºC.

[0090] In some embodiments of the present invention, the compound (methanesulfonate) shown in formula (VI) above, in crystal form Type A, has the following DSC spectrum: Figure 14 As shown.

[0091] In some embodiments of the present invention, the thermogravimetric analysis curve of the compound (methanesulfonate) of the Type A crystal form shown in formula (VI) above shows a weight loss of 6.4% during heating to 220ºC.

[0092] In some embodiments of the present invention, the compound (methanesulfonate) shown in formula (VI) above, in crystal form Type A, has the following TGA spectrum: Figure 15 As shown.

[0093] This invention further provides the compound (p-toluenesulfonate) of formula (VII) in crystal form Type A, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 5.52 ± 0.2. ° 14.12±0.2 ° ,

[0094] .

[0095] In some embodiments of the present invention, the X-ray powder diffraction pattern of the compound (p-toluenesulfonate) of formula (VII) above, in crystal form Type A, exhibits a characteristic diffraction peak at the following 2θ angle: 5.52 ± 0.2. ° 6.20±0.2 ° 14.12±0.2 ° 18.01±0.2 ° .

[0096] In some embodiments of the present invention, the X-ray powder diffraction pattern of the compound (p-toluenesulfonate) of formula (VII) above, in crystal form Type A, exhibits a characteristic diffraction peak at the following 2θ angle: 5.52 ± 0.2. ° 6.20±0.2 ° 9.42±0.2 ° 11.14±0.2 ° 11.55±0.2 ° 12.45±0.2 ° 12.93±0.2 ° 14.12±0.2 ° 15.99±0.2 ° 17.17±0.2 ° 18.01±0.2 ° .

[0097] In some embodiments of the present invention, the X-ray powder diffraction pattern of the compound (p-toluenesulfonate) of formula (VII) above, in crystal form Type A, exhibits a characteristic diffraction peak at the following 2θ angle: 5.52 ± 0.2. ° 6.20±0.2 ° 9.42±0.2 ° 11.14±0.2 ° 11.55±0.2 ° 12.45±0.2 ° 12.93±0.2 ° 14.12±0.2 ° 15.99±0.2 ° 17.17±0.2 ° 18.01±0.2 °20.56±0.2 ° 22.62±0.2 ° 25.37±0.2 ° 25.98±0.2 ° .

[0098] In some embodiments of the present invention, the compound (p-toluenesulfonate) of formula (VII) above, in crystal form Type A, has the following XPRD spectrum: Figure 16 As shown.

[0099] In some embodiments of the present invention, the XPRD spectral analysis data of the compound (p-toluenesulfonate) of the Type A crystal form shown in formula (Ⅶ) above are shown in Table 6.

[0100]

[0101] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (p-toluenesulfonate) of the Type A crystal form shown in formula (Ⅶ) above has a relatively broad endothermic signal corresponding to TGA weight loss at around 48ºC.

[0102] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (p-toluenesulfonate) of the Type A crystal form shown in formula (Ⅶ) above has an endothermic peak at 218±3ºC.

[0103] In some embodiments of the present invention, the compound (p-toluenesulfonate) of formula (VII) above, in crystal form Type A, has the following DSC spectrum: Figure 17 As shown.

[0104] In some embodiments of the present invention, the thermogravimetric analysis curve of the Type A crystal form of the compound (p-toluenesulfonate) shown in formula (VII) above shows a weight loss of 2.4% during heating to 160ºC.

[0105] In some embodiments of the present invention, the compound (p-toluenesulfonate) of formula (VII) above, in crystal form Type A, has the following TGA spectrum: Figure 18 As shown.

[0106] The present invention further provides the compound (L-camphor sulfonate) of formula (VIII) in crystal form Type A, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 4.39 ± 0.2. ° 12.61±0.2 ° ,

[0107] .

[0108] In some embodiments of the present invention, the X-ray powder diffraction pattern of the compound (L-camphor sulfonate) of formula (VIII) above, type A, exhibits a characteristic diffraction peak at the following 2θ angle: 4.39 ± 0.2. ° 12.61±0.2 ° 13.18±0.2 ° 13.82±0.2 ° 14.46±0.2 ° 16.21±0.2 ° .

[0109] In some embodiments of the present invention, the X-ray powder diffraction pattern of the compound (L-camphor sulfonate) of formula (VIII) above, type A, exhibits a characteristic diffraction peak at the following 2θ angle: 4.39 ± 0.2. ° 9.05±0.2 ° 11.39±0.2 ° 12.61±0.2 ° 13.18±0.2 ° 13.82±0.2 ° 14.46±0.2 ° 15.67±0.2 ° 16.21±0.2 ° 16.72±0.2 ° 17.51±0.2 ° 17.97±0.2 ° .

[0110] In some embodiments of the present invention, the X-ray powder diffraction pattern of the compound (L-camphor sulfonate) of formula (VIII) above, type A, exhibits a characteristic diffraction peak at the following 2θ angle: 4.39 ± 0.2. ° 9.05±0.2 ° 11.39±0.2 ° 12.61±0.2 ° 13.18±0.2 ° 13.82±0.2 ° 14.46±0.2 ° 15.67±0.2 ° 16.21±0.2 ° 16.72±0.2 ° 17.51±0.2 ° 17.97±0.2 ° 19.36±0.2 ° 20.29±0.2 ° 23.05±0.2° 23.84±0.2 ° 24.53±0.2 ° 25.35±0.2 ° 26.40±0.2 ° 27.54±0.2 ° .

[0111] In some embodiments of the present invention, the compound (L-camphor sulfonate) of formula (VIII) above, in crystal form Type A, has the following XPRD spectrum: Figure 19 As shown.

[0112] In some embodiments of the present invention, the XPRD spectral analysis data of the compound (L-camphor sulfonate) of the Type A crystal form shown in formula (VIII) above are shown in Table 7.

[0113]

[0114] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (L-camphor sulfonate) of the Type A crystal form shown in formula (VIII) above has a relatively broad endothermic signal corresponding to TGA weight loss at around 56ºC.

[0115] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (L-camphor sulfonate) of the Type A crystal form shown in formula (VIII) above has an endothermic peak at 238±3ºC.

[0116] In some embodiments of the present invention, the compound (L-camphor sulfonate) of formula (VIII) above, in crystal form Type A, has the following DSC spectrum: Figure 20 As shown.

[0117] In some embodiments of the present invention, the thermogravimetric analysis curve of the compound (L-camphor sulfonate) of the Type A crystal form shown in formula (VIII) above shows a weight loss of 2.4% during heating to 100ºC.

[0118] In some embodiments of the present invention, the compound (L-camphor sulfonate) of formula (VIII) above, in crystal form Type A, has the following TGA spectrum: Figure 21 As shown.

[0119] The present invention further provides the compound (L-camphor sulfonate) of formula (VIII) in crystal form Type B, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 12.52 ± 0.2. ° 13.73±0.2 ° 16.09±0.2 ° .

[0120] In some embodiments of the present invention, the X-ray powder diffraction pattern of the compound (L-camphor sulfonate) of formula (VIII) above, in crystal form Type B, exhibits characteristic diffraction peaks at the following 2θ angle: 4.44 ± 0.2. ° 12.52±0.2 ° 13.73±0.2 ° 16.09±0.2 ° 16.79±0.2 ° .

[0121] In some embodiments of the present invention, the X-ray powder diffraction pattern of the compound (L-camphor sulfonate) of formula (VIII) above, in crystal form Type B, exhibits characteristic diffraction peaks at the following 2θ angle: 4.44 ± 0.2. ° 8.38±0.2 ° 12.52±0.2 ° 13.73±0.2 ° 15.67±0.2 ° 16.09±0.2 ° 16.79±0.2 ° 17.98±0.2 ° .

[0122] In some embodiments of the present invention, the X-ray powder diffraction pattern of the compound (L-camphor sulfonate) of formula (VIII) above, in crystal form Type B, exhibits characteristic diffraction peaks at the following 2θ angle: 4.44 ± 0.2. ° 8.38±0.2 ° 9.45±0.2 ° 11.22±0.2 ° 12.52±0.2 ° 13.73±0.2 ° 15.67±0.2 ° 16.09±0.2 ° 16.79±0.2 ° 17.98±0.2 ° 18.49±0.2 ° 19.53±0.2 ° 20.15±0.2 ° 20.94±0.2 ° 22.75±0.2 ° 24.40±0.2 ° 24.93±0.2 ° 26.27±0.2 ° 27.45±0.2 ° 29.01±0.2° 31.90±0.2 ° .

[0123] In some embodiments of the present invention, the compound (L-camphor sulfonate) of formula (VIII) above, in crystal form Type B, has the following XPRD spectrum: Figure 22 As shown.

[0124] In some embodiments of the present invention, the XPRD spectral analysis data of the Type B crystal form of the compound (L-camphor sulfonate) shown in formula (VIII) above are shown in Table 8.

[0125]

[0126] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (L-camphor sulfonate) of the Type B crystal form shown in formula (VIII) above has a relatively broad endothermic signal corresponding to TGA weight loss at around 65ºC.

[0127] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (L-camphor sulfonate) of the Type B crystal form shown in formula (VIII) above has an endothermic peak at 215±3ºC.

[0128] In some embodiments of the present invention, the compound (L-camphor sulfonate) of formula (VIII) above, in crystal form Type B, has the following DSC spectrum: Figure 23 As shown.

[0129] In some embodiments of the present invention, the thermogravimetric analysis curve of the Type B crystal form of the compound (L-camphor sulfonate) shown in formula (VIII) above shows a weight loss of 5.3% during heating to 180ºC.

[0130] In some embodiments of the present invention, the compound (L-camphor sulfonate) of formula (VIII) above, in crystal form Type B, has the following TGA spectrum: Figure 24 As shown.

[0131] The present invention further provides the compound (oxalate) of formula (IX) in crystal form Type A, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 9.59 ± 0.2. ° 15.49±0.2 ° ,

[0132] .

[0133] In some embodiments of the present invention, the X-ray powder diffraction pattern of the compound (oxalate) of type A crystal form shown in formula (IX) above exhibits a characteristic diffraction peak at the following 2θ angle: 7.73 ± 0.2. °9.59±0.2 ° 10.20±0.2 ° 14.06±0.2 ° 15.49±0.2 ° .

[0134] In some embodiments of the present invention, the X-ray powder diffraction pattern of the compound (oxalate) of type A crystal form shown in formula (IX) above exhibits a characteristic diffraction peak at the following 2θ angle: 5.09 ± 0.2. ° 7.73±0.2 ° 9.59±0.2 ° 10.20±0.2 ° 11.65±0.2 ° 14.06±0.2 ° 15.49±0.2 ° 16.45±0.2 ° 16.93±0.2 ° 17.50±0.2 ° 20.31±0.2 ° .

[0135] In some embodiments of the present invention, the X-ray powder diffraction pattern of the compound (oxalate) of type A crystal form shown in formula (IX) above exhibits a characteristic diffraction peak at the following 2θ angle: 5.09 ± 0.2. ° 7.73±0.2 ° 9.59±0.2 ° 10.20±0.2 ° 11.65±0.2 ° 14.06±0.2 ° 15.49±0.2 ° 15.91±0.2 ° 16.45±0.2 ° 16.93±0.2 ° 17.50±0.2 ° 18.36±0.2 ° 19.31±0.2 ° 19.78±0.2 ° 20.31±0.2 ° 21.08±0.2 ° 22.18±0.2 ° 22.93±0.2 ° 23.97±0.2 ° 24.86±0.2 ° 25.86±0.2 °26.71±0.2 ° 28.29±0.2 ° 31.53±0.2 ° 32.64±0.2 ° 33.44±0.2 ° .

[0136] In some embodiments of the present invention, the compound (oxalate) of formula (IX) above, in crystal form Type A, has the following XPRD spectrum: Figure 25 As shown.

[0137] In some embodiments of the present invention, the XPRD spectral analysis data of the compound (oxalate) of the Type A crystal form shown in formula (IX) above are shown in Table 9.

[0138]

[0139] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (oxalate) of the Type A crystal form shown in formula (IX) above has a relatively broad endothermic signal corresponding to TGA weight loss at around 41ºC.

[0140] In some embodiments of the present invention, the differential scanning calorimetry curves of the compound (oxalate) of the Type A crystal form shown in formula (IX) above have endothermic peaks at 195±3ºC and 222±3ºC.

[0141] In some embodiments of the present invention, the compound (oxalate) of formula (IX) above, in crystal form Type A, has the following DSC spectrum: Figure 26 As shown.

[0142] In some embodiments of the present invention, the thermogravimetric analysis curve of the compound (oxalate) of the Type A crystal form shown in formula (IX) above shows a weight loss of 3.7% during heating to 140ºC and a weight loss of 16.2% during the process of 140ºC-270ºC, which may correspond to the process of removing oxalic acid.

[0143] In some embodiments of the present invention, the TGA spectrum of the compound (oxalate) Type A crystal form shown in formula (IX) above is as follows: Figure 27 As shown.

[0144] The present invention further provides the Type B crystal form of the compound (oxalate) shown in formula (IX) above, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angle: 5.44±0.2. ° 11.31±0.2 ° 15.26±0.2 ° .

[0145] The present invention further provides the Type B crystal form of the compound (oxalate) shown in formula (IX) above, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angle: 5.44±0.2. ° 11.31±0.2 ° 13.70±0.2 ° 15.26±0.2 ° 16.98±0.2 ° 17.85±0.2 ° .

[0146] The present invention further provides the Type B crystal form of the compound (oxalate) shown in formula (IX) above, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angle: 5.44±0.2. ° 11.31±0.2 ° 13.70±0.2 ° 15.26±0.2 ° 16.98±0.2 ° 17.85±0.2 ° 19.98±0.2 ° 21.24±0.2 ° 22.16±0.2 ° 24.23±0.2 ° 28.34±0.2 ° .

[0147] In some embodiments of the present invention, the compound (oxalate) Type B crystal form shown in formula (IX) above has the following XPR spectrum: Figure 28 As shown.

[0148] In some embodiments of the present invention, the XPRD spectral analysis data of the compound (oxalate) of the Type B crystal form shown in formula (IX) above are shown in Table 10.

[0149]

[0150] In some embodiments of the present invention, the differential scanning calorimetry curves of the Type B crystal form of the compound (oxalate) shown in formula (IX) above have endothermic peaks at 214±3ºC and 221±3ºC.

[0151] In some embodiments of the present invention, the compound (oxalate) Type B crystal form shown in formula (IX) above has the following DSC spectrum: Figure 29 As shown.

[0152] In some embodiments of the present invention, the thermogravimetric analysis curve of the compound (oxalate) Type B crystal form shown in formula (IX) above shows a weight loss of 1.6% during heating to 100ºC and a weight loss of 19.6% during the process of 100ºC-260ºC, which may correspond to the process of removing oxalic acid.

[0153] In some embodiments of the present invention, the TGA spectrum of the compound (oxalate) Type B crystal form shown in formula (IX) above is as follows: Figure 30 As shown.

[0154] The present invention further provides the Type A crystal form of the compound (fumarate) shown in formula (X), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angle: 5.59±0.2. ° 5.90±0.2 ° ,

[0155] .

[0156] The present invention further provides the Type A crystal form of the compound (fumarate) shown in formula (X), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angle: 5.59±0.2. ° 5.90±0.2 ° 11.27±0.2 ° 16.50±0.2 ° .

[0157] The present invention further provides the Type A crystal form of the compound (fumarate) shown in formula (X), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angle: 5.59±0.2. ° 5.90±0.2 ° 8.42±0.2 ° 8.90±0.2 ° 9.97±0.2 ° 11.27±0.2 ° 11.80±0.2 ° 13.08±0.2 ° 14.08±0.2 ° 14.90±0.2 ° 15.30±0.2 ° 16.25±0.2 ° 16.50±0.2 ° 16.94±0.2 ° 17.31±0.2 ° 17.85±0.2 ° 18.70±0.2 °19.24±0.2 ° 19.85±0.2 ° 21.47±0.2 ° 21.92±0.2 ° 22.31±0.2 ° 22.98±0.2 ° 24.51±0.2 ° 25.23±0.2 ° 25.69±0.2 ° 26.33±0.2 ° 27.02±0.2 ° 28.55±0.2 ° 30.49±0.2 ° 31.47±0.2 ° .

[0158] In some embodiments of the present invention, the compound (fumarate) of formula (X) above, in crystal form Type A, has the following XPRD spectrum: Figure 31 As shown.

[0159] In some embodiments of the present invention, the XPRD spectral analysis data of the Type A crystal form of the compound (fumarate) shown in formula (X) above are shown in Table 11.

[0160]

[0161] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (fumarate) of the Type A crystal form shown in formula (X) above has a relatively broad endothermic signal corresponding to TGA weight loss at around 71ºC.

[0162] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (fumarate) of the Type A crystal form shown in formula (X) above has an endothermic peak at 197±3ºC.

[0163] In some embodiments of the present invention, the compound (fumarate) of formula (X) above, in crystal form Type A, has the following DSC spectrum: Figure 32 As shown.

[0164] In some embodiments of the present invention, the thermogravimetric analysis curve of the compound (fumarate) of the Type A crystal form shown in formula (X) above shows a weight loss of 4.0% during heating to 100ºC and a weight loss of 8.1% during the process of 100ºC-270ºC, which may correspond to the process of removing fumaric acid.

[0165] In some embodiments of the present invention, the compound (fumarate) shown in formula (X) above, in Type A crystal form, has the following TGA spectrum: Figure 33 As shown.

[0166] The present invention further provides the Type B crystal form of the compound (fumarate) shown in formula (X) above, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angle: 5.51±0.2. ° 11.18±0.2 ° .

[0167] The present invention further provides the Type B crystal form of the compound (fumarate) shown in formula (X) above, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angle: 5.51±0.2. ° 11.18±0.2 ° 14.17±0.2 ° 15.84±0.2 ° 16.66±0.2 ° 17.64±0.2 ° 19.70±0.2 ° .

[0168] The present invention further provides the Type B crystal form of the compound (fumarate) shown in formula (X) above, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angle: 5.51±0.2. ° 11.18±0.2 ° 14.17±0.2 ° 15.84±0.2 ° 16.66±0.2 ° 17.64±0.2 ° 19.01±0.2 ° 19.70±0.2 ° 22.29±0.2 ° 24.30±0.2 ° 26.31±0.2 ° .

[0169] In some embodiments of the present invention, the compound (fumarate) of formula (X) shown above, in its Type B crystal form, has the following XPRD spectrum: Figure 34 As shown.

[0170] In some embodiments of the present invention, the XPRD spectral analysis data of the Type B crystal form of the compound (fumarate) shown in formula (X) above are shown in Table 12.

[0171]

[0172] In some embodiments of the present invention, the differential scanning calorimetry curve of the Type B crystal form of the compound (fumarate) shown in formula (X) above has a relatively broad endothermic signal corresponding to TGA weight loss at around 53ºC.

[0173] In some embodiments of the present invention, the differential scanning calorimetry curve of the Type B crystal form of the compound (fumarate) shown in formula (X) above has an endothermic peak at 193±3ºC.

[0174] In some embodiments of the present invention, the compound (fumarate) of formula (X) shown above, in its Type B crystal form, has the following DSC spectrum: Figure 35 As shown.

[0175] In some embodiments of the present invention, the thermogravimetric analysis curve of the Type B crystal form of the compound (fumarate) shown in formula (X) above shows a weight loss of 4.2% during heating to 120ºC and a weight loss of 11.7% during the process of 120ºC-270ºC, which may correspond to the process of removing fumaric acid.

[0176] In some embodiments of the present invention, the compound (fumarate) shown in formula (X) above, in its Type B crystal form, has the following TGA spectrum: Figure 36 As shown.

[0177] The present invention further provides the compound (L-tartrate) of formula (XI) in crystal form Type A, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 5.51 ± 0.2. ° 8.42±0.2 ° 11.10±0.2 ° 14.38±0.2 ° ,

[0178] .

[0179] The present invention further provides the compound (L-tartrate) of formula (XI) in crystal form Type A, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 5.51 ± 0.2. ° 8.42±0.2 ° 10.31±0.2 ° 11.10±0.2 ° 13.37±0.2 ° 14.38±0.2 ° 16.80±0.2 ° .

[0180] The present invention further provides the compound (L-tartrate) of formula (XI) in crystal form Type A, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 5.51 ± 0.2. ° 8.42±0.2 ° 10.31±0.2 ° 11.10±0.2 ° 13.37±0.2 ° 14.38±0.2 ° 16.33±0.2 ° 16.80±0.2 ° 17.44±0.2 ° 19.33±0.2 ° 22.17±0.2 ° 24.47±0.2 ° 26.87±0.2 ° .

[0181] In some embodiments of the present invention, the compound (L-tartrate) of formula (XI) above, in crystal form Type A, has the following XPRD spectrum: Figure 37 As shown.

[0182] In some embodiments of the present invention, the XPRD spectral analysis data of the compound (L-tartrate) of the Type A crystal form shown in formula (XI) above are shown in Table 13.

[0183]

[0184] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (L-tartrate) of the Type A crystal form shown in formula (XI) above has a relatively broad endothermic signal corresponding to TGA weight loss at around 56ºC.

[0185] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (L-tartrate) of the above formula (XI) in crystal form Type A has an endothermic peak at 194±3ºC.

[0186] In some embodiments of the present invention, the compound (L-tartrate) of formula (XI) above, in crystal form Type A, has the following DSC spectrum: Figure 38 As shown.

[0187] In some embodiments of the present invention, the thermogravimetric analysis curve of the compound (L-tartrate) of the Type A crystal form shown in formula (XI) above shows a weight loss of 3.4% during heating to 120ºC and a weight loss of 12.1% during the process of 120ºC-260ºC, which may correspond to the process of removing L-tartaric acid.

[0188] In some embodiments of the present invention, the compound (L-tartrate) of formula (XI) above, in crystal form Type A, has the following TGA spectrum: Figure 39 As shown.

[0189] The present invention further provides the compound (L-tartrate) of formula (XII) in crystal form Type B, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 5.26 ± 0.2. ° 15.41±0.2 ° 16.01±0.2 ° 16.68±0.2 ° 18.14±0.2 ° ,

[0190] .

[0191] The present invention further provides the compound (L-tartrate) of formula (XII) in crystal form Type B, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 4.09 ± 0.2. ° 4.55±0.2 ° 5.26±0.2 ° 12.30±0.2 ° 15.41±0.2 ° 16.01±0.2 ° 16.68±0.2 ° 18.14±0.2 ° .

[0192] The present invention further provides the compound (L-tartrate) of formula (XII) in crystal form Type B, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 4.09 ± 0.2. ° 4.55±0.2 ° 5.26±0.2 ° 6.62±0.2 ° 9.08±0.2 ° 12.30±0.2 ° 13.35±0.2 ° 14.36±0.2 ° 15.41±0.2 ° 16.01±0.2 ° 16.68±0.2 ° 18.14±0.2 ° 22.79±0.2 ° 24.05±0.2 °25.37±0.2 ° .

[0193] In some embodiments of the present invention, the compound (L-tartrate) of formula (XII) above, in crystal form Type B, has the following XPRD spectrum: Figure 40 As shown.

[0194] In some embodiments of the present invention, the XPRD spectral analysis data of the compound (L-tartrate) of the above formula (XII) in crystal form Type B are shown in Table 14.

[0195]

[0196] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (L-tartrate) of the Type B crystal form shown in formula (XII) above has a relatively broad endothermic signal corresponding to TGA weight loss at around 63ºC.

[0197] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (L-tartrate) of the above formula (XII) in the Type B crystal form has an endothermic peak at 116±3ºC.

[0198] In some embodiments of the present invention, the compound (L-tartrate) of formula (XII) above, in crystal form Type B, has the following DSC spectrum: Figure 41 As shown.

[0199] In some embodiments of the present invention, the thermogravimetric analysis curve of the compound (L-tartrate) of the Type B crystal form shown in formula (XII) above shows a weight loss of 2.8% during heating to 100ºC, a weight loss of 16.1% during heating from 100ºC to 170ºC, and a weight loss of 18.3% during heating from 170ºC to 260ºC, which may correspond to the process of removing L-tartaric acid.

[0200] In some embodiments of the present invention, the compound (L-tartrate) of formula (XII) above, in crystal form Type B, has the following TGA spectrum: Figure 42 As shown.

[0201] The present invention further provides the compound (L-malate) of formula (XIII) in crystal form Type A, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 5.72 ± 0.2. ° 11.56±0.2 ° 14.40±0.2 ° 17.40±0.2 ° ,

[0202] .

[0203] The present invention further provides the compound (L-malate) of formula (XIII) in crystal form Type A, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 5.72 ± 0.2. ° 8.61±0.2 ° 11.56±0.2 ° 13.03±0.2 ° 14.40±0.2 ° 15.63±0.2 ° 16.83±0.2 ° 17.40±0.2 ° 19.18±0.2 ° .

[0204] The present invention further provides the compound (L-malate) of formula (XIII) in crystal form Type A, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 5.72 ± 0.2. ° 8.61±0.2 ° 10.35±0.2 ° 11.56±0.2 ° 12.20±0.2 ° 13.03±0.2 ° 13.29±0.2 ° 14.40±0.2 ° 15.08±0.2 ° 15.63±0.2 ° 16.34±0.2 ° 16.83±0.2 ° 17.40±0.2 ° 18.31±0.2 ° 19.18±0.2 ° 20.29±0.2 ° 21.13±0.2 ° 22.09±0.2 ° 22.88±0.2 ° 23.94±0.2 ° 24.56±0.2 ° 25.78±0.2 ° 26.99±0.2 ° 27.67±0.2 ° 28.70±0.2 ° 29.41±0.2 ° 30.35±0.2 °32.31±0.2 ° .

[0205] In some embodiments of the present invention, the compound (L-malate) of formula (XIII) above, in crystal form Type A, has the following XPRD spectrum: Figure 43 As shown.

[0206] In some embodiments of the present invention, the XPRD spectral analysis data of the compound (L-malate) of the above formula (XIII) in crystal form Type A are shown in Table 15.

[0207]

[0208] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (L-malate) of the above formula (XIII) Type A crystal form has a relatively broad endothermic signal corresponding to TGA weight loss at around 46ºC.

[0209] In some embodiments of the present invention, the differential scanning calorimetry curves of the compound (L-malate) of the above formula (XIII) Type A crystal form have endothermic peaks at 192±3ºC and 208±3ºC.

[0210] In some embodiments of the present invention, the compound (L-malate) of formula (XIII) above, in crystal form Type A, has the following DSC spectrum: Figure 44 As shown.

[0211] In some embodiments of the present invention, the thermogravimetric analysis curve of the compound (L-malate) of the Type A crystal form shown in formula (XIII) above shows a weight loss of 2.8% during heating to 100ºC and a weight loss of 11.0% during the process of 100ºC-260ºC, which may correspond to the process of removing L-malic acid.

[0212] In some embodiments of the present invention, the compound (L-malate) of formula (XIII) above, in crystal form Type A, has the following TGA spectrum: Figure 45 As shown.

[0213] The present invention further provides the compound (L-malate) of formula (XIV) in crystal form Type B, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 5.06 ± 0.2. ° 5.47±0.2 ° ,

[0214] .

[0215] The present invention further provides the compound (L-malate) of formula (XIV) in crystal form Type B, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 5.06 ± 0.2. ° 5.47±0.2 ° 10.26±0.2 ° 11.44±0.2 ° 12.74±0.2 ° 13.29±0.2 ° 14.36±0.2 ° 15.53±0.2 ° 16.33±0.2 ° 16.81±0.2 ° 17.33±0.2 ° 18.17±0.2 ° 18.99±0.2 ° .

[0216] The present invention further provides the compound (L-malate) of formula (XIV) in crystal form Type B, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 5.06 ± 0.2. ° 5.47±0.2 ° 7.48±0.2 ° 8.59±0.2 ° 10.26±0.2 ° 11.44±0.2 ° 12.74±0.2 ° 13.29±0.2 ° 14.36±0.2 ° 15.53±0.2 ° 16.33±0.2 ° 16.81±0.2 ° 17.33±0.2 ° 18.17±0.2 ° 18.99±0.2 ° 21.07±0.2 ° 22.08±0.2 ° 22.68±0.2 ° 24.32±0.2 ° 26.04±0.2 ° 26.90±0.2 ° 29.51±0.2 ° 30.35±0.2 ° .

[0217] In some embodiments of the present invention, the compound (L-malate) of formula (XIV) above, in crystal form Type B, has the following XPRD spectrum: Figure 46 As shown.

[0218] In some embodiments of the present invention, the XPRD spectral analysis data of the Type B crystal form of the compound (L-malate) shown in formula (XIV) above are shown in Table 16.

[0219]

[0220] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (L-malate) of the above formula (XIV) Type B crystal form has a relatively broad endothermic signal corresponding to TGA weight loss at around 60ºC.

[0221] In some embodiments of the present invention, the differential scanning calorimetry curves of the compound (L-malate) of the above formula (XIV) Type B crystal form have endothermic peaks at 183±3ºC and 201±3ºC.

[0222] In some embodiments of the present invention, the compound (L-malate) of formula (XIV) above, in crystal form Type B, has the following DSC spectrum: Figure 47 As shown.

[0223] In some embodiments of the present invention, the thermogravimetric analysis curve of the compound (L-malate) of the Type B crystal form shown in formula (XIV) above shows a weight loss of 2.8% during heating to 100ºC and a weight loss of 17.4% during the process of 100ºC-270ºC, which may correspond to the process of removing L-malic acid.

[0224] In some embodiments of the present invention, the compound (L-malate) of formula (XIV) above, in its Type B crystal form, has the following TGA spectrum: Figure 48 As shown.

[0225] This invention further provides the compound (hydrochloride) of formula (XV) in crystal form Type A, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 16.35 ± 0.2. ° ,

[0226] .

[0227] The present invention further provides the compound (hydrochloride) of formula (XV) in crystal form Type A, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 13.48 ± 0.2. ° 16.35±0.2 ° .

[0228] The present invention further provides the compound (hydrochloride) of formula (XV) in crystal form Type A, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 13.48 ± 0.2. ° 16.35±0.2 ° 20.63±0.2 ° .

[0229] The present invention further provides the compound (hydrochloride) of formula (XV) in crystal form Type A, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 13.48 ± 0.2. ° 16.35±0.2 ° 20.63±0.2 ° 22.75±0.2 ° .

[0230] The present invention further provides the compound (hydrochloride) of formula (XV) in crystal form Type A, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 13.48 ± 0.2. ° 16.35±0.2 ° 20.63±0.2 ° 22.75±0.2 ° 26.08±0.2 ° 33.04±0.2 ° .

[0231] In some embodiments of the present invention, the compound (hydrochloride) of the above formula (XV) in crystal form Type A has the following XPRD spectrum: Figure 49 As shown.

[0232] In some embodiments of the present invention, the XPRD spectral analysis data of the compound (hydrochloride) of the above formula (XV) in crystal form Type A are shown in Table 17.

[0233]

[0234] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (hydrochloride) of the above formula (XV) Type A crystal form has a relatively broad endothermic signal corresponding to TGA weight loss at around 54ºC.

[0235] In some embodiments of the present invention, the differential scanning calorimetry curve of the Type A crystal form of the compound (hydrochloride) shown in the above formula (XV) may have an endothermic signal after 240ºC.

[0236] In some embodiments of the present invention, the compound (hydrochloride) of the above formula (XV) in crystal form Type A has the following DSC spectrum: Figure 50 As shown.

[0237] In some embodiments of the present invention, the thermogravimetric analysis curve of the compound (hydrochloride) of the Type A crystal form shown in the above formula (XV) shows a weight loss of 2.9% during heating to 100ºC.

[0238] In some embodiments of the present invention, the compound (hydrochloride) of the above formula (XV) in crystal form Type A has a TGA spectrum as shown below. Figure 51 As shown.

[0239] The present invention further provides the Type B crystal form of the compound (hydrochloride) shown in formula (XV), whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 6.40±0.2. ° .

[0240] The present invention further provides the Type B crystal form of the compound (hydrochloride) shown in formula (XV), whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 6.40±0.2. ° 12.85±0.2 ° .

[0241] The present invention further provides the Type B crystal form of the compound (hydrochloride) shown in formula (XV), whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 6.40±0.2. ° 12.85±0.2 ° 16.26±0.2 ° 19.09±0.2 ° 26.09±0.2 ° .

[0242] In some embodiments of the present invention, the compound (hydrochloride) of the above formula (XV) in crystal form Type B has the following XPRD spectrum: Figure 52 As shown.

[0243] In some embodiments of the present invention, the XPRD spectral analysis data of the Type B crystal form of the compound (hydrochloride) shown in the above formula (XV) are shown in Table 18.

[0244]

[0245] In some embodiments of the present invention, the differential scanning calorimetry curve of the Type B crystal form of the compound (hydrochloride) shown in the above formula (XV) has a relatively broad endothermic signal corresponding to TGA weight loss at around 71ºC.

[0246] In some embodiments of the present invention, the differential scanning calorimetry curve of the Type B crystal form of the compound (hydrochloride) shown in formula (XV) above may decompose after 280ºC.

[0247] In some embodiments of the present invention, the compound (hydrochloride) of the above formula (XV) in crystal form Type B has the following DSC spectrum: Figure 53 As shown.

[0248] In some embodiments of the present invention, the thermogravimetric analysis curve of the Type B crystal form of the compound (hydrochloride) shown in the above formula (XV) shows a weight loss of 3.6% during heating to 100ºC.

[0249] In some embodiments of the present invention, the compound (hydrochloride) of the above formula (XV) in crystal form Type B has a TGA spectrum as shown below. Figure 54 As shown.

[0250] The present invention further provides the compound (hydrochloride) of formula (XV) in crystal form Type C, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 16.64 ± 0.2. ° 23.66±0.2 ° .

[0251] The present invention further provides the compound (hydrochloride) of formula (XV) in crystal form Type C, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 14.68 ± 0.2. ° 16.64±0.2 ° 23.66±0.2 ° 27.98±0.2 ° .

[0252] The present invention further provides the compound (hydrochloride) of formula (XV) in crystal form Type C, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 6.52 ± 0.2. ° 12.64±0.2 ° 14.68±0.2 ° 16.33±0.2 ° 16.64±0.2 ° 17.19±0.2 ° 18.08±0.2 ° 18.41±0.2 ° 19.79±0.2 ° 22.30±0.2 ° 23.66±0.2 ° 24.59±0.2° 26.81±0.2 ° 27.98±0.2 ° .

[0253] The present invention further provides the compound (hydrochloride) of formula (XV) in crystal form Type C, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 6.52 ± 0.2. ° 8.31±0.2 ° 9.53±0.2 ° 10.46±0.2 ° 11.07±0.2 ° 11.65±0.2 ° 12.23±0.2 ° 12.64±0.2 ° 13.24±0.2 ° 14.04±0.2 ° 14.68±0.2 ° 15.38±0.2 ° 16.33±0.2 ° 16.64±0.2 ° 17.19±0.2 ° 18.08±0.2 ° 18.41±0.2 ° 19.00±0.2 ° 19.79±0.2 ° 20.40±0.2 ° 21.39±0.2 ° 22.30±0.2 ° 22.82±0.2 ° 23.66±0.2 ° 24.59±0.2 ° 26.81±0.2 ° 27.98±0.2 ° 30.75±0.2 ° 32.11±0.2 ° 33.16±0.2 ° 34.08±0.2 ° 35.26±0.2 ° 36.62±0.2 ° 39.19±0.2 ° 42.30±0.2 ° .

[0254] In some embodiments of the present invention, the compound (hydrochloride) of the above formula (XV) in crystal form Type C has the following XPRD spectrum: Figure 55 As shown.

[0255] In some embodiments of the present invention, the XPRD spectral analysis data of the compound (hydrochloride) of the Type C crystal form shown in the above formula (XV) are shown in Table 19.

[0256]

[0257] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (hydrochloride) of the Type C crystal form shown in the above formula (XV) has a relatively broad endothermic signal corresponding to TGA weight loss at around 61ºC.

[0258] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (hydrochloride) of the Type C crystal form shown in the above formula (XV) has an endothermic peak at 234±3ºC.

[0259] In some embodiments of the present invention, the compound (hydrochloride) of the above formula (XV) in crystal form Type C has the following DSC spectrum: Figure 56 As shown.

[0260] In some embodiments of the present invention, the thermogravimetric analysis curve of the compound (hydrochloride) of the Type C crystal form shown in the above formula (XV) shows a weight loss of 7.9% during heating to 240ºC.

[0261] In some embodiments of the present invention, the compound (hydrochloride) of the above formula (XV) in the Type C crystal form has the TGA spectrum as shown below. Figure 57 As shown.

[0262] The present invention further provides the compound (maleate) of formula (XVI) in crystal form Type A, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 5.65 ± 0.2. ° ,

[0263] .

[0264] The present invention further provides the compound (maleate) of formula (XVI) in crystal form Type A, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 5.65 ± 0.2. ° 10.33±0.2 ° 14.38±0.2 ° .

[0265] The present invention further provides the compound (maleate) of formula (XVI) in crystal form Type A, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 5.65 ± 0.2. ° 8.53±0.2 ° 10.33±0.2 ° 13.07±0.2 ° 13.41±0.2 ° 14.38±0.2 ° 14.75±0.2 ° 16.75±0.2 ° .

[0266] The present invention further provides the compound (maleate) of formula (XVI) in crystal form Type A, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 5.65 ± 0.2. ° 8.53±0.2 ° 8.92±0.2 ° 10.33±0.2 ° 10.84±0.2 ° 11.39±0.2 ° 11.59±0.2 ° 12.20±0.2 ° 13.07±0.2 ° 13.41±0.2 ° 14.38±0.2 ° 14.75±0.2 ° 15.13±0.2 ° 15.74±0.2 ° 16.30±0.2 ° 16.75±0.2 ° 17.14±0.2 ° 17.40±0.2 ° 18.18±0.2 ° 19.08±0.2 ° 20.10±0.2 ° 20.41±0.2 ° 20.70±0.2 ° 21.59±0.2 ° 22.42±0.2 ° 23.76±0.2 ° 24.11±0.2 ° 24.77±0.2 ° 26.00±0.2 °26.41±0.2 ° 27.02±0.2 ° 27.72±0.2 ° 29.48±0.2 ° 30.32±0.2 ° .

[0267] In some embodiments of the present invention, the compound (maleate) of formula (XVI) above, in crystal form Type A, has the following XPRD spectrum: Figure 58 As shown.

[0268] In some embodiments of the present invention, the XPRD spectral analysis data of the compound (maleate) of the above formula (XVI) in crystal form Type A are shown in Table 20.

[0269]

[0270] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (maleate) of the above formula (XVI) Type A crystal form has a relatively broad endothermic signal corresponding to TGA weight loss at around 38ºC.

[0271] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (maleate) of the above formula (XVI) Type A crystal form has an endothermic peak at 203±3ºC.

[0272] In some embodiments of the present invention, the compound (maleate) of formula (XVI) above, in crystal form Type A, has the following DSC spectrum: Figure 59 As shown.

[0273] In some embodiments of the present invention, the thermogravimetric analysis curve of the compound (maleate) of the Type A crystal form shown in formula (XVI) above shows a weight loss of 1.5% during heating to 100ºC and a weight loss of 10.2% during the process of heating from 100ºC to 260ºC, which may correspond to the process of removing maleic acid.

[0274] In some embodiments of the present invention, the compound (maleate) of formula (XVI) above, in crystal form Type A, has the following TGA spectrum: Figure 60 As shown.

[0275] The present invention further provides the compound (maleate) of formula (XVII) in crystal form Form A, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 5.53 ± 0.2. ° ,

[0276] .

[0277] The present invention further provides the compound (maleate) of formula (XVII) in crystal form Form A, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 5.53 ± 0.2. ° 13.59±0.2 ° 24.42±0.2 ° 26.50±0.2 ° .

[0278] The present invention further provides the compound (maleate) of formula (XVII) in crystal form Form A, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 5.53 ± 0.2. ° 8.64±0.2 ° 11.09±0.2 ° 12.80±0.2 ° 13.59±0.2 ° 15.01±0.2 ° 16.10±0.2 ° 16.66±0.2 ° 16.97±0.2 ° 17.40±0.2 ° 17.77±0.2 ° 19.31±0.2 ° 20.28±0.2 ° 21.91±0.2 ° 22.55±0.2 ° 23.62±0.2 ° 23.89±0.2 ° 24.42±0.2 ° 26.50±0.2 ° 27.68±0.2 ° 29.59±0.2 ° 32.89±0.2 ° .

[0279] In some embodiments of the present invention, the compound (maleate) of formula (XVII) in crystal form Form A has the following XPRD spectrum: Figure 61 As shown.

[0280] In some embodiments of the present invention, the XPRD spectral analysis data of the Form A crystal form of the compound (maleate) shown in formula (XVII) above are shown in Table 21.

[0281]

[0282] In some embodiments of the present invention, the differential scanning calorimetry curve of the Form A crystal form of the compound (maleate) shown in formula (XVII) above has a relatively broad endothermic signal corresponding to TGA weight loss at around 50ºC.

[0283] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (maleate) Form A crystal form shown in formula (XVII) above shows an endothermic signal of decomposition at around 184ºC.

[0284] In some embodiments of the present invention, the compound (maleate) Form A crystal form of the above formula (XVII) has the following DSC spectrum: Figure 62 As shown.

[0285] In some embodiments of the present invention, the thermogravimetric analysis curve of the compound (maleate) Form A crystal form shown in formula (XVII) above shows a weight loss of 3.5% during heating to 150ºC, and decomposition may occur above 170ºC.

[0286] In some embodiments of the present invention, the compound (maleate) Form A crystal form shown in formula (XVII) above has the following TGA spectrum: Figure 63 As shown.

[0287] The present invention further provides the compound (maleate) of formula (XVII) in crystal form Form B, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 5.20 ± 0.2. ° .

[0288] The present invention further provides the compound (maleate) of formula (XVII) in crystal form Form B, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 5.20 ± 0.2. ° 10.29±0.2 ° .

[0289] The present invention further provides the compound (maleate) of formula (XVII) in crystal form Form B, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 5.20 ± 0.2. ° 10.29±0.2 ° 15.44±0.2 ° 16.24±0.2 ° 17.62±0.2 ° 20.65±0.2 ° 22.30±0.2 ° 25.86±0.2 ° 31.14±0.2 ° .

[0290] In some embodiments of the present invention, the compound (maleate) Form B crystal form shown in formula (XVII) above has the following XPRD spectrum: Figure 64 As shown.

[0291] In some embodiments of the present invention, the XPRD spectral analysis data of the Form B crystal form of the compound (maleate) shown in formula (XVII) above are shown in Table 22.

[0292]

[0293] In some embodiments of the present invention, the differential scanning calorimetry curve of the Form B crystal form of the compound (maleate) shown in formula (XVII) above has a relatively broad endothermic signal corresponding to TGA weight loss at around 134ºC.

[0294] In some embodiments of the present invention, the differential scanning calorimetry curve of the Form B crystal form of the compound (maleate) shown in formula (XVII) above shows an endothermic signal of decomposition at around 178ºC.

[0295] In some embodiments of the present invention, the compound (maleate) Form B crystal form shown in formula (XVII) above has the following DSC spectrum: Figure 65 As shown.

[0296] In some embodiments of the present invention, the thermogravimetric analysis curve of the Form B crystal form of the compound (maleate) shown in formula (XVII) above shows a weight loss of 6.1% during heating to 150ºC, and continues to lose weight before the decomposition temperature.

[0297] In some embodiments of the present invention, the TGA spectrum of the compound (maleate) Form B shown in formula (XVII) above is as follows. Figure 66 As shown.

[0298] The present invention further provides the Form C crystal form of the compound (maleate) shown in formula (XVII), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angle: 5.57±0.2. ° 25.14±0.2 ° .

[0299] The present invention further provides the Form C crystal form of the compound (maleate) shown in formula (XVII), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angle: 5.57±0.2. ° 13.26±0.2 ° 16.59±0.2 ° 19.36±0.2 °20.26±0.2 ° 25.14±0.2 ° .

[0300] The present invention further provides the Form C crystal form of the compound (maleate) shown in formula (XVII), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angle: 5.57±0.2. ° 8.71±0.2 ° 10.09±0.2 ° 11.16±0.2 ° 11.94±0.2 ° 13.26±0.2 ° 13.61±0.2 ° 14.20±0.2 ° 15.34±0.2 ° 16.02±0.2 ° 16.59±0.2 ° 17.34±0.2 ° 17.64±0.2 ° 18.24±0.2 ° 19.09±0.2 ° 19.36±0.2 ° 20.26±0.2 ° 21.68±0.2 ° 22.30±0.2 ° 23.17±0.2 ° 23.82±0.2 ° 25.14±0.2 ° 26.36±0.2 ° 28.38±0.2 ° 29.80±0.2 ° 31.77±0.2 ° 33.09±0.2 ° .

[0301] In some embodiments of the present invention, the compound (maleate) of formula (XVII) in Form C crystal form has the following XPRD spectrum: Figure 67 As shown.

[0302] In some embodiments of the present invention, the XPRD spectral analysis data of the Form C crystal form of the compound (maleate) shown in formula (XVII) above are shown in Table 23.

[0303]

[0304] In some embodiments of the present invention, the differential scanning calorimetry curve of the Form C crystal form of the compound (maleate) shown in formula (XVII) above has a relatively broad endothermic signal corresponding to TGA weight loss at around 48ºC.

[0305] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (maleate) Form C crystal form shown in formula (XVII) above shows an endothermic signal of decomposition at around 177ºC.

[0306] In some embodiments of the present invention, the compound (maleate) of formula (XVII) in Form C crystal form has the following DSC spectrum: Figure 68 As shown.

[0307] In some embodiments of the present invention, the thermogravimetric analysis curve of the Form C crystal form of the compound (maleate) shown in formula (XVII) above shows a weight loss of 7.2% during heating to 150ºC, and decomposition may occur above 170ºC.

[0308] In some embodiments of the present invention, the compound (maleate) of formula (XVII) in Form C crystal form has a TGA spectrum as shown below. Figure 69 As shown.

[0309] The present invention further provides the compound (maleate) of formula (XVII) in crystal form Form D, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 5.49 ± 0.2. ° .

[0310] The present invention further provides the compound (maleate) of formula (XVII) in crystal form Form D, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 5.49 ± 0.2. ° 16.39±0.2 ° .

[0311] The present invention further provides the compound (maleate) of formula (XVII) in crystal form Form D, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 5.49 ± 0.2. ° 8.89±0.2 ° 10.91±0.2 ° 13.24±0.2 ° 15.15±0.2 ° 16.39±0.2 ° 17.71±0.2 ° 18.92±0.2 ° 19.75±0.2 ° 21.09±0.2° 21.85±0.2 ° 23.43±0.2 ° 25.02±0.2 ° 27.41±0.2 ° 29.80±0.2 ° 32.97±0.2 ° .

[0312] In some embodiments of the present invention, the compound (maleate) of formula (XVII) in Form D crystal form has the following XPRD spectrum: Figure 70 As shown.

[0313] In some embodiments of the present invention, the XPRD spectral analysis data of the Form D crystal form of the compound (maleate) shown in formula (XVII) above are shown in Table 24.

[0314]

[0315] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (maleate) Form D crystal form shown in formula (XVII) above has a relatively broad endothermic peak corresponding to TGA weight loss at around 105ºC.

[0316] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (maleate) Form D crystal form shown in formula (XVII) above shows an endothermic signal of decomposition at around 180ºC.

[0317] In some embodiments of the present invention, the compound (maleate) of formula (XVII) in crystal form Form D has the following DSC spectrum: Figure 71 As shown.

[0318] In some embodiments of the present invention, the thermogravimetric analysis curve of the compound (maleate) Form D crystal form shown in formula (XVII) above shows an 8.4% weight loss during heating to 150ºC, and decomposition may occur above 175ºC.

[0319] In some embodiments of the present invention, the compound (maleate) of formula (XVII) in Form D crystal form has a TGA spectrum as shown below. Figure 72 As shown.

[0320] The present invention further provides the compound (maleate) of formula (XVII) in Form E crystal form, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 5.74 ± 0.2. ° .

[0321] The present invention further provides the compound (maleate) of formula (XVII) in Form E crystal form, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 5.74 ± 0.2. ° 11.42±0.2 ° 14.25±0.2 ° 19.99±0.2 ° .

[0322] The present invention further provides the compound (maleate) of formula (XVII) in Form E crystal form, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 4.55 ± 0.2. ° 5.74±0.2 ° 8.58±0.2 ° 11.42±0.2 ° 14.25±0.2 ° 16.80±0.2 ° 17.11±0.2 ° 18.12±0.2 ° 19.99±0.2 ° 22.84±0.2 ° 25.76±0.2 ° 31.57±0.2 ° .

[0323] In some embodiments of the present invention, the compound (maleate) of formula (XVII) in Form E crystal form has the following XPRD spectrum: Figure 73 As shown.

[0324] In some embodiments of the present invention, the XPRD spectral analysis data of the Form E crystal form of the compound (maleate) shown in formula (XVII) above are shown in Table 25.

[0325]

[0326] XRPD results show that Form E is a poorly crystallizable solid, and after vacuum drying at room temperature, it tends to transform into Form A. In conclusion, Form E is a metastable crystal form.

[0327] The present invention further provides the compound (maleate) of formula (XVII) in crystal form Type F, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 4.85 ± 0.2. ° .

[0328] The present invention further provides the compound (maleate) of formula (XVII) in crystal form Type F, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 4.24 ± 0.2. ° 4.85±0.2 ° 5.45±0.2 ° .

[0329] The present invention further provides the compound (maleate) of formula (XVII) in crystal form Type F, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 4.24 ± 0.2. ° 4.85±0.2 ° 5.45±0.2 ° 5.88±0.2 ° 9.69±0.2 ° 10.91±0.2 ° 11.82±0.2 ° 12.66±0.2 ° 15.09±0.2 ° 16.88±0.2 ° 17.83±0.2 ° 19.42±0.2 ° 24.24±0.2 ° 25.49±0.2 ° 26.81±0.2 ° 29.12±0.2 ° 29.78±0.2 ° .

[0330] In some embodiments of the present invention, the compound (maleate) of formula (XVII) above, in crystal form Type F, has the following XPRD spectrum: Figure 74 As shown.

[0331] In some embodiments of the present invention, the XPRD spectral analysis data of the compound (maleate) of the above formula (XVII) in the Type F crystal form are shown in Table 26.

[0332]

[0333] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (maleate) of the above formula (XVII) Type F crystal form has a relatively broad endothermic signal corresponding to TGA weight loss at around 64ºC.

[0334] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (maleate) of the above formula (XVII) Type F crystal form shows an endothermic signal of decomposition at around 187ºC.

[0335] In some embodiments of the present invention, the compound (maleate) of formula (XVII) above, in crystal form Type F, has the following DSC spectrum: Figure 75 As shown.

[0336] In some embodiments of the present invention, the thermogravimetric analysis curve of the compound (maleate) of the Type F crystal form shown in formula (XVII) above shows a weight loss of 4.7% during heating to 150ºC, and decomposition may occur after 180ºC.

[0337] In some embodiments of the present invention, the compound (maleate) of formula (XVII) above, in crystal form Type F, has the following TGA spectrum: Figure 76 As shown.

[0338] The present invention further provides the compound (maleate) Form G crystal form shown in formula (XVII), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angle: 4.69±0.2 ° .

[0339] The present invention further provides the compound (maleate) Form G crystal form shown in formula (XVII), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angle: 4.69±0.2 ° 16.49±0.2 ° 18.88±0.2 ° .

[0340] The present invention further provides the compound (maleate) Form G crystal form shown in formula (XVII), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angle: 4.69±0.2 ° 9.39±0.2 ° 9.72±0.2 ° 13.81±0.2 ° 14.14±0.2 ° 16.16±0.2 ° 16.49±0.2 ° 17.17±0.2 ° 17.40±0.2 ° 17.75±0.2 ° 18.88±0.2 ° 19.66±0.2 ° 19.89±0.2° 20.57±0.2 ° 21.74±0.2 ° 22.26±0.2 ° 23.08±0.2 ° 23.93±0.2 ° 25.00±0.2 ° 26.79±0.2 ° 28.46±0.2 ° 29.22±0.2 ° .

[0341] In some embodiments of the present invention, the compound (maleate) Form G crystal form shown in formula (XVII) above has the following XPRD spectrum: Figure 77 As shown.

[0342] In some embodiments of the present invention, the XPRD spectral analysis data of the Form G crystal form of the compound (maleate) shown in formula (XVII) above are shown in Table 27.

[0343]

[0344] XRPD results showed that Form G was a poorly crystallizable solid. Due to the presence of dimethyl sulfoxide solvent residue in the Form G sample, which was not easily dried and removed, it was converted into Form H after further vacuum drying at 40ºC.

[0345] The present invention further provides the Form H crystal form of the compound (maleate) shown in formula (XVII), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angle: 5.02 ± 0.2. ° .

[0346] The present invention further provides the Form H crystal form of the compound (maleate) shown in formula (XVII), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angle: 5.02 ± 0.2. ° 9.90±0.2 ° 19.85±0.2 ° .

[0347] The present invention further provides the Form H crystal form of the compound (maleate) shown in formula (XVII), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angle: 5.02 ± 0.2. ° 9.90±0.2 ° 14.93±0.2 ° 17.25±0.2 ° 19.85±0.2° 24.05±0.2 ° 25.06±0.2 ° 27.04±0.2 ° .

[0348] In some embodiments of the present invention, the compound (maleate) of formula (XVII) in the Form H crystal form has the following XPRD spectrum: Figure 78 As shown.

[0349] In some embodiments of the present invention, the XPRD spectral analysis data of the Form H crystal form of the compound (maleate) shown in formula (XVII) above are shown in Table 28.

[0350]

[0351] In some embodiments of the present invention, the differential scanning calorimetry curve of the Form H crystal form of the compound (maleate) shown in formula (XVII) above has a relatively broad endothermic signal corresponding to TGA weight loss at around 132ºC.

[0352] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (maleate) Form H crystal form shown in formula (XVII) above shows an endothermic signal of decomposition at around 184ºC.

[0353] In some embodiments of the present invention, the compound (maleate) Form H crystal form shown in formula (XVII) above has the following DSC spectrum: Figure 79 As shown.

[0354] In some embodiments of the present invention, the thermogravimetric analysis curve of the Form H crystal form of the compound (maleate) shown in formula (XVII) above shows a weight loss of 10.4% during heating to 150ºC, and continues to lose weight before the decomposition temperature.

[0355] In some embodiments of the present invention, the compound (maleate) Form H crystal form shown in formula (XVII) above has the following TGA spectrum: Figure 80 As shown.

[0356] Online variable temperature XRPD test results show that Form H tends to transform into Form A when heated to 150ºC.

[0357] The present invention further provides the Form I crystal form of the compound (maleate) shown in formula (XVII), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angle: 5.95±0.2. ° .

[0358] The present invention further provides the Form I crystal form of the compound (maleate) shown in formula (XVII), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angle: 5.95±0.2. ° 11.88±0.2 ° 17.85±0.2 ° .

[0359] The present invention further provides the Form I crystal form of the compound (maleate) shown in formula (XVII), whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 4.07 ± 0.2. ° 5.95±0.2 ° 9.22±0.2 ° 11.88±0.2 ° 15.05±0.2 ° 16.70±0.2 ° 17.85±0.2 ° 19.42±0.2 ° 23.89±0.2 ° 25.70±0.2 ° 26.89±0.2 ° 29.94±0.2 ° .

[0360] In some embodiments of the present invention, the compound (maleate) of formula (XVII) in Form I crystal form has the following XPRD spectrum: Figure 81 As shown.

[0361] In some embodiments of the present invention, the XPRD spectral analysis data of the Form I crystal form of the compound (maleate) shown in formula (XVII) above are shown in Table 29.

[0362]

[0363] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (maleate) Form I crystal form shown in formula (XVII) above shows an endothermic signal of decomposition at around 190ºC.

[0364] In some embodiments of the present invention, the compound (maleate) Form I crystal form shown in formula (XVII) above has the following DSC spectrum: Figure 82 As shown.

[0365] In some embodiments of the present invention, the thermogravimetric analysis curve of the compound (maleate) Form I crystal form shown in formula (XVII) above shows a weight loss of 2.3% during heating to 150ºC, and decomposition may occur after 170ºC.

[0366] In some embodiments of the present invention, the compound (maleate) Form I crystal form shown in formula (XVII) above has the following TGA spectrum: Figure 83 As shown.

[0367] The present invention further provides the compound (maleate) of formula (XVII) in crystal form Form J, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 4.59 ± 0.2. ° .

[0368] The present invention further provides the compound (maleate) of formula (XVII) in crystal form Form J, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 4.59 ± 0.2. ° 18.12±0.2 ° .

[0369] The present invention further provides the compound (maleate) of formula (XVII) in crystal form Form J, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 4.59 ± 0.2. ° 9.08±0.2 ° 13.59±0.2 ° 18.12±0.2 ° 23.91±0.2 ° 25.00±0.2 ° 27.33±0.2 ° .

[0370] In some embodiments of the present invention, the compound (maleate) of formula (XVII) in the Form J crystal form has the following XPRD spectrum: Figure 84 As shown.

[0371] In some embodiments of the present invention, the XPRD spectral analysis data of the Form J crystal form of the compound (maleate) shown in formula (XVII) above are shown in Table 30.

[0372]

[0373] XRPD results showed that Form J was a poorly crystallizable solid. After drying, Form J transformed into a mixed crystal of Form A and Form B.

[0374] The present invention further provides the compound (maleate) of formula (XVII) in crystal form Form K, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 4.75 ± 0.2. ° .

[0375] The present invention further provides the compound (maleate) of formula (XVII) in crystal form Form K, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 4.75 ± 0.2. ° 19.27±0.2 ° .

[0376] The present invention further provides the compound (maleate) of formula (XVII) in crystal form Form K, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 4.75 ± 0.2. ° 5.31±0.2 ° 9.57±0.2 ° 14.41±0.2 ° 16.95±0.2 ° 19.27±0.2 ° 24.20±0.2 ° 29.08±0.2 ° .

[0377] In some embodiments of the present invention, the compound (maleate) Form K crystal form shown in formula (XVII) above has the following XPRD spectrum: Figure 85 As shown.

[0378] In some embodiments of the present invention, the XPRD spectral analysis data of the Form K crystal form of the compound (maleate) shown in formula (XVII) above are shown in Table 31.

[0379]

[0380] In some embodiments of the present invention, the differential scanning calorimetry curve of the Form K crystal form of the compound (maleate) shown in formula (XVII) above has a relatively broad endothermic signal corresponding to TGA weight loss at around 122ºC.

[0381] In some embodiments of the present invention, the differential scanning calorimetry curve of the Form K crystal form of the compound (maleate) shown in formula (XVII) above shows an endothermic signal of decomposition at around 178ºC.

[0382] In some embodiments of the present invention, the compound (maleate) Form K crystal form shown in formula (XVII) above has the following DSC spectrum: Figure 86 As shown.

[0383] In some embodiments of the present invention, the thermogravimetric analysis curve of the Form K crystal form of the compound (maleate) shown in formula (XVII) above shows a weight loss of 10.6% during heating to 150ºC, and continues to lose weight before the decomposition temperature.

[0384] In some embodiments of the present invention, the TGA spectrum of the compound (maleate) Form K crystal form shown in formula (XVII) above is as follows: Figure 87 As shown.

[0385] The thermal conversion results show that Form K is transformed into Form I after being heated to 150ºC and cooled to room temperature.

[0386] The present invention further provides the compound (maleate) of formula (XVII) in crystal form Type L, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angles: 5.10 ± 0.2. ° .

[0387] The present invention further provides the compound (maleate) of formula (XVII) in crystal form Type L, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 3.21 ± 0.2. ° 5.10±0.2 ° 17.07±0.2 ° .

[0388] The present invention further provides the compound (maleate) of formula (XVII) in crystal form Type L, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 3.21 ± 0.2. ° 5.10±0.2 ° 8.50±0.2 ° 9.03±0.2 ° 10.25±0.2 ° 10.91±0.2 ° 12.45±0.2 ° 13.53±0.2 ° 14.88±0.2 ° 15.52±0.2 ° 17.07±0.2 ° 17.97±0.2 ° 18.55±0.2 ° 20.76±0.2 ° 21.78±0.2 ° 23.31±0.2 ° 26.56±0.2 ° 29.65±0.2 ° .

[0389] In some embodiments of the present invention, the compound (maleate) of formula (XVII) above, in the Type L crystal form, has the following XPRD spectrum: Figure 88 As shown.

[0390] In some embodiments of the present invention, the XPRD spectral analysis data of the compound (maleate) of the above formula (XVII) in the Type L crystal form are shown in Table 32.

[0391]

[0392] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (maleate) of the above formula (XVII) Type L crystal form has a relatively broad endothermic signal corresponding to TGA weight loss at around 120ºC.

[0393] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (maleate) of the above formula (XVII) Type L crystal form shows an endothermic signal of decomposition at around 169ºC.

[0394] In some embodiments of the present invention, the compound (maleate) of formula (XVII) above, in the Type L crystal form, has the following DSC spectrum: Figure 89 As shown.

[0395] In some embodiments of the present invention, the thermogravimetric analysis curve of the compound (maleate) of the Type L crystal form shown in formula (XVII) above shows a weight loss of 7.1% during heating to 150ºC, and continues to lose weight before the decomposition temperature.

[0396] In some embodiments of the present invention, the compound (maleate) of formula (XVII) above, in its Type L crystal form, has the following TGA spectrum: Figure 90 As shown.

[0397] The present invention further provides the compound (maleate) of formula (XVII) in crystal form Form M, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 13.38 ± 0.2. ° 17.50±0.2 ° .

[0398] The present invention further provides the compound (maleate) of formula (XVII) in crystal form Form M, whose X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2θ angle of 10.97±0.2. ° 13.38±0.2 ° 17.50±0.2 ° 18.59±0.2 ° .

[0399] The present invention further provides the compound (maleate) of formula (XVII) in Form M crystal form, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 8.62 ± 0.2. ° 10.97±0.2 ° 13.38±0.2 ° 13.79±0.2 ° 17.23±0.2 ° 17.50±0.2 ° 17.91±0.2 ° 18.59±0.2 ° .

[0400] The present invention further provides the compound (maleate) of formula (XVII) in Form M crystal form, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 6.96 ± 0.2. ° 8.62±0.2 ° 9.30±0.2 ° 10.35±0.2 ° 10.97±0.2 ° 12.10±0.2 ° 13.38±0.2 ° 13.79±0.2 ° 14.88±0.2 ° 15.75±0.2 ° 16.24±0.2 ° 16.59±0.2 ° 17.23±0.2 ° 17.50±0.2 ° 17.91±0.2 ° 18.59±0.2 ° 18.94±0.2 ° 20.24±0.2 ° 20.67±0.2 ° 22.01±0.2 ° 22.40±0.2 ° 24.20±0.2 ° 24.87±0.2 ° 25.97±0.2 ° 26.69±0.2 ° 27.68±0.2 ° 30.27±0.2 ° 32.06±0.2 ° 34.27±0.2 ° .

[0401] In some embodiments of the present invention, the compound (maleate) of formula (XVII) in the Form M crystal form has the following XPRD spectrum: Figure 91 As shown.

[0402] In some embodiments of the present invention, the XPRD spectral analysis data of the Form M crystal form of the compound (maleate) shown in formula (XVII) above are shown in Table 33.

[0403]

[0404] In some embodiments of the present invention, the differential scanning calorimetry curve of the compound (maleate) Form M crystal form shown in formula (XVII) above has an endothermic signal at around 131ºC-176ºC.

[0405] In some embodiments of the present invention, the compound (maleate) Form M crystal form shown in formula (XVII) above has the following DSC spectrum: Figure 92 As shown.

[0406] In some embodiments of the present invention, the thermogravimetric analysis curve of the compound (maleate) Form M crystal form shown in formula (XVII) above shows a weight loss of 5.6% during heating to 150ºC, and decomposition may occur after 170ºC.

[0407] In some embodiments of the present invention, the compound (maleate) Form M crystal form shown in formula (XVII) above has the following TGA spectrum: Figure 93 As shown.

[0408] The thermal conversion results show that Form M is transformed into Form I after being heated to 150ºC and cooled to room temperature.

[0409] The present invention further provides the compound (maleate) of formula (XVII) in Form N crystal form, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 5.04 ± 0.2. ° 10.00±0.2 ° .

[0410] The present invention further provides the compound (maleate) of formula (XVII) in Form N crystal form, whose X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2θ angle: 5.04 ± 0.2. ° 10.00±0.2 ° 14.91±0.2 ° 17.40±0.2 ° 19.95±0.2 ° .

[0411] The present invention further provides the compound (maleate) of formula (XVII) in Form N crystal form, whose X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 5.04 ± 0.2. ° 10.00±0.2 ° 13.22±0.2 ° 14.91±0.2 ° 16.90±0.2 ° 17.40±0.2 ° 19.95±0.2 ° 23.85±0.2 ° 25.00±0.2 ° 26.94±0.2 ° 30.04±0.2 ° .

[0412] In some embodiments of the present invention, the compound (maleate) of formula (XVII) in the Form N crystal form has the following XPRD spectrum: Figure 94 As shown.

[0413] In some embodiments of the present invention, the XPRD spectral analysis data of the Form N crystal form of the compound (maleate) shown in formula (XVII) above are shown in Table 34.

[0414]

[0415] In some embodiments of the present invention, the differential scanning calorimetry curve of the Form N crystal form of the compound (maleate) shown in formula (XVII) above has an endothermic signal at around 116ºC-182ºC.

[0416] In some embodiments of the present invention, the compound (maleate) Form N crystal form shown in formula (XVII) above has the following DSC spectrum: Figure 95 As shown.

[0417] In some embodiments of the present invention, the thermogravimetric analysis curve of the compound (maleate) Form N crystal form shown in formula (XVII) above shows an 8.3% weight loss during heating to 150ºC, and decomposition may occur after 170ºC.

[0418] In some embodiments of the present invention, the compound (maleate) Form N crystal form shown in formula (XVII) above has the following TGA spectrum: Figure 96 As shown.

[0419] XRPD results show that Form N is a poorly crystallizable solid. The XRPD results of Form N and Form H are quite similar, indicating that they are isomorphous heterostructures.

[0420] This invention further provides a method for preparing a salt from the compound shown in formula (I) above with a basic compound, specifically comprising the following steps:

[0421] 1) Weigh appropriate amounts of the compound and the basic compound and add them to a certain amount of solvent;

[0422] 2) Suspend in the dark at a certain temperature;

[0423] 3) Centrifuge the suspension to separate the solids or allow it to stand in the dark and open at a certain temperature (any temperature range from room temperature to reflux temperature) until the solvent has completely evaporated to obtain the solids;

[0424] 4) The solid is vacuum dried at a certain temperature to obtain the salt form;

[0425] in,

[0426] The amount of alkaline compound used in step 1) is preferably 1 equivalent.

[0427] In step 1), the solvent is selected from methanol, ethanol, acetone, ethyl acetate, n-heptane, methyl tert-butyl ether, ethylene glycol methyl ether, dimethyl sulfoxide, dichloromethane, tetrahydrofuran, water, isopropanol, trifluoroethanol, or a mixture of two or more of these solvents; preferably methanol, tetrahydrofuran and acetone, tetrahydrofuran and methyl tert-butyl ether, isopropanol and tetrahydrofuran, isopropanol and acetone, isopropanol and methyl tert-butyl ether, isopropanol and dichloromethane, trifluoroethanol and tetrahydrofuran. The solvents are: trifluoroethanol and acetone, trifluoroethanol and methyl tert-butyl ether, trifluoroethanol and isopropanol, and trifluoroethanol and ethyl acetate; more preferably, methanol, tetrahydrofuran and acetone, tetrahydrofuran and methyl tert-butyl ether, trifluoroethanol and acetone, trifluoroethanol and methyl tert-butyl ether, trifluoroethanol and isopropanol, and trifluoroethanol and ethyl acetate; most preferably, tetrahydrofuran and acetone, tetrahydrofuran and methyl tert-butyl ether, trifluoroethanol and ethyl acetate, and trifluoroethanol and methyl tert-butyl ether.

[0428] In step 2), the preferred temperature is room temperature;

[0429] The preferred suspension time in step 2) is 3 days;

[0430] In step 3), the preferred temperature is room temperature;

[0431] In step 4), the preferred temperature is room temperature.

[0432] The present invention further provides a method for preparing a salt from the compound shown in formula (I) above with an acidic compound, specifically comprising the following steps:

[0433] 1) Weigh appropriate amounts of the compound and the acidic compound and add them to a certain amount of solvent;

[0434] 2) Suspend in the dark at a certain temperature;

[0435] 3) Centrifuge the suspension to separate the solids or allow it to stand in the dark and open at a certain temperature (any temperature range from room temperature to reflux temperature) until the solvent has completely evaporated to obtain the solids;

[0436] 4) The solid is vacuum dried at a certain temperature to obtain the salt form;

[0437] in,

[0438] In step 1), the amount of acidic compound used is selected from 1 to 2 equivalents; preferably 2 equivalents.

[0439] The solvent in step 1) is selected from methanol, ethanol, n-propanol, acetone, 4-methyl-2-pentanone, ethyl acetate, isopropyl acetate, ethyl formate, butyl formate, n-heptane, cyclohexane, dioxane, diethyl ether, methyl tert-butyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, acetonitrile, toluene, N, N'-dimethylformamide, chloroform, dimethyl sulfoxide, dichloromethane, tetrahydrofuran, water, isopropanol, trifluoroethanol, or a mixture of two or more of these solvents; preferably methanol, a mixture of tetrahydrofuran and acetone, tetrahydrofuran and methyl tert-butyl ether, isopropanol and tetrahydrofuran, isopropanol and acetone, isopropanol and methyl tert-butyl ether, isopropanol and dichloromethane, trifluoroethanol and tetrahydrofuran, trifluoroethanol and acetone, trifluoroethanol and methyl tert-butyl ether, trifluoroethanol and isopropanol, and trifluoroethanol and ethyl acetate; more preferably methanol, a mixture of tetrahydrofuran and acetone, tetrahydrofuran and methyl tert-butyl ether, trifluoroethanol and acetone, trifluoroethanol and methyl tert-butyl ether, trifluoroethanol and isopropanol, and trifluoroethanol and ethyl acetate; most preferably tetrahydrofuran and acetone, tetrahydrofuran and methyl tert-butyl ether, trifluoroethanol and ethyl acetate, and trifluoroethanol and methyl tert-butyl ether.

[0440] In step 2), the preferred temperature is room temperature;

[0441] The preferred suspension time in step 2) is 3 days;

[0442] In step 3), the preferred temperature is room temperature;

[0443] In step 4), the preferred temperature is room temperature.

[0444] After the compound shown in formula (I) above is formed into salts with different acids or bases, the present invention also provides methods for preparing different crystal forms of the corresponding salts by solvent evaporation, suspension, dissolution crystallization, cooling, gas-phase diffusion, and thermal transfer crystallization, as further described below:

[0445] Solvent evaporation method: Weigh an appropriate amount of sample, dissolve it in a single or binary solvent of your choice, and let the resulting clear solution stand at room temperature in an open container until the solvent has completely evaporated to obtain a solid.

[0446] Suspension method: 1) Room temperature suspension: Weigh an appropriate amount of sample, add a certain amount of sample to the selected single or binary solvent until a suspension is formed, stir at room temperature for a certain time, centrifuge the suspension, and vacuum dry the solid at room temperature. 2) 50°C suspension: Weigh an appropriate amount of sample, add a certain amount of sample to the selected solvent until a suspension is formed, stir at 50°C for 24 hours, centrifuge the suspension, and vacuum dry the solid at room temperature.

[0447] Dissolution-crystallization method: 1) Binary solvent forward titration method: 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 and add it dropwise to 10 or 20 times the volume of poor solvent. After stirring for 1 h, centrifuge the system with solid precipitation and dry the solid under vacuum at room temperature; continue stirring the clear solution for 24 h. If no solid precipitates, place the system at -15ºC. Centrifuge the system with solid precipitates and dry the solid under vacuum at room temperature. If no solid precipitates, let the solution stand open at room temperature until the solvent completely evaporates to obtain a solid. 2) Binary solvent reverse titration method: 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 and add it dropwise to poor solvent until solid precipitates. After stirring at room temperature for 1 h, the system with precipitated solids was centrifuged and the solids were dried under vacuum at room temperature. The clear solution was stirred for another 24 h. The system without precipitated solids was placed in a -15ºC refrigerator. The system with precipitated solids was centrifuged and the solids were dried under vacuum at room temperature. If no solids precipitated, the solution was left to stand open at room temperature until the solvent completely evaporated to obtain a solid.

[0448] Cooling methods: 1) Single solvent cooling method: Weigh an appropriate amount of sample and add preheated selected solvent at 50ºC until the solid is just completely dissolved. Quickly transfer the solution to room temperature. Let it stand at room temperature for more than 2 hours. If no sufficient solid precipitates, cool the solution further at 4ºC. If no sufficient solid precipitates, cool the solution further at -15ºC. For systems with sufficient solid precipitates, centrifuge and vacuum dry the solid at room temperature. 2) Binary solvent cooling method: Weigh an appropriate amount of sample and mix it with a certain amount of unsuitable solvent at 50ºC to form a suspension. Gradually add preheated good solvent until the solid is just completely dissolved. Transfer the solution to room temperature. Let it stand at room temperature for more than 2 hours. If no sufficient solid precipitates, cool the solution further at 4ºC. If no sufficient solid precipitates, cool the solution further at -15ºC. For systems with sufficient solid precipitates, centrifuge and vacuum dry the solid at room temperature.

[0449] Gas phase diffusion method: 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, place the clear solution in a poor solvent atmosphere and let it stand at room temperature until solid precipitates. Remove the solution in the system with solid precipitate using a syringe, and perform XRPD test on the wet sample;

[0450] Thermal crystallization method: The Instec HCS424GXY hot stage (Instec Inc., US) was used. 6-8 mg of sample was placed on a glass slide on the hot stage and heated to the target temperature at a rate of 10ºC / min. The temperature was held for 1 min and then allowed to cool naturally to room temperature to obtain a solid.

[0451] The solvent used in 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, diethyl 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 mixture of two or more of these solvents. Preferred solvents include, but are not limited to, methanol, ethanol, isopropanol, acetone, tetrahydrofuran, ethyl acetate and methyl tert-butyl ether, tetrahydrofuran and acetone, tetrahydrofuran and methyl tert-butyl ether, isopropanol and tetrahydrofuran, isopropanol and acetone, isopropanol and methyl tert-butyl ether, isopropanol and dichloromethane, trifluoroethanol and tetrahydrofuran, trifluoroethanol and acetone, trifluoroethanol and methyl tert-butyl ether, trifluoroethanol and isopropanol, and mixed solvents of trifluoroethanol and ethyl acetate; more preferably, ethanol, The preferred solvents are isopropanol, acetone, tetrahydrofuran, ethyl acetate methyl tert-butyl ether, tetrahydrofuran and acetone, tetrahydrofuran and methyl tert-butyl ether, trifluoroethanol and acetone, trifluoroethanol and methyl tert-butyl ether, trifluoroethanol and isopropanol, and trifluoroethanol and ethyl acetate.

[0452] The present invention also provides the use of the above-described compound or crystal form, or the crystal form prepared according to the above method, in the preparation of small molecule immunomodulatory drugs.

[0453] Technical effect

[0454] The crystal form of the compound of the present invention exhibits excellent stability under high temperature, high humidity, light irradiation and accelerated conditions, which indicates that the compound of the present invention has excellent pharmaceutical characteristics;

[0455] The compounds of the present invention have excellent pharmacokinetic characteristics that can be absorbed orally, with ideal in vivo exposure levels and duration of exposure. They also have targeting properties for tumor tissues, can accumulate in tumor tissues and form higher tumor tissue exposure concentrations, which helps to better exert anti-tumor activity during treatment, thereby achieving better therapeutic effects.

[0456] Definitions and Explanations

[0457] Unless otherwise stated, all the following terms and phrases in this invention are intended to have the following meanings. A particular phrase or term, if not specifically defined, should not be considered uncertain or unclear, but should be understood in its ordinary sense.

[0458] The intermediate compounds of the present invention can be prepared by various synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0459] The chemical reactions in the specific embodiments of this invention are carried out in a suitable solvent, which must be suitable for the chemical changes of this invention and the reagents and materials required therefor. To obtain the compounds of this invention, sometimes those skilled in the art need to modify or select the synthesis steps or reaction processes based on existing embodiments.

[0460] The "pharmaceutically acceptable salt" as described in this invention refers to an acid addition salt obtained by reacting the compounds of this invention with a pharmaceutically acceptable acid, or a salt formed by reacting a compound having an acidic group with a basic compound. These pharmaceutically acceptable salts are easily separated and can be purified using conventional separation methods, such as solvent extraction, dilution, recrystallization, column chromatography, and preparative thin-layer chromatography.

[0461] The pharmaceutical compositions of the present invention contain all of the above-described compounds, or their isomers, pharmaceutically acceptable salts, precursors and metabolites as active ingredients.

[0462] The compounds described in this invention may optionally be used in combination with one or more other active ingredients, and the dosage and ratio of each ingredient may be adjusted by those skilled in the art according to the specific disease, the patient's specific condition, and clinical needs.

[0463] All compounds described in this invention, or their isomers, pharmaceutically acceptable salts, precursors and metabolites, can be prepared by those skilled in the art (based on experience or references).

[0464] When the structural formula of the compound described in this invention does not match its Chinese name, the chemical structural formula shall prevail.

[0465] When the peaks in the XPRD spectrum are not very sharp diffraction peaks, the peak values ​​calculated by different software may vary, but all of these are within the scope of this invention.

[0466] In this invention, the temperatures are allowed to have a certain margin of error. Unless otherwise specified, ±5°C is preferred, ±3°C is more preferred, ±2°C is even more preferred, and ±1°C is the most preferred. For example, "the differential scanning calorimetry curve of the Form A crystal form of the compound shown in formula (XVII) shows an endothermic signal of decomposition at around 184°C" means that "the differential scanning calorimetry curve of the Form A crystal form of the compound shown in formula (XVII) shows an endothermic signal of decomposition at 184±5°C", more preferred "the differential scanning calorimetry curve of the Form A crystal form of the compound shown in formula (XVII) shows an endothermic signal of decomposition at 184±3°C", even more preferred "the differential scanning calorimetry curve of the Form A crystal form of the compound shown in formula (XVII) shows an endothermic signal of decomposition at 184±2°C", and the most preferred "the differential scanning calorimetry curve of the Form A crystal form of the compound shown in formula (XVII) shows an endothermic signal of decomposition at 184±1°C". Attached Figure Description

[0467] Figure 1 The image shows the XPRD spectrum of the sodium salt (type A) of the compound shown in formula (II).

[0468] Figure 2 The DSC spectrum of the compound (sodium salt) of formula (II) in crystal form Type A is shown.

[0469] Figure 3 The TGA spectrum of the sodium salt (type A) of the compound shown in formula (II) is shown.

[0470] Figure 4 The image shows the XPRD spectrum of the compound (potassium salt) of formula (Ⅲ) in crystal form Type A.

[0471] Figure 5 The DSC spectrum of the compound (potassium salt) of formula (Ⅲ) in crystal form Type A is shown.

[0472] Figure 6 The TGA spectrum of the compound (potassium salt) of formula (Ⅲ) in crystal form Type A is shown.

[0473] Figure 7 The image shows the XPRD spectrum of the compound (glucamine salt) of formula (Ⅳ) in crystal form Type A.

[0474] Figure 8 The DSC spectrum of the compound (glucamine salt) of formula (Ⅳ) in crystal form Type A is shown.

[0475] Figure 9 The TGA spectrum of the compound (glucamine salt) of formula (Ⅳ) in crystal form Type A is shown.

[0476] Figure 10The image shows the XPRD spectrum of the compound (sulfate) Type A crystal form shown in formula (V).

[0477] Figure 11 The image shows the DSC spectrum of the compound (sulfate) in crystal form Type A as shown in formula (V).

[0478] Figure 12 The TGA spectrum of the compound (sulfate) Type A crystal form shown in formula (V) is shown.

[0479] Figure 13 The image shows the XPRD spectrum of the compound (methanesulfonate) in crystal form Type A, as shown in formula (VI).

[0480] Figure 14 The image shows the DSC spectrum of the compound (methanesulfonate) in crystal form Type A as shown in formula (VI).

[0481] Figure 15 The TGA spectrum of the compound (p-toluenesulfonate) in the Type A crystal form shown in formula (VI) is shown.

[0482] Figure 16 The image shows the XPRD spectrum of the compound (p-toluenesulfonate) in the Type A crystal form as shown in formula (Ⅶ).

[0483] Figure 17 The DSC spectrum of the compound (p-toluenesulfonate) of formula (VII) in crystal form Type A is shown.

[0484] Figure 18 The TGA spectrum of the compound (p-toluenesulfonate) in the Type A crystal form shown in formula (Ⅶ) is shown.

[0485] Figure 19 The image shows the XPRD spectrum of the compound (L-camphor sulfonate) of formula (VIII) in crystal form Type A.

[0486] Figure 20 The DSC spectrum of the compound (L-camphor sulfonate) of formula (VIII) in crystal form Type A is shown.

[0487] Figure 21 The TGA spectrum of the compound (L-camphor sulfonate) of formula (VIII) in crystal form Type A is shown.

[0488] Figure 22 The image shows the XPRD spectrum of the Type B crystal form of the compound (L-camphor sulfonate) shown in formula (VIII).

[0489] Figure 23 The DSC spectrum of the compound (L-camphor sulfonate) of formula (VIII) in its Type B crystal form is shown.

[0490] Figure 24 The TGA spectrum of the compound (L-camphor sulfonate) of formula (VIII) in its Type B crystal form is shown.

[0491] Figure 25 The image shows the XPRD spectrum of the compound (oxalate) in crystal form Type A as shown in formula (IX).

[0492] Figure 26 The image shows the DSC spectrum of the compound (oxalate) of type A crystal form (IX).

[0493] Figure 27 The TGA spectrum of the compound (oxalate) of formula (IX) in crystal form Type A is shown.

[0494] Figure 28 The image shows the XPRD spectrum of the Type B crystal form of the compound (oxalate) shown in formula (IX).

[0495] Figure 29 The image shows the DSC spectrum of the Type B crystal form of the compound (oxalate) shown in formula (IX).

[0496] Figure 30 The TGA spectrum of the compound (oxalate) of formula (IX) in crystal form Type B is shown.

[0497] Figure 31 The image shows the XPRD spectrum of the Type A crystal form of the compound (fumarate) represented by formula (X).

[0498] Figure 32 The image shows the DSC spectrum of the compound (fumarate) of formula (X) in crystal form Type A.

[0499] Figure 33 The TGA spectrum of the compound (fumarate) of formula (X) in crystal form Type A is shown.

[0500] Figure 34 The image shows the XPRD spectrum of the Type B crystal form of the compound (fumarate) represented by formula (X).

[0501] Figure 35 The image shows the DSC spectrum of the Type B crystal form of the compound (fumarate) shown in formula (X).

[0502] Figure 36 The TGA spectrum of the compound (fumarate) Type B crystal form shown in formula (X) is shown.

[0503] Figure 37 The image shows the XPRD spectrum of the compound (L-tartrate) in crystal form (XI) of formula (XI) in crystal form A.

[0504] Figure 38 The DSC spectrum of the compound (L-tartrate) of formula (XI) in crystal form Type A is shown.

[0505] Figure 39 The TGA spectrum of the compound (L-tartrate) of formula (XI) in crystal form Type A is shown.

[0506] Figure 40 The image shows the XPRD spectrum of the compound (L-tartrate) of formula (XII) in crystal form Type B.

[0507] Figure 41 The DSC spectrum of the compound (L-tartrate) of formula (XII) in crystal form Type B is shown.

[0508] Figure 42 The TGA spectrum of the compound (L-tartrate) of formula (XII) in crystal form Type B is shown.

[0509] Figure 40 The image shows the XPRD spectrum of the compound (L-tartrate) of formula (XII) in crystal form Type B.

[0510] Figure 41 The DSC spectrum of the compound (L-tartrate) of formula (XII) in crystal form Type B is shown.

[0511] Figure 42 The TGA spectrum of the compound (L-tartrate) of formula (XII) in crystal form Type B is shown.

[0512] Figure 43 The image shows the XPRD spectrum of the compound (L-malate) of formula (XIII) in crystal form Type A.

[0513] Figure 44 The DSC spectrum of the compound (L-malate) of formula (XIII) in crystal form Type A is shown.

[0514] Figure 45 The TGA spectrum of the compound (L-malate) of formula (XIII) in crystal form Type A is shown.

[0515] Figure 46 The image shows the XPRD spectrum of the Type B crystal form of the compound (L-malate) represented by formula (XIV).

[0516] Figure 47 The image shows the DSC spectrum of the compound (L-malate) of formula (XIV) in its Type B crystal form.

[0517] Figure 48The TGA spectrum of the compound (L-malate) of formula (XIV) in its Type B crystal form is shown.

[0518] Figure 49 The image shows the XPRD spectrum of the compound (hydrochloride) of type A crystal form (XV).

[0519] Figure 50 The image shows the DSC spectrum of the compound (hydrochloride) of type A crystal form (XV).

[0520] Figure 51 The TGA spectrum of the compound (hydrochloride) of formula (XV) in crystal form Type A is shown.

[0521] Figure 52 The image shows the XPRD spectrum of the Type B crystal form of the compound (hydrochloride) represented by formula (XV).

[0522] Figure 53 The image shows the DSC spectrum of the compound (hydrochloride) of type B crystal form (XV).

[0523] Figure 54 The TGA spectrum of the compound (hydrochloride) of formula (XV) in crystal form Type B is shown.

[0524] Figure 55 The image shows the XPRD spectrum of the compound (hydrochloride) of type C crystal form (XV).

[0525] Figure 56 The image shows the DSC spectrum of the compound (hydrochloride) of type C crystal form (XV).

[0526] Figure 57 The TGA spectrum of the compound (hydrochloride) of type C crystal form shown in formula (XV) is shown.

[0527] Figure 58 The image shows the XPRD spectrum of the compound (maleate) of formula (XVI) in crystal form Type A.

[0528] Figure 59 The image shows the DSC spectrum of the compound (maleate) of formula (XVI) in crystal form Type A.

[0529] Figure 60 The TGA spectrum of the compound (maleate) in the Type A crystal form shown in formula (XVI) is shown.

[0530] Figure 61 The image shows the XPRD spectrum of the compound (maleate) Form A crystal form as shown in formula (XVII).

[0531] Figure 62The DSC spectrum of the compound (maleate) Form A crystal form shown in formula (XVII) is shown.

[0532] Figure 63 The TGA spectrum of the compound (maleate) Form A crystal form shown in formula (XVII) is shown.

[0533] Figure 64 The image shows the XPRD spectrum of the Form B crystal form of the compound (maleate) shown in formula (XVII).

[0534] Figure 65 The DSC spectrum of the Form B crystal form of the compound (maleate) shown in formula (XVII) is shown.

[0535] Figure 66 The TGA spectrum of the Form B crystal form of the compound (maleate) shown in formula (XVII) is shown.

[0536] Figure 67 The image shows the XPRD spectrum of the Form C crystal form of the compound (maleate) shown in formula (XVII).

[0537] Figure 68 The DSC spectrum of the Form C crystal form of the compound (maleate) shown in formula (XVII) is shown.

[0538] Figure 69 The TGA spectrum of the Form C crystal form of the compound (maleate) shown in formula (XVII) is shown.

[0539] Figure 70 The image shows the XPRD spectrum of the Form D crystal form of the compound (maleate) shown in formula (XVII).

[0540] Figure 71 The DSC spectrum of the compound (maleate) Form D crystal form shown in formula (XVII) is shown.

[0541] Figure 72 The TGA spectrum of the compound (maleate) in Form D crystal form as shown in formula (XVII) is shown.

[0542] Figure 73 The image shows the XPRD spectrum of the Form E crystal form of the compound (maleate) shown in formula (XVII).

[0543] Figure 74 The image shows the XPRD spectrum of the compound (maleate) of formula (XVII) in its Type F crystal form.

[0544] Figure 75 The DSC spectrum of the compound (maleate) of formula (XVII) in crystal form Type F is shown.

[0545] Figure 76 The TGA spectrum of the compound (maleate) of formula (XVII) in crystal form Type F is shown.

[0546] Figure 77 The image shows the XPRD spectrum of the Form G crystal form of the compound (maleate) shown in formula (XVII).

[0547] Figure 78 The image shows the XPRD spectrum of the Form H crystal form of the compound (maleate) shown in formula (XVII).

[0548] Figure 79 The DSC spectrum of the compound (maleate) Form H crystal form shown in formula (XVII) is shown.

[0549] Figure 80 The TGA spectrum of the Form H crystal form of the compound (maleate) shown in formula (XVII) is shown.

[0550] Figure 81 The image shows the XPRD spectrum of the Form I crystal form of the compound (maleate) shown in formula (XVII).

[0551] Figure 82 The DSC spectrum of the Form I crystal form of the compound (maleate) shown in formula (XVII) is shown.

[0552] Figure 83 The TGA spectrum of the compound (maleate) Form I crystal form shown in formula (XVII) is shown.

[0553] Figure 84 The image shows the XPRD spectrum of the Form J crystal form of the compound (maleate) shown in formula (XVII).

[0554] Figure 85 The image shows the XPRD spectrum of the Form K crystal form of the compound (maleate) shown in formula (XVII).

[0555] Figure 86 The DSC spectrum of the compound (maleate) Form K crystal form shown in formula (XVII) is shown.

[0556] Figure 87 The TGA spectrum of the Form K crystal form of the compound (maleate) shown in formula (XVII) is shown.

[0557] Figure 88 The image shows the XPRD spectrum of the compound (maleate) of formula (XVII) in its Type L crystal form.

[0558] Figure 89The DSC spectrum of the compound (maleate) of formula (XVII) in the Type L crystal form is shown.

[0559] Figure 90 The TGA spectrum of the compound (maleate) of formula (XVII) in the Type L crystal form is shown.

[0560] Figure 91 The image shows the XPRD spectrum of the Form M crystal form of the compound (maleate) shown in formula (XVII).

[0561] Figure 92 The DSC spectrum of the compound (maleate) Form M crystal form shown in formula (XVII) is shown.

[0562] Figure 93 The TGA spectrum of the compound (maleate) Form M crystal form shown in formula (XVII) is shown.

[0563] Figure 94 The image shows the XPRD spectrum of the Form N crystal form of the compound (maleate) shown in formula (XVII).

[0564] Figure 95 The DSC spectrum of the Form N crystal form of the compound (maleate) shown in formula (XVII) is shown.

[0565] Figure 96 The TGA spectrum of the Form N crystal form of the compound (maleate) shown in formula (XVII) is shown.

[0566] Figure 97 The DVS spectrum is shown for the Type A crystal form of the compound (hydrochloride) represented by formula (XV).

[0567] Figure 98 The image shows the superimposed XPRD data before and after DVS testing of the Type A crystal form of the compound (hydrochloride) shown in formula (XV).

[0568] Figure 99 The DVS spectrum is shown for the Type C crystal form of the compound (hydrochloride) represented by formula (XV).

[0569] Figure 100 The image shows the superimposed XPRD data before and after DVS testing of the Type C crystal form of the compound (hydrochloride) shown in formula (XV).

[0570] Figure 101 The DVS spectrum of the compound (maleate) Form A crystal form shown in formula (XV) is shown.

[0571] Figure 102The image shows the superimposed XPRD data before and after DVS testing of the compound (maleate) Form A crystal form, as shown in formula (XV).

[0572] Figure 103 XRPD data superposition spectrum for stability study of the Type A crystal form of the compound (hydrochloride) shown in formula (XV).

[0573] Figure 104 XRPD data superposition spectrum for stability study of the Form A crystal form of the compound (maleate) shown in formula (XVII). Detailed Implementation

[0574] The following examples further illustrate the content of this invention, but the scope of protection of this invention is not limited to these examples. Unless otherwise specified, all percentages mentioned in this invention are weight percentages. The numerical ranges described in the specification, such as units of measurement, reaction conditions, physical states of compounds, or percentages, are provided for the purpose of providing clear and unambiguous written reference. Those skilled in the art, when practicing this patent, will still obtain the expected results by using temperatures, concentrations, quantities, carbon numbers, etc., outside these ranges or different from individual values.

[0575] All compounds and intermediates involved in this invention can be purified using common separation methods, such as extraction, recrystallization, silica gel column chromatography, and preparative TLC separation. The 200-300 mesh silica gel and TLC plates used were manufactured by Qingdao Marine Chemical Plant. The solvents and chemical reagents used were commercially available analytical grade or chemically pure reagents, and were used without further purification.

[0576] The present invention provides an X-ray powder diffraction (XRPD) analysis method:

[0577] The solid samples obtained in the experiment were analyzed using a PANalytical Empyrean X-ray powder diffractometer (PANAlytical, NL). The 2θ scanning angle ranged from 3º to 45º, the scanning step size was 0.013º, and the total testing time was 4 minutes. The phototube voltage and current for the tested samples were 45 kV and 40 mA, respectively, and the sample disk was a zero-background sample disk.

[0578] The differential scanning calorimetry (DSC) method of this invention:

[0579] The differential scanning calorimeter was a TA Discovery 250 (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 purging at a rate of 50 mL / min.

[0580] Thermogravimetric analysis (TGA) method of this invention:

[0581] The thermogravimetric analyzer was a TA Discovery 550 (TA, US). 2–5 mg of sample was placed in a pre-equilibrated open aluminum sample pan and automatically weighed inside the TGA furnace. The sample was heated to the final temperature at a rate of 10ºC / min, with nitrogen purging at 60 mL / min at the sample location and 40 mL / min at the balance location.

[0582] The present invention provides a dynamic water vapor adsorption-desorption analysis (DVS) method:

[0583] Dynamic water vapor adsorption-desorption analysis was performed using DVS Intrinsic (SMS, UK). The test employed a gradient mode with humidity variations of 50%-95%-0%-50%. Within the 0% to 90% range, each gradient represented a 10% change in humidity. The gradient endpoint was determined using the dm / dt method, with a dm / dt value less than 0.002% maintained for 10 minutes as the endpoint. After the test, XRPD analysis was performed on the samples to confirm whether the solid morphology had changed.

[0584]

[0585] This invention's nuclear magnetic resonance (NMR) 1 H-NMR analysis method:

[0586] 1 H-NMR was performed at room temperature using a BRUKER AVANCE-400 MHz nuclear magnetic resonance spectrometer in deuterated dimethyl sulfoxide (DMSO-d6) or deuterated chloroform (CDCl3) with tetramethylsilane (TMS) as an internal standard. Signal peaks were represented as s (singleton), d (doublet), t (triplet), q (quartet), m (multiplet), and dd (doublet). The coupling constant (J) is expressed in Hertz (Hz).

[0587] Example 1 Preparation of compound (I)

[0588]

[0589]

[0590] first step

[0591] 1a (530.00 mg, 1.13 mmol, 1.0 eq, synthetic reference CN202111092852.4) was dissolved in 1,4-dioxane (10 mL), and trifluoroacetic acid (5 mL) was added. 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). Then, 1b (583.08 mg, 1.13 mmol, 1.0 eq, synthetic reference CN202111092852.4), 1,1'-bis(dicyclohexylphosphino)ferrocene palladium 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 microwaved to 110ºC and reacted for 1 h, then cooled to ambient temperature. The reaction solution was concentrated, and the crude product was separated by silica gel column chromatography (dichloromethane / methanol (v / v) = 40 / 1~20 / 1) to give solid 1c (363.00 mg, yield 47.3%). LC-MS MS-ESI(m / z) 679.6 [M+H]+.

[0592] Step 2

[0593] Intermediate 1c (363.00 mg, 0.53 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), followed by the addition of triethylamine (1 mL) and 1d (143.78 mg, 0.79 mmol, 1.5 eq, synthesis reference CN202111092852.4). The resulting mixture was stirred at ambient temperature for 1 h, and then sodium borohydride acetate (674.16 mg, 3.18 mmol, 6.0 eq) was added, with stirring continuing for another 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 obtain solid 1e. (363.00 mg, yield 47.3%). LC-MS MS-ESI (m / z) 845.9 [M+H]+.

[0594] Step 3

[0595] 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 solution was concentrated, and the residue was dissolved in dichloromethane (10 mL) and concentrated again. The resulting trifluoroacetate solid was used directly in the next stage. The above trifluoroacetate 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 sodium borohydride acetate (508.80 mg, 2.40 mmol, 6.0 eq) was added. Stirring was continued for 16 h. The reaction solution 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 yield 1 g (307.00 mg, yield 82.9%). LC-MS MS-ESI (m / z) 926.0 [M+H] + .

[0596] Step 4

[0597] 1 g (307.00 mg, 0.33 mmol, 1.0 eq) of the intermediate 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 give off-white solid I (84.00 mg, yield 27.9%). LC-MS MS-ESI (m / z) 912.0 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.89 (s, 2H), 8.38 (d, J = 8.4 Hz, 2H), 7.49 (t, J = 8.0 Hz, 2H), 7.14 (d, J = 7.4 Hz, 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).

[0598] Example 2 Preparation of salts formed by compounds of formula (I) with different basic compounds

[0599] Approximately 27.5 mg (0.03 mmol) of compound (I) and 1 equivalent of the basic compound were weighed and added to tetrahydrofuran / acetone (v / v, 3:7) or tetrahydrofuran / methyl tert-butyl ether (v / v, 1:1). The mixtures were stirred in the dark at room temperature for 3 days. The suspensions were then centrifuged, and the solids were dried under vacuum at room temperature. The experimental results are shown in Table 35.

[0600]

[0601] Example 3 Preparation of salts formed by compounds of formula (I) with different acidic compounds

[0602] Approximately 27.5 mg (0.03 mmol) of compound (I) and 2 equivalents of the acidic compound were weighed and added to methanol, tetrahydrofuran / acetone (v / v, 3:7), or tetrahydrofuran / methyl tert-butyl ether (v / v, 1:1). The mixtures were stirred for 3 days at room temperature in the dark. The suspensions were then centrifuged, and the solids were dried under vacuum at room temperature. If a clear solution was obtained, it was allowed to stand at room temperature in the dark until the solvent had completely evaporated. The experimental results are shown in Table 36.

[0603]

[0604] Example 4 Preparation of hydrochloride and maleate salts of compound (I)

[0605] Formulas (XV) and (XVII) were used to further screen other crystal forms of the hydrochloride and maleate described in this invention, and the preparation process is shown in Table 37.

[0606]

[0607] Example 5: Preparation methods of different crystal forms of formula (XV)

[0608] 5.1 Suspension Method

[0609] A certain amount of sample of formula (XV) was weighed and suspended in the selected solvent at room temperature for 7 days in the dark, and at 50°C for 24 hours in the selected solvent, respectively, to prepare different crystal forms of formula (XV). The results are shown in Table 38.

[0610]

[0611] 5.2 Dissolution-crystallization method

[0612] The binary solvent back-tipping method involves using ethylene glycol methyl ether, N,N'-dimethylformamide, or dimethyl sulfoxide as good solvents, combined with various unsuitable solvents, and conducting a dissolution and crystallization experiment using the back-tipping method. The binary solvent forward-tipping method involves using ethylene glycol methyl ether, N,N'-dimethylformamide, or dimethyl sulfoxide as good solvents, combined with various unsuitable solvents, and conducting a dissolution and crystallization experiment using the forward-tipping method. The results are shown in Table 39.

[0613]

[0614] 5.3 Cooling Method

[0615] 1) Single solvent cooling method, that is, using different solvents to carry out single solvent cooling crystallization experiments, the results are shown in Table 40.

[0616]

[0617] 2) Multi-solvent cooling method: Ethylene glycol methyl ether, dimethyl sulfoxide, water, methanol or trifluoroethanol were used as good solvents and combined with various unsuitable solvents to carry out cooling crystallization experiments of binary solvents at different temperatures. The results are shown in Table 41.

[0618]

[0619] 5.4 Gas-phase diffusion method

[0620] 1) Solution vapor diffusion method: a certain amount of sample (XV) is dissolved in a good solvent, the resulting solution is placed in a volatile, undesirable solvent atmosphere, and allowed to stand at room temperature in the dark for solution vapor diffusion experiments. The results are shown in Table 42.

[0621]

[0622] 2) Solid vapor diffusion method: a certain amount of sample is placed in a volatile solvent atmosphere and left to stand at room temperature in the dark to carry out solid vapor diffusion experiment. The results are shown in Table 43.

[0623]

[0624] Example 6: Preparation methods of different crystal forms of formula (XVII)

[0625] 6.1 Volatilization method

[0626] A certain amount of sample of formula (XVII) was weighed and dissolved in the selected single solvent or binary solvent. The clear solution was left to stand at room temperature until the solvent was completely evaporated to obtain a solid. The results are shown in Table 44.

[0627]

[0628] 6.2 Suspension Method

[0629] A certain amount of sample of formula (XVII) was weighed and suspended in the selected solvent at room temperature for 7 days in the dark, and at 50°C for 24 h in the selected solvent, respectively, to prepare different crystal forms of formula (XVII). The results are shown in Table 45.

[0630]

[0631] 6.3 Dissolution-crystallization method

[0632] The binary solvent back-tipping method involves using ethylene glycol methyl ether, N,N'-dimethylformamide, or dimethyl sulfoxide as good solvents, combined with various unsuitable solvents, and conducting a dissolution and crystallization experiment using the back-tipping method. The binary solvent forward-tipping method involves using ethylene glycol methyl ether, N,N'-dimethylformamide, or dimethyl sulfoxide as good solvents, combined with various unsuitable solvents, and conducting a dissolution and crystallization experiment using the forward-tipping method. The results are shown in Table 46.

[0633]

[0634] 6.4 Cooling Method

[0635] 1) Single solvent cooling method, that is, using different solvents to carry out single solvent cooling crystallization experiments, the results are shown in Table 47.

[0636]

[0637] 2) Multi-solvent cooling method: Ethylene glycol methyl ether, N,N'-dimethylformamide, ethanol / dioxane (v / v, 1:1) or ethanol / acetonitrile (v / v, 1:1) were used as good solvents in combination with various unsuitable solvents. Cooling crystallization experiments were carried out at 50ºC, and the results are shown in Table 48.

[0638]

[0639] 6.5 Gas-phase diffusion method

[0640] A certain amount of sample of formula (XVII) was dissolved in a good solvent, and the resulting solution was placed in an atmosphere of volatile and undesirable solvent. After standing at room temperature, a gas phase diffusion experiment was conducted, and the results are shown in Table 49.

[0641]

[0642] 6.6 Thermal transfer crystal method

[0643] Using different crystal forms as raw materials, the solids were heated to the target temperature using a hot stage and held at that temperature for 1 min. After cooling to room temperature, XRPD tests were performed on the solids, and the results are shown in Table 50.

[0644]

[0645] Example 7: Study on the hygroscopic properties of different compounds

[0646] Based on the aforementioned Dynamic Water Vapor Adsorption-Desorption Analysis (DVS) method, this invention evaluates the hygroscopicity of the target compound. After the test is completed, XRPD analysis is performed on the sample to confirm whether the solid morphology has changed. The results are shown in Table 51.

[0647]

[0648] Experimental conclusions: The Type A and Type C crystal forms of the compound shown in formula (XV) of the present invention are hygroscopic or slightly hygroscopic, and the crystal forms remain consistent before and after the DVS test; the Form A crystal form of the compound shown in formula (XVII) is slightly hygroscopic, and the crystal forms remain consistent before and after the DVS test.

[0649] Example 8: Solid stability study of different compounds

[0650] 8.1 Weigh approximately 30 mg of the sample and conduct stability studies on the Type A crystal form of formula (XV) under high temperature (60ºC), high humidity (25ºC / 92.5% RH), light exposure (25ºC / 4500 Lux), and accelerated conditions (40ºC / 75% RH). Samples were taken at 5 days and 10 days for XRPD characterization. The results are shown in Table 52.

[0651]

[0652] 8.2 Weigh approximately 25 mg of the sample and conduct stability studies on the Form A crystal form of formula (XVII) under high temperature (60ºC), high humidity (25ºC / 92.5% RH), light irradiation (25ºC / 4500 Lux), and accelerated (40ºC / 75% RH) conditions. Samples were taken at 7 days and 15 days for XRPD characterization. The results are shown in Table 53.

[0653]

[0654] a XPRD data overlay comparison see Figure 104

[0655] Experimental conclusion: The Type A crystal form of the compound shown in formula (XV) and the Form A crystal form of the compound shown in formula (XVII) of this invention exhibit excellent stability characteristics under high temperature, high humidity, light irradiation and acceleration conditions.

[0656] Example 9 Pharmacokinetic Study

[0657] Twelve male beagle dogs, weighing 8-9 kg (purchased from Nanjing Chaimen Biotechnology Co., Ltd.), were used. The Type A crystal forms of formulas (I), (XV), and (XVII) of the test compound were prepared in purified water containing 20% ​​PEG400. A single oral administration of 10 mg / kg of the compound was administered. Animals were fasted overnight before administration. Blood was collected via venous sampling from the upper limb at 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 24 h, 32 h, and 48 h. Approximately 0.2 mL of blood was collected in heparin sodium anticoagulant tubes, centrifuged at 5000 rpm for 5 min, and the plasma was separated and stored at -20°C for analysis. After plasma sample processing, the concentration of the compound in the plasma was determined using liquid chromatography-mass spectrometry (LC-MS / MS). Pharmacokinetic parameters were calculated using Phoenix WinNonlin 7.0 software. The data are summarized in Table 54.

[0658]

[0659] Experimental conclusion: Compared with compound (I), the two representative salt compounds of this invention, formulas (XV) and (XVII), showed lower plasma exposure (AUC) after a single oral dose of 10 mg / kg in beagle dogs. （0-t） ) and peak concentration (C max The values ​​of (XV) and (XVII) are higher than those of compound (I), and they also have higher relative oral bioavailability, indicating that compounds (XV) and (XVII) have superior oral absorption characteristics.

Claims

1. A pharmaceutically acceptable salt of the compound shown in formula (I) or a solvate of said pharmaceutically acceptable salt, 。 2. The pharmaceutically acceptable salt or a solvate of the pharmaceutically acceptable salt according to claim 1, characterized in that, The pharmaceutically usable salt is formed by the compound of formula (I) and a basic compound, wherein the basic compound includes an inorganic base or an organic base; Preferably, the inorganic base is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, lithium hydroxide, sodium carbonate, and sodium bicarbonate, with sodium hydroxide and potassium hydroxide being more preferred, and sodium hydroxide being the most preferred. Preferably, the organic base is selected from meglumine, ethanolamine, diethanolamine, triethanolamine, tert-butylamine, basic amino acids, diethylamine, triethylamine, cyclohexylamine, dicyclohexylamine, benzylamine, dibenzylamine, N-methylbenzylamine, and more preferably meglumine.

3. The pharmaceutically acceptable salt or a solvate of the pharmaceutically acceptable salt according to claim 2, characterized in that, The salt formation ratio of the compound shown in formula (I) to the basic compound is 1:2 to 2:1, preferably 1:

1.

4. The pharmaceutically acceptable salt or a solvate of the pharmaceutically acceptable salt according to claim 1, characterized in that, The pharmaceutically usable salt is formed by the reaction of the compound of formula (I) with an acidic compound, wherein the acidic compound includes an inorganic acid or an organic acid; Preferably, the inorganic acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, and nitric acid; more preferably, hydrochloric acid, sulfuric acid, and phosphoric acid; more preferably, hydrochloric acid and sulfuric acid; and most preferably, hydrochloric acid. Preferably, the organic acid is selected from methanesulfonic acid, p-toluenesulfonic acid, L-camphorsulfonic acid, oxalic acid, maleic acid, fumaric acid, L-tartaric acid, citric acid, L-malic acid, acidic amino acids, benzenesulfonic acid, benzoic acid, succinic acid, and glycolic acid. More preferably, it is methanesulfonic acid, p-toluenesulfonic acid, L-camphorsulfonic acid, oxalic acid, maleic acid, fumaric acid, L-tartaric acid, citric acid, and L-malic acid. More preferably, it is methanesulfonic acid, oxalic acid, maleic acid, fumaric acid, and citric acid. Most preferably, it is maleic acid.

5. The pharmaceutically acceptable salt or a solvate of the pharmaceutically acceptable salt according to claim 4, characterized in that, The salt formation ratio of the compound shown in formula (I) to the acidic compound is 1:2 to 2:1, preferably 1:

2.

6. The Type A crystal form of the compound shown in formula (II), characterized in that, Its X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 8.11±0.2 ° 9.39±0.2 ° 11.88±0.2 ° , ； Preferably, the X-ray powder diffraction pattern of the Type A crystal form of the compound shown in formula (II) has a characteristic diffraction peak at the following 2θ angle: 5.78 ± 0.

2. ° 8.11±0.2 ° 9.39±0.2 ° 11.30±0.2 ° 11.88±0.2 ° 12.43±0.2 ° 13.35±0.2 ° 16.31±0.2 ° 18.36±0.2 ° 18.85±0.2 ° 20.33±0.2 ° ; More preferably, the X-ray powder diffraction pattern of the Type A crystal form of the compound shown in formula (II) exhibits characteristic diffraction peaks at the following 2θ angle: 5.78 ± 0.

2. ° 8.11±0.2 ° 9.39±0.2 ° 11.30±0.2 ° 11.88±0.2 ° 12.43±0.2 ° 13.01±0.2 ° 13.35±0.2 ° 15.29±0.2 ° 16.31±0.2 ° 16.66±0.2 ° 18.07±0.2 ° 18.36±0.2 ° 18.85±0.2 ° 20.33±0.2 ° ; Preferably, the X-ray powder diffraction pattern of the Type A crystal form of the compound shown in formula (II) exhibits characteristic diffraction peaks at the following 2θ angle: 5.78 ± 0.

2. ° 8.11±0.2 ° 9.39±0.2 ° 11.30±0.2 ° 11.88±0.2 ° 12.43±0.2 ° 13.01±0.2 ° 13.35±0.2 ° 15.29±0.2 ° 16.31±0.2 ° 16.66±0.2 ° 17.23±0.2 ° 18.07±0.2 ° 18.36±0.2 ° 18.85±0.2 ° 20.33±0.2 ° 21.36±0.2 ° 22.70±0.2 ° 23.65±0.2 ° 24.56±0.2 ° 24.78±0.2 ° 25.83±0.2 ° 26.62±0.2 ° 27.29±0.2 ° 27.65±0.2 ° 28.34±0.2 ° 29.41±0.2 ° 32.32±0.2 ° 33.13±0.2 ° 34.60±0.2 ° ; Most preferably, the XPRD spectrum of the Type A crystal form of the compound shown in formula (II) is shown in Figure 1.

7. The Type A crystal form of the compound of formula (II) according to claim 6, characterized in that, It has one or two of the following characteristics: (1) The differential scanning calorimetry curve of the Type A crystal form of the compound shown in formula (II) has endothermic peaks at 187±3ºC and 283±3ºC; preferably, its DSC spectrum is shown in Figure 2; (2) The thermogravimetric analysis curve of the Type A crystal form of the compound shown in formula (II) shows a weight loss of 9.6% during heating to 150ºC; preferably, its TGA spectrum is shown in Figure 3.

8. The Type A crystal form of the compound shown in formula (Ⅳ), characterized in that, Its X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 4.98±0.2 ° , ； Preferably, the X-ray powder diffraction pattern of the Type A crystal form of the compound shown in formula (Ⅳ) has a characteristic diffraction peak at the following 2θ angle: 3.43±0.2 ° 4.98±0.2 ° 6.43±0.2 ° ; More preferably, the X-ray powder diffraction pattern of the Type A crystal form of the compound shown in formula (Ⅳ) exhibits characteristic diffraction peaks at the following 2θ angle: 3.43 ± 0.2 ° 4.98±0.2 ° 6.43±0.2 ° 8.41±0.2 ° 8.91±0.2 ° Furthermore, preferably, the X-ray powder diffraction pattern of the Type A crystal form of the compound shown in formula (Ⅳ) exhibits characteristic diffraction peaks at the following 2θ angles: 3.43±0.2 ° 4.98±0.2 ° 6.43±0.2 ° 8.41±0.2 ° 8.91±0.2 ° 12.82±0.2 ° 16.72±0.2 ° 19.81±0.2 ° ; Most preferably, the XPRD spectrum of the Type A crystal form of the compound shown in formula (Ⅳ) is shown in Figure 7.

9. The Type A crystal form of the compound of formula (IV) according to claim 8, characterized in that, It has one or two of the following characteristics: (1) The differential scanning calorimetry curve of the Type A crystal form of the compound shown in formula (Ⅳ) has an endothermic peak at 170±3ºC; preferably, its DSC spectrum is shown in Figure 8; (2) The thermogravimetric analysis curve of the Type A crystal form of the compound shown in formula (Ⅳ) shows an 8.0% weight loss during heating to 180ºC; preferably, its TGA spectrum is shown in Figure 9.

10. The Type A crystal form of the compound shown in formula (XV), characterized in that, Its X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 16.35±0.2 ° , ； Preferably, the X-ray powder diffraction pattern of the Type A crystal form of the compound shown in formula (XV) exhibits characteristic diffraction peaks at the following 2θ angle: 13.48 ± 0.

2. ° 16.35±0.2 ° ; More preferably, the X-ray powder diffraction pattern of the Type A crystal form of the compound shown in formula (XV) exhibits characteristic diffraction peaks at the following 2θ angle: 13.48 ± 0.

2. ° 16.35±0.2 ° 20.63±0.2 ° ; Preferably, the X-ray powder diffraction pattern of the Type A crystal form of the compound shown in formula (XV) exhibits characteristic diffraction peaks at the following 2θ angle: 13.48 ± 0.

2. ° 16.35±0.2 ° 20.63±0.2 ° 22.75±0.2 ° ; Most preferably, the XPRD spectrum of the Type A crystal form of the compound shown in formula (XV) is shown in Figure 49.

11. The Type A crystal form of the compound of formula (XV) according to claim 10, characterized in that, It has one or two of the following characteristics: (1) The differential scanning calorimetry curve of the Type A crystal form of the compound shown in formula (XV) has an endothermic signal after 240ºC; preferably, its DSC spectrum is shown in Figure 50. (2) The thermogravimetric analysis curve of the Type A crystal form of the compound shown in formula (XV) shows a weight loss of 2.9% during heating to 100ºC; preferably, its TGA spectrum is shown in Figure 51.

12. The compound of formula (XV) in crystal form Type B, characterized in that, Its X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 6.40±0.2 ° , ； Preferably, the X-ray powder diffraction pattern of the Type B crystal form of the compound shown in formula (XV) exhibits characteristic diffraction peaks at the following 2θ angle: 6.40 ± 0.

2. ° 12.85±0.2 ° ; More preferably, the X-ray powder diffraction pattern of the Type B crystal form of the compound shown in formula (XV) exhibits characteristic diffraction peaks at the following 2θ angle: 6.40 ± 0.

2. ° 12.85±0.2 ° 16.26±0.2 ° 19.09±0.2 ° 26.09±0.2 ° ; Preferably, the XPRD spectrum of the Type B crystal form of the compound shown in formula (XV) is shown in Figure 52.

13. The Type B crystal form of the compound of formula (XV) according to claim 12, characterized in that, It has one or two of the following characteristics: (1) The differential scanning calorimetry curve of the Type B crystal form of the compound shown in formula (XV) decomposes after 280ºC; preferably, its DSC spectrum is shown in Figure 53; (2) The thermogravimetric analysis curve of the Type B crystal form of the compound shown in formula (XV) shows a weight loss of 3.6% during heating to 100ºC; preferably, its TGA spectrum is shown in Figure 54.

14. The Type C crystal form of the compound shown in formula (XV), characterized in that, Its X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 16.64±0.2 ° 23.66±0.2 ° , ； Preferably, the X-ray powder diffraction pattern of the Type C crystal form of the compound shown in formula (XV) exhibits characteristic diffraction peaks at the following 2θ angle: 14.68 ± 0.

2. ° 16.64±0.2 ° 23.66±0.2 ° 27.98±0.2 ° ; More preferably, the X-ray powder diffraction pattern of the Type C crystal form of the compound shown in formula (XV) exhibits characteristic diffraction peaks at the following 2θ angle: 6.52 ± 0.

2. ° 12.64±0.2 ° 14.68±0.2 ° 16.33±0.2 ° 16.64±0.2 ° 17.19±0.2 ° 18.08±0.2 ° 18.41±0.2 ° 19.79±0.2 ° 22.30±0.2 ° 23.66±0.2 ° 24.59±0.2 ° 26.81±0.2 ° 27.98±0.2 ° ; Preferably, the X-ray powder diffraction pattern of the Type C crystal form of the compound shown in formula (XV) exhibits characteristic diffraction peaks at the following 2θ angle: 6.52 ± 0.

2. ° 8.31±0.2 ° 9.53±0.2 ° 10.46±0.2 ° 11.07±0.2 ° 11.65±0.2 ° 12.23±0.2 ° 12.64±0.2 ° 13.24±0.2 ° 14.04±0.2 ° 14.68±0.2 ° 15.38±0.2 ° 16.33±0.2 ° 16.64±0.2 ° 17.19±0.2 ° 18.08±0.2 ° 18.41±0.2 ° 19.00±0.2 ° 19.79±0.2 ° 20.40±0.2 ° 21.39±0.2 ° 22.30±0.2 ° 22.82±0.2 ° 23.66±0.2 ° 24.59±0.2 ° 26.81±0.2 ° 27.98±0.2 ° 30.75±0.2 ° 32.11±0.2 ° 33.16±0.2 ° 34.08±0.2 ° 35.26±0.2 ° 36.62±0.2 ° 39.19±0.2 ° 42.30±0.2 ° ; Most preferably, the XPRD spectrum of the Type C crystal form of the compound shown in formula (XV) is shown in Figure 55.

15. The Type C crystal form of the compound of formula (XV) according to claim 14, characterized in that, It has one or two of the following characteristics: (1) The differential scanning calorimetry curve of the Type C crystal form of the compound shown in formula (XV) has an endothermic peak at 234±3ºC; preferably, its DSC spectrum is shown in Figure 56. (2) The thermogravimetric analysis curve of the Type C crystal form of the compound shown in formula (XV) shows a weight loss of 7.9% during heating to 240ºC; preferably, its TGA spectrum is shown in Figure 57.

16. The Form A crystal form of the compound shown in formula (XVII), characterized in that, Its X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angle: 5.53±0.

2. ° , ； Preferably, the X-ray powder diffraction pattern of the Form A crystal form of the compound shown in formula (XVII) exhibits characteristic diffraction peaks at the following 2θ angle: 5.53 ± 0.

2. ° 13.59±0.2 ° 24.42±0.2 ° 26.50±0.2 ° ; More preferably, the X-ray powder diffraction pattern of the Form A crystal form of the compound shown in formula (XVII) exhibits characteristic diffraction peaks at the following 2θ angle: 5.53 ± 0.

2. ° 8.64±0.2 ° 11.09±0.2 ° 12.80±0.2 ° 13.59±0.2 ° 15.01±0.2 ° 16.10±0.2 ° 16.66±0.2 ° 16.97±0.2 ° 17.40±0.2 ° 17.77±0.2 ° 19.31±0.2 ° 20.28±0.2 ° 21.91±0.2 ° 22.55±0.2 ° 23.62±0.2 ° 23.89±0.2 ° 24.42±0.2 ° 26.50±0.2 ° 27.68±0.2 ° 29.59±0.2 ° 32.89±0.2 ° ; Preferably, the XPRD spectrum of the Form A crystal form of the compound shown in formula (XVII) is shown in Figure 61.

17. The Form A crystal form of the compound of formula (XVII) according to claim 16, characterized in that, It has one or two of the following characteristics: (1) The differential scanning calorimetry curve of the Form A crystal form of the compound shown in formula (XVII) shows an endothermic signal of decomposition at around 184ºC; preferably, its DSC spectrum is shown in Figure 62. (2) The thermogravimetric analysis curve of the Form A crystal form of the compound shown in formula (XVII) shows a weight loss of 3.5% during heating to 150ºC and decomposition above 170ºC; preferably, its TGA spectrum is shown in Figure 63.

18. The use of a pharmaceutically acceptable salt of the compound of formula (I) according to any one of claims 1-5, or a solvate of the pharmaceutically acceptable salt, or the crystal form according to any one of claims 6-17, in the preparation of a medicament for treating immune-modulation-related diseases.

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