Crystal form of acid salt of sulfoximine compound as well as preparation method and application of crystal form

Abstract

The invention relates to a crystal form of a sulfoximine compound as well as a preparation method and application of the crystal form. Specifically, the invention discloses a crystal form of a compound as shown in formula (I) and a preparation method and application thereof, and the crystal form has excellent stability and can be widely applied to preparation of drugs for preventing and / or treating diseases related to increase of activity and expression quantity of FGFR2 (Fibroblast Growth Factor Receptor 2). The preferable crystal form of the # imgabs0 is a hydrochloride crystal form I of a compound shown in a formula I, and an X-ray powder diffraction pattern of the hydrochloride crystal form I has a 2 theta angle selected from the following groups: 6.68 + / -0.2 degrees, 13.34 + / -0.2 degrees and 21.42 + / -0.2 degrees.

Description

Technical Field

[0001] The present invention belongs to the field of drug development, and particularly relates to a crystalline form of an acid salt of a sulfoximine compound, a preparation method thereof, and uses thereof. Background Art

[0002] Fibroblast growth factor receptor (FGFR) is a receptor for fibroblast growth factor (FGF) signal transduction. Its family consists of four members (FGFR1, FGFR2, FGFR3, FGFR4), which are glycoproteins composed of an extracellular immunoglobulin (Ig)-like domain, a hydrophobic transmembrane region, and an intracellular portion including a tyrosine kinase region. Binding of the FGF ligand causes receptor dimerization and conformational changes in the intracellular domain, thereby causing intermolecular transphosphorylation of the kinase domain and the intracellular tail. Phosphorylated residues serve as docking sites for adaptor proteins, which promote downstream signal cascades, thereby generating cellular behaviors including proliferation, survival, differentiation, migration, and angiogenesis. Abnormal FGFRs signaling is involved in various cancer types, including liver cancer, intrahepatic cholangiocarcinoma, bladder cancer, endometrial cancer, breast cancer, and lung cancer, and disease progression occurs through overexpression, point mutations, and / or chromosomal translocations.

[0003] With the continuous in-depth research, pan-FGFR1-3 inhibitors have shown clinical responses to various cancers with FGFR alterations, but also exhibit target-restricted toxicity, resulting in adverse side effects such as hyperphosphatemia and tissue mineralization, which is due to the regulation of phosphate reabsorption being mediated by FGFR1 and FGFR3. Some studies have outlined the occurrence of FGFR2 translocations in 14% of intrahepatic cholangiocarcinomas; FGFR2 mutations occur in 12 - 14% of endometrial cancers and 5% of squamous non-small cell lung cancers; FGFR2 is amplified in 12 - 14% of gastric cancers and 4% of breast cancers. FGFR2 plays a role in promoting acquired resistance to human epidermal growth factor receptor 2 (HER2)-targeted therapy by indirectly overactivating FGFR2 in tumor-associated fibroblasts.

[0004] Therefore, based on the unmet clinical needs, the development of FGFR2-selective inhibitors for treatment has great value and prospects. Summary of the Invention

[0005] The object of the present invention is to develop a pharmaceutical salt form, a crystalline form of a sulfoximine FGFR inhibitor compound, and a preparation method thereof.

[0006] In one aspect of the present invention, there is provided a compound of formula (I),

[0007]

[0008] in amorphous or crystalline form or a solvate thereof;

[0009] wherein, m is 1, 2, 3, 4, 5, 6, 7, 8 or 9;

[0010] n is 0, 0.5, 1, 1.5, 2, 2.5 or 3; and X is selected from the group consisting of: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid or phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, hippuric acid, glycolic acid or glutaric acid.

[0011] In another preferred embodiment, the structure of the compound of formula I-1 is as follows:

[0012]

[0013] The present invention provides the A crystal form of the compound of formula I-1, whose X-ray powder diffraction pattern has specific diffraction peaks at the following 2θ angles: 11.59 ± 0.2°, 12.00 ± 0.2°, 14.16 ± 0.2°, 15.50 ± 0.2°, 16.74 ± 0.2°, 18.38 ± 0.2°, 18.81 ± 0.2°, 21.32 ± 0.2°, 21.80 ± 0.2°, 23.01 ± 0.2°, 24.37 ± 0.2°, 26.50 ± 0.2°, 28.90 ± 0.2°.

[0014] In some embodiments of the present invention, the A crystal form of the above-mentioned compound of formula I-1 has specific diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 8.44 ± 0.2°, 11.59 ± 0.2°, 12.00 ± 0.2°, 12.34 ± 0.2°, 14.16 ± 0.2°, 15.50 ± 0.2°, 16.50 ± 0.2°, 16.74 ± 0.2°, 18.38 ± 0.2°, 18.81 ± 0.2°, 19.79 ± 0.2°, 20.44 ± 0.2°, 21.32 ± 0.2°, 21.53 ± 0.2°, 21.80 ± 0.2°, 22.24 ± 0.2°, 23.01 ± 0.2°, 24.37 ± 0.2°, 25.43 ± 0.2°, 26.50 ± 0.2°, 27.13 ± 0.2°, 27.74 ± 0.2°, 28.90 ± 0.2°, 29.72 ± 0.2°, 29.93 ± 0.2°, 30.83 ± 0.2°, 31.56 ± 0.2°, 32.47 ± 0.2°, 33.64 ± 0.2°, 34.12 ± 0.2°, 35.03 ± 0.2°, 36.17 ± 0.2°.

[0015] In some embodiments of the present invention, the A crystal form of the above-mentioned compound of formula I-1 has an XRPD pattern as Figure 1 shown.

[0016] Table 1: XRPD Analysis Data of Form A of the Compound of Formula I-1

[0017]

[0018]

[0019] In some embodiments of the present invention, for Form A of the above-mentioned compound of Formula I-1, the differential scanning calorimetry curve has starting points of endothermic peaks at 26.10°C ± 2°C and 223.34°C ± 2°C.

[0020] In some embodiments of the present invention, for Form A of the above-mentioned compound of Formula I-1, its DSC pattern is as Figure 2 shown.

[0021] In some embodiments of the present invention, for Form A of the above-mentioned compound of Formula I-1, its thermogravimetric analysis curve has three relatively small weight loss steps at 24.00°C ± 2°C, 110.00°C ± 2°C, and 200.00°C ± 2°C, and starts to decompose after 250.00°C ± 2°C.

[0022] In some embodiments of the present invention, for Form A of the above-mentioned compound of Formula I-1, its TGA pattern is as Figure 3 shown.

[0023] The present invention also provides a method for preparing Form A of the above-mentioned compound of Formula I-1, which includes adding the compound of Formula I-1 to acetonitrile, an alcohol solvent, an ester solvent, an ether solvent, or a mixed solvent of an alcohol solvent and water, and recrystallizing or slurrying to obtain it. The alcohol solvent is selected from methanol, ethanol, isopropanol, etc.; the ester solvent is selected from ethyl acetate, isopropyl acetate, formic acid formate, ethyl formate, isopropyl formate, etc.; the ether solvent is selected from methyl tert-butyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, etc. The mixed solvent of an alcohol solvent and water is selected from a mixed solvent of methanol and water, a mixed solvent of ethanol and water, or a mixed solvent of isopropanol and water. In the mixed solvent of an alcohol solvent and water, the volume ratio of the alcohol solvent to water is selected from 1:0.1 to 1.5.

[0024] The present invention also provides Form A of the maleate salt of the above-mentioned compound of Formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 5.82 ± 0.2°, 9.86 ± 0.2°, 11.29 ± 0.2°, 12.72 ± 0.2°, 13.04 ± 0.2°, 15.17 ± 0.2°, 17.88 ± 0.2°, 18.11 ± 0.2°, 22.28 ± 0.2°, 23.02 ± 0.2°, 24.42 ± 0.2°, 25.34 ± 0.2°, 26.77 ± 0.2°.

[0025] In some embodiments of the present invention, the maleate crystal form A of the above-mentioned compound of formula I-1 has specific diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 8.44±0.2°, 11.59±0.2°, 12.00±0.2°, 12.34±0.2°, 14.16±0.2°, 15.50±0.2°, 16.50±0.2°, 16.74±0.2°, 18.38±0.2°, 18.81±0.2°, 19.79±0.2°, 20.44±0.2°, 21.32±0.2°, 21.53±0.2°, 21.80±0.2°, 22.24±0.2°, 23.01±0.2°, 24.37±0.2°, 25.43±0.2°, 26.50±0.2°, 27.13±0.2°, 27.74±0.2°, 28.90±0.2°, 29.72±0.2°, 29.93±0.2°, 30.83±0.2°, 31.56±0.2°, 32.47±0.2°, 33.64±0.2°, 34.12±0.2°, 35.03±0.2°, 36.17±0.2°.

[0026] In some embodiments of the present invention, the XRPD pattern of the maleate crystal form A of the above-mentioned compound of formula I-1 is as Figure 4 shown.

[0027] Table 2 XRPD analysis data of the maleate crystal form A of the compound of formula I-1

[0028]

[0029]

[0030] The present invention also provides a method for preparing the crystal form A of the above-mentioned compound of formula I-1, which comprises adding the compound of formula I-1 and maleic acid to acetonitrile and dichloromethane, and performing recrystallization or slurrying to obtain it. The ratio of the compound of formula I-1 to maleic acid is selected from: 0.8 to 1.2.

[0031] The present invention also provides polymorph B of the monomaleate salt of the above-mentioned compound of formula I-1, whose X-ray powder diffraction pattern has specific diffraction peaks at the following 2θ angles: 7.98±0.2°, 8.29±0.2°, 11.61±0.2°, 13.21±0.2°, 13.99±0.2°, 15.25±0.2°, 15.95±0.2°, 16.57±0.2°, 17.38±0.2°, 18.06±0.2°, 20.39±0.2°, 21.25±0.2°, 21.61±0.2°, 22.17±0.2°, 23.54±0.2°, 24.70±0.2°, 25.91±0.2°, 27.24±0.2°, 29.47±0.2°, 29.71±0.2°, 32.64±0.2°.

[0032] In some embodiments of the present invention, polymorph B of the monomaleate salt of the above-mentioned compound of formula I-1 has specific diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 7.98±0.2°, 8.29±0.2°, 10.27±0.2°, 11.61±0.2°, 13.21±0.2°, 13.99±0.2°, 14.52±0.2°, 15.25±0.2°, 15.95±0.2°, 16.57±0.2°, 16.89±0.2°, 17.38±0.2°, 18.06±0.2°, 20.39±0.2°, 20.61±0.2°, 21.25±0.2°, 21.61±0.2°, 22.17±0.2°, 23.31±0.2°, 23.54±0.2°, 23.98±0.2°, 24.70±0.2°, 24.93±0.2°, 25.32±0.2°, 25.91±0.2°, 26.55±0.2°, 27.24±0.2°, 28.23±0.2°, 28.54±0.2°, 29.00±0.2°, 29.47±0.2°, 29.71±0.2°, 32.64±0.2°, 35.12±0.2°.

[0033] In some embodiments of the present invention, polymorph B of the monomaleate salt of the above-mentioned compound of formula I-1 has an XRPD pattern as Figure 5 shown.

[0034] Table 3 XRPD analysis data of polymorph B of the monomaleate salt of the compound of formula I-1

[0035]

[0036]

[0037] In some embodiments of the present invention, for the monomaleate crystal form B of the compound of formula I-1, the differential scanning calorimetry curve has a starting point of an endothermic peak at 213.92 °C ± 2 °C.

[0038] In some embodiments of the present invention, for the monomaleate crystal form B of the compound of formula I-1, its DSC pattern is as Figure 6 shown.

[0039] In some embodiments of the present invention, for the monomaleate crystal form B of the compound of formula I-1, its thermogravimetric analysis curve has two weight loss steps at 24.00 °C ± 2 °C and 180.00 °C ± 2 °C, and decomposition starts after 250.00 °C ± 2 °C.

[0040] In some embodiments of the present invention, for the monomaleate crystal form B of the compound of formula I-1, its TGA pattern is as Figure 7 shown.

[0041] The present invention also provides a method for preparing the monomaleate crystal form B of the compound of formula I-1, which comprises adding the compound of formula I-1 and maleic acid to tetrahydrofuran, and preparing it by recrystallization or slurrying. The ratio of the compound of formula I-1 to maleic acid is selected from: 0.8 - 1.2.

[0042] The present invention also provides the fumarate crystal form A of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 5.11 ± 0.2°, 10.20 ± 0.2°, 14.23 ± 0.2°, 17.03 ± 0.2°, 18.79 ± 0.2°, 28.85 ± 0.2°, 29.46 ± 0.2°.

[0043] In some embodiments of the present invention, for the fumarate crystal form A of the compound of formula I-1, its X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 5.11 ± 0.2°, 7.26 ± 0.2°, 10.20 ± 0.2°, 10.51 ± 0.2°, 14.23 ± 0.2°, 14.47 ± 0.2°, 14.93 ± 0.2°, 16.17 ± 0.2°, 17.03 ± 0.2°, 17.90 ± 0.2°, 18.79 ± 0.2°, 19.44 ± 0.2°, 20.19 ± 0.2°, 20.80 ± 0.2°, 22.48 ± 0.2°, 23.07 ± 0.2°, 23.74 ± 0.2°, 24.07 ± 0.2°, 27.06 ± 0.2°, 27.85 ± 0.2°, 28.30 ± 0.2°, 28.85 ± 0.2°, 29.46 ± 0.2°, 38.24 ± 0.2°.

[0044] In some embodiments of the present invention, for the fumarate crystal form A of the compound of formula I-1, its XRPD pattern is asFigure 8 as shown

[0045] XRPD analysis data of fumarate crystal form A of the compound of formula I-1

[0046] Name Angle d Value Net Intensity Gross Intensity Rel.Intensity FWHM Peak#1 5.106943 17.29001 66.02386 80.74232 0.6328462 0.100 Peak#2 7.257269 12.17109 15.48998 32.61639 0.1484732 0.123 Peak#3 10.20005 8.665302 44.82843 61.36366 0.4296856 0.171 Peak#4 10.50647 8.413257 25.31782 41.40717 0.2426742 0.100 Peak#5 14.22988 6.219109 94.52111 109.7326 0.9059956 0.138 Peak#6 14.46519 6.118463 44.95081 60.22918 0.4308586 0.153 Peak#7 14.93302 5.927817 26.26917 41.2175 0.251793 0.100 Peak#8 16.16592 5.478399 35.9365 51.60095 0.3444554 0.117 Peak#9 17.02807 5.202913 44.72762 61.55038 0.4287193 0.100 Peak#10 17.90158 4.950956 21.9525 40.30973 0.2104172 0.178 Peak#11 18.78968 4.718902 49.85003 67.55918 0.4778182 0.107 Peak#12 19.44071 4.562319 28.59071 45.95156 0.2740452 0.100 Peak#13 20.19247 4.394129 33.90914 52.76979 0.325023 0.149 Peak#14 20.79758 4.267629 33.02869 51.93834 0.3165837 0.201 Peak#15 22.48454 3.951108 11.28123 28.946 0.1081319 0.169 Peak#16 23.06632 3.852751 12.43236 31.23554 0.1191656 0.167 Peak#17 23.73916 3.745054 18.25035 37.17823 0.1749317 0.152 Peak#18 24.07149 3.694097 20.07611 38.59465 0.1924318 0.207 Peak#19 27.06206 3.292275 40.86212 66.92372 0.3916681 0.119 Peak#20 27.84687 3.201246 20.41484 49.1985 0.1956785 0.160 Peak#21 28.29739 3.151295 22.67108 52.42942 0.2173048 0.199 Peak#22 28.84687 3.092505 104.3285 134.4994 1 0.101 Peak#23 29.46212 3.02931 23.97766 53.60007 0.2298286 0.138 Peak#24 38.24442 2.351456 16.4544 35.48725 0.1577173 0.165

[0047] The present invention also provides a method for preparing fumarate crystal form A of the above-mentioned compound of formula I-1, which comprises adding the compound of formula I-1 and fumaric acid into acetonitrile and dichloromethane, and performing recrystallization or slurrying to obtain it. The ratio of the compound of formula I-1 to fumaric acid is selected from: 0.8 to 1.2.

[0048] The present invention also provides semi-fumarate crystal form B of the above-mentioned compound of formula I-1, and its X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 5.12±0.2°, 10.20±0.2°, 10.53±0.2°, 14.24±0.2°, 16.99±0.2°, 18.81±0.2°, 19.45±0.2°, 20.22±0.2°, 20.43±0.2°, 20.84±0.2°, 27.04±0.2:°, 27.904±0.2°, 28.254±0.2°, 28.754±0.2°.

[0049] In some embodiments of the present invention, semi-fumarate crystal form B of the above-mentioned compound of formula I-1 has special diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 5.12±0.2°, 7.27±0.2°, 7.48±0.2°, 8.77±0.2°, 9.18±0.2°, 9.74±0.2°, 10.20±0.2°, 10.53±0.2°, 14.24±0.2°, 14.96±0.2°, 16.09±0.2°, 16.99±0.2°, 17.61±0.2°, 17.95±0.2°, 18.81±0.2°, 19.45±0.2°, 20.22±0.2°, 20.43±0.2°, 20.84±0.2°, 22.51±0.2°, 23.11±0.2°, 23.76±0.2°, 24.19±0.2°, 25.24±0.2°, 27.04±0.2°, 27.90±0.2°, 28.25±0.2°, 28.75±0.2°, 29.73±0.2°, 30.14±0.2°, 30.77±0.2°, 31.28±0.2°, 33.95±0.2°, 34.52±0.2°, 37.07±0.2°, 38.26±0.2°.

[0050] In some embodiments of the present invention, semi-fumarate crystal form B of the above-mentioned compound of formula I-1 has an XRPD pattern as Figure 9as shown

[0051] Table 5 XRPD analysis data of the hemifumarate salt crystal form B of the compound of formula I-1

[0052]

[0053]

[0054] In some embodiments of the present invention, for the hemifumarate salt crystal form B of the above-mentioned compound of formula I-1, its differential scanning calorimetry curve has the starting points of endothermic peaks at 21.34°C ± 2°C, 172.21°C ± 2°C, and 234.34°C ± 2°C.

[0055] In some embodiments of the present invention, for the hemifumarate salt crystal form B of the above-mentioned compound of formula I-1, its DSC pattern is as Figure 10 shown

[0056] In some embodiments of the present invention, for the hemifumarate salt crystal form B of the above-mentioned compound of formula I-1, its thermogravimetric analysis curve has three weight loss steps at three temperatures of 31.90°C ± 2°C, 90.00°C ± 2°C, and 190.00°C ± 2°C, and starts to decompose after 270.00°C ± 2°C.

[0057] In some embodiments of the present invention, for the hemifumarate salt crystal form B of the above-mentioned compound of formula I-1, its TGA pattern is as Figure 11 shown

[0058] The present invention also provides a method for preparing the hemifumarate salt crystal form B of the above-mentioned compound of formula I-1, which comprises adding the compound of formula I-1 and fumaric acid to tetrahydrofuran, and obtaining it by recrystallization or slurrying. The ratio of the compound of formula I-1 to fumaric acid is selected from: 1.6 - 2.4.

[0059] The present invention also provides the monoethanolate salt crystal form A of the above-mentioned compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 6.37 ± 0.2°, 10.37 ± 0.2°, 12.69 ± 0.2°, 13.55 ± 0.2°, 14.06 ± 0.2°, 18.22 ± 0.2°, 18.47 ± 0.2°, 21.25 ± 0.2°, 22.83 ± 0.2°, 23.49 ± 0.2°, 26.41 ± 0.2°, 30.96 ± 0.2°.

[0060] In some embodiments of the present invention, the monoethanolate crystal form A of the compound of formula I-1 has specific diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 6.37 ± 0.2°, 10.37 ± 0.2°, 11.09 ± 0.2°, 11.70 ± 0.2°, 12.69 ± 0.2°, 13.55 ± 0.2°, 14.06 ± 0.2°, 15.97 ± 0.2°, 17.34 ± 0.2°, 18.22 ± 0.2°, 18.47 ± 0.2°, 19.09 ± 0.2°, 20.41 ± 0.2°, 20.71 ± 0.2°, 21.25 ± 0.2°, 22.06 ± 0.2°, 22.43 ± 0.2°, 22.83 ± 0.2°, 23.49 ± 0.2°, 24.09 ± 0.2°, 24.79 ± 0.2°, 25.21 ± 0.2°, 26.41 ± 0.2°, 27.23 ± 0.2°, 28.00 ± 0.2°, 29.59 ± 0.2°, 30.44 ± 0.2°, 30.96 ± 0.2°, 38.67 ± 0.2°.

[0061] In some embodiments of the present invention, the monoethanolate crystal form A of the compound of formula I-1 has an XRPD pattern as Figure 12 shown.

[0062] Table 6 XRPD analysis data of the monoethanolate crystal form A of the compound of formula I-1

[0063]

[0064]

[0065] In some embodiments of the present invention, the monoethanolate crystal form A of the compound of formula I-1 has the starting points of endothermic peaks at 109.66 °C ± 2 °C and 198.83 °C ± 2 °C in its differential scanning calorimetry curve.

[0066] In some embodiments of the present invention, the monoethanolate crystal form A of the compound of formula I-1 has a DSC pattern as Figure 13 shown.

[0067] In some embodiments of the present invention, the monoethanolate crystal form A of the compound of formula I-1 has three weight loss steps at 33.00 °C ± 2 °C, 100.00 °C ± 2 °C and 165.00 °C ± 2 °C in its thermogravimetric analysis curve and starts to decompose after 200.00 °C ± 2 °C.

[0068] In some embodiments of the present invention, the monoethanolate crystal form A of the compound of formula I-1 has a TGA pattern as Figure 14 shown.

[0069] The present invention also provides a method for preparing the monoethanolate crystal form A of the above-mentioned compound of formula I-1, which comprises adding the compound of formula I-1 and glycolic acid to acetonitrile and preparing by recrystallization or slurrying. The ratio of the compound of formula I-1 to glycolic acid is selected from: 0.8 to 1.2.

[0070] The present invention also provides the glycolate crystal form B of the above-mentioned compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 5.95±0.2°, 12.20±0.2°, 13.87±0.2°, 15.79±0.2°, 15.97±0.2°, 16.44±0.2°, 16.63±0.2°, 16.79±0.2°, 17.30±0.2°, 19.49±0.2°, 23.50±0.2°, 26.68±0.2°.

[0071] In some embodiments of the present invention, the glycolate crystal form B of the above-mentioned compound of formula I-1 has special diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 5.95±0.2°, 11.06±0.2°, 12.20±0.2°, 13.87±0.2°, 15.01±0.2°, 15.79±0.2°, 15.97±0.2°, 16.44±0.2°, 16.63±0.2°, 16.79±0.2°, 17.30±0.2°, 17.90±0.2°, 18.33±0.2°, 18.91±0.2°, 19.49±0.2°, 21.59±0.2°, 22.18±0.2°, 22.80±0.2°, 23.16±0.2°, 23.50±0.2°, 23.93±0.2°, 24.49±0.2°, 25.13±0.2°, 26.68±0.2°, 27.95±0.2°, 30.49±0.2°, 31.62±0.2°, 32.27±0.2°.

[0072] In some embodiments of the present invention, the XRPD pattern of the glycolate crystal form B of the above-mentioned compound of formula I-1 is as Figure 15 shown.

[0073] Table 7 XRPD analysis data of the glycolate crystal form B of the compound of formula I-1

[0074] Name Angle d Value Net Intensity Gross Intensity Rel.Intensity FWHM Peak#1 5.94826 14.84628 47.21226 62.80721 0.2820042 0.100 Peak#2 11.05959 7.993703 27.85228 46.52969 0.1663649 0.100 Peak#3 12.19964 7.249135 42.98131 61.03759 0.2567323 0.100 Peak#4 13.8704 6.379468 111.6527 128.6609 0.6669146 0.100 Peak#5 15.01254 5.896596 26.83811 41.78902 0.1603071 0.100 Peak#6 15.78903 5.60831 44.40633 61.01559 0.2652441 0.100 Peak#7 15.97478 5.543516 34.20984 51.4254 0.2043393 0.100 Peak#8 16.43714 5.388608 14.20148 32.83326 0.08482705 0.166 Peak#9 16.6293 5.326771 22.48186 41.62296 0.1342867 0.166 Peak#10 16.79174 5.275602 31.88576 51.36475 0.1904573 0.100 Peak#11 17.30051 5.12159 142.7281 162.7214 0.8525316 0.100 Peak#12 17.89638 4.952384 43.38684 63.59336 0.2591546 0.100 Peak#13 18.32724 4.836915 84.93102 104.8279 0.5073028 0.100 Peak#14 18.91279 4.688461 18.65536 37.72074 0.1114306 0.100 Peak#15 19.48954 4.550999 167.4168 186.2042 1 0.100 Peak#16 21.58975 4.112796 17.46467 35.08154 0.1043185 0.100 Peak#17 22.18036 4.0046 52.74449 72.09505 0.3150489 0.100 Peak#18 22.80481 3.896337 60.85134 82.53977 0.363472 0.173 Peak#19 23.15596 3.83804 45.15902 67.61517 0.26974 0.125 Peak#20 23.49665 3.783154 107.6953 130.5205 0.6432761 0.100 Peak#21 23.92768 3.715973 15.04318 37.80346 0.08985461 0.191 Peak#22 24.49098 3.631765 17.92286 39.70282 0.1070553 0.161 Peak#23 25.12531 3.541494 38.13791 58.55093 0.2278021 0.119 Peak#24 26.67703 3.338912 82.84576 102.2695 0.4948473 0.100 Peak#25 27.94708 3.189994 33.99763 54.5564 0.2030717 0.107 Peak#26 30.48514 2.929944 31.34254 53.22852 0.1872126 0.100 Peak#27 31.62302 2.827063 15.2675 32.42916 0.09119453 0.100 Peak#28 32.26844 2.771976 22.99334 38.4986 0.1373419 0.192

[0075] The present invention also provides a method for preparing the glycolate crystal form B of the above-mentioned compound of formula I-1, which comprises adding the compound of formula I-1 and glycolic acid to tetrahydrofuran and dichloromethane and preparing by recrystallization or slurrying. The ratio of the compound of formula I-1 to glycolic acid is selected from: 0.8 to 1.2.

[0076] The present invention also provides crystalline form A of the mono-L-malate salt of the above-mentioned compound of formula I-1, and its X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 6.01 ± 0.2°, 15.15 ± 0.2°, 17.27 ± 0.2°, 17.99 ± 0.2°, 18.58 ± 0.2°, 22.58 ± 0.2°, 24.00 ± 0.2°, 24.50 ± 0.2°, 25.00 ± 0.2°, 29.40 ± 0.2°, 30.53 ± 0.2°.

[0077] In some embodiments of the present invention, crystalline form A of the mono-L-malate salt of the above-mentioned compound of formula I-1 has special diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 6.01 ± 0.2°, 10.06 ± 0.2°, 11.04 ± 0.2°, 11.98 ± 0.2°, 12.66 ± 0.2°, 12.86 ± 0.2°, 13.39 ± 0.2°, 15.15 ± 0.2°, 15.62 ± 0.2°, 16.46 ± 0.2°, 17.27 ± 0.2°, 17.99 ± 0.2°, 18.58 ± 0.2°, 19.53 ± 0.2°, 19.77 ± 0.2°, 20.25 ± 0.2°, 21.01 ± 0.2°, 21.57 ± 0.2°, 22.04 ± 0.2°, 22.58 ± 0.2°, 23.67 ± 0.2°, 24.00 ± 0.2°, 24.50 ± 0.2°, 25.00 ± 0.2°, 27.34 ± 0.2°, 28.54 ± 0.2°, 28.91 ± 0.2°, 29.40 ± 0.2°, 29.89 ± 0.2°, 30.53 ± 0.2°, 31.33 ± 0.2°, 33.67 ± 0.2°, 36.16 ± 0.2°.

[0078] In some embodiments of the present invention, for crystalline form A of the mono-L-malate salt of the above-mentioned compound of formula I-1, its XRPD pattern is as Figure 16 shown.

[0079] Table 8 XRPD analysis data of crystalline form A of the mono-L-malate salt of the compound of formula I-1

[0080]

[0081]

[0082] In some embodiments of the present invention, for crystalline form A of the mono-L-malate salt of the above-mentioned compound of formula I-1, the starting point of the endothermic peak in its differential scanning calorimetry curve is at 204.74°C ± 2°C.

[0083] In some embodiments of the present invention, for crystalline form A of the mono-L-malate salt of the above-mentioned compound of formula I-1, its DSC pattern is as Figure 17 shown.

[0084] In some embodiments of the present invention, for the monohydrate L-malate crystal form A of the above formula I-1 compound, its thermogravimetric analysis curve has two weight loss steps at 33.00°C ± 2°C and 185.00°C ± 2°C, and starts to decompose after 250.00°C ± 2°C.

[0085] In some embodiments of the present invention, for the monohydrate L-malate crystal form A of the above formula I-1 compound, its TGA spectrum is as Figure 18 shown.

[0086] The present invention also provides a method for preparing the monohydrate L-malate crystal form A of the above formula I-1 compound, which includes adding the formula I-1 compound and L-malate into acetonitrile, tetrahydrofuran, dichloromethane, and obtaining it by recrystallization or slurrying. The ratio of the formula I-1 compound to L-malate is selected from: 0.8 to 1.2.

[0087] The present invention also provides the monohydrate succinate crystal form A of the above formula I-1 compound, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 6.15 ± 0.2°, 12.26 ± 0.2°, 17.59 ± 0.2°, 18.40 ± 0.2°, 18.89 ± 0.2°, 19.11 ± 0.2°, 19.73 ± 0.2°, 20.90 ± 0.2°, 23.12 ± 0.2°, 23.83 ± 0.2°, 24.09 ± 0.2°, 24.35 ± 0.2°, 24.62 ± 0.2°, 24.93 ± 0.2°, 25.17 ± 0.2°.

[0088] In some embodiments of the present invention, the monosuccinate crystal form A of the compound of formula I-1 has specific diffraction peaks in the X-ray powder diffraction pattern at the following 2θ angles: 6.15 ± 0.2°, 9.64 ± 0.2°, 9.95 ± 0.2°, 11.19 ± 0.2°, 12.26 ± 0.2°, 12.70 ± 0.2°, 13.30 ± 0.2°, 14.95 ± 0.2°, 15.25 ± 0.2°, 16.18 ± 0.2°, 17.59 ± 0.2°, 18.40 ± 0.2°, 18.89 ± 0.2°, 19.11 ± 0.2°, 19.73 ± 0.2°, 20.28 ± 0.2°, 20.90 ± 0.2°, 21.27 ± 0.2°, 21.64 ± 0.2°, 22.12 ± 0.2°, 23.12 ± 0.2°, 23.83 ± 0.2°, 24.09 ± 0.2°, 24.35 ± 0.2°, 24.62 ± 0.2°, 24.93 ± 0.2°, 25.17 ± 0.2°, 26.05 ± 0.2°, 27.00 ± 0.2°, 28.27 ± 0.2°, 28.72 ± 0.2°, 30.12 ± 0.2°, 31.20 ± 0.2°, 33.57 ± 0.2°, 34.13 ± 0.2°, 34.58 ± 0.2°, 35.60 ± 0.2°, 38.23 ± 0.2°.

[0089] In some embodiments of the present invention, the monosuccinate crystal form A of the compound of formula I-1 has an XRPD pattern as Figure 19 shown.

[0090] Table 9 XRPD analysis data of the monosuccinate crystal form A of the compound of formula I-1

[0091]

[0092]

[0093]

[0094] In some embodiments of the present invention, the monosuccinate crystal form A of the compound of formula I-1 has the starting points of endothermic peaks at 72.75 °C ± 2 °C, 146.41 °C ± 2 °C, and 175.72 °C ± 2 °C in the differential scanning calorimetry curve.

[0095] In some embodiments of the present invention, the monosuccinate crystal form A of the compound of formula I-1 has a DSC pattern as Figure 20 shown.

[0096] In some embodiments of the present invention, the monosuccinate crystal form A of the compound of formula I-1 has three weight loss steps at 33.00 °C ± 2 °C, 90.00 °C ± 2 °C and 160.00 °C ± 2 °C in its thermogravimetric analysis curve, and starts to decompose after 260.00 °C ± 2 °C.

[0097] In some embodiments of the present invention, the TGA pattern of the monosuccinate crystal form A of the compound of formula I-1 is as Figure 21 shown.

[0098] The present invention also provides a method for preparing the monosuccinate crystal form A of the compound of formula I-1, which comprises adding the compound of formula I-1 and succinic acid into acetonitrile, tetrahydrofuran, dichloromethane, and recrystallizing or slurrying to obtain it. The ratio of the compound of formula I-1 to succinic acid is selected from: 0.8 - 1.2.

[0099] The present invention also provides the sulfate crystal form A of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 6.74 ± 0.2°, 9.56 ± 0.2°, 12.89 ± 0.2°, 13.78 ± 0.2°, 14.97 ± 0.2°, 15.70 ± 0.2°, 18.68 ± 0.2°, 19.87 ± 0.2°, 20.21 ± 0.2°, 21.54 ± 0.2°, 21.76 ± 0.2°, 22.58 ± 0.2°, 23.75 ± 0.2°, 24.11 ± 0.2°, 24.50 ± 0.2°, 25.25 ± 0.2°, 25.86 ± 0.2°, 27.73 ± 0.2°, 28.41 ± 0.2°, 29.70 ± 0.2°, 30.21 ± 0.2°, 30.99 ± 0.2°.

[0100] In some embodiments of the present invention, for the sulfate crystal form A of the compound of formula I-1, its X-ray powder diffraction pattern has specific diffraction peaks at the following 2θ angles: 6.74±0.2°, 9.56±0.2°, 12.89±0.2°, 13.78±0.2°, 14.68±0.2°, 14.97±0.2°, 15.49±0.2°, 15.70±0.2°, 16.41±0.2°, 16.90±0.2°, 18.47±0.2°, 18.68±0.2°, 18.86±0.2°, 19.33±0.2°, 19.87±0.2°, 20.21±0.2°, 20.70±0.2°, 21.54±0.2°, 21.76±0.2°, 22.25±0.2°, 22.58±0.2°, 23.75±0.2°, 24.11±0.2°, 24.50±0.2°, 25.25±0.2°, 25.86±0.2°, 26.10±0.2°, 26.71±0.2°, 26.96±0.2°, 27.73±0.2°, 28.41±0.2°, 28.90±0.2°, 29.70±0.2°, 30.21±0.2°, 30.99±0.2°.

[0101] In some embodiments of the present invention, for the sulfate crystal form A of the compound of formula I-1, its XRPD pattern is as Figure 22 shown.

[0102] Table 10 XRPD analysis data of the sulfate crystal form A of the compound of formula I-1

[0103]

[0104]

[0105] The present invention also provides a method for preparing the sulfate crystal form A of the compound of formula I-1, which includes adding the compound of formula I-1 and sulfuric acid to acetonitrile and obtaining it by recrystallization or slurrying. The ratio of the compound of formula I-1 to sulfuric acid is selected from: 0.8 to 1.2.

[0106] The present invention also provides L-tartrate crystal form A of the above-mentioned compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 5.53±0.2°, 8.90±0.2°, 9.35±0.2°, 11.05±0.2°, 12.54±0.2°, 12.90±0.2°, 14.35±0.2°, 14.64±0.2°, 16.95±0.2°, 18.70±0.2°, 19.45±0.2°, 19.74±0.2°, 20.38±0.2°, 20.79±0.2°, 21.45±0.2°, 21.94±0.2°, 22.88±0.2°, 23.80±0.2°, 25.01±0.2°, 25.77±0.2°, 27.33±0.2°, 27.80±0.2°, 28.65±0.2°, 29.41±0.2°, 30.00±0.2°, 31.09±0.2°.

[0107] In some embodiments of the present invention, L-tartrate crystal form A of the above-mentioned compound of formula I-1 has special diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 5.53±0.2°, 8.90±0.2°, 9.35±0.2°, 11.05±0.2°, 12.54±0.2°, 12.90±0.2°, 14.35±0.2°, 14.64±0.2°, 16.95±0.2°, 18.70±0.2°, 19.45±0.2°, 19.74±0.2°, 20.38±0.2°, 20.79±0.2°, 21.45±0.2°, 21.94±0.2°, 22.88±0.2°, 23.80±0.2°, 25.01±0.2°, 25.77±0.2°, 27.33±0.2°, 27.80±0.2°, 28.65±0.2°, 29.41±0.2°, 30.00±0.2°, 31.09±0.2°.

[0108] In some embodiments of the present invention, L-tartrate crystal form A of the above-mentioned compound of formula I-1 has an XRPD pattern as Figure 23 shown.

[0109] Table 11 XRPD analysis data of L-tartrate crystal form A of the compound of formula I-1

[0110] Name Angle d Value Net Intensity Gross Intensity Rel.Intensity FWHM Peak#1 5.532435 15.96118 109.1809 126.6481 0.7936769 0.100 Peak#2 8.902002 9.925714 17.76301 34.91975 0.129126 0.100 Peak#3 9.347501 9.453633 20.67122 38.23275 0.1502669 0.107 Peak#4 11.05106 7.999851 40.37062 57.19987 0.2934692 0.100 Peak#5 12.53919 7.053588 73.71306 91.06278 0.5358478 0.100 Peak#6 12.8953 6.859589 31.62126 49.20035 0.2298668 0.106 Peak#7 14.3487 6.167873 24.90215 41.21078 0.1810231 0.181 Peak#8 14.63806 6.046594 38.96151 55.6525 0.2832258 0.169 Peak#9 16.94772 5.227398 113.6682 132.2339 0.8262969 0.100 Peak#10 18.69887 4.741615 16.89806 36.56548 0.1228383 0.100 Peak#11 19.44714 4.560826 31.79594 53.59855 0.2311366 0.134 Peak#12 19.74014 4.493786 40.01748 62.17728 0.290902 0.139 Peak#13 20.37972 4.354178 102.8208 125.9592 0.7474431 0.112 Peak#14 20.79081 4.269002 137.5634 161.0057 1 0.100 Peak#15 21.45161 4.138969 104.2521 127.0696 0.7578474 0.100 Peak#16 21.942 4.047562 66.40536 87.87263 0.4827255 0.118 Peak#17 22.88227 3.883322 13.39118 34.40554 0.09734552 0.175 Peak#18 23.79606 3.736227 26.73411 47.92166 0.1943403 0.100 Peak#19 25.01189 3.557295 31.7189 53.23115 0.2305766 0.117 Peak#20 25.77077 3.454237 53.50304 75.36505 0.3889337 0.121 Peak#21 27.33488 3.260032 22.88951 45.80283 0.1663924 0.213 Peak#22 27.80017 3.206517 29.94634 54.00067 0.2176912 0.141 Peak#23 28.65149 3.113149 48.81897 74.25991 0.3548834 0.140 Peak#24 29.40593 3.034971 65.22767 90.68871 0.4741644 0.100 Peak#25 30.00085 2.976129 29.92109 54.13644 0.2175076 0.149 Peak#26 31.09079 2.874235 31.22145 54.13402 0.2269605 0.100

[0111] The present invention also provides a preparation method of L-tartrate crystal form A of the above-mentioned compound of formula I-1, which comprises adding the compound of formula I-1 and L-tartaric acid into acetonitrile, and obtaining it by recrystallization or slurry. The ratio of the compound of formula I-1 to L-tartaric acid is selected from: 0.8 to 1.2.

[0112] The present invention also provides the hippurate crystal form A of the above-mentioned compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 6.17±0.2°, 6.52±0.2°, 12.30±0.2°, 14.18±0.2°, 15.62±0.2°, 16.06±0.2°, 16.78±0.2°, 17.64±0.2°, 18.78±0.2°, 20.42±0.2°, 21.15±0.2°, 21.29±0.2°, 21.79±0.2°, 24.42±0.2°, 26.45±0.2°.

[0113] In some embodiments of the present invention, the hippurate crystal form A of the above-mentioned compound of formula I-1 has special diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 6.17±0.2°, 6.52±0.2°, 8.77±0.2°, 10.74±0.2°, 11.16±0.2°, 12.30±0.2°, 14.18±0.2°, 14.70±0.2°, 15.62±0.2°, 16.06±0.2°, 16.78±0.2°, 17.64±0.2°, 18.78±0.2°, 20.42±0.2°, 21.15±0.2°, 21.29±0.2°, 21.79±0.2°, 23.03±0.2°, 24.05±0.2°, 24.42±0.2°, 25.32±0.2°, 26.45±0.2°, 26.87±0.2°, 28.85±0.2°.

[0114] In some embodiments of the present invention, the XRPD pattern of the hippurate crystal form A of the above-mentioned compound of formula I-1 is as Figure 24 shown.

[0115] Table 12 XRPD analysis data of the hippurate crystal form A of the compound of formula I-1

[0116] Name Angle d Value Net Intensity Gross Intensity Rel.Intensity FWHM Peak#1 6.165727 14.32313 46.84962 63.97629 0.3607576 0.100 Peak#2 6.518609 13.54852 37.30031 54.89573 0.2872247 0.183 Peak#3 8.770015 10.07479 10.25155 31.52564 0.07894034 0.100 Peak#4 10.73528 8.23445 17.72863 43.06414 0.1365163 0.199 Peak#5 11.15514 7.925448 11.28448 37.4897 0.08689421 0.131 Peak#6 12.30332 7.188276 107.018 134.0704 0.8240739 0.100 Peak#7 14.18347 6.239351 32.73286 58.3698 0.2520539 0.100 Peak#8 14.69591 6.022922 13.75151 40.19582 0.1058912 0.226 Peak#9 15.6192 5.668907 24.5425 53.66223 0.1889853 0.216 Peak#10 16.064 5.512926 40.11842 71.12805 0.3089251 0.160 Peak#11 16.78293 5.278353 30.71124 63.47039 0.2364867 0.100 Peak#12 17.64042 5.02366 38.97564 76.05798 0.3001254 0.146 Peak#13 18.78433 4.720233 129.8645 172.2274 1 0.106 Peak#14 20.41602 4.346517 36.85044 83.07684 0.2837606 0.194 Peak#15 21.14778 4.197742 32.82731 78.65607 0.2527812 0.181 Peak#16 21.29136 4.169756 29.05938 74.61411 0.2237668 0.155 Peak#17 21.79278 4.074936 27.59339 71.68633 0.2124783 0.186 Peak#18 23.02744 3.859168 22.89831 60.05222 0.1763246 0.100 Peak#19 24.05033 3.697299 16.04067 52.94743 0.1235185 0.171 Peak#20 24.42373 3.641612 21.46288 58.33859 0.1652713 0.230 Peak#21 25.32431 3.514113 21.20499 56.21917 0.1632854 0.182 Peak#22 26.44801 3.367302 20.40374 50.96436 0.1571156 0.203 Peak#23 26.8689 3.315503 12.99294 41.55479 0.1000499 0.117 Peak#24 28.85276 3.091887 14.44897 46.59393 0.1112619 0.138

[0117] The present invention also provides a preparation method of the hippurate crystal form A of the above-mentioned compound of formula I-1, which comprises adding the compound of formula I-1 and hippuric acid into tetrahydrofuran, and preparing it by recrystallization or slurrying. The ratio of the compound of formula I-1 to hippuric acid is selected from: 0.8 to 1.2.

[0118] The present invention also provides the glutarate salt crystal form A of the above-mentioned compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 11.82±0.2°, 12.75±0.2°, 13.19±0.2°, 14.87±0.2°, 15.10±0.2°, 17.10±0.2°, 17.82±0.2°, 18.35±0.2°, 19.75±0.2°, 20.14±0.2°, 20.70±0.2°, 22.23±0.2°, 23.20±0.2°, 24.26±0.2°, 24.47±0.2°, 29.92±0.2°.

[0119] In some embodiments of the present invention, the glutarate salt crystal form A of the above-mentioned compound of formula I-1 has special diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 9.86±0.2°, 10.97±0.2°, 11.82±0.2°, 12.29±0.2°, 12.75±0.2°, 13.19±0.2°, 14.87±0.2°, 15.10±0.2°, 15.37±0.2°, 16.33±0.2°, 17.10±0.2°, 17.82±0.2°, 18.35±0.2°, 19.17±0.2°, 19.75±0.2°, 20.14±0.2°, 20.70±0.2°, 21.14±0.2°, 22.23±0.2°, 23.20±0.2°, 24.26±0.2°, 24.47±0.2°, 24.86±0.2°, 25.28±0.2°, 29.92±0.2°.

[0120] In some embodiments of the present invention, the glutarate salt crystal form A of the above-mentioned compound of formula I-1 has an XRPD pattern as Figure 25 shown.

[0121] Table 13 XRPD analysis data of the glutarate salt crystal form A of the compound of formula I-1

[0122]

[0123]

[0124] The present invention also provides a method for preparing the glutarate salt crystal form A of the above-mentioned compound of formula I-1, which comprises adding the compound of formula I-1 and glutaric acid into acetonitrile and dichloromethane, and performing recrystallization or slurrying to obtain it. The ratio of the compound of formula I-1 to glutaric acid is selected from: 0.8 to 1.2.

[0125] The present invention also provides crystalline form A of the p-toluenesulfonate salt of the above-mentioned compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 7.08 ± 0.2°, 10.23 ± 0.2°, 13.36 ± 0.2°, 14.16 ± 0.2°, 17.77 ± 0.2°, 18.10 ± 0.2°, 18.90 ± 0.2°, 19.12 ± 0.2°, 20.11 ± 0.2°, 20.53 ± 0.2°, 20.91 ± 0.2°, 24.41 ± 0.2°, 25.51 ± 0.2°, 28.28 ± 0.2°, 29.95 ± 0.2°, 30.98 ± 0.2°, 35.22 ± 0.2°.

[0126] In some embodiments of the present invention, crystalline form A of the p-toluenesulfonate salt of the above-mentioned compound of formula I-1 has special diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 7.08 ± 0.2°, 8.00 ± 0.2°, 9.39 ± 0.2°, 10.23 ± 0.2°, 13.36 ± 0.2°, 14.16 ± 0.2°, 14.81 ± 0.2°, 15.77 ± 0.2°, 16.21 ± 0.2°, 17.77 ± 0.2°, 18.10 ± 0.2°, 18.90 ± 0.2°, 19.12 ± 0.2°, 20.11 ± 0.2°, 20.53 ± 0.2°, 20.91 ± 0.2°, 21.29 ± 0.2°, 22.49 ± 0.2°, 23.11 ± 0.2°, 24.41 ± 0.2°, 25.51 ± 0.2°, 26.77 ± 0.2°, 28.28 ± 0.2°, 28.81 ± 0.2°, 29.22 ± 0.2°, 29.95 ± 0.2°, 30.98 ± 0.2°, 35.22 ± 0.2°.

[0127] In some embodiments of the present invention, crystalline form A of the p-toluenesulfonate salt of the above-mentioned compound of formula I-1 has an XRPD pattern as Figure 26 shown.

[0128] Table 14 XRPD analysis data of crystalline form A of the p-toluenesulfonate salt of the compound of formula I-1

[0129]

[0130]

[0131] The present invention also provides a method for preparing crystalline form A of the p-toluenesulfonate salt of the above-mentioned compound of formula I-1, which comprises adding the compound of formula I-1 and p-toluenesulfonic acid to acetonitrile, and preparing it by recrystallization or slurrying. The ratio of the compound of formula I-1 to p-toluenesulfonic acid is selected from: 0.8 to 1.2.

[0132] The present invention also provides the p-toluenesulfonate crystal form B of the above-mentioned compound of formula I-1, and its X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 8.27±0.2°, 13.69±0.2°, 13.95±0.2°, 16.15±0.2°, 17.72±0.2°, 19.52±0.2°, 21.05±0.2°, 22.45±0.2°, 23.91±0.2°, 25.40±0.2°, 27.33±0.2°, 29.25±0.2°.

[0133] In some embodiments of the present invention, the p-toluenesulfonate crystal form B of the above-mentioned compound of formula I-1 has special diffraction peaks at the following 2θ angles: 8.27±0.2°, 12.59±0.2°, 13.69±0.2°, 13.95±0.2°, 14.63±0.2°, 16.15±0.2°, 17.72±0.2°, 18.68±0.2°, 19.52±0.2°, 20.75±0.2°, 21.05±0.2°, 21.92±0.2°, 22.45±0.2°, 23.23±0.2°, 23.91±0.2°, 25.40±0.2°, 27.33±0.2°, 29.25±0.2°.

[0134] In some embodiments of the present invention, the XRPD pattern of the p-toluenesulfonate crystal form B of the above-mentioned compound of formula I-1 is as Figure 27 shown.

[0135] XRPD analysis data of the p-toluenesulfonate crystal form B of the compound of formula I-1 in Table 15

[0136]

[0137]

[0138] The present invention also provides a method for preparing the p-toluenesulfonate crystal form B of the above-mentioned compound of formula I-1, which comprises adding the compound of formula I-1 and p-toluenesulfonic acid to tetrahydrofuran, and preparing it by recrystallization or slurrying. The ratio of the compound of formula I-1 to p-toluenesulfonic acid is selected from: 0.8 to 1.2.

[0139] The present invention also provides crystalline form A of the mesylate salt of the above-mentioned compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 6.70±0.2°, 9.10±0.2°, 9.81±0.2°, 10.16±0.2°, 13.34±0.2°, 13.87±0.2°, 14.27±0.2°, 15.37±0.2°, 17.21±0.2°, 19.57±0.2°, 21.16±0.2°, 22.09±0.2°, 23.86±0.2°, 24.30±0.2°, 24.99±0.2°, 27.18±0.2°.

[0140] In some embodiments of the present invention, crystalline form A of the mesylate salt of the above-mentioned compound of formula I-1 has special diffraction peaks at the following 2θ angles: 6.70±0.2°, 9.10±0.2°, 9.81±0.2°, 10.16±0.2°, 13.34±0.2°, 13.87±0.2°, 14.27±0.2°, 15.37±0.2°, 15.79±0.2°, 17.21±0.2°, 18.75±0.2°, 19.57±0.2°, 21.16±0.2°, 22.09±0.2°, 23.31±0.2°, 23.86±0.2°, 24.30±0.2°, 24.99±0.2°, 27.18±0.2°, 28.04±0.2°, 28.83±0.2°.

[0141] In some embodiments of the present invention, the XRPD pattern of crystalline form A of the mesylate salt of the above-mentioned compound of formula I-1 is as Figure 28 shown.

[0142] Table 16 XRPD analysis data of crystalline form A of the mesylate salt of the compound of formula I-1

[0143]

[0144]

[0145] The present invention also provides a method for preparing crystalline form A of the mesylate salt of the above-mentioned compound of formula I-1, which comprises adding the compound of formula I-1 and methanesulfonic acid to tetrahydrofuran, and preparing it by recrystallization or slurrying. The ratio of the compound of formula I-1 to methanesulfonic acid is selected from: 0.8 to 1.2.

[0146] The present invention also provides crystalline form C1 of the hydrochloride salt of the above-mentioned compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 7.47±0.2°, 7.73±0.2°, 12.25±0.2°, 13.18±0.2°, 13.51±0.2°, 14.96±0.2°, 15.46±0.2°, 17.31±0.2°, 18.56±0.2°, 19.34±0.2°, 19.57±0.2°, 19.78±0.2°, 20.01±0.2°, 20.41±0.2°, 20.76±0.2°, 24.36±0.2°, 25.63±0.2°, 26.47±0.2°, 27.51±0.2°.

[0147] In some embodiments of the present invention, crystalline form C1 of the hydrochloride salt of the above-mentioned compound of formula I-1 has special diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 7.47±0.2°, 7.73±0.2°, 9.63±0.2°, 11.46±0.2°, 12.25±0.2°, 13.18±0.2°, 13.51±0.2°, 14.96±0.2°, 15.46±0.2°, 16.79±0.2°, 17.04±0.2°, 17.31±0.2°, 17.72±0.2°, 18.56±0.2°, 19.34±0.2°, 19.57±0.2°, 19.78±0.2°, 20.01±0.2°, 20.41±0.2°, 20.76±0.2°, 22.60±0.2°, 23.09±0.2°, 23.80±0.2°, 24.36±0.2°, 25.63±0.2°, 26.47±0.2°, 27.51±0.2°, 29.09±0.2°, 30.76±0.2°, 31.99±0.2°, 36.24±0.2°.

[0148] In some embodiments of the present invention, crystalline form C1 of the hydrochloride salt of the above-mentioned compound of formula I-1 has an XRPD pattern as Figure 29 shown.

[0149] Table 17 XRPD analysis data of crystalline form C1 of the hydrochloride salt of the compound of formula I-1

[0150]

[0151]

[0152] In some embodiments of the present invention, crystalline form C1 of the hydrochloride salt of the above-mentioned compound of formula I-1 has starting points of endothermic peaks at 39.76°C±2°C and 153.80°C±2°C in its differential scanning calorimetry curve, and the sample decomposes at 214.75°C±2°C.

[0153] In some embodiments of the present invention, for the hydrochloride crystal form C1 of the compound of formula I-1, its DSC pattern is as Figure 30 shown.

[0154] In some embodiments of the present invention, for the hydrochloride crystal form C1 of the compound of formula I-1, its thermogravimetric analysis curve has three weight loss steps at 26.03°C ± 2°C, 100.00°C ± 2°C, and 150.00°C ± 2°C.

[0155] In some embodiments of the present invention, for the hydrochloride crystal form C1 of the compound of formula I-1, its TGA pattern is as Figure 31 shown.

[0156] The present invention also provides a method for preparing the hydrochloride crystal form C1 of the compound of formula I-1, which comprises adding the compound of formula I-1 and hydrochloric acid into ethyl acetate, and performing recrystallization or slurrying to obtain it. The ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2. The hydrochloride crystal form C1 of the compound of formula I-1 is an ethyl acetate solvent and hydrate crystal form, with the ethyl acetate content being 0.62 equivalents and the water content being 3.0 equivalents.

[0157] The present invention also provides the hydrochloride crystal form C2 of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 7.56 ± 0.2°, 7.79 ± 0.2°, 12.32 ± 0.2°, 13.21 ± 0.2°, 13.63 ± 0.2°, 15.10 ± 0.2°, 15.56 ± 0.2°, 18.58 ± 0.2°, 19.36 ± 0.2°, 19.66 ± 0.2°, 19.82 ± 0.2°, 20.91 ± 0.2°, 24.35 ± 0.2°, 26.56 ± 0.2°, 30.74 ± 0.2°.

[0158] In some embodiments of the present invention, for the hydrochloride crystal form C2 of the compound of formula I-1, its X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 7.56±0.2°, 7.79±0.2°, 9.65±0.2°, 11.48±0.2°, 12.32±0.2°, 13.21±0.2°, 13.63±0.2°, 15.10±0.2°, 15.56±0.2°, 16.86±0.2°, 17.16±0.2°, 17.41±0.2°, 17.77±0.2°, 18.58±0.2°, 19.36±0.2°, 19.66±0.2°, 19.82±0.2°, 20.32±0.2°, 20.91±0.2°, 22.71±0.2°, 23.21±0.2°, 23.80±0.2°, 24.35±0.2°, 25.71±0.2°, 26.56±0.2°, 27.53±0.2°, 27.80±0.2°, 28.20±0.2°, 29.15±0.2°, 30.74±0.2°, 32.06±0.2°, 36.30±0.2°, 38.22±0.2°.

[0159] In some embodiments of the present invention, for the hydrochloride crystal form C2 of the compound of formula I-1, its XRPD pattern is as Figure 32 shown.

[0160] Table 18 XRPD analysis data of the hydrochloride crystal form C2 of the compound of formula I-1

[0161]

[0162]

[0163] In some embodiments of the present invention, for the hydrochloride crystal form C2 of the compound of formula I-1, its differential scanning calorimetry curve has the starting points of endothermic peaks at 33.27°C±2°C and 155.72°C±2°C, and the sample starts to decompose at 212.45°C±2°C.

[0164] In some embodiments of the present invention, for the hydrochloride crystal form C2 of the compound of formula I-1, its DSC pattern is as Figure 33 shown.

[0165] In some embodiments of the present invention, for the hydrochloride crystal form C2 of the compound of formula I-1, its thermogravimetric analysis curve has three weight loss steps at 28.19°C±2°C, 115.00°C±2°C, and 150.00°C±2°C.

[0166] In some embodiments of the present invention, for the hydrochloride crystal form C2 of the compound of formula I-1, its TGA pattern is as Figure 34 shown.

[0167] The present invention also provides a method for preparing crystalline form C2 of the hydrochloride salt of the above-mentioned compound of formula I-1, which comprises adding the compound of formula I-1 and hydrochloric acid to 2-methyltetrahydrofuran, and performing recrystallization or slurrying to obtain it. The ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2. The crystalline form C2 of the hydrochloride salt of the compound of formula I-1 is a 2-methyltetrahydrofuran solvent and hydrate crystalline form, and the content of 2-methyltetrahydrofuran is 0.21 equivalent, and the water content is 2.8 equivalents.

[0168] The present invention also provides crystalline form D of the hydrochloride salt of the above-mentioned compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 6.60±0.2°, 7.79±0.2°, 9.84±0.2°, 13.31±0.2°, 15.23±0.2°, 15.93±0.2°, 20.09±0.2°, 20.41±0.2°, 21.23±0.2°, 21.80±0.2°.

[0169] In some embodiments of the present invention, crystalline form D of the hydrochloride salt of the above-mentioned compound of formula I-1 has special diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 6.60±0.2°, 7.26±0.2°, 7.79±0.2°, 8.48±0.2°, 9.84±0.2°, 11.18±0.2°, 13.31±0.2°, 13.89±0.2°, 14.64±0.2°, 14.98±0.2°, 15.23±0.2°, 15.93±0.2°, 16.27±0.2°, 17.04±0.2°, 18.21±0.2°, 19.33±0.2°, 20.09±0.2°, 20.41±0.2°, 21.23±0.2°, 21.80±0.2°, 23.49±0.2°, 24.79±0.2°, 28.43±0.2°.

[0170] In some embodiments of the present invention, crystalline form D of the hydrochloride salt of the above-mentioned compound of formula I-1, its XRPD pattern is as Figure 35 shown.

[0171] Table 19 XRPD analysis data of crystalline form D of the hydrochloride salt of the compound of formula I-1

[0172]

[0173]

[0174] In some embodiments of the present invention, crystalline form D of the hydrochloride salt of the above-mentioned compound of formula I-1 has starting points of endothermic peaks at 55.20°C±2°C and 164.37°C±2°C in its differential scanning calorimetry curve, and the sample starts to decompose at 211.35°C±2°C.

[0175] In some embodiments of the present invention, for the hydrochloride crystal form D of the compound of formula I-1, its DSC pattern is as Figure 36 shown.

[0176] In some embodiments of the present invention, for the hydrochloride crystal form D of the compound of formula I-1, its thermogravimetric analysis curve has two weight loss steps at 36.24°C ± 2°C and 110.00°C ± 2°C.

[0177] In some embodiments of the present invention, for the hydrochloride crystal form D of the compound of formula I-1, its TGA pattern is as Figure 37 shown.

[0178] The present invention also provides a method for preparing the hydrochloride crystal form D of the compound of formula I-1, which includes adding the compound of formula I-1 and hydrochloric acid to methyl ethyl ketone, and obtaining it by recrystallization or slurrying. The ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 - 1.2, and the hydrochloride crystal form D of the compound of formula I-1 is an anhydrous crystal form.

[0179] The present invention also provides the hydrochloride crystal form E1 of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 6.15 ± 0.2°, 7.66 ± 0.2°, 7.90 ± 0.2°, 13.06 ± 0.2°, 14.06 ± 0.2°, 16.25 ± 0.2°, 18.37 ± 0.2°, 19.01 ± 0.2°, 19.75 ± 0.2°, 20.19 ± 0.2°, 21.81 ± 0.2°, 23.56 ± 0.2°, 24.95 ± 0.2°, 25.18 ± 0.2°, 25.63 ± 0.2°, 26.71 ± 0.2°, 27.10 ± 0.2°, 27.91 ± 0.2°, 29.81 ± 0.2°, 32.93 ± 0.2°.

[0180] In some embodiments of the present invention, the hydrochloride crystal form E1 of the compound of formula I-1 has specific diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 6.15 ± 0.2°, 7.66 ± 0.2°, 7.90 ± 0.2°, 8.41 ± 0.2°, 9.49 ± 0.2°, 9.91 ± 0.2°, 10.88 ± 0.2°, 11.42 ± 0.2°, 13.06 ± 0.2°, 13.66 ± 0.2°, 14.06 ± 0.2°, 14.69 ± 0.2°, 15.32 ± 0.2°, 15.52 ± 0.2°, 15.88 ± 0.2°, 16.25 ± 0.2°, 16.81 ± 0.2°, 17.35 ± 0.2°, 18.37 ± 0.2°, 19.01 ± 0.2°, 19.75 ± 0.2°, 20.19 ± 0.2°, 21.15 ± 0.2°, 21.51 ± 0.2°, 21.81 ± 0.2°, 22.50 ± 0.2°, 22.87 ± 0.2°, 23.56 ± 0.2°, 24.95 ± 0.2°, 25.18 ± 0.2°, 25.63 ± 0.2°, 26.71 ± 0.2°, 27.10 ± 0.2°, 27.91 ± 0.2°, 28.47 ± 0.2°, 29.30 ± 0.2°, 29.81 ± 0.2°, 30.12 ± 0.2°, 32.93 ± 0.2°, 34.96 ± 0.2°.

[0181] In some embodiments of the present invention, the hydrochloride crystal form E1 of the compound of formula I-1 has an XRPD pattern as Figure 38 shown.

[0182] Table 20 XRPD analysis data of the hydrochloride crystal form E1 of the compound of formula I-1

[0183]

[0184]

[0185] In some embodiments of the present invention, the hydrochloride crystal form E1 of the compound of formula I-1 has the starting points of endothermic peaks at 13.36 °C ± 2 °C and 174.06 °C ± 2 °C in its differential scanning calorimetry curve, and the sample starts to decompose at 211.29 °C ± 2 °C.

[0186] In some embodiments of the present invention, the hydrochloride crystal form E1 of the compound of formula I-1 has a DSC pattern as Figure 39 shown.

[0187] In some embodiments of the present invention, the hydrochloride crystal form E1 of the compound of formula I-1 has three weight loss steps at 25.81 °C ± 2 °C, 120.00 °C ± 2 °C and 160.00 °C ± 2 °C in its thermogravimetric analysis curve.

[0188] In some embodiments of the present invention, for the hydrochloride crystal form E1 of the compound of formula I-1, its TGA spectrum is as follows Figure 40 shown.

[0189] The present invention also provides a method for preparing the hydrochloride crystal form E1 of the compound of formula I-1, which includes adding the compound of formula I-1 and hydrochloric acid to ethanol, and performing recrystallization or slurrying to obtain it. The ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2. The hydrochloride crystal form E1 of the compound of formula I-1 is a hydrate crystal form with a water content of 1.7 equivalents.

[0190] The present invention also provides the hydrochloride crystal form E2 of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 7.88±0.2°, 10.90±0.2°, 13.10±0.2°, 14.14±0.2°, 16.30±0.2°, 19.01±0.2°, 19.75±0.2°, 21.54±0.2°, 21.84±0.2°, 23.63±0.2°, 24.96±0.2°, 26.78±0.2°, 29.91±0.2°.

[0191] In some embodiments of the present invention, for the hydrochloride crystal form E2 of the compound of formula I-1, its X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 7.88±0.2°, 9.51±0.2°, 10.90±0.2°, 11.49±0.2°, 13.10±0.2°, 13.64±0.2°, 14.14±0.2°, 14.76±0.2°, 15.39±0.2°, 15.75±0.2°, 16.30±0.2°, 16.93±0.2°, 19.01±0.2°, 19.75±0.2°, 20.69±0.2°, 21.54±0.2°, 21.84±0.2°, 22.19±0.2°, 22.57±0.2°, 23.01±0.2°, 23.63±0.2°, 24.96±0.2°, 25.90±0.2°, 26.32±0.2°, 26.78±0.2°, 27.19±0.2°, 27.48±0.2°, 27.94±0.2°, 28.68±0.2°, 29.07±0.2°, 29.50±0.2°, 29.91±0.2°, 31.74±0.2°, 32.96±0.2°, 33.66±0.2°.

[0192] In some embodiments of the present invention, for the hydrochloride crystal form E2 of the compound of formula I-1, its XRPD spectrum is as follows Figure 41 shown.

[0193] XRPD Analysis Data of the Hydrochloride Salt Crystal Form E2 of Compound I-1

[0194]

[0195]

[0196] In some embodiments of the present invention, for the hydrochloride salt crystal form E2 of the above-mentioned compound I-1, its differential scanning calorimetry curve has starting points of endothermic peaks at 14.99 °C ± 2 °C and 174.19 °C ± 2 °C, and the sample starts to decompose at 213.17 °C ± 2 °C.

[0197] In some embodiments of the present invention, for the hydrochloride salt crystal form E2 of the above-mentioned compound I-1, its DSC pattern is as Figure 42 shown.

[0198] In some embodiments of the present invention, for the hydrochloride salt crystal form E2 of the above-mentioned compound I-1, its thermogravimetric analysis curve has three weight loss steps at 33.18 °C ± 2 °C, 90.00 °C ± 2 °C and 140.00 °C ± 2 °C.

[0199] In some embodiments of the present invention, for the hydrochloride salt crystal form E2 of the above-mentioned compound I-1, its TGA pattern is as Figure 43 shown.

[0200] The present invention also provides a preparation method of the hydrochloride salt crystal form E2 of the above-mentioned compound I-1, which is prepared by drying the hydrochloride salt crystal form F of the compound I-1 under vacuum at 25 °C, 50 °C or 100 °C. The ratio of the compound I-1 to hydrochloric acid is selected from: 0.8 - 1.2. The hydrochloride salt crystal form E2 of the compound I-1 is a hydrate crystal form with a water content of 1.8 equivalents.

[0201] The present invention also provides the hydrochloride salt crystal form F of the above-mentioned compound I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 7.65 ± 0.2 °, 11.47 ± 0.2 °, 13.93 ± 0.2 °, 14.80 ± 0.2 °, 15.25 ± 0.2 °, 19.84 ± 0.2 °, 20.09 ± 0.2 °, 21.51 ± 0.2 °, 23.22 ± 0.2 °, 25.06 ± 0.2 °, 26.68 ± 0.2 °, 28.87 ± 0.2 °, 32.45 ± 0.2 °, 33.59 ± 0.2 °.

[0202] In some embodiments of the present invention, for the hydrochloride crystal form F of the compound of formula I-1, its X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 6.85±0.2°, 7.65±0.2°, 10.21±0.2°, 10.70±0.2°, 11.47±0.2°, 13.93±0.2°, 14.80±0.2°, 15.25±0.2°, 16.60±0.2°, 16.88±0.2°, 17.84±0.2°, 19.00±0.2°, 19.16±0.2°, 19.84±0.2°, 20.09±0.2°, 20.34±0.2°, 21.51±0.2°, 22.35±0.2°, 23.22±0.2°, 23.86±0.2°, 25.06±0.2°, 25.31±0.2°, 25.63±0.2°, 26.68±0.2°, 28.10±0.2°, 28.87±0.2°, 30.53±0.2°, 32.45±0.2°, 33.59±0.2°.

[0203] In some embodiments of the present invention, for the hydrochloride crystal form F of the compound of formula I-1, its XRPD pattern is as Figure 44 shown.

[0204] Table 22 XRPD analysis data of the hydrochloride crystal form F of the compound of formula I-1

[0205]

[0206]

[0207] In some embodiments of the present invention, for the hydrochloride crystal form F of the compound of formula I-1, its differential scanning calorimetry curve has starting points of endothermic peaks at 36.03°C±2°C and 172.45°C±2°C, and the sample starts to decompose at 212.66°C±2°C.

[0208] In some embodiments of the present invention, for the hydrochloride crystal form F of the compound of formula I-1, its DSC pattern is as Figure 45 shown.

[0209] In some embodiments of the present invention, for the hydrochloride crystal form F of the compound of formula I-1, its thermogravimetric analysis curve has three weight loss steps at 33.35°C±2°C, 100.00°C±2°C and 150.00°C±2°C.

[0210] In some embodiments of the present invention, for the hydrochloride crystal form F of the compound of formula I-1, its TGA pattern is as Figure 46 shown.

[0211] The present invention also provides a method for preparing the hydrochloride crystal form F of the above-mentioned compound of formula I-1, which comprises adding the compound of formula I-1 and hydrochloric acid into a mixed solvent of ethanol, acetone, ethyl acetate, acetonitrile, tetrahydrofuran or methyl isobutyl ketone / trifluoroethanol, and performing recrystallization or slurry at 50 °C. The ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2. The hydrochloride crystal form F of the compound of formula I-1 is a hydrate crystal form, and the water content is 2.0 equivalents.

[0212] The present invention also provides the hydrochloride crystal form G of the above-mentioned compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 5.83 ± 0.2°, 9.97 ± 0.2°, 13.26 ± 0.2°, 14.17 ± 0.2°, 15.52 ± 0.2°, 16.77 ± 0.2°, 18.37 ± 0.2°, 20.27 ± 0.2°, 20.48 ± 0.2°, 21.35 ± 0.2°, 21.82 ± 0.2°, 22.65 ± 0.2°, 23.04 ± 0.2°, 24.43 ± 0.2°, 26.24 ± 0.2°, 26.54 ± 0.2°, 28.94 ± 0.2°, 30.18 ± 0.2°.

[0213] In some embodiments of the present invention, the hydrochloride crystal form G of the above-mentioned compound of formula I-1 has special diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 5.83 ± 0.2°, 7.18 ± 0.2°, 9.97 ± 0.2°, 11.63 ± 0.2°, 12.00 ± 0.2°, 12.35 ± 0.2°, 13.26 ± 0.2°, 13.58 ± 0.2°, 14.17 ± 0.2°, 14.60 ± 0.2°, 15.52 ± 0.2°, 16.77 ± 0.2°, 17.64 ± 0.2°, 18.37 ± 0.2°, 18.81 ± 0.2°, 19.14 ± 0.2°, 19.80 ± 0.2°, 20.27 ± 0.2°, 20.48 ± 0.2°, 21.35 ± 0.2°, 21.82 ± 0.2°, 22.65 ± 0.2°, 23.04 ± 0.2°, 23.35 ± 0.2°, 24.43 ± 0.2°, 25.47 ± 0.2°, 26.24 ± 0.2°, 26.54 ± 0.2°, 26.84 ± 0.2°, 27.92 ± 0.2°, 28.94 ± 0.2°, 29.31 ± 0.2°, 30.18 ± 0.2°.

[0214] In some embodiments of the present invention, the hydrochloride crystal form G of the above-mentioned compound of formula I-1 has an XRPD pattern as Figure 47 shown.

[0215] Table 23 XRPD analysis data of the hydrochloride crystal form G of the compound of formula I-1

[0216]

[0217]

[0218] In some embodiments of the present invention, for the hydrochloride crystal form G of the compound of formula I-1, the differential scanning calorimetry curve has starting points of endothermic peaks at 59.42°C ± 2°C, 151.02°C ± 2°C, and 166.01°C ± 2°C.

[0219] In some embodiments of the present invention, for the hydrochloride crystal form G of the compound of formula I-1, its DSC pattern is as Figure 48 shown.

[0220] In some embodiments of the present invention, for the hydrochloride crystal form G of the compound of formula I-1, its thermogravimetric analysis curve has three weight loss steps at 26.28°C ± 2°C, 120.00°C ± 2°C, and 150.00°C ± 2°C.

[0221] In some embodiments of the present invention, for the hydrochloride crystal form G of the compound of formula I-1, its TGA pattern is as Figure 49 shown.

[0222] The present invention also provides a method for preparing the hydrochloride crystal form G of the compound of formula I-1, which includes adding the compound of formula I-1 and hydrochloric acid to water, and preparing it by suspension recrystallization or slurry at 25°C, 50°C, or by temperature rise and fall. The ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 - 1.2. The hydrochloride crystal form G of the compound of formula I-1 is a hydrate crystal form with a water content of 3.0 equivalents.

[0223] The present invention also provides the hydrochloride crystal form H of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 5.83 ± 0.2°, 7.16 ± 0.2°, 10.02 ± 0.2°, 11.64 ± 0.2°, 13.23 ± 0.2°, 14.58 ± 0.2°, 16.67 ± 0.2°, 18.40 ± 0.2°, 18.62 ± 0.2°, 20.23 ± 0.2°, 20.54 ± 0.2°, 21.40 ± 0.2°, 22.62 ± 0.2°, 22.78 ± 0.2°, 23.36 ± 0.2°, 24.73 ± 0.2°, 26.23 ± 0.2°, 26.57 ± 0.2°, 26.91 ± 0.2°, 29.30 ± 0.2°, 30.21 ± 0.2°.

[0224] In some embodiments of the present invention, the hydrochloride crystal form H of the compound of formula I-1 has specific diffraction peaks in the X-ray powder diffraction pattern at the following 2θ angles: 5.83 ± 0.2°, 7.16 ± 0.2°, 10.02 ± 0.2°, 11.64 ± 0.2°, 12.35 ± 0.2°, 13.23 ± 0.2°, 13.59 ± 0.2°, 14.58 ± 0.2°, 15.51 ± 0.2°, 15.97 ± 0.2°, 16.67 ± 0.2°, 17.63 ± 0.2°, 18.40 ± 0.2°, 18.62 ± 0.2°, 19.11 ± 0.2°, 20.23 ± 0.2°, 20.54 ± 0.2°, 21.40 ± 0.2°, 22.07 ± 0.2°, 22.62 ± 0.2°, 22.78 ± 0.2°, 23.36 ± 0.2°, 24.73 ± 0.2°, 24.98 ± 0.2°, 26.23 ± 0.2°, 26.57 ± 0.2°, 26.91 ± 0.2°, 27.88 ± 0.2°, 29.01 ± 0.2°, 29.30 ± 0.2°, 29.61 ± 0.2°, 30.21 ± 0.2°, 31.21 ± 0.2°, 32.12 ± 0.2°, 34.66 ± 0.2°.

[0225] In some embodiments of the present invention, the hydrochloride crystal form H of the compound of formula I-1 has an XRPD pattern as Figure 50 shown.

[0226] Table 24 XRPD analysis data of the hydrochloride crystal form H of the compound of formula I-1

[0227]

[0228]

[0229] In some embodiments of the present invention, the hydrochloride crystal form H of the compound of formula I-1 has the starting points of endothermic peaks at 51.49 °C ± 2 °C and 153.61 °C ± 2 °C in the differential scanning calorimetry curve, and the sample starts to decompose at 211.73 °C ± 2 °C.

[0230] In some embodiments of the present invention, the hydrochloride crystal form H of the compound of formula I-1 has a DSC pattern as Figure 51 shown.

[0231] In some embodiments of the present invention, the hydrochloride crystal form H of the compound of formula I-1 has three weight loss steps at 26.12 °C ± 2 °C, 110.00 °C ± 2 °C and 150.00 °C ± 2 °C in the thermogravimetric analysis curve.

[0232] In some embodiments of the present invention, the hydrochloride crystal form H of the compound of formula I-1 has a TGA pattern as Figure 52as shown

[0233] The present invention also provides a method for preparing the hydrochloride crystal form H of the above-mentioned compound of formula I-1, which includes adding the compound of formula I-1 and hydrochloric acid into a methanol / water mixed solvent and obtaining it by suspension recrystallization or slurry at 25°C or 50°C. The ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2. The hydrochloride crystal form H of the compound of formula I-1 is a hydrate crystal form with a water content of 3.9 equivalents.

[0234] The present invention also provides the hydrochloride crystal form I of the above-mentioned compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 6.68±0.2°, 12.31±0.2°, 12.54±0.2°, 13.34±0.2°, 14.05±0.2°, 14.96±0.2°, 17.92±0.2°, 19.03±0.2°, 19.74±0.2°, 19.99±0.2°, 20.96±0.2°, 21.42±0.2°, 21.62±0.2°, 26.81±0.2°, 27.21±0.2°, 27.60±0.2°, 27.78±0.2°, 30.07±0.2°, 31.00±0.2°, 34.83±0.2°.

[0235] In some embodiments of the present invention, the hydrochloride crystal form I of the above-mentioned compound of formula I-1 has special diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 6.68±0.2°, 9.50±0.2°, 12.31±0.2°, 12.54±0.2°, 13.34±0.2°, 14.05±0.2°, 14.96±0.2°, 15.38±0.2°, 17.18±0.2°, 17.92±0.2°, 19.03±0.2°, 19.74±0.2°, 19.99±0.2°, 20.96±0.2°, 21.42±0.2°, 21.62±0.2°, 21.99±0.2°, 22.98±0.2°, 23.52±0.2°, 23.80±0.2°, 24.38±0.2°, 25.92±0.2°, 26.81±0.2°, 27.21±0.2°, 27.60±0.2°, 27.78±0.2°, 28.26±0.2°, 28.74±0.2°, 30.07±0.2°, 31.00±0.2°, 32.69±0.2°, 34.02±0.2°, 34.83±0.2°.

[0236] In some embodiments of the present invention, the hydrochloride crystal form I of the above-mentioned compound of formula I-1 has an XRPD pattern as Figure 53 as shown

[0237] XRPD Analysis Data of Crystal Form I of the Hydrochloride Salt of Compound of Formula I-1

[0238]

[0239]

[0240] In some embodiments of the present invention, for the crystal form I of the hydrochloride salt of the above-mentioned compound of formula I-1, the differential scanning calorimetry curve has starting points of endothermic peaks at 18.15 °C ± 2 °C and 194.49 °C ± 2 °C, and the sample starts to decompose at 215.51 °C ± 2 °C.

[0241] In some embodiments of the present invention, for the crystal form I of the hydrochloride salt of the above-mentioned compound of formula I-1, its DSC pattern is as Figure 54 shown.

[0242] In some embodiments of the present invention, for the crystal form I of the hydrochloride salt of the above-mentioned compound of formula I-1, its thermogravimetric analysis curve has three weight loss steps at 28.31 °C ± 2 °C, 70.00 °C ± 2 °C and 173.00 °C ± 2 °C.

[0243] In some embodiments of the present invention, for the crystal form I of the hydrochloride salt of the above-mentioned compound of formula I-1, its TGA pattern is as Figure 55 shown.

[0244] The present invention also provides a method for preparing the crystal form I of the hydrochloride salt of the above-mentioned compound of formula I-1, which includes adding the compound of formula I-1 and hydrochloric acid into a methanol or methanol / methyl tert-butyl ether mixed solvent, and performing suspension recrystallization or slurrying at 25 °C to obtain it. The ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 - 1.2, and the crystal form I of the hydrochloride salt of the compound of formula I-1 is an anhydrous crystal form.

[0245] The present invention also provides the crystal form J1 of the hydrochloride salt of the above-mentioned compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 6.80 ± 0.2 °, 11.69 ± 0.2 °, 14.87 ± 0.2 °, 15.98 ± 0.2 °, 18.05 ± 0.2 °, 19.49 ± 0.2 °, 20.41 ± 0.2 °, 21.55 ± 0.2 °, 21.70 ± 0.2 °, 22.06 ± 0.2 °, 23.69 ± 0.2 °, 24.92 ± 0.2 °, 25.13 ± 0.2 °, 29.07 ± 0.2 °, 30.16 ± 0.2 °.

[0246] In some embodiments of the present invention, the hydrochloride crystal form J1 of the compound of formula I-1 has specific diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 6.80 ± 0.2°, 7.82 ± 0.2°, 7.95 ± 0.2°, 10.08 ± 0.2°, 11.69 ± 0.2°, 12.30 ± 0.2°, 12.60 ± 0.2°, 13.60 ± 0.2°, 14.87 ± 0.2°, 15.98 ± 0.2°, 16.25 ± 0.2°, 18.05 ± 0.2°, 18.60 ± 0.2°, 18.79 ± 0.2°, 19.49 ± 0.2°, 20.41 ± 0.2°, 20.82 ± 0.2°, 21.55 ± 0.2°, 21.70 ± 0.2°, 22.06 ± 0.2°, 22.88 ± 0.2°, 23.69 ± 0.2°, 24.92 ± 0.2°, 25.13 ± 0.2°, 26.19 ± 0.2°, 26.57 ± 0.2°, 29.07 ± 0.2°, 30.16 ± 0.2°, 31.85 ± 0.2°, 32.80 ± 0.2°.

[0247] In some embodiments of the present invention, the hydrochloride crystal form J1 of the compound of formula I-1 has an XRPD pattern as Figure 56 shown.

[0248] Table 26 XRPD analysis data of the hydrochloride crystal form J1 of the compound of formula I-1

[0249]

[0250]

[0251] In some embodiments of the present invention, the hydrochloride crystal form J1 of the compound of formula I-1 has starting points of endothermic peaks at 70.82 °C ± 2 °C and 165.48 °C ± 2 °C in its differential scanning calorimetry curve, and the sample starts to decompose at 212.96 °C ± 2 °C.

[0252] In some embodiments of the present invention, the hydrochloride crystal form J1 of the compound of formula I-1 has a DSC pattern as Figure 57 shown.

[0253] In some embodiments of the present invention, the hydrochloride crystal form J1 of the compound of formula I-1 has two weight loss steps at 33.94 °C ± 2 °C and 110.00 °C ± 2 °C in its thermogravimetric analysis curve.

[0254] In some embodiments of the present invention, the hydrochloride crystal form J1 of the compound of formula I-1 has a TGA pattern as Figure 58 shown.

[0255] The present invention also provides a method for preparing crystalline form J1 of the hydrochloride salt of the above-mentioned compound of formula I-1, which comprises adding the compound of formula I-1 and hydrochloric acid to 2-methyltetrahydrofuran, and preparing it by suspension or heating and cooling recrystallization or slurrying at 500. The ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2. Crystalline form J1 of the hydrochloride salt of the compound of formula I-1 is a solvate of 2-methyltetrahydrofuran and water, with the content of 2-methyltetrahydrofuran being 0.75 equivalents and the content of water being 0.98 equivalents.

[0256] The present invention also provides crystalline form J2 of the hydrochloride salt of the above-mentioned compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 6.78±0.2°, 11.59±0.2°, 12.24±0.2°, 13.56±0.2°, 14.69±0.2°, 17.45±0.2°, 18.12±0.2°, 18.89±0.2°, 19.51±0.2°, 21.28±0.2°, 21.46±0.2°, 22.23±0.2°, 24.09±0.2°, 24.86±0.2°, 24.99±0.2°, 29.00±0.2°.

[0257] In some embodiments of the present invention, crystalline form J2 of the hydrochloride salt of the above-mentioned compound of formula I-1 has special diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 6.78±0.2°, 7.96±0.2°, 8.31±0.2°, 11.59±0.2°, 12.24±0.2°, 13.56±0.2°, 14.69±0.2°, 16.44±0.2°, 16.63±0.2°, 17.45±0.2°, 18.12±0.2°, 18.89±0.2°, 19.51±0.2°, 20.12±0.2°, 20.35±0.2°, 20.49±0.2°, 21.28±0.2°, 21.46±0.2°, 22.23±0.2°, 22.75±0.2°, 23.27±0.2°, 24.09±0.2°, 24.86±0.2°, 24.99±0.2°, 25.37±0.2°, 25.65±0.2°, 26.54±0.2°, 27.62±0.2°, 28.61±0.2°, 29.00±0.2°, 30.43±0.2°, 32.10±0.2°, 33.01±0.2°, 36.96±0.2°.

[0258] In some embodiments of the present invention, crystalline form J2 of the hydrochloride salt of the above-mentioned compound of formula I-1 has an XRPD pattern as Figure 59 shown.

[0259] Table 27 XRPD analysis data of crystalline form J2 of the hydrochloride salt of the compound of formula I-1

[0260]

[0261]

[0262] In some embodiments of the present invention, for the hydrochloride crystal form J2 of the above formula I-1 compound, the differential scanning calorimetry curve has starting points of endothermic peaks at 77.60 °C ± 2 °C and 163.47 °C ± 2 °C, and the sample starts to decompose at 211.78 °C ± 2 °C.

[0263] In some embodiments of the present invention, for the hydrochloride crystal form J2 of the above formula I-1 compound, its DSC pattern is as Figure 60 shown.

[0264] In some embodiments of the present invention, for the hydrochloride crystal form J2 of the above formula I-1 compound, its thermogravimetric analysis curve has two weight loss steps at 28.73 °C ± 2 °C and 120.00 °C ± 2 °C.

[0265] In some embodiments of the present invention, for the hydrochloride crystal form J2 of the above formula I-1 compound, its TGA pattern is as Figure 61 shown.

[0266] The present invention also provides a method for preparing the hydrochloride crystal form J2 of the above formula I-1 compound, which includes heating the hydrochloride crystal form J1 of the formula I-1 compound to 110 °C. The ratio of the formula I-1 compound to hydrochloric acid is selected from: 0.8 - 1.2. The hydrochloride crystal form J2 of the formula I-1 compound is a solvate of 2-methyltetrahydrofuran and water, with the 2-methyltetrahydrofuran content being 0.39 equivalent and the water content being 0.94 equivalent.

[0267] The present invention also provides the hydrochloride crystal form K of the above formula I-1 compound, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 6.79 ± 0.2 °, 11.61 ± 0.2 °, 14.93 ± 0.2 °, 16.08 ± 0.2 °, 18.05 ± 0.2 °, 18.63 ± 0.2 °, 20.49 ± 0.2 °, 20.64 ± 0.2 °, 21.52 ± 0.2 °, 21.72 ± 0.2 °, 21.93 ± 0.2 °, 23.68 ± 0.2 °, 25.19 ± 0.2 °, 26.25 ± 0.2 °, 26.57 ± 0.2 °, 29.91 ± 0.2 °, 32.56 ± 0.2 °.

[0268] In some embodiments of the present invention, the hydrochloride crystal form K of the compound of formula I-1 has specific diffraction peaks in the X-ray powder diffraction pattern at the following 2θ angles: 6.79 ± 0.2°, 7.83 ± 0.2°, 8.04 ± 0.2°, 10.00 ± 0.2°, 10.74 ± 0.2°, 11.61 ± 0.2°, 12.25 ± 0.2°, 12.64 ± 0.2°, 13.57 ± 0.2°, 14.93 ± 0.2°, 16.08 ± 0.2°, 18.05 ± 0.2°, 18.63 ± 0.2°, 19.43 ± 0.2°, 20.15 ± 0.2°, 20.49 ± 0.2°, 20.64 ± 0.2°, 21.52 ± 0.2°, 21.72 ± 0.2°, 21.93 ± 0.2°, 23.27 ± 0.2°, 23.68 ± 0.2°, 24.73 ± 0.2°, 25.19 ± 0.2°, 26.25 ± 0.2°, 26.57 ± 0.2°, 27.42 ± 0.2°, 28.02 ± 0.2°, 28.67 ± 0.2°, 29.13 ± 0.2°, 29.91 ± 0.2°, 32.56 ± 0.2°.

[0269] In some embodiments of the present invention, the XRPD pattern of the hydrochloride crystal form K of the compound of formula I-1 is as Figure 62 shown.

[0270] Table 28 XRPD analysis data of the hydrochloride crystal form K of the compound of formula I-1

[0271]

[0272]

[0273] In some embodiments of the present invention, the differential scanning calorimetry curve of the hydrochloride crystal form K of the compound of formula I-1 has starting points of endothermic peaks at 80.73 °C ± 2 °C and 171.74 °C ± 2 °C, and the sample starts to decompose at 211.42 °C ± 2 °C.

[0274] In some embodiments of the present invention, the DSC pattern of the hydrochloride crystal form K of the compound of formula I-1 is as Figure 63 shown.

[0275] In some embodiments of the present invention, the thermogravimetric analysis curve of the hydrochloride crystal form K of the compound of formula I-1 has three weight loss steps at 33.39 °C ± 2 °C, 125.00 °C ± 2 °C and 155.00 °C ± 2 °C.

[0276] In some embodiments of the present invention, the TGA pattern of the hydrochloride crystal form K of the compound of formula I-1 is as Figure 64 shown.

[0277] The present invention also provides a method for preparing the hydrochloride crystal form K of the above-mentioned compound of formula I-1, which comprises adding the compound of formula I-1 and hydrochloric acid into methyl tert-butyl ether, and preparing it by suspending at 500 or by heating and cooling for recrystallization or pulping. The ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2. The hydrochloride crystal form K of the compound of formula I-1 is a solvate of methyl tert-butyl ether and water, with the content of methyl tert-butyl ether being 0.5 equivalent and the content of water being 0.93 equivalent.

[0278] The present invention also provides the hydrochloride crystal form L of the above-mentioned compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 8.15±0.2°, 12.72±0.2°, 13.59±0.2°, 15.07±0.2°, 15.56±0.2°, 16.60±0.2°, 16.89±0.2°, 17.56±0.2°, 19.74±0.2°, 20.52±0.2°, 21.69±0.2°, 22.60±0.2°, 25.57±0.2°, 27.48±0.2°, 29.54±0.2°, 29.80±0.2°.

[0279] In some embodiments of the present invention, the hydrochloride crystal form L of the above-mentioned compound of formula I-1 has special diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 7.70±0.2°, 8.15±0.2°, 8.82±0.2°, 9.85±0.2°, 11.25±0.2°, 12.72±0.2°, 13.59±0.2°, 14.68±0.2°, 15.07±0.2°, 15.56±0.2°, 16.60±0.2°, 16.89±0.2°, 17.56±0.2°, 18.53±0.2°, 18.98±0.2°, 19.74±0.2°, 20.29±0.2°, 20.52±0.2°, 21.30±0.2°, 21.69±0.2°, 22.60±0.2°, 22.79±0.2°, 24.38±0.2°, 25.57±0.2°, 26.21±0.2°, 26.50±0.2°, 26.97±0.2°, 27.48±0.2°, 28.17±0.2°, 28.60±0.2°, 29.54±0.2°, 29.80±0.2°, 31.17±0.2°, 33.28±0.2°.

[0280] In some embodiments of the present invention, for the hydrochloride crystal form L of the above-mentioned compound of formula I-1, its XRPD pattern is as Figure 65 shown.

[0281] Table 29 XRPD analysis data of the hydrochloride crystal form L of the compound of formula I-1

[0282]

[0283]

[0284] In some embodiments of the present invention, for the hydrochloride crystal form L of the compound of formula I-1, the differential scanning calorimetry curve has a starting point of an endothermic peak at 180.17°C ± 2°C, and the sample starts to decompose at 212.43°C ± 2°C.

[0285] In some embodiments of the present invention, for the hydrochloride crystal form L of the compound of formula I-1, its DSC pattern is as Figure 66 shown.

[0286] In some embodiments of the present invention, for the hydrochloride crystal form L of the compound of formula I-1, its thermogravimetric analysis curve has two weight loss steps at 33.53°C ± 2°C and 140.00°C ± 2°C.

[0287] In some embodiments of the present invention, for the hydrochloride crystal form L of the compound of formula I-1, its TGA pattern is as Figure 67 shown.

[0288] The present invention also provides a method for preparing the hydrochloride crystal form L of the compound of formula I-1, which includes adding the compound of formula I-1 and hydrochloric acid to toluene, and obtaining it by suspending or heating and cooling for recrystallization or slurrying at 25°C or 500°C. The ratio of the compound of formula I-1 to hydrochloric acid is selected from 0.8 to 1.2. The hydrochloride crystal form L of the compound of formula I-1 is a solvate of toluene, and the toluene content is 0.46 equivalent.

[0289] The present invention also provides the hydrochloride crystal form M of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 6.84 ± 0.2°, 7.21 ± 0.2°, 14.17 ± 0.2°, 14.90 ± 0.2°, 18.94 ± 0.2°, 19.46 ± 0.2°, 19.71 ± 0.2°, 19.96 ± 0.2°, 20.82 ± 0.2°, 22.60 ± 0.2°, 24.17 ± 0.2°, 25.17 ± 0.2°, 25.45 ± 0.2°, 27.17 ± 0.2°, 28.09 ± 0.2°, 28.88 ± 0.2°.

[0290] In some embodiments of the present invention, the hydrochloride crystal form M of the compound of formula I-1 has specific diffraction peaks in the X-ray powder diffraction pattern at the following 2θ angles: 6.84±0.2°, 7.21±0.2°, 8.92±0.2°, 10.07±0.2°, 10.69±0.2°, 10.89±0.2°, 11.24±0.2°, 13.23±0.2°, 14.17±0.2°, 14.90±0.2°, 15.59±0.2°, 16.74±0.2°, 17.67±0.2°, 18.29±0.2°, 18.94±0.2°, 19.46±0.2°, 19.71±0.2°, 19.96±0.2°, 20.82±0.2°, 21.49±0.2°, 21.83±0.2°, 22.60±0.2°, 23.14±0.2°, 23.54±0.2°, 24.17±0.2°, 25.17±0.2°, 25.45±0.2°, 26.10±0.2°, 27.17±0.2°, 27.61±0.2°, 28.09±0.2°, 28.88±0.2°, 29.42±0.2°, 30.12±0.2°, 32.48±0.2°, 35.22±0.2°.

[0291] In some embodiments of the present invention, the hydrochloride crystal form M of the compound of formula I-1 has an XRPD pattern as Figure 68 shown.

[0292] Table 30 XRPD analysis data of the hydrochloride crystal form M of the compound of formula I-1

[0293]

[0294]

[0295] In some embodiments of the present invention, the hydrochloride crystal form M of the compound of formula I-1 has starting points of endothermic peaks at 31.74°C ± 2°C and 150.05°C ± 2°C in the differential scanning calorimetry curve, and the sample starts to decompose at 215.09°C ± 2°C.

[0296] In some embodiments of the present invention, the hydrochloride crystal form M of the compound of formula I-1 has a DSC pattern as Figure 69 shown.

[0297] In some embodiments of the present invention, the hydrochloride crystal form M of the compound of formula I-1 has two weight loss steps at 32.98°C ± 2°C and 115.00°C ± 2°C in the thermogravimetric analysis curve.

[0298] In some embodiments of the present invention, the hydrochloride crystal form M of the compound of formula I-1 has a TGA pattern as Figure 70 shown.

[0299] The present invention also provides a method for preparing the hydrochloride crystal form M of the above-mentioned compound of formula I-1, which includes adding the compound of formula I-1 and hydrochloric acid into a mixed solvent of isopropanol / dimethyl sulfoxide, isopropyl acetate / dimethyl sulfoxide, or water / dimethyl sulfoxide, and performing suspension recrystallization or slurrying at 25 °C or 50 °C to obtain the product. The ratio of the compound of formula I-1 to hydrochloric acid is selected from 0.8 to 1.2. The hydrochloride crystal form M of the compound of formula I-1 is a solvate of dimethyl sulfoxide and water, with the content of dimethyl sulfoxide being 3.4 equivalents and the content of water being 13.7 equivalents.

[0300] The present invention also provides the hydrochloride crystal form N of the above-mentioned compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 6.61±0.2°, 7.80±0.2°, 13.17±0.2°, 15.24±0.2°, 16.02±0.2°, 16.19±0.2°, 20.10±0.2°, 21.57±0.2°, 21.95±0.2°, 28.42±0.2°.

[0301] In some embodiments of the present invention, the hydrochloride crystal form N of the above-mentioned compound of formula I-1 has special diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 6.61±0.2°, 7.80±0.2°, 9.75±0.2°, 11.19±0.2°, 12.53±0.2°, 13.17±0.2°, 14.61±0.2°, 15.24±0.2°, 16.02±0.2°, 16.19±0.2°, 18.51±0.2°, 19.36±0.2°, 20.10±0.2°, 21.57±0.2°, 21.95±0.2°, 23.47±0.2°, 25.60±0.2°, 27.32±0.2°, 28.42±0.2°, 29.12±0.2°.

[0302] In some embodiments of the present invention, the XRPD pattern of the hydrochloride crystal form N of the above-mentioned compound of formula I-1 is as Figure 71 shown.

[0303] Table 31 XRPD analysis data of the hydrochloride crystal form N of the compound of formula I-1

[0304]

[0305] In some embodiments of the present invention, the differential scanning calorimetry curve of the hydrochloride crystal form N of the above-mentioned compound of formula I-1 has the starting points of endothermic peaks at 47.38 °C±2 °C and 167.91 °C±2 °C, and the sample starts to decompose at 212.57 °C±2 °C.

[0306] In some embodiments of the present invention, for the hydrochloride crystal form N of the compound of formula I-1, its DSC spectrum is as follows Figure 72 shown.

[0307] In some embodiments of the present invention, for the hydrochloride crystal form N of the compound of formula I-1, its thermogravimetric analysis curve has three weight loss steps at 33.22 °C ± 2 °C, 75.00 °C ± 2 °C and 150.00 °C ± 2 °C.

[0308] In some embodiments of the present invention, for the hydrochloride crystal form N of the compound of formula I-1, its TGA spectrum is as follows Figure 73 shown.

[0309] The present invention also provides a method for preparing the hydrochloride crystal form N of the compound of formula I-1, which comprises adding the compound of formula I-1 and hydrochloric acid into methanol, and performing suspension recrystallization or slurrying at 25 °C to obtain it. The ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 - 1.2. The hydrochloride crystal form N of the compound of formula I-1 is a hydrate crystal form, and the water content is 3.0 equivalents.

[0310] The present invention also provides the hydrochloride crystal form O of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 6.14 ± 0.2 °, 9.90 ± 0.2 °, 13.54 ± 0.2 °, 14.40 ± 0.2 °, 15.33 ± 0.2 °, 15.51 ± 0.2 °, 15.87 ± 0.2 °, 16.79 ± 0.2 °, 18.36 ± 0.2 °, 20.17 ± 0.2 °, 21.14 ± 0.2 °, 22.51 ± 0.2 °, 22.84 ± 0.2 °, 24.59 ± 0.2 °, 25.28 ± 0.2 °, 26.82 ± 0.2 °, 27.07 ± 0.2 °, 27.93 ± 0.2 °.

[0311] In some embodiments of the present invention, for the hydrochloride crystal form O of the compound of formula I-1, its X-ray powder diffraction pattern has specific diffraction peaks at the following 2θ angles: 6.14±0.2°, 8.39±0.2°, 9.90±0.2°, 11.28±0.2°, 13.19±0.2°, 13.54±0.2°, 14.40±0.2°, 15.33±0.2°, 15.51±0.2°, 15.87±0.2°, 16.79±0.2°, 17.32±0.2°, 18.36±0.2°, 19.03±0.2°, 19.38±0.2°, 19.84±0.2°, 20.17±0.2°, 20.39±0.2°, 21.14±0.2°, 21.82±0.2°, 22.51±0.2°, 22.84±0.2°, 23.77±0.2°, 24.59±0.2°, 25.28±0.2°, 26.21±0.2°, 26.82±0.2°, 27.07±0.2°, 27.93±0.2°, 28.45±0.2°, 29.24±0.2°, 29.70±0.2°, 30.12±0.2°, 30.91±0.2°, 31.32±0.2°, 32.02±0.2°, 32.81±0.2°, 33.99±0.2°, 35.51±0.2°, 37.27±0.2°.

[0312] In some embodiments of the present invention, for the hydrochloride crystal form O of the compound of formula I-1, its XRPD pattern is as Figure 74 shown.

[0313] Table 32 XRPD analysis data of the hydrochloride crystal form O of the compound of formula I-1

[0314]

[0315]

[0316] In some embodiments of the present invention, for the hydrochloride crystal form O of the compound of formula I-1, its differential scanning calorimetry curve has the starting points of endothermic peaks at 12.36°C ± 2°C and 174.87°C ± 2°C, and the sample starts to decompose at 212.00°C ± 2°C.

[0317] In some embodiments of the present invention, for the hydrochloride crystal form O of the compound of formula I-1, its DSC pattern is as Figure 75 shown.

[0318] In some embodiments of the present invention, for the hydrochloride crystal form O of the compound of formula I-1, its thermogravimetric analysis curve has three weight loss steps at 27.70°C ± 2°C, 115.00°C ± 2°C and 160.00°C ± 2°C.

[0319] In some embodiments of the present invention, for the hydrochloride crystal form O of the compound of formula I-1, its TGA spectrum is as Figure 76 shown.

[0320] The present invention also provides a method for preparing the hydrochloride crystal form O of the compound of formula I-1, which includes adding the compound of formula I-1 and hydrochloric acid into dichloromethane, and performing suspension recrystallization or slurrying at 25 °C to obtain it. The ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 - 1.2. The hydrochloride crystal form O of the compound of formula I-1 is a hydrate crystal form, and the water content is 0.9 equivalent.

[0321] On the other hand, the present invention provides a method for preparing a pharmaceutically acceptable salt crystal form of the above-mentioned compound of formula (I), which is characterized by including the following steps:

[0322] a. Dissolving or dispersing the compound of formula (I) and an acid in a molar ratio of 1:(0.8 - 3) into 1 - 20 times the volume of solvent A;

[0323] b. Suspending, recrystallizing or slurrying;

[0324] wherein, the acid is not hydrochloric acid (preferably, the acid is selected from the following group: maleic acid, fumaric acid, glycolic acid, L-malic acid, succinic acid, sulfuric acid, L-tartaric acid, hippuric acid, glutaric acid, p-toluenesulfonic acid or methanesulfonic acid);

[0325] The solvent A is selected from the following group: acetonitrile, dichloromethane, tetrahydrofuran, or a combination thereof;

[0326] or the acid is hydrochloric acid or dioxane hydrochloride; and the solvent A is selected from the following group: ethyl acetate, 2-methyltetrahydrofuran, methyl ethyl ketone, ethanol, acetone, ethyl acetate, acetonitrile, tetrahydrofuran, methyl isobutyl ketone, trifluoroethanol, water, methanol, methyl tert-butyl ether, toluene, isopropanol, dimethyl sulfoxide, isopropyl acetate, dichloromethane, or a combination thereof.

[0327] In another preferred embodiment, the solvent A is selected from the following group: methyl isobutyl ketone / trifluoroethanol, methanol / water, methanol / methyl tert-butyl ether, isopropanol / dimethyl sulfoxide, isopropyl acetate / dimethyl sulfoxide, water / dimethyl sulfoxide.

[0328] In another preferred embodiment, the suspension includes the following steps:

[0329] a. Suspending the compound of formula (I), the acid and the solvent at 45 - 65 °C for 1 - 3 h;

[0330] b. Naturally cooling to 20 - 30 °C and continuing to suspend for at least 48 h;

[0331] c. Centrifuge the resulting suspension through a 0.4 - 0.5 μm filter membrane at a speed of 12000 - 16000 rpm;

[0332] d. Vacuum dry the resulting solid at 45 - 65 °C.

[0333] On the other hand, the present invention provides a method for a crystalline form of a pharmaceutically acceptable salt of the above - mentioned compound of formula (I), characterized in that the method is a method of crystal form transformation, which transforms one crystalline form of the pharmaceutically acceptable salt of the compound of formula (I) into another crystalline form of this salt;

[0334] Among them, the method of crystal form transformation includes the following steps:

[0335] a. Dissolve or disperse one crystalline form of the pharmaceutically acceptable salt of the compound of formula (I) in 1 - 20 times the volume of solvent A;

[0336] b. Suspend;

[0337] c. Centrifuge and filter the resulting suspension through a 0.4 - 0.5 μm filter membrane at a speed of 12000 - 16000 rpm;

[0338] Among them, solvent A is selected from the following group: ethanol, acetone, ethyl acetate, acetonitrile, tetrahydrofuran, methyl isobutyl ketone, trifluoroethanol, methanol, 2 - methyltetrahydrofuran, methyl tert - butyl ether, toluene, isopropanol, dimethyl sulfoxide, isopropyl acetate, dimethyl sulfoxide, methanol, dichloromethane, water or a combination thereof.

[0339] In another preferred example, solvent A is selected from the following group: methyl isobutyl ketone / trifluoroethanol, methanol / water, isopropanol / dimethyl sulfoxide, isopropyl acetate / dimethyl sulfoxide, dimethyl sulfoxide / water.

[0340] In another preferred example, the suspension includes the steps of: stirring at a rate of 300 - 400 rpm at 20 - 30 °C.

[0341] In another preferred example, the suspension includes the steps of: stirring at a rate of 300 - 400 rpm at 40 - 60 °C.

[0342] In another preferred example, the suspension includes the steps of: performing 8 - 12 heating - cooling cycles at a rate of 0.05 - 0.2 °C / min between 5 - 50 °C, while stirring at a rate of 300 - 400 rpm, and the final temperature of the suspension is 10 - 15 °C.

[0343] In another preferred example, the suspension includes the steps of: filtering through a 0.4 - 0.5 μm filter membrane to obtain a clear solution, and then suspending after adding methyl tert - butyl ether in a ratio of 1:(8 - 12).

[0344] On the other hand, the present invention also provides a pharmaceutical composition, comprising the above-mentioned compound of formula (I), the above-mentioned crystalline form A, or the crystalline form of the above-mentioned compound of formula (I);

[0345] and

[0346] one or more pharmaceutically acceptable carriers, excipients, adjuvants, auxiliary materials and / or diluents.

[0347] In another preferred embodiment, the pharmaceutical composition further comprises other therapeutic agents.

[0348] In another preferred embodiment, the other therapeutic agents are selected from the group consisting of: chemotherapeutic drugs, kinase inhibitors, targeted epigenetic regulators, antibody drugs, immune checkpoint inhibitors, or combinations thereof. In another preferred embodiment, the chemotherapeutic drugs are selected from the group consisting of: cisplatin, doxorubicin, paclitaxel, etoposide, irinotecan, cyclophosphamide, gemcitabine, ifosfamide, tamoxifen, toremifene, fulvestrant, anastrozole, exemestane, goserelin, leuprorelin, melphalan, chlorambucil, busulfan, floxuridine, cytarabine, oxaliplatin, leucovorin, pentostatin, diethylstilbestrol.

[0349] In another preferred embodiment, the kinase inhibitors are selected from the group consisting of: Akt, TGF-βR, Pim, PKA, PKG, PKC, CaM kinase, CDK2, CDK4, CDK4 / 6, MEK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, PDGFαR, PDGFβR, CSFIR, KIT, c-Met, TRKA, TRKB, TRKC, FLT3, VEGFR, BTK, FAK, SYK, FRK, JAK, HPK1, AXL, ALK, B-Raf inhibitors. In another preferred embodiment, the targeted epigenetic regulators are selected from the group consisting of: bromodomain inhibitors, histone lysine methyltransferases, histone arginine methyltransferases, histone demethylases, histone deacetylases, histone acetyltransferases, DNA methyltransferases. In another preferred embodiment, the antibody drugs are selected from the group consisting of: anti-HER 2 antibody, anti-VEGFR antibody, anti-EGFR antibody, anti-c-MET antibody, anti-CD20 antibody.

[0350] In another preferred embodiment, the immune checkpoint inhibitors are selected from the group consisting of: CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1, PD-L1, PD-L2.

[0351] On the other hand, the present invention also provides the use of the above-mentioned compound of formula (I), the above-mentioned crystalline form A, the crystalline form of the above-mentioned compound of formula (I), and the above-mentioned pharmaceutical composition in the preparation of a medicament for preventing and / or treating diseases related to increased activity or expression level of FGFR2.

[0352] In another preferred embodiment, the increase in the activity or expression level of FGFR2 is selected from the group consisting of: FGFR2 amplification, FGFR2 gene mutation, FGFR2 gene fusion / rearrangement, FGFR2 gene translocation, and FGFR2 gene activation.

[0353] In another preferred embodiment, the diseases related to the increase in the activity or expression level of FGFR2 are selected from the group consisting of: cholangiocarcinoma, liver cancer, breast cancer, prostate cancer, lung cancer, thyroid cancer, gastric cancer, ovarian cancer, esophageal cancer, pancreatic cancer, cervical cancer, colorectal cancer, salivary gland cancer, endometrial cancer, and urothelial cancer, etc.

[0354] In another preferred embodiment, the cholangiocarcinoma is intrahepatic cholangiocarcinoma.

[0355] In another preferred embodiment, the liver cancer is hepatocellular carcinoma.

[0356] In another preferred embodiment, the lung cancer is squamous cell lung cancer or non-small cell lung cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0357] Figure 1 It is the XRPD pattern of crystalline form A of compound I-1.

[0358] Figure 2 It is the DSC pattern of crystalline form A of compound I-1.

[0359] Figure 3 It is the TGA pattern of crystalline form A of compound I-1.

[0360] Figure 4 It is the XRPD pattern of crystalline form A of compound I-1 maleate.

[0361] Figure 5 It is the XRPD pattern of crystalline form B of compound I-1 monomaleate.

[0362] Figure 6 It is the DSC pattern of crystalline form B of compound I-1 monomaleate.

[0363] Figure 7 It is the TGA pattern of crystalline form B of compound I-1 monomaleate.

[0364] Figure 8 It is the XRPD pattern of crystalline form A of compound I-1 fumarate.

[0365] Figure 9XRPD pattern of Compound I-1 hemifumarate Form B.

[0366] Figure 10 DSC curve of Compound I-1 hemifumarate Form B.

[0367] Figure 11 TGA curve of Compound I-1 hemifumarate Form B.

[0368] Figure 12 XRPD pattern of Compound I-1 monoethanolate Form A.

[0369] Figure 13 DSC curve of Compound I-1 monoethanolate Form A.

[0370] Figure 14 TGA curve of Compound I-1 monoethanolate Form A.

[0371] Figure 15 XRPD pattern of Compound I-1 ethanolate Form B.

[0372] Figure 16 XRPD pattern of Compound I-1 mono-L-malate Form A.

[0373] Figure 17 DSC curve of Compound I-1 mono-L-malate Form A.

[0374] Figure 18 TGA curve of Compound I-1 mono-L-malate Form A.

[0375] Figure 19 XRPD pattern of Compound I-1 monosuccinate Form A.

[0376] Figure 20 DSC curve of Compound I-1 monosuccinate Form A.

[0377] Figure 21 TGA curve of Compound I-1 monosuccinate Form A.

[0378] Figure 22 XRPD pattern of Compound I-1 sulfate Form A.

[0379] Figure 23 XRPD pattern of Compound I-1 L-tartrate Form A.

[0380] Figure 24 XRPD pattern of Compound I-1 hippurate Form A.

[0381] Figure 25XRPD pattern of Compound I-1 Glutarate Polymorph A.

[0382] Figure 26 XRPD pattern of Compound I-1 p-Toluenesulfonate Polymorph A.

[0383] Figure 27 XRPD pattern of Compound I-1 p-Toluenesulfonate Polymorph B.

[0384] Figure 28 XRPD pattern of Compound I-1 Methanesulfonate Polymorph A.

[0385] Figure 29 XRPD pattern of Compound I-1 Hydrochloride Polymorph C1.

[0386] Figure 30 DSC pattern of Compound I-1 Hydrochloride Polymorph C1.

[0387] Figure 31 TGA pattern of Compound I-1 Hydrochloride Polymorph C1.

[0388] Figure 32 XRPD pattern of Compound I-1 Hydrochloride Polymorph C2.

[0389] Figure 33 DSC pattern of Compound I-1 Hydrochloride Polymorph C2.

[0390] Figure 34 TGA pattern of Compound I-1 Hydrochloride Polymorph C2.

[0391] Figure 35 XRPD pattern of Compound I-1 Hydrochloride Polymorph D.

[0392] Figure 36 DSC pattern of Compound I-1 Hydrochloride Polymorph D.

[0393] Figure 37 TGA pattern of Compound I-1 Hydrochloride Polymorph D.

[0394] Figure 38 XRPD pattern of Compound I-1 Hydrochloride Polymorph E1.

[0395] Figure 39 DSC pattern of Compound I-1 Hydrochloride Polymorph E1.

[0396] Figure 40 TGA pattern of Compound I-1 Hydrochloride Polymorph E1.

[0397] Figure 41 XRPD pattern of Compound I-1 Hydrochloride Polymorph E2.

[0398] Figure 42 It is the DSC pattern of crystalline form E2 of compound I-1 hydrochloride.

[0399] Figure 43 It is the TGA pattern of crystalline form E2 of compound I-1 hydrochloride.

[0400] Figure 44 It is the XRPD pattern of crystalline form F of compound I-1 hydrochloride.

[0401] Figure 45 It is the DSC pattern of crystalline form F of compound I-1 hydrochloride.

[0402] Figure 46 It is the TGA pattern of crystalline form F of compound I-1 hydrochloride.

[0403] Figure 47 It is the XRPD pattern of crystalline form G of compound I-1 hydrochloride.

[0404] Figure 48 It is the DSC pattern of crystalline form G of compound I-1 hydrochloride.

[0405] Figure 49 It is the TGA pattern of crystalline form G of compound I-1 hydrochloride.

[0406] Figure 50 It is the XRPD pattern of crystalline form H of compound I-1 hydrochloride.

[0407] Figure 51 It is the DSC pattern of crystalline form H of compound I-1 hydrochloride.

[0408] Figure 52 It is the TGA pattern of crystalline form H of compound I-1 hydrochloride.

[0409] Figure 53 It is the XRPD pattern of crystalline form I of compound I-1 hydrochloride.

[0410] Figure 54 It is the DSC pattern of crystalline form I of compound I-1 hydrochloride.

[0411] Figure 55 It is the TGA pattern of crystalline form I of compound I-1 hydrochloride.

[0412] Figure 56 It is the XRPD pattern of crystalline form J1 of compound I-1 hydrochloride.

[0413] Figure 57 It is the DSC pattern of crystalline form J1 of compound I-1 hydrochloride.

[0414] Figure 58It is the TGA graph of crystalline form J1 of compound I-1 hydrochloride.

[0415] Figure 59 It is the XRPD graph of crystalline form J2 of compound I-1 hydrochloride.

[0416] Figure 60 It is the DSC graph of crystalline form J2 of compound I-1 hydrochloride.

[0417] Figure 61 It is the TGA graph of crystalline form J2 of compound I-1 hydrochloride.

[0418] Figure 62 It is the XRPD graph of crystalline form K of compound I-1 hydrochloride.

[0419] Figure 63 It is the DSC graph of crystalline form K of compound I-1 hydrochloride.

[0420] Figure 64 It is the TGA graph of crystalline form K of compound I-1 hydrochloride.

[0421] Figure 65 It is the XRPD graph of crystalline form L of compound I-1 hydrochloride.

[0422] Figure 66 It is the DSC graph of crystalline form L of compound I-1 hydrochloride.

[0423] Figure 67 It is the TGA graph of crystalline form L of compound I-1 hydrochloride.

[0424] Figure 68 It is the XRPD graph of crystalline form M of compound I-1 hydrochloride.

[0425] Figure 69 It is the DSC graph of crystalline form M of compound I-1 hydrochloride.

[0426] Figure 70 It is the TGA graph of crystalline form M of compound I-1 hydrochloride.

[0427] Figure 71 It is the XRPD graph of crystalline form N of compound I-1 hydrochloride.

[0428] Figure 72 It is the DSC graph of crystalline form N of compound I-1 hydrochloride.

[0429] Figure 73 It is the TGA graph of crystalline form N of compound I-1 hydrochloride.

[0430] Figure 74 It is the XRPD graph of crystalline form O of compound I-1 hydrochloride.

[0431] Figure 75 DSC pattern of crystalline form O of Compound I-1 hydrochloride

[0432] Figure 76 TGA pattern of crystalline form O of Compound I-1 hydrochloride Detailed implementation manners

[0433] To solve the problems existing in the prior art, the inventors deeply studied different forms of the compound of formula (I), developed various crystalline forms of the compound of formula (I) and crystalline forms of acid salts, especially hydrochloride salts, which greatly improved the physical and chemical properties such as solubility, hygroscopicity and chemical stability of the compound of formula (I). The raw materials of the crystalline acid salt compounds meet the requirements of industrial production, can meet the needs of clinical drug formulation development, have very important clinical application value, and are expected to accelerate the development into a new generation of FGFR2 inhibitors. On this basis, the present invention was completed.

[0434] Definitions

[0435] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term should not be considered indeterminate or unclear without a special definition, but should be understood in its ordinary meaning. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0436] As used herein, the term "n or more 2θ values selected from the following group" means including n and any positive integer greater than n (for example, n, n + 1,...), where the upper limit Nup is the number of all 2θ peaks in the group. For example, "1 or more" includes not only each positive integer from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,... up to the upper limit Nup, but also ranges such as "2 or more", "3 or more", "4 or more", "5 or more", "6 or more", "7 or more", "8 or more", "9 or more", "10 or more". For example, "3 or more" includes not only each positive integer from 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,... up to the upper limit Nup, but also ranges such as "4 or more", "5 or more", "6 or more", "7 or more", "8 or more", "9 or more", "10 or more".

[0437] As used herein, "dissolving or dispersing the compound of formula (I) in 1 to 5 volumes of a solvent" means dissolving or dispersing 1 gram of the compound of formula (I) in 1 to 5 milliliters of a solvent, where the solvent includes but is not limited to acetonitrile, alcohol solvents, ester solvents, ether solvents, or a mixed solvent of an alcohol solvent and water.

[0438] The intermediate compounds of the present invention can be prepared by a variety of synthetic methods well-known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by the combination of the same with other chemical synthesis methods, and equivalent substitution methods well-known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0439] The chemical reactions of the specific embodiments of the present invention are carried out in a suitable solvent, and the solvent must be suitable for the chemical changes of the present invention and the required reagents and materials. In order to obtain the compounds of the present invention, sometimes those skilled in the art need to modify or select the synthesis steps or reaction processes on the basis of the existing embodiments.

[0440] The present invention will be specifically described below through examples, and these examples do not imply any limitation to the present invention.

[0441] All solvents used in the present invention are commercially available and can be used without further purification.

[0442] Common abbreviations used in the present invention are as follows:

[0443] Abbreviation Full Name EtOH Ethanol MeOH Methanol IPA Isopropyl Alcohol MTBE Methyl Tert-Butyl Ether MIBK Methyl Isobutyl Ketone EA Ethyl Acetate IPAc Isopropyl Acetate ACN Acetonitrile THF Tetrahydrofuran 2-MeTHF 2-Methyltetrahydrofuran DCM Dichloromethane DMSO Dimethyl Sulfoxide FaSSGF Fasted State Simulated Gastric Fluid FaSSIF-v1 Fasted State Simulated Intestinal Fluid - Version 1 FeSSIF-v1 Fed State Simulated Intestinal Fluid - Version 1 XRPD X-Ray Powder Diffraction DSC Differential Scanning Calorimetry TGA Thermogravimetric Analysis DVS Dynamic Vapor Sorption PLM Polarizing Light Microscopy <![CDATA 1 H-NMR]]> 1H NMR KF Karl Fischer (Titrator) HPLC High Performance Liquid Chromatography IC Ion Chromatography LOQ Limit of Quantitation

[0444] The test items and methods used in the present invention are as follows:

[0445]

[0446]

[0447]

[0448] To better understand the content of the present invention, the following will be further described in combination with specific examples, but the specific embodiments are not limitations to the content of the present invention.

[0449] Example 1: Preparation of the compound of formula (I-1)

[0450]

[0451] First step:

[0452] Compound a (5.0 g, 26.3 mmol) and triethylamine (8.0 g, 11 ml) were dissolved in DCM (50 ml). At 0 °C, 2-methylacryloyl chloride (3.03 g, 2.8 ml) was added dropwise to the reaction solution, and the reaction was stirred for 1 h. The reaction solution was diluted with water (100 ml) and extracted three times with DCM (100 ml). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (EA / PE = 1 / 4) to obtain compound b (4.9 g, 72%), a pale yellowish-white solid.

[0453] MS(ESI) m / z 258, 260 [M+H] + 。

[0454] Step 2:

[0455] Compound b (2.0 g, 7.75 mmol), pinacol diboron (3.94 g, 15.5 mmol), Pd(dppf)Cl2 (567 mg, 0.77 mmol), AcOK (2.28 g, 23.25 mmol), and 1,4-dioxane (20 ml) were added to a sealed tube and purged with argon three times. The mixture was reacted at 90 °C for 5 h. The reaction was quenched with water and extracted with DCM. The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (EA / PE = 1 / 8 to 1 / 4) to obtain compound c (1.52 g, 64%), a yellow solid.

[0456] MS(ESI) m / z 306 [M+H] + 。

[0457] 1 1H NMR (500 MHz, CDCl3) δ 7.70 - 7.65 (m, 2H), 7.53 (dd, J = 11.5, 1.9 Hz, 1H), 7.20 (dd, J = 8.2, 1.9 Hz, 1H), 5.78 (s, 1H), 5.48 (d, J = 1.7 Hz, 1H), 2.04 (s, 3H), 1.34 (s, 12H).

[0458] Step 3:

[0459] Compound d (2.00 g, 19.6 mmol) and ammonium carbamate (2.29 g, 29.4 mmol) were successively added to a flask, and then MeOH (40 mL) and diethyl iodobenzene dicarboxylate (13.24 g, 41.1 mmol) were added. The reaction solution was stirred open to the air at room temperature for 30 min and then concentrated under reduced pressure to remove the solvent to obtain a crude product. The crude product was purified by column chromatography (MeOH / DCM = 1 / 80) to obtain compound e (1.62 g), a white solid.

[0460] MS(ESI) m / z 120 [M+H] + 。

[0461] Step 4:

[0462] Compound e (282 mg, 2.35 mmol), cesium carbonate (892 mg, 2.74 mmol), 1-bromo-4-iodobenzene (552 mg, 1.96 mmol), Pd2(dba)3 (40 mg, 0.05 mmol), and Xantphos (77 mg, 0.13 mmol) were added to 1,4-dioxane (10 mL). The reaction mixture was heated to 105 °C and reacted for 13 h. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate (50 mL), saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (PE / EtOAc = 4 / 1 to 1 / 1) to obtain compound f (410 mg), a yellow oily liquid.

[0463] MS(ESI) m / z 274 [M+H] + 。

[0464] Step 5:

[0465] Compound f (1.02 g, 3.10 mmol), bis(pinacolato)diboron (0.973 g, 3.83 mmol), Pd(dppf)Cl2 (0.461 mg, 0.63 mmol), potassium acetate (0.943 g, 9.61 mmol), and 1,4-dioxane (20 mL) were successively added to a 100 mL round-bottom flask. The temperature was raised to 100 °C and reacted for 4 h. After monitoring the completion of the reaction, it was cooled to room temperature, filtered through diatomaceous earth, extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated brine (50 mL), and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (PE / EtOAc = 1 / 1) to obtain compound g (0.80 g), a yellow solid.

[0466] 1 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8.3 Hz, 2H), 6.98 (d, J = 8.3 Hz, 2H), 3.37–3.30 (m, 1H), 3.15–3.08 (m, 1H), 2.20 (dd, J = 29.3, 6.9 Hz, 2H), 1.26 (s, 6H).

[0467] Step 6:

[0468] Dissolve compound h (10.6 g, 0.0466 mol) in dichloromethane (100 mL) and trifluoroacetic acid (26.7 g, 0.2334 mol), stir at 10 °C, add N-iodosuccinimide (10.5 g, 0.0466 mol) portionwise, react for 4 h. After the reaction is completed, slowly add 150 mL of saturated aqueous sodium bicarbonate dropwise at 10 °C. A solid precipitates out. Filter and dry to obtain compound i (13.4 g), a purple solid.

[0469] 1 H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 5.61 (s, 2H), 3.80 (s, 3H).

[0470] Step 7:

[0471] Add compound i (2 g, 6.5 mmol), compound c (2.3 g, 6.5 mmol), tetrakis(triphenylphosphine)palladium (0.65 g, 0.56 mmol) and potassium phosphate (3.6 g, 0.017 mol) to a reaction flask, displace with nitrogen 3 times, and add DMF (35 mL) and water (5 mL). Stir at 50 °C for 16 h. After the reaction is completed, add water (150 mL) and dichloromethane (200 mL), extract and separate the layers. Wash the organic phase with saturated brine. Concentrate the organic phase to obtain a crude product. Purify the crude product by column chromatography to obtain compound j (1.1 g), a pale yellow solid.

[0472] ESI-MS m / z 404.2 [M+H] +

[0473] 1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.82 (dd, J = 11.7, 2.1 Hz, 1H), 7.69 (s, 1H), 7.44–7.33 (m, 2H), 5.87 (s, 1H), 5.66 (s, 2H), 5.58 (q, J = 1.5 Hz, 1H), 3.66 (d, J = 1.1 Hz, 3H), 2.12 (dd, J = 1.6, 0.9 Hz, 3H).

[0474] Step 8:

[0475] To a 25 mL round-bottom flask were successively added compound g (45 mg, 0.14 mmol), compound j (50 mg, 0.12 mmol), Pd(dppf)Cl2 (20 mg, 0.03 mmol), potassium phosphate (80 mg, 0.38 mmol), 1,4-dioxane (5 mL) and water (1 mL). The temperature was raised to 80 °C and the reaction was carried out for 0.5 h. After monitoring the completion of the reaction, it was cooled to room temperature, filtered through diatomaceous earth, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated brine (20 mL), and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 6 / 1) to obtain the compound of formula I-1 (22 mg), a white solid.

[0476] MS(ESI) m / z 519.4 [M+H] +

[0477] 1 1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.65–7.61 (m, 1H), 7.48 (s, 1H), 7.05 (d, J = 7.7 Hz, 2H), 7.00 (t, J = 4.1 Hz, 2H), 6.91 (d, J = 8.5 Hz, 2H), 5.73 (s, 1H), 5.45 (d, J = 1.3 Hz, 1H), 4.98 (s, 2H), 3.59 (d, J = 0.9 Hz, 3H), 3.36 (dd, J = 12.6, 6.0 Hz, 2H), 3.13 (dd, J = 12.8, 6.6 Hz, 2H), 2.29–2.19 (m, 3H), 1.99 (d, J = 10.1 Hz, 3H).

[0478] Example 2: Preparation of polymorph A of the compound of formula I-1

[0479] The above compound of formula I-1 (61 g) was added to ethyl acetate (100 mL), stirred at room temperature overnight, filtered, and dried to obtain a sample of polymorph A of the compound of formula I-1 (58.2 g), a white solid.

[0480] Example 3: Preparation of polymorph A of the maleate salt of the compound of formula I-1

[0481] 3.1: Weigh about 20 mg of the compound of formula I-1 and 1.0 equivalent of maleic acid and place them in a 2 mL glass bottle. Add 0.15 mL of acetonitrile and carry out a screening experiment by the suspension method. The obtained sample was suspended at 50 °C for 2 h, then naturally cooled to 25 °C, and suspended at 25 °C for at least 48 h. The obtained suspension was centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane, and the obtained solid was dried under vacuum at 50 °C for 2 h to obtain a sample of polymorph A of the maleate salt of the compound of formula I-1.

[0482] 3.2: Weigh approximately 20 mg of the compound of Formula I-1 and 1.0 equivalent of the counterion, place them in a 2 mL glass bottle, add 0.15 mL of dichloromethane, and conduct a screening experiment by the suspension method. The obtained sample is suspended at 50 °C for 2 h, then cooled naturally to 25 °C, and suspended at 25 °C for at least 48 h. The obtained suspension is centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane, and the obtained solid is dried in vacuo at 50 °C for 2 h to obtain a sample of the maleate polymorph A of the compound of Formula I-1.

[0483] Example 4: Preparation of the monomaleate polymorph B of the compound of Formula I-1

[0484] Weigh approximately 20 mg of the compound of Formula I-1 and 1.0 equivalent of maleic acid, place them in a 2 mL glass bottle, add 0.15 mL of tetrahydrofuran, and conduct a screening experiment by the suspension method. The obtained sample is suspended at 50 °C for 2 h, then cooled naturally to 25 °C, and suspended at 25 °C for at least 48 h. The obtained suspension is centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane, and the obtained solid is dried in vacuo at 50 °C for 2 h to obtain a sample of the monomaleate polymorph B of the compound of Formula I-1.

[0485] Example 5: Preparation of the fumarate polymorph A of the compound of Formula I-1

[0486] 5.1: Weigh approximately 20 mg of the compound of Formula I-1 and 1.0 equivalent of fumaric acid, place them in a 2 mL glass bottle, add 0.15 mL of acetonitrile, and conduct a screening experiment by the suspension method. The obtained sample is suspended at 50 °C for 2 h, then cooled naturally to 25 °C, and suspended at 25 °C for at least 48 h. The obtained suspension is centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane, and the obtained solid is dried in vacuo at 50 °C for 2 h to obtain a sample of the fumarate polymorph A of the compound of Formula I-1.

[0487] 5.2: Weigh approximately 20 mg of the compound of Formula I-1 and 1.0 equivalent of fumaric acid, place them in a 2 mL glass bottle, add 0.15 mL of dichloromethane, and conduct a screening experiment by the suspension method. The obtained sample is suspended at 50 °C for 2 h, then cooled naturally to 25 °C, and suspended at 25 °C for at least 48 h. The obtained suspension is centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane, and the obtained solid is dried in vacuo at 50 °C for 2 h to obtain a sample of the fumarate polymorph A of the compound of Formula I-1.

[0488] Example 6: Preparation of the hemifumarate polymorph B of the compound of Formula I-1

[0489] Weigh approximately 20 mg of the compound of Formula I-1 and 1.0 equivalent of fumaric acid and place them in a 2 mL glass bottle. Add 0.15 mL of tetrahydrofuran and conduct a screening experiment by the suspension method. The obtained sample is suspended at 50 °C for 2 h, then naturally cooled to 25 °C, and suspended at 25 °C for at least 48 h. The obtained suspension is centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane. The obtained solid is vacuum dried at 50 °C for 2 h to obtain a sample of the hemifumarate crystal form B of the compound of Formula I-1.

[0490] Example 7: Preparation of the monoethanolate crystal form A of the compound of Formula I-1

[0491] Weigh approximately 20 mg of the compound of Formula I-1 and 1.0 equivalent of glycolic acid and place them in a 2 mL glass bottle. Add 0.15 mL of acetonitrile and conduct a screening experiment by the suspension method. The obtained sample is suspended at 50 °C for 2 h, then naturally cooled to 25 °C, and suspended at 25 °C for at least 48 h. The obtained suspension is centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane. The obtained solid is vacuum dried at 50 °C for 2 h to obtain a sample of the monoethanolate crystal form A of the compound of Formula I-1.

[0492] Example 8: Preparation of the glycolate crystal form B of the compound of Formula I-1

[0493] 8.1: Weigh approximately 20 mg of the compound of Formula I-1 and 1.0 equivalent of glycolic acid and place them in a 2 mL glass bottle. Add 0.15 mL of tetrahydrofuran and conduct a screening experiment by the suspension method. The obtained sample is suspended at 50 °C for 2 h, then naturally cooled to 25 °C, and suspended at 25 °C for at least 48 h. The obtained suspension is centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane. The obtained solid is vacuum dried at 50 °C for 2 h to obtain a sample of the glycolate crystal form B of the compound of Formula I-1.

[0494] 8.2: Weigh approximately 20 mg of the compound of Formula I-1 and 1.0 equivalent of glycolic acid and place them in a 2 mL glass bottle. Add 0.15 mL of dichloromethane and conduct a screening experiment by the suspension method. The obtained sample is suspended at 50 °C for 2 h, then naturally cooled to 25 °C, and suspended at 25 °C for at least 48 h. The obtained suspension is centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane. The obtained solid is vacuum dried at 50 °C for 2 h to obtain a sample of the glycolate crystal form B of the compound of Formula I-1.

[0495] Example 9: Preparation of the monoiso-L-malate crystal form A of the compound of Formula I-1

[0496] 9.1: Weigh approximately 20 mg of the compound of formula I-1 and 1.0 equivalent of L-malic acid and place them in a 2 mL glass bottle. Add 0.15 mL of tetrahydrofuran and conduct a screening experiment by the suspension method. The obtained sample is suspended at 50 °C for 2 h, then naturally cooled to 25 °C, and suspended at 25 °C for at least 48 h. The obtained suspension is centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane. The obtained solid is vacuum dried at 50 °C for 2 h to obtain a sample of crystalline form A of the monolithium L-malate of the compound of formula I-1.

[0497] 9.2: Weigh approximately 20 mg of the compound of formula I-1 and 1.0 equivalent of glycolic acid and place them in a 2 mL glass bottle. Add 0.15 mL of dichloromethane and conduct a screening experiment by the suspension method. The obtained sample is suspended at 50 °C for 2 h, then naturally cooled to 25 °C, and suspended at 25 °C for at least 48 h. The obtained suspension is centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane. The obtained solid is vacuum dried at 50 °C for 2 h to obtain a sample of crystalline form A of the monolithium L-malate of the compound of formula I-1.

[0498] 9.3: Weigh approximately 20 mg of the compound of formula I-1 and 1.0 equivalent of glycolic acid and place them in a 2 mL glass bottle. Add 0.15 mL of acetonitrile and conduct a screening experiment by the suspension method. The obtained sample is suspended at 50 °C for 2 h, then naturally cooled to 25 °C, and suspended at 25 °C for at least 48 h. The obtained suspension is centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane. The obtained solid is vacuum dried at 50 °C for 2 h to obtain a sample of crystalline form A of the monolithium L-malate of the compound of formula I-1.

[0499] Example 10: Preparation of crystalline form A of the monosuccinate of the compound of formula I-1

[0500] 10.1: Weigh approximately 20 mg of the compound of formula I-1 and 1.0 equivalent of succinic acid and place them in a 2 mL glass bottle. Add 0.15 mL of acetonitrile and conduct a screening experiment by the suspension method. The obtained sample is suspended at 50 °C for 2 h, then naturally cooled to 25 °C, and suspended at 25 °C for at least 48 h. The obtained suspension is centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane. The obtained solid is vacuum dried at 50 °C for 2 h to obtain a sample of crystalline form A of the monosuccinate of the compound of formula I-1.

[0501] 10.2: Weigh approximately 20 mg of the compound of formula I-1 and 1.0 equivalent of succinic acid and place them in a 2 mL glass bottle. Add 0.15 mL of dichloromethane and conduct a screening experiment by the suspension method. The obtained sample is suspended at 50 °C for 2 h, then naturally cooled to 25 °C, and suspended at 25 °C for at least 48 h. The obtained suspension is centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane. The obtained solid is vacuum dried at 50 °C for 2 h to obtain a sample of the monosuccinate crystal form A of the compound of formula I-1.

[0502] Example 11: Preparation of the sulfate crystal form A of the compound of formula I-1

[0503] Weigh approximately 20 mg of the compound of formula I-1 and 1.0 equivalent of sulfuric acid and place them in a 2 mL glass bottle. Add 0.15 mL of acetonitrile and conduct a screening experiment by the suspension method. The obtained sample is suspended at 50 °C for 2 h, then naturally cooled to 25 °C, and suspended at 25 °C for at least 48 h. The obtained suspension is centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane. The obtained solid is vacuum dried at 50 °C for 2 h to obtain a sample of the sulfate crystal form A of the compound of formula I-1.

[0504] Example 12: Preparation of the L-tartrate crystal form A of the compound of formula I-1

[0505] Weigh approximately 20 mg of the compound of formula I-1 and 1.0 equivalent of L-tartaric acid and place them in a 2 mL glass bottle. Add 0.15 mL of acetonitrile and conduct a screening experiment by the suspension method. The obtained sample is suspended at 50 °C for 2 h, then naturally cooled to 25 °C, and suspended at 25 °C for at least 48 h. The obtained suspension is centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane. The obtained solid is vacuum dried at 50 °C for 2 h to obtain a sample of the L-tartrate crystal form A of the compound of formula I-1.

[0506] Example 13: Preparation of the hippurate crystal form A of the compound of formula I-1

[0507] Weigh approximately 20 mg of the compound of formula I-1 and 1.0 equivalent of hippuric acid and place them in a 2 mL glass bottle. Add 0.15 mL of tetrahydrofuran and conduct a screening experiment by the suspension method. The obtained sample is suspended at 50 °C for 2 h, then naturally cooled to 25 °C, and suspended at 25 °C for at least 48 h. The obtained suspension is centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane. The obtained solid is vacuum dried at 50 °C for 2 h to obtain a sample of the hippurate crystal form A of the compound of formula I-1.

[0508] Example 14: Preparation of the glutarate crystal form A of the compound of formula I-1

[0509] 14.1: Weigh approximately 20 mg of the compound of formula I-1 and 1.0 equivalent of glutaric acid into a 2 mL glass bottle, add 0.15 mL of acetonitrile, and conduct a screening experiment by the suspension method. The obtained sample is suspended at 50 °C for 2 h, then naturally cooled to 25 °C, and suspended at 25 °C for at least 48 h. The obtained suspension is centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane, and the obtained solid is vacuum dried at 50 °C for 2 h to obtain a sample of the glutarate crystal form A of the compound of formula I-1.

[0510] 14.2: Weigh approximately 20 mg of the compound of formula I-1 and 1.0 equivalent of glutaric acid into a 2 mL glass bottle, add 0.15 mL of dichloromethane, and conduct a screening experiment by the suspension method. The obtained sample is suspended at 50 °C for 2 h, then naturally cooled to 25 °C, and suspended at 25 °C for at least 48 h. The obtained suspension is centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane, and the obtained solid is vacuum dried at 50 °C for 2 h to obtain a sample of the glutarate crystal form A of the compound of formula I-1.

[0511] Example 15: Preparation of the p-toluenesulfonate crystal form A of the compound of formula I-1

[0512] Weigh approximately 20 mg of the compound of formula I-1 and 1.0 equivalent of p-toluenesulfonic acid into a 2 mL glass bottle, add 0.15 mL of acetonitrile, and conduct a screening experiment by the suspension method. The obtained sample is suspended at 50 °C for 2 h, then naturally cooled to 25 °C, and suspended at 25 °C for at least 48 h. The obtained suspension is centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane, and the obtained solid is vacuum dried at 50 °C for 2 h to obtain a sample of the p-toluenesulfonate crystal form A of the compound of formula I-1.

[0513] Example 16: Preparation of the p-toluenesulfonate crystal form B of the compound of formula I-1

[0514] Weigh approximately 20 mg of the compound of formula I-1 and 1.0 equivalent of p-toluenesulfonic acid into a 2 mL glass bottle, add 0.15 mL of tetrahydrofuran, and conduct a screening experiment by the suspension method. The obtained sample is suspended at 50 °C for 2 h, then naturally cooled to 25 °C, and suspended at 25 °C for at least 48 h. The obtained suspension is centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane, and the obtained solid is vacuum dried at 50 °C for 2 h to obtain a sample of the p-toluenesulfonate crystal form B of the compound of formula I-1.

[0515] Example 17: Preparation of the methanesulfonate crystal form A of the compound of formula I-1

[0516] Weigh approximately 20 mg of the compound of formula I-1 and 1.0 equivalent of methanesulfonic acid into a 2 mL glass bottle, add 0.15 mL of tetrahydrofuran, and conduct a screening experiment by the suspension method. The obtained sample is suspended at 50 °C for 2 h, then naturally cooled to 25 °C, and suspended at 25 °C for at least 48 h. The obtained suspension is centrifuged through a 0.45 μm nylon filter membrane at 14,000 rpm, and the obtained solid is vacuum dried at 50 °C for 2 h to obtain a sample of crystalline form A of the methanesulfonate of the compound of formula I-1.

[0517] Example 18: Preparation of crystalline form C1 of the hydrochloride of the compound of formula I-1

[0518] The compound of formula I-1 (16.5 g) was added to ethyl acetate (165 mL), cooled to about 0 °C, and 1.0 equivalent of a 4M hydrogen chloride dioxane solution was added dropwise. After addition, the mixture was restored to room temperature and stirred overnight, filtered, and dried to obtain a sample (18.3 g) of crystalline form C1 of the hydrochloride of the compound of formula I-1, a white solid.

[0519] Example 19: Preparation of crystalline form C2 of the hydrochloride of the compound of formula I-1

[0520] Weigh approximately 40 mg of crystalline form E1 of the hydrochloride of the compound of formula I-1, add 0.2 - 0.5 mL of 2-methyltetrahydrofuran, and suspend it at 25 °C at a rate of 300 - 400 rpm under magnetic stirring. The obtained suspension was centrifuged and filtered through a 0.45 μm nylon filter membrane centrifugal tube at 14,000 rpm, and the solid part obtained is the sample of crystalline form C2 of the hydrochloride of the compound of formula I-1.

[0521] Example 20: Preparation of crystalline form D of the hydrochloride of the compound of formula I-1

[0522] Weigh approximately 40 mg of the compound of formula I-1 and 1.05 equivalents of hydrochloric acid (dilute hydrochloric acid diluted 10 times with methyl ethyl ketone) into a 2 mL glass bottle, add a screening solvent, and conduct a screening experiment by the suspension method. The obtained sample is suspended at 50 °C (35 °C, dichloromethane) for 2 h, then naturally cooled to 25 °C, and suspended at 25 °C for at least 48 h. The obtained suspension is centrifuged through a 0.45 μm nylon filter membrane at 14,000 rpm, and the obtained solid is vacuum dried at 50 °C for 2 h to obtain a sample of crystalline form D of the hydrochloride of the compound of formula I-1.

[0523] Example 21: Preparation of crystalline form E1 of the hydrochloride of the compound of formula I-1

[0524] Weigh 3.0 g of the compound of Formula I-1 and place it in a 40 mL glass bottle. Add 4.6 mL of ethanol and approximately 1.2 equivalents of HCl (12 N HCl aqueous solution diluted to 1.2 N with ethanol), and stir at 50 °C for 10 min. Add approximately 5 mg of the hydrochloride crystal form E2 seed crystal of the compound of Formula I-1 to the above system. After stirring at 50 °C for 2 h, naturally cool the solution system to 25 °C and stir at 25 °C for 3 days. Add approximately 0.1 equivalent of HCl (12 N HCl aqueous solution diluted to 1.2 N with ethanol) to the above system, and continue to stir at 25 °C for 1 day. Collect the solid part by suction filtration, and dry the obtained solid under vacuum at 25 °C for approximately 17 h. Then dry the obtained solid under vacuum at 50 °C for 2 h to obtain a sample (2.8 g) of the hydrochloride crystal form E1 of the compound of Formula I-1, a pale white solid.

[0525] Example 22: Preparation of the hydrochloride crystal form E2 of the compound of Formula I-1

[0526] Weigh approximately 40 mg of the compound of Formula I-1 and 1.05 equivalents of hydrochloric acid (dilute hydrochloric acid diluted 10 times with ethanol) and place them in a 2 mL glass bottle. Add a screening solvent and conduct a screening experiment by the suspension method. The obtained sample is suspended at 50 °C (35 °C, dichloromethane) for 2 h, then naturally cooled to 25 °C, and suspended at 25 °C for at least 48 h. Centrifuge the obtained suspension through a 0.45 μm nylon filter membrane at a speed of 14,000 rpm. The obtained solid is a sample of the hydrochloride crystal form F of the compound of Formula I-1. After drying it under vacuum at 50 °C for 2 h, a sample of the hydrochloride crystal form E2 of the compound of Formula I-1 is prepared.

[0527] Example 23: Preparation of the hydrochloride crystal form F of the compound of Formula I-1

[0528] 23.1: Weigh approximately 40 mg of the hydrochloride crystal form E1 of the compound of Formula I-1, add 0.2 - 0.5 mL of ethanol, and suspend it under magnetic stirring at a rate of 300 - 400 rpm at 25 °C. Centrifuge and filter the obtained suspension through a 0.45 μm nylon filter membrane centrifuge tube at 14,000 rpm. The obtained solid is a sample of the hydrochloride crystal form F of the compound of Formula I-1.

[0529] 23.2: Weigh approximately 40 mg of the hydrochloride crystal form E1 of the compound of Formula I-1, add 0.2 - 0.5 mL of acetone, and suspend it under magnetic stirring at a rate of 300 - 400 rpm at 25 °C. Centrifuge and filter the obtained suspension through a 0.45 μm nylon filter membrane centrifuge tube at 14,000 rpm. The obtained solid is a sample of the hydrochloride crystal form F of the compound of Formula I-1.

[0530] 23.3: Weigh approximately 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.2 - 0.5 mL of acetonitrile, and suspend it with magnetic stirring at a rate of 300 - 400 rpm at 25 °C. Centrifuge and filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm. The resulting solid is the sample of the hydrochloride crystal form F of the compound of formula I-1.

[0531] 23.4: Weigh approximately 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.2 - 0.5 mL of tetrahydrofuran, and suspend it with magnetic stirring at a rate of 300 - 400 rpm at 25 °C. Centrifuge and filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm. The resulting solid is the sample of the hydrochloride crystal form F of the compound of formula I-1.

[0532] 23.5: Weigh approximately 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.2 - 0.5 mL of methyl isobutyl ketone / trifluoroethanol (9 / 1, v / v), and suspend it with magnetic stirring at a rate of 300 - 400 rpm at 25 °C. Centrifuge and filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm. The resulting solid is the sample of the hydrochloride crystal form F of the compound of formula I-1.

[0533] 23.6: Weigh approximately 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1 - 0.5 mL of ethanol, and suspend it with magnetic stirring at a rate of 300 - 400 rpm at 50 °C. Centrifuge and filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm. The resulting solid is the sample of the hydrochloride crystal form F of the compound of formula I-1.

[0534] 23.7: Weigh approximately 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1 - 0.5 mL of acetone, and suspend it with magnetic stirring at a rate of 300 - 400 rpm at 50 °C. Centrifuge and filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm. The resulting solid is the sample of the hydrochloride crystal form F of the compound of formula I-1.

[0535] 23.8: Weigh approximately 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1 - 0.5 mL of ethyl acetate, and suspend it with magnetic stirring at a rate of 300 - 400 rpm at 50 °C. Centrifuge and filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm. The resulting solid is the sample of the hydrochloride crystal form F of the compound of formula I-1.

[0536] 23.9: Weigh approximately 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1 - 0.5 mL of acetonitrile, and suspend it at 50 °C with a magnetic stirrer at a rate of 300 - 400 rpm. Centrifuge and filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm. The resulting solid is the sample of the hydrochloride crystal form F of the compound of formula I-1.

[0537] 23.10: Weigh approximately 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1 - 0.5 mL of tetrahydrofuran, and suspend it at 50 °C with a magnetic stirrer at a rate of 300 - 400 rpm. Centrifuge and filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm. The resulting solid is the sample of the hydrochloride crystal form F of the compound of formula I-1.

[0538] 23.11: Weigh approximately 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1 - 0.5 mL of methyl isobutyl ketone / trifluoroethanol (9 / 1, v / v), and suspend it at 50 °C with a magnetic stirrer at a rate of 300 - 400 rpm. Centrifuge and filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm. The resulting solid is the sample of the hydrochloride crystal form F of the compound of formula I-1.

[0539] 23.12: Weigh approximately 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1 - 0.5 mL of ethanol, perform 10 heating and cooling cycles at a rate of 0.1 °C / min between 5 °C and 50 °C, and at the same time suspend it with a magnetic stirrer at a rate of 300 - 400 rpm. The sampling temperature is 10 °C. Centrifuge and filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 10 °C and 14,000 rpm. The resulting solid is the sample of the hydrochloride crystal form F of the compound of formula I-1.

[0540] 23.13: Weigh approximately 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1 - 0.5 mL of acetone, perform 10 heating and cooling cycles at a rate of 0.1 °C / min between 5 °C and 50 °C, and at the same time suspend it with a magnetic stirrer at a rate of 300 - 400 rpm. The sampling temperature is 10 °C. Centrifuge and filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 10 °C and 14,000 rpm. The resulting solid is the sample of the hydrochloride crystal form F of the compound of formula I-1.

[0541] 23.14: Weigh approximately 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1 - 0.5 mL of ethyl acetate, perform 10 heating and cooling cycles at a rate of 0.1 °C / min between 5 °C and 50 °C, and at the same time perform suspension under magnetic stirring at a rate of 300 - 400 rpm. The sampling temperature is 10 °C. Centrifuge and filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm at 10 °C. The obtained solid is the sample of the hydrochloride crystal form F of the compound of formula I-1.

[0542] 23.15: Weigh approximately 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1 - 0.5 mL of acetonitrile, perform 10 heating and cooling cycles at a rate of 0.1 °C / min between 5 °C and 50 °C, and at the same time perform suspension under magnetic stirring at a rate of 300 - 400 rpm. The sampling temperature is 10 °C. Centrifuge and filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm at 10 °C. The obtained solid is the sample of the hydrochloride crystal form F of the compound of formula I-1.

[0543] 23.16: Weigh approximately 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1 - 0.5 mL of tetrahydrofuran, perform 10 heating and cooling cycles at a rate of 0.1 °C / min between 5 °C and 50 °C, and at the same time perform suspension under magnetic stirring at a rate of 300 - 400 rpm. The sampling temperature is 10 °C. Centrifuge and filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm at 10 °C. The obtained solid is the sample of the hydrochloride crystal form F of the compound of formula I-1.

[0544] 23.17: Weigh approximately 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1 - 0.5 mL of methyl isobutyl ketone / trifluoroethanol (9 / 1, v / v), perform 10 heating and cooling cycles at a rate of 0.1 °C / min between 5 °C and 50 °C, and at the same time perform suspension under magnetic stirring at a rate of 300 - 400 rpm. The sampling temperature is 10 °C. Centrifuge and filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm at 10 °C. The obtained solid is the sample of the hydrochloride crystal form F of the compound of formula I-1.

[0545] Example 24: Preparation of the hydrochloride crystal form G of the compound of formula I-1

[0546] 24.1: Weigh approximately 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.2 - 0.5 mL of water, and perform suspension under magnetic stirring at a rate of 300 - 400 rpm at 25 °C. Centrifuge and filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm. The obtained solid is the sample of the hydrochloride crystal form G of the compound of formula I-1.

[0547] 24.2: Weigh approximately 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1 - 0.5 mL of methanol, and suspend it with magnetic stirring at a rate of 300 - 400 rpm at 50 °C. Centrifuge and filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm. The resulting solid is the sample of the hydrochloride crystal form G of the compound of formula I-1.

[0548] 24.3: Weigh approximately 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1 - 0.5 mL of methyl isobutyl ketone / trifluoroethanol (9 / 1, v / v), perform 10 heating and cooling cycles at a rate of 0.1 °C / min between 5 °C and 50 °C, and at the same time suspend it with magnetic stirring at a rate of 300 - 400 rpm. The sampling temperature is 10 °C. Centrifuge and filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 10 °C and 14,000 rpm. The resulting solid is the sample of the hydrochloride crystal form G of the compound of formula I-1.

[0549] Example 25: Preparation of the hydrochloride crystal form H of the compound of formula I-1

[0550] 25.1: Weigh approximately 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.2 - 0.5 mL of methanol / water (1 / 1, v / v), and suspend it with magnetic stirring at a rate of 300 - 400 rpm at 25 °C. Centrifuge and filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm. The resulting solid is the sample of the hydrochloride crystal form H of the compound of formula I-1.

[0551] 25.2: Weigh approximately 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1 - 0.5 mL of methanol / water (1 / 1, v / v), and suspend it with magnetic stirring at a rate of 300 - 400 rpm at 50 °C. Centrifuge and filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm. The resulting solid is the sample of the hydrochloride crystal form H of the compound of formula I-1.

[0552] Example 26: Preparation of the hydrochloride crystal form I of the compound of formula I-1

[0553] 26.1: Weigh approximately 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1 - 0.5 mL of methanol, and suspend it with magnetic stirring at a rate of 300 - 400 rpm at 50 °C. Centrifuge and filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm. The resulting solid is the sample of the hydrochloride crystal form I of the compound of formula I-1.

[0554] 26.2: Weigh approximately 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add the minimum volume of methanol, and fully dissolve it at 25 °C. The resulting thin suspension is passed through a 0.45 μm nylon membrane syringe filter to obtain a clear solution. Take 0.8 mL of each clear solution and slowly add 8 mL of methyl tert-butyl ether to the above-mentioned clear solution. The resulting suspension is centrifugally filtered through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm, and the obtained solid is the sample of the hydrochloride crystal form I of the compound of formula I-1.

[0555] Example 27: Preparation of the hydrochloride crystal form J1 of the compound of formula I-1

[0556] 27.1: Weigh approximately 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1 - 0.5 mL of 2-methyltetrahydrofuran, and suspend it at 50 °C at a rate of 300 - 400 rpm under magnetic stirring. The resulting suspension is centrifugally filtered through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm, and the obtained solid is the sample of the hydrochloride crystal form J1 of the compound of formula I-1.

[0557] 27.2: Weigh approximately 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1 - 0.5 mL of 2-methyltetrahydrofuran, perform 10 heating and cooling cycles at a rate of 0.1 °C / min between 5 °C and 50 °C, and at the same time suspend it at a rate of 300 - 400 rpm under magnetic stirring. The sampling temperature is 10 °C. The resulting suspension is centrifugally filtered through a 0.45 μm nylon membrane centrifuge tube at 10 °C at 14,000 rpm, and the obtained solid is the sample of the hydrochloride crystal form J1 of the compound of formula I-1.

[0558] Example 28: Preparation of the hydrochloride crystal form J2 of the compound of formula I-1

[0559] Heat the above sample of the hydrochloride crystal form J1 of the compound of formula I-1 to 110 °C, and the obtained solid is the sample of the hydrochloride crystal form J2 of the compound of formula I-1.

[0560] Example 29: Preparation of the hydrochloride crystal form K of the compound of formula I-1

[0561] 29.1: Weigh approximately 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1 - 0.5 mL of methyl tert-butyl ether, and suspend it at 50 °C at a rate of 300 - 400 rpm under magnetic stirring. The resulting suspension is centrifugally filtered through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm, and the obtained solid is the sample of the hydrochloride crystal form K of the compound of formula I-1.

[0562] 29.2: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of methyl tert-butyl ether, and perform 10 heating and cooling cycles between 5°C and 50°C at a rate of 0.1°C / min, while suspending under magnetic stirring at a rate of 300-400 rpm, and the temperature during sampling is 10°C. The obtained suspension is centrifuged and filtered at 14,000 rpm at 10°C using a 0.45 μm nylon filter centrifuge tube, and the obtained solid is the hydrochloride crystal form K sample of the compound of formula I-1.

[0563] 29.3: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of toluene, and perform 10 heating and cooling cycles between 5°C and 50°C at a rate of 0.1°C / min, while suspending under magnetic stirring at a rate of 300-400 rpm, and the temperature during sampling is 10°C. The resulting suspension is centrifuged and filtered at 14,000 rpm at 10°C using a 0.45 μm nylon filter centrifuge tube, and the resulting solid is the hydrochloride crystal form K sample of the compound of formula I-1.

[0564] Example 30: Preparation of Hydrochloride Form L of Compound of Formula I-1

[0565] 30.1: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of toluene, and suspend under magnetic stirring at 25°C at a speed of 300-400 rpm. The resulting suspension is centrifuged and filtered at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube to obtain a solid sample of the hydrochloride crystal form L of the compound of formula I-1.

[0566] 30.2: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of toluene, and suspend under magnetic stirring at 50°C at a speed of 300-400 rpm. The resulting suspension is centrifuged and filtered at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube to obtain a solid sample of the hydrochloride crystal form L of the compound of formula I-1.

[0567] Example 31: Preparation of Hydrochloride Form M of Compound of Formula I-1

[0568] 31.1: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of isopropanol / dimethyl sulfoxide (9 / 1, v / v), and suspend under magnetic stirring at 25° C. at a rate of 300-400 rpm. The resulting suspension is centrifuged and filtered at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube, and the resulting solid is the hydrochloride crystal form M sample of the compound of formula I-1.

[0569] 31.2: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of isopropyl acetate / dimethyl sulfoxide (9 / 1, v / v), and suspend under magnetic stirring at 300-400 rpm at 25° C. The resulting suspension is centrifuged at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube to obtain a solid sample of the hydrochloride crystal form M of the compound of formula I-1.

[0570] 31.3: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of dimethyl sulfoxide / water (1 / 1, v / v), and suspend under magnetic stirring at 25° C. at a rate of 300-400 rpm. The resulting suspension is centrifuged and filtered at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube, and the resulting solid is the hydrochloride crystal form M sample of the compound of formula I-1.

[0571] 31.4: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of isopropanol / dimethyl sulfoxide (9 / 1, v / v), and suspend under magnetic stirring at 50° C. at a rate of 300-400 rpm. The resulting suspension is centrifuged and filtered at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube, and the resulting solid is the hydrochloride crystal form M sample of the compound of formula I-1.

[0572] 31.5: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of isopropyl acetate / dimethyl sulfoxide (9 / 1, v / v), and suspend under magnetic stirring at 50° C. at a rate of 300-400 rpm. The resulting suspension is centrifuged and filtered at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube, and the resulting solid is the hydrochloride crystal form M sample of the compound of formula I-1.

[0573] 31.6: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of dimethyl sulfoxide / water (1 / 1, v / v), and suspend at 50° C. at 300-400 rpm under magnetic stirring. The resulting suspension is centrifuged at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube to obtain a solid sample of the hydrochloride crystal form M of the compound of formula I-1.

[0574] 31.7: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of isopropanol / dimethyl sulfoxide (9 / 1, v / v), perform 10 heating and cooling cycles between 5°C and 50°C at a rate of 0.1°C / min, and suspend under magnetic stirring at a rate of 300-400 rpm. The temperature during sampling is 10°C. The obtained suspension is centrifuged and filtered at 14,000 rpm at 10°C using a 0.45 μm nylon filter centrifuge tube, and the obtained solid is the hydrochloride crystal form M sample of the compound of formula I-1.

[0575] 31.8: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of isopropyl acetate / dimethyl sulfoxide (9 / 1, v / v), perform 10 heating and cooling cycles between 5°C and 50°C at a rate of 0.1°C / min, and suspend under magnetic stirring at a rate of 300-400 rpm. The temperature during sampling is 10°C. The obtained suspension is centrifuged and filtered at 14,000 rpm at 10°C using a 0.45 μm nylon filter centrifuge tube, and the obtained solid is the hydrochloride crystal form M sample of the compound of formula I-1.

[0576] 31.9: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of dimethyl sulfoxide / water (1 / 1, v / v), perform 10 heating and cooling cycles between 5°C and 50°C at a rate of 0.1°C / min, and suspend under magnetic stirring at a rate of 300-400 rpm. The temperature during sampling is 10°C. The obtained suspension is centrifuged and filtered at 14,000 rpm at 10°C using a 0.45 μm nylon filter centrifuge tube, and the obtained solid is the hydrochloride crystal form M sample of the compound of formula I-1.

[0577] Example 32: Preparation of Hydrochloride Form N of Compound of Formula I-1

[0578] 32.1: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.2-0.5 mL of methanol, and suspend under magnetic stirring at 25°C at a speed of 300-400 rpm. The resulting suspension is centrifuged at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube to obtain a solid sample of the hydrochloride crystal form N of the compound of formula I-1.

[0579] 32.2: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of methanol, and perform 10 heating and cooling cycles at a rate of 0.1°C / min between 5°C and 50°C, while suspending under magnetic stirring at a rate of 300-400 rpm, and the temperature during sampling is 10°C. The resulting suspension is centrifuged and filtered at 14,000 rpm at 10°C using a 0.45 μm nylon filter centrifuge tube, and the resulting solid is the hydrochloride crystal form N sample of the compound of formula I-1.

[0580] Example 33: Preparation of Hydrochloride Form O of Compound I-1

[0581] Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.2-0.5 mL of dichloromethane, and suspend under magnetic stirring at 300-400 rpm at 25° C. The resulting suspension is centrifuged at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube to obtain a solid sample of the hydrochloride crystal form O of the compound of formula I-1.

[0582] Experimental Example 1: Solid Stability and Solubility of Hydrochloride Form I of Compound I-1

[0583] 1.1 Solid Stability of Hydrochloride Form I of Compound I-1

[0584] The open container containing the hydrochloride crystal form I of the compound of formula I-1 was placed at 25°C / 60% RH for 1 week. The sealed container containing the hydrochloride crystal form I of the compound of formula I-1 was placed at 60°C for 1 week. The stability samples under these conditions were subjected to XRPD, HPLC and stoichiometric ratio tests, and the samples were observed for color changes.

[0585] Table 33 Solid stability of hydrochloride salt of compound of formula I-1 Form I

[0586]

[0587] 1.2 Solubility of Free Form A of Compound I-1

[0588] Weigh 10 mg of the free form A of the compound of formula I-1 or 10.8 mg (equivalent to 10 mg of the free anhydrous substance) of the hydrochloride form I of the compound of formula I-1 into an 8 mL glass bottle. Add 5 mL of the dissolution medium. The resulting suspension / clear solution is stirred at 400 rpm for 2 h, 8 h and 24 h at 37 ° C, and then the resulting suspension / clear solution is centrifuged at 14,000 rpm for 5 min at 37 ° C. The solubility of the supernatant is detected by HPLC, the pH of the supernatant is measured by a pH meter, and the residual solid is detected by XRPD.

[0589] Table 34 Solubility test of free crystal form A of compound of formula I-1

[0590]

[0591]

[0592] Table 35 Solubility test of hydrochloride crystal form I of compound of formula I-1

[0593]

[0594] Conclusion: The total impurity content and crystal form of the hydrochloride crystal form I of the compound of formula I-1 did not change, showing good physical stability. Moreover, the hydrochloride crystal form I of the compound of formula I-1 has a greater solubility improvement in the four media compared to the free crystal form of the compound of formula I-1.

[0595] Experimental Example 2: FGFR2 receptor activity inhibition test of hydrochloride crystal form I Experiment 2.3 Test of the hydrochloride crystal form I of the formula I-1 compound on FGFR2 background cell activity

[0596] This experiment studied the inhibitory effect of the compounds on cell proliferation by detecting the effects of the test compounds on in vitro cell activity in 7 tumor cell lines (KATO III, NCI-H716, SNU-16, AN3CA, MFE-296, SUM52PE, and MFM223).

[0597] The cell line was cultured in an incubator at 37°C and 5% CO2, passaged regularly, and cells in the logarithmic growth phase were used for plating. The test compound was prepared into a 10 mM solution with DMSO.

[0598] Prepare compound storage plate (tube): dilute with DMSO from the highest concentration 4 times to the lowest concentration, a total of 9 concentrations, and dilute the internal control compound 4 times, a total of 9 concentrations. Then, prepare the compound working solution: add 98μL cell culture medium to a flat-bottomed 96-well transparent medicine plate, draw 2μL of compound from the compound storage plate and add it to the cell culture medium of the 96-well transparent medicine plate. Add 2μL DMSO to the solvent control. After adding the compound or DMSO, use a spray gun to mix it evenly.

[0599] Cell plating and drug administration: 1) Use trypan blue to stain cells and count live cells, requiring cell viability to be above 90%; 2) Adjust cell concentration to an appropriate concentration; 3) Add 95 μL of cell suspension (6000-10000 cells / well) to each well of the compound detection cell plate, and add culture medium without cells (containing 0.1%) to the Min control well; 4) Add drugs to the compound detection cell plate: Take 5 μL of 20× compound working solution and add it to the cell culture plate as shown in Table 1. Add 5 μL of DMSO-cell culture medium mixture to the Max control. The final concentration of DMSO is 0.1%; 5) Incubate the culture plate in a 37°C, 5% CO2 incubator for 72-96 hours.

[0600] Follow the instructions of the Promega CellTiter-Glo Luminescent Cell Activity Assay Kit (Promega-G7573): 1) Melt the CellTiter-Glo buffer and bring to room temperature; 2) Bring the CellTiter-Glo substrate to room temperature; 3) Add the CellTiter-Glo buffer to a bottle of CellTiter-Glo substrate to dissolve the substrate, thereby preparing the CellTiter-Glo working solution; 4) Slowly vortex to fully dissolve; 5) Remove the cell culture plate and let it stand for 10 minutes to equilibrate to room temperature; 6) Add 50 μL (equal to half the volume of the cell culture solution in each well) of the CellTiter-Glo working solution to each well; 7) Shake the culture plate on an orbital shaker for 2 minutes to induce cell lysis; 8) Let the culture plate stand at room temperature for 10 minutes to stabilize the luminescent signal; 9) Detect the luminescent signal on a SpectraMax Paradigm plate reader.

[0601] The cell proliferation inhibition rate (Inhibition Rate) data was processed using the following formula:

[0602] Inhibition Rate(Inh%)=100-(RLU Drug -RLU Min ) / (RLU Max -RLU Min )*100%.

[0603] The inhibition rates corresponding to different concentrations of compounds were calculated in EXCEL, and then the inhibition rate curve was plotted using GraphPad Prism software and related parameters were calculated, including the maximum and minimum inhibition rates of cells, IC 50 value.

[0604] Table 36 Test compound inhibition results of FGFR2 background cell line proliferation

[0605] Cell Line Form I of the Hydrochloride Salt of the Compound of Formula I-1 KATO III 0.8 NCI-H716 2.4 SNU-16 3.0 AN3CA 9.9 MFE-296 14.9 SUM52PE 6.2 MFM223 1.0

[0606] As can be seen from Table 36, the compounds of the present invention have a good inhibitory effect on cell proliferation in the FGFR2 background.

[0607] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A compound of formula (I), an amorphous or crystalline form or a solvate thereof; in, m is 1, 2, 3, 4, 5, 6, 7, 8 or 9; n is 0, 0.5, 1, 1.5, 2, 2.5 or 3; and X is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid or phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, hippuric acid, glycolic acid or glutaric acid.

2. The crystalline form A of the compound of formula (I) according to claim 1, characterized in that: The compound of formula (I) is I-1, n=0, and the X-ray powder diffraction pattern of the crystalline form A has a 2θ angle selected from the following group: 14.16±0.2°, 16.74±0.2°, 23.01±0.2°. In another preferred embodiment, the crystalline form A further has one or more characteristics selected from the following group: a. The X-ray powder diffraction pattern of the crystalline form A also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the group consisting of 8.44±0.2°, 11.59±0.2°, 12.00±0.2°, 12.34±0.2°, 15.50±0.2°, 16.50±0.2°, 18.38±0.2°, 18.81±0.2°, 19.79±0.2°, 20.44±0.2°, 21.32±0.2°, 21.53±0.2 °, 21.80±0.2°, 22.24±0.2°, 24.37±0.2°, 25.43±0.2°, 26.50±0.2°, 27.13±0.2°, 27.74±0.2°, 28.90±0.2°, 29.72±0.2°, 29.93±0.2°, 30.83±0.2°, 31.56±0.2°, 32.47±0.2°, 33.64±0.2°, 34.12±0.2°, 35.03±0.2°, 36.17±0.2°; b. The differential scanning calorimetry curve of the crystalline form A has two starting points of endothermic peaks at 26.10°C ± 2°C and 223.34°C ± 2°C; c. The thermogravimetric analysis curve of the crystalline form A has three smaller weight loss steps at 24.00℃±2℃, 110.00℃±2℃ and 200.00℃±2℃, and begins to decompose after 250.00℃±2℃. In another preferred embodiment, the crystalline form A has an X-ray powder diffraction pattern substantially as shown in FIG1 . In another preferred example, the crystalline form A has a differential scanning calorimetry diagram substantially as shown in FIG. 2 . In another preferred example, the crystalline form A has a thermogravimetric analysis diagram substantially as shown in FIG. 3 .

3. A method for preparing the crystalline form A as claimed in claim 2, characterized in that: The method comprises the following steps: a. dissolving or dispersing compound I-1 in 1 to 5 times the volume of acetonitrile, an alcohol solvent, an ester solvent, an ether solvent, or a mixed solvent of an alcohol solvent and water; b. Recrystallization or beating; Wherein, the alcohol solvent is selected from the group consisting of methanol, ethanol, isopropanol, or a combination thereof; The ester solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, formic acid, ethyl formate, isopropyl formate, or a combination thereof; The ether solvent is selected from the group consisting of methyl tert-butyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, or a combination thereof; The mixed solvent of alcohol solvent and water is selected from the following group: a mixed solvent of methanol and water, a mixed solvent of ethanol and water, and a mixed solvent of isopropanol and water; wherein the volume ratio of the alcohol solvent to water is 1:(0.1-1.5).

4. The crystalline form of the compound of formula (I) according to claim 1, characterized in that: The compound of formula (I) is a salt formed by compound I-1 and an acid; wherein the acid is an inorganic acid or an organic acid; Preferably, the inorganic acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid or phosphoric acid; Preferably, the organic acid is selected from the group consisting of formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, hippuric acid, glycolic acid or glutaric acid; Preferably, the molar ratio of the compound I-1 to the acid is 1:(0.8-3); more preferably, 1:(0.8-2).

5. The crystal form according to claim 4, characterized in that The crystal form is maleate crystal form A of the compound of formula I-1, and the X-ray powder diffraction pattern of the maleate crystal form A has a 2θ angle selected from the following group: 15.17±0.2°, 23.02±0.2°, 24.42±0.2°. In another preferred embodiment, the X-ray powder diffraction pattern of the maleate salt form A further has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 5.82±0.2°, 9.86±0.2°, 11.06±0.2°, 11.29±0.2°, 11.64±0.2°, 11.90±0.2°, 12.72±0.2°, 13.04±0.2°, 15.66±0.2°, 16.36±0.2°, 17.70±0.2°, 17.8 8±0.2°, 18.11±0.2°, 18.35±0.2°, 18.61±0.2°, 19.41±0.2°, 20.16±0.2°, 20.38±0.2°, 20.69±0.2°, 21.32±0.2°, 21.62±0.2°, 22.28±0.2°, 22.71±0.2°, 25.00±0.2°, 25.34±0.2°, 26.24±0.2°, 26.77±0.2°, 29.85±0.2°, and 34.09±0.2°. In another preferred embodiment, the maleate salt form A has an X-ray powder diffraction pattern substantially as shown in FIG. 4 .

6. The crystal form according to claim 4, characterized in that The crystal form is the monomaleate crystal form B of the compound of formula I-1, and the X-ray powder diffraction pattern of the monomaleate crystal form B has a 2θ angle selected from the following group: 16.57±0.2°, 17.38±0.2°, 20.39±0.2°. In another preferred embodiment, the monomaleate salt form B further has one or more characteristics selected from the following group: a. The X-ray powder diffraction pattern of the monomaleate salt form B also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the group consisting of: 7.98±0.2°, 8.29±0.2°, 10.27±0.2°, 11.61±0.2°, 13.21±0.2°, 13.99±0.2°, 14.52±0.2°, 15.25±0.2°, 15.95±0.2°, 16.89±0.2°, 18.06±0.2°, 20.61±0.2°, 21.25±0.2°, .2°, 21.61±0.2°, 22.17±0.2°, 23.31±0.2°, 23.54±0.2°, 23.98±0.2°, 24.70±0.2°, 24.93±0.2°, 25.32±0.2°, 25.91±0.2°, 26.55±0.2°, 27.24±0.2°, 28.23±0.2°, 28.54±0.2°, 29.00±0.2°, 29.47±0.2°, 29.71±0.2°, 32.64±0.2°, 35.12±0.2°; b. The differential scanning calorimetry curve of the monomaleate salt form B has a starting point of an endothermic peak at 213.92°C ± 2°C; c. The thermogravimetric analysis curve of the monomaleate salt form B has two weight loss steps at 24.00°C±2°C and 180.00°C±2°C, and begins to decompose after 250.00°C±2°C. In another preferred embodiment, the maleate salt form B has an X-ray powder diffraction pattern substantially as shown in FIG. 5 . In another preferred embodiment, the maleate salt form B has a differential scanning calorimetry diagram substantially as shown in FIG. 6 . In another preferred embodiment, the maleate salt form B has a thermogravimetric analysis diagram substantially as shown in FIG. 7 .

7. The crystal form according to claim 4, characterized in that The crystal form is the fumarate crystal form A of the compound of formula I-1, and the X-ray powder diffraction pattern of the fumarate crystal form A has a 2θ angle selected from the following group: 5.11±0.2°, 14.23±0.2°, 28.85±0.2°. In another preferred embodiment, the X-ray powder diffraction pattern of the fumarate salt form A further has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 7.26 ± 0.2°, 10.20 ± 0.2°, 10.51 ± 0.2°, 14.47 ± 0.2°, 14.93 ± 0.2°, 16.17 ± 0.2°, 17.03 ± 0.2°, 17.9 0±0.2°, 18.79±0.2°, 19.44±0.2°, 20.19±0.2°, 20.80±0.2°, 22.48±0.2°, 23.07±0.2°, 23.74±0.2°, 24.07±0.2°, 27.06±0.2°, 27.85±0.2°, 28.30±0.2°, 29.46±0.2°, 38.24±0.2°. In another preferred embodiment, the fumarate salt form A has an X-ray powder diffraction pattern substantially as shown in FIG. 8 .

8. The crystal form according to claim 4, characterized in that The crystal form is hemi-fumarate crystal form B of the compound of formula I-1, and the X-ray powder diffraction pattern of the hemi-fumarate crystal form B has a 2θ angle selected from the following group: 5.12±0.2°, 14.24±0.2°, 10.20±0.2°. In another preferred embodiment, the hemi-fumarate salt form B further has one or more characteristics selected from the following group: a. The X-ray powder diffraction pattern of the hemi-fumarate salt form B also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the group consisting of 7.27±0.2°, 7.48±0.2°, 8.77±0.2°, 9.18±0.2°, 9.74±0.2°, 10.53±0.2°, 14.96±0.2°, 16.09±0.2°, 16.99±0.2°, 17.61±0.2°, 17.95±0.2°, 18.81±0.2°, 19.45±0.2°, 20.22±0.2°, 21.80±0.2°, 23.37±0.2°, 24.70±0.2°, 25.91±0.2°, 26.33±0.2°, 27.70±0.2°, 28.61±0.2°, 29.81±0.2°, 30. 2°, 20.43±0.2°, 20.84±0.2°, 22.51±0.2°, 23.11±0.2°, 23.76±0.2°, 24.19±0.2°, 25.24±0.2°, 27.04±0.2°, 27.90±0.2°, 28.25±0.2°, 28.75±0.2°, 29.73±0.2°, 30.14±0.2°, 30.77±0.2°, 31.28±0.2°, 33.95±0.2°, 34.52±0.2°, 37.07±0.2°, 38.26±0.2°; b. The differential scanning calorimetry curve of the hemi-fumarate salt form B has three starting points of endothermic peaks at 21.34°C ± 2°C, 172.21°C ± 2°C, and 234.34°C ± 2°C; c. The thermogravimetric analysis curve of the hemi-fumarate salt form B has three weight loss steps at three temperatures of 31.90°C±2°C, 90.00°C±2°C and 190.00°C±2°C, and begins to decompose after 270.00°C±2°C. In another preferred embodiment, the hemi-fumarate salt form B has an X-ray powder diffraction pattern substantially as shown in FIG. 9 . In another preferred example, the hemi-fumarate salt form B has a differential scanning calorimetry diagram substantially as shown in FIG. 10 . In another preferred embodiment, the hemi-fumarate salt form B has a thermogravimetric analysis diagram substantially as shown in FIG. 11 .

9. The crystal form according to claim 4, characterized in that The crystal form is the monoglycolate crystal form A of the compound of formula I-1, and the X-ray powder diffraction pattern of the monoglycolate crystal form A has a 2θ angle selected from the following group: 18.22±0.2°, 22.83±0.2°, 26.41±0.2°. In another preferred embodiment, the monoglycolate crystalline form A further has one or more characteristics selected from the following group: a. The X-ray powder diffraction pattern of the monoglycolic acid salt form A also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the group consisting of 6.37±0.2°, 10.37±0.2°, 11.09±0.2°, 11.70±0.2°, 12.69±0.2°, 13.55±0.2°, 14.06±0.2°, 15.97±0.2°, 17.34±0.2°, 18.47±0.2°, 1 9.09±0.2°, 20.41±0.2°, 20.71±0.2°, 21.25±0.2°, 22.06±0.2°, 22.43±0.2°, 23.49±0.2°, 24.09±0.2°, 24.79±0.2°, 25.21±0.2°, 27.23±0.2°, 28.00±0.2°, 29.59±0.2°, 30.44±0.2°, 30.96±0.2°, 38.67±0.2°; b. The differential scanning calorimetry curve of the monoglycolate salt form A has two starting points of endothermic peaks at 109.66°C ± 2°C and 198.83°C ± 2°C; c. The thermogravimetric analysis curve of the monoglycolate crystal form A has three weight loss steps at 33.00℃±2℃, 100.00℃±2℃ and 165.00℃±2℃, and begins to decompose after 200.00℃±2℃. In another preferred example, the monoglycolic acid salt form A has an X-ray powder diffraction pattern substantially as shown in FIG. 12 . In another preferred example, the monoglycolic acid salt form A has a differential scanning calorimetry diagram substantially as shown in FIG. 13 . In another preferred example, the monoglycolic acid salt form A has a thermogravimetric analysis diagram substantially as shown in FIG. 14 .

10. The crystal form according to claim 4, characterized in that The crystal form is the glycolate crystal form B of the compound of formula I-1, and the X-ray powder diffraction pattern of the glycolate crystal form B has a 2θ angle selected from the following group: 13.87±0.2°, 17.30±0.2°, 19.49±0.2°, 23.50±0.2°. In another preferred embodiment, the X-ray powder diffraction pattern of the glycolate crystalline form B further has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 5.95±0.2°, 11.06±0.2°, 12.20±0.2°, 15.01±0.2°, 15.79±0.2°, 15.97±0.2°, 16.44±0.2°, 16.63±0.2°, 16.79±0.2 °, 17.90±0.2°, 18.33±0.2°, 18.91±0.2°, 21.59±0.2°, 22.18±0.2°, 22.80±0.2°, 23.16±0.2°, 23.93±0.2°, 24.49±0.2°, 25.13±0.2°, 26.68±0.2°, 27.95±0.2°, 30.49±0.2°, 31.62±0.2°, and 32.27±0.2°. In another preferred embodiment, the glycolate salt form B has an X-ray powder diffraction pattern substantially as shown in FIG. 15 .

11. The crystal form according to claim 4, characterized in that: The crystal form is of the compound of formula I-1, and the X-ray powder diffraction pattern of the mono L-malate crystal form A has a 2θ angle selected from the following group: 17.99±0.2°, 22.58±0.2°, 24.00±0.2°. In another preferred embodiment, the mono L-malate crystalline form A further has one or more characteristics selected from the following group: a. The X-ray powder diffraction pattern of the mono L-malate crystalline form A further comprises one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the group consisting of 6.01 ± 0.2°, 10.06 ± 0.2°, 11.04 ± 0.2°, 11.98 ± 0.2°, 12.66 ± 0.2°, 12.86 ± 0.2°, 13.39 ± 0.2°, 15.15 ± 0.2°, 15.62 ± 0.2°, 16.46 ± 0.2°, 17.27 ± 0.2°, 18.58 ± 0.2°, 19.53±0.2°, 19.77±0.2°, 20.25±0.2°, 21.01±0.2°, 21.57±0.2°, 22.04±0.2°, 23.67±0.2°, 24.50±0.2°, 25.00±0.2°, 27.34±0.2°, 28.54±0.2°, 28.91±0.2°, 29.40±0.2°, 29.89±0.2°, 30.53±0.2°, 31.33±0.2°, 33.67±0.2°, 36.16±0.2°; b. The differential scanning calorimetry curve of the mono L-malate salt form A has a starting point of an endothermic peak at 204.74°C ± 2°C; c. The thermogravimetric analysis curve of the mono L-malate salt form A has two weight loss steps at 33.00°C±2°C and 185.00°C±2°C, and begins to decompose after 250.00°C±2°C. In another preferred example, the mono L-malate crystalline form A has an X-ray powder diffraction pattern substantially as shown in FIG. 16 . In another preferred example, the mono L-malate crystalline form A has a differential scanning calorimetry diagram substantially as shown in FIG. 17 . In another preferred example, the mono L-malate crystal form A has a thermogravimetric analysis diagram substantially as shown in FIG. 18 .

12. The crystal form according to claim 4, characterized in that The crystal form is a monosuccinate crystal form A of the compound of formula I-1, characterized in that the X-ray powder diffraction pattern of the monosuccinate crystal form A has a 2θ angle selected from the following group: 18.40±0.2°, 24.09±0.2°, 24.62±0.2°. In another preferred embodiment, the monosuccinate crystalline form A further has one or more characteristics selected from the following group: a. The X-ray powder diffraction pattern of the monosuccinate crystalline form A also has one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the group consisting of 6.15±0.2°, 9.64±0.2°, 9.95±0.2°, 11.19±0.2°, 12.26±0.2°, 12.70±0.2°, 13.30±0.2°, 14.95±0.2°, 15.25±0.2°, 16.18±0.2°, 17.59±0.2°, 18.89±0.2°, 19.11±0.2°, 19.73±0.2°, 20.28±0.2°, .2°, 20.90±0.2°, 21.27±0.2°, 21.64±0.2°, 22.12±0.2°, 23.12±0.2°, 23.83±0.2°, 24.35±0.2°, 24.93±0.2°, 25.17±0.2°, 26.05±0.2°, 27.00±0.2°, 28.27±0.2°, 28.72±0.2°, 30.12±0.2°, 31.20±0.2°, 33.57±0.2°, 34.13±0.2°, 34.58±0.2°, 35.60±0.2°, 38.23±0.2°; b. The differential scanning calorimetry curve of the monosuccinate salt form A has three starting points of endothermic peaks at 72.75°C ± 2°C, 146.41°C ± 2°C and 175.72°C ± 2°C; c. The thermogravimetric analysis curve of the monosuccinate crystal form A has three weight loss steps at 33.00℃±2℃, 90.00℃±2℃ and 160.00℃±2℃, and begins to decompose after 260.00℃±2℃. In another preferred example, the monosuccinate salt form A has an X-ray powder diffraction pattern substantially as shown in Figure 19. In another preferred example, the monosuccinate salt form A has a differential scanning calorimetry diagram substantially as shown in Figure 20. In another preferred example, the monosuccinate salt form A has a thermogravimetric analysis diagram substantially as shown in Figure 21.

13. The crystal form according to claim 4, characterized in that The crystal form is sulfate crystal form A of the compound of formula I-1, and the X-ray powder diffraction pattern of the sulfate crystal form A has a 2θ angle selected from the following group: 14.97±0.2°, 20.21±0.2°, 22.58±0.2°. In another preferred embodiment, the X-ray powder diffraction pattern of the sulfate crystalline form A also has 1 or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 6.74±0.2°, 9.56±0.2°, 12.89±0.2°, 13.78±0.2°, 14.68±0.2°, 15.49±0.2°, 15.70±0.2°, 16.41±0.2°, 16.90±0.2°, 18.47±0.2°, 18.68±0.2°, 18.86±0.2°, 19.33±0.2° , 19.87±0.2°, 20.70±0.2°, 21.54±0.2°, 21.76±0.2°, 22.25±0.2°, 23.75±0.2°, 24.11±0.2°, 24.50±0.2°, 25.25±0.2°, 25.86±0.2°, 26.10±0.2°, 26.71±0.2°, 26.96±0.2°, 27.73±0.2°, 28.41±0.2°, 28.90±0.2°, 29.70±0.2°, 30.21±0.2°, 30.99±0.2°. In another preferred example, the sulfate crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 22.

14. The crystal form according to claim 4, characterized in that The crystal form is L-tartrate crystal form A of the compound of formula I-1, and the X-ray powder diffraction pattern of the L-tartrate crystal form A has a 2θ angle selected from the following group: 5.53±0.2°, 16.95±0.2°, 20.79±0.2°. In another preferred embodiment, the X-ray powder diffraction pattern of the L-tartrate salt form A also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 8.90±0.2°, 9.35±0.2°, 11.05±0.2°, 12.54±0.2°, 12.90±0.2°, 14.35±0.2°, 14.64±0.2°, 18.70±0.2°, 19. 45±0.2°, 19.74±0.2°, 20.38±0.2°, 21.45±0.2°, 21.94±0.2°, 22.88±0.2°, 23.80±0.2°, 25.01±0.2°, 25.77±0.2°, 27.33±0.2°, 27.80±0.2°, 28.65±0.2°, 29.41±0.2°, 30.00±0.2°, 31.09±0.2°. In another preferred example, the L-tartrate salt form A has an X-ray powder diffraction pattern substantially as shown in Figure 23.

15. The crystal form according to claim 4, characterized in that The crystal form is hippurate crystal form A of the compound of formula I-1, and the X-ray powder diffraction pattern of the hippurate crystal form A has a 2θ angle selected from the following group: 6.17±0.2°, 12.30±0.2°, 18.78±0.2°. In another preferred embodiment, the X-ray powder diffraction pattern of the hippurate crystalline form A also has 1 or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 6.52±0.2°, 8.77±0.2°, 10.74±0.2°, 11.16±0.2°, 14.18±0.2°, 14.70±0.2°, 15.62±0.2°, 16.0 6±0.2°, 16.78±0.2°, 17.64±0.2°, 20.42±0.2°, 21.15±0.2°, 21.29±0.2°, 21.79±0.2°, 23.03±0.2°, 24.05±0.2°, 24.42±0.2°, 25.32±0.2°, 26.45±0.2°, 26.87±0.2°, 28.85±0.2°. In another preferred embodiment, the hippurate salt form A has an X-ray powder diffraction pattern substantially as shown in Figure 24.

16. The crystal form according to claim 4, characterized in that: The crystal form is the glutaric acid salt crystal form A of the compound of formula I-1, and the X-ray powder diffraction spectrum of the glutaric acid salt crystal form A has a 2θ angle selected from the following group: 17.82±0.2°, 23.20±0.2°, 24.47±0.2°. In another preferred embodiment, the X-ray powder diffraction pattern of the glutaric acid salt form A further has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 9.86±0.2°, 10.97±0.2°, 11.82±0.2°, 12.29±0.2°, 12.75±0.2°, 13.19±0.2°, 14.87±0.2°, 15.10±0.2 °, 15.37±0.2°, 16.33±0.2°, 17.10±0.2°, 18.35±0.2°, 19.17±0.2°, 19.75±0.2°, 20.14±0.2°, 20.70±0.2°, 21.14±0.2°, 22.23±0.2°, 24.26±0.2°, 24.86±0.2°, 25.28±0.2°, 29.92±0.2°. In another preferred example, the glutaric acid salt form A has an X-ray powder diffraction pattern substantially as shown in Figure 25.

17. The crystal form according to claim 4, characterized in that The crystal form is the p-toluenesulfonate crystal form A of the compound of formula I-1, and the X-ray powder diffraction spectrum of the p-toluenesulfonate crystal form A has a 2θ angle selected from the following group: 19.12±0.2°, 20.11±0.2°, 20.53±0.2°. In another preferred embodiment, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form A further has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 7.08±0.2°, 8.00±0.2°, 9.39±0.2°, 10.23±0.2°, 13.36±0.2°, 14.16±0.2°, 14.81±0.2°, 15.77±0.2°, 16.21±0.2°, 17.7 7±0.2°, 18.10±0.2°, 18.90±0.2°, 20.91±0.2°, 21.29±0.2°, 22.49±0.2°, 23.11±0.2°, 24.41±0.2°, 25.51±0.2°, 26.77±0.2°, 28.28±0.2°, 28.81±0.2°, 29.22±0.2°, 29.95±0.2°, 30.98±0.2°, 35.22±0.2°. In another preferred example, the p-toluenesulfonate salt form A has an X-ray powder diffraction pattern substantially as shown in Figure 26.

18. The crystal form according to claim 4, characterized in that The crystal form is the p-toluenesulfonate crystal form B of the compound of formula I-1, and the X-ray powder diffraction spectrum of the p-toluenesulfonate crystal form B has a 2θ angle selected from the following group: 13.95±0.2°, 19.52±0.2°, 25.40±0.2°. In another preferred embodiment, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form B also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 8.27±0.2°, 12.59±0.2°, 13.69±0.2°, 14.63±0.2°, 16.15±0.2°, 17.72±0.2°, 18.68±0.2°, 20.75±0.2°, 21.05±0.2°, 21.92±0.2°, 22.45±0.2°, 23.23±0.2°, 23.91±0.2°, 27.33±0.2°, 29.25±0.2°. In another preferred example, the p-toluenesulfonate salt form B has an X-ray powder diffraction pattern substantially as shown in FIG. 27 .

19. The crystal form according to claim 4, characterized in that: The crystal form is the mesylate crystal form A of the compound of formula I-1, and the X-ray powder diffraction pattern of the mesylate crystal form A has a 2θ angle selected from the following group: 19.57±0.2°, 14.27±0.2°, 24.99±0.2°. In another preferred embodiment, the X-ray powder diffraction pattern of the mesylate salt form A also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 6.70±0.2°, 9.10±0.2°, 9.81±0.2°, 10.16±0.2°, 13.34±0.2°, 13.87±0.2° , 15.37±0.2°, 15.79±0.2°, 17.21±0.2°, 18.75±0.2°, 21.16±0.2°, 22.09±0.2°, 23.31±0.2°, 23.86±0.2°, 24.30±0.2°, 27.18±0.2°, 28.04±0.2°, 28.83±0.2°. In another preferred example, the mesylate salt form A has an X-ray powder diffraction pattern substantially as shown in Figure 28.

20. The crystal form according to claim 4, characterized in that The crystal form is the hydrochloride crystal form C1 of the compound of formula I-1, and the X-ray powder diffraction pattern of the hydrochloride crystal form C1 has a 2θ angle selected from the following group: 7.73±0.2°, 19.57±0.2°, 19.78±0.2°. In another preferred embodiment, the hydrochloride salt form C1 further has one or more characteristics selected from the following group: a. The X-ray powder diffraction pattern of the hydrochloride salt form C1 also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 7.47±0.2°, 9.63±0.2°, 11.46±0.2°, 12.25±0.2°, 13.18±0.2°, 13.51±0.2°, 14.96±0.2°, 15.46±0.2°, 16.79±0.2°, 17.04±0.2°, 17.31±0.2°, 17. .72±0.2°, 18.56±0.2°, 19.34±0.2°, 20.01±0.2°, 20.41±0.2°, 20.76±0.2°, 22.60±0.2°, 23.09±0.2°, 23.80±0.2°, 24.36±0.2°, 25.63±0.2°, 26.47±0.2°, 27.51±0.2°, 29.09±0.2°, 30.76±0.2°, 31.99±0.2°, 36.24±0.2°; b. The differential scanning calorimetry curve of the hydrochloride salt form C1 has two starting points of endothermic peaks at 39.76°C ± 2°C and 153.80°C ± 2°C; c. The thermogravimetric analysis curve of the hydrochloride salt form C1 has three weight loss steps at 26.03°C±2°C, 100.00°C±2°C and 150.00°C±2°C, and decomposes at 214.75°C±2°C. In another preferred embodiment, the hydrochloride salt form C1 has an X-ray powder diffraction pattern substantially as shown in Figure 29. In another preferred embodiment, the hydrochloride salt form C1 has a differential scanning calorimetry diagram substantially as shown in FIG. 30 . In another preferred embodiment, the hydrochloride salt form C1 has a thermogravimetric analysis diagram substantially as shown in FIG. 31 . In another preferred embodiment, the hydrochloride salt crystal form C1 is an ethyl acetate solvent and a hydrate crystal form, wherein the ethyl acetate content is 0.1 to 1 equivalents, and the water content is 1 to 5 equivalents.

21. The crystal form according to claim 4, characterized in that The crystal form is the hydrochloride crystal form C2 of the compound of formula I-1, and the X-ray powder diffraction pattern of the hydrochloride crystal form C2 has a 2θ angle selected from the following group: 7.79±0.2°, 19.66±0.2°, 19.82±0.2°. In another preferred embodiment, the hydrochloride salt form C2 further has one or more characteristics selected from the following group: a. The X-ray powder diffraction pattern of the hydrochloride salt form C2 also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 7.56±0.2°, 9.65±0.2°, 11.48±0.2°, 12.32±0.2°, 13.21±0.2°, 13.63±0.2°, 15.10±0.2°, 15.56±0.2°, 16.86±0.2°, 17.16±0.2°, 17.41±0.2°, 17.77±0.2°, 18 .58±0.2°, 19.36±0.2°, 20.32±0.2°, 20.91±0.2°, 22.71±0.2°, 23.21±0.2°, 23.80±0.2°, 24.35±0.2°, 25.71±0.2°, 26.56±0.2°, 27.53±0.2°, 27.80±0.2°, 28.20±0.2°, 29.15±0.2°, 30.74±0.2°, 32.06±0.2°, 36.30±0.2°, 38.22±0.2°; b. The differential scanning calorimetry curve of the hydrochloride salt form C2 has two starting points of endothermic peaks at 33.27°C ± 2°C and 155.72°C ± 2°C; c. The thermogravimetric analysis curve of the hydrochloride salt form C2 has three weight loss steps at 28.19°C±2°C, 115.00°C±2°C and 150.00°C±2°C, and begins to decompose at 212.45°C±2°C. In another preferred embodiment, the hydrochloride salt form C2 has an X-ray powder diffraction pattern substantially as shown in Figure 32. In another preferred embodiment, the hydrochloride salt form C2 has a differential scanning calorimetry diagram substantially as shown in Figure 33. In another preferred embodiment, the hydrochloride salt form C2 has a thermogravimetric analysis diagram substantially as shown in Figure 34. In another preferred embodiment, the hydrochloride salt crystal form C2 is a 2-methyltetrahydrofuran solvent and a hydrate crystal form, wherein the 2-methyltetrahydrofuran content is 0.05 to 0.5 equivalents, and the water content is 1 to 5 equivalents.

22. The crystal form according to claim 4, characterized in that The crystal form is the hydrochloride crystal form D of the compound of formula I-1, and the X-ray powder diffraction pattern of the hydrochloride crystal form D has a 2θ angle selected from the following group: 15.93±0.2°, 20.09±0.2°, 20.41±0.2°. In another preferred embodiment, the hydrochloride salt form D further has one or more characteristics selected from the following group: a. The X-ray powder diffraction pattern of the hydrochloride salt form D also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 6.60±0.2°, 7.26±0.2°, 7.79±0.2°, 8.48±0.2°, 9.84±0.2°, 11.18±0.2°, 13.31±0.2°, 13.8 9±0.2°, 14.64±0.2°, 14.98±0.2°, 15.23±0.2°, 16.27±0.2°, 17.04±0.2°, 18.21±0.2°, 19.33±0.2°, 21.23±0.2°, 21.80±0.2°, 23.49±0.2°, 24.79±0.2°, 28.43±0.2°; b. The differential scanning calorimetry curve of the hydrochloride salt form D has two starting points of endothermic peaks at 55.20°C ± 2°C and 164.37°C ± 2°C, c. The thermogravimetric analysis curve of the hydrochloride salt form D has two weight loss steps at 36.24°C±2°C and 110.00°C±2°C, and starts to decompose at 211.35°C±2°C. In another preferred example, the hydrochloride salt form D has an X-ray powder diffraction pattern substantially as shown in Figure 35. In another preferred example, the hydrochloride salt form D has a differential scanning calorimetry diagram substantially as shown in Figure 36. In another preferred example, the hydrochloride salt form D has a thermogravimetric analysis diagram substantially as shown in Figure 37.

23. The crystal form according to claim 4, characterized in that The crystal form is the hydrochloride crystal form E1 of the compound of formula I-1, and the X-ray powder diffraction pattern of the hydrochloride crystal form E1 has a 2θ angle selected from the following group: 7.90±0.2°, 14.06±0.2°, 20.19±0.2°. In another preferred embodiment, the hydrochloride salt form E1 further has one or more characteristics selected from the following group: a. The X-ray powder diffraction pattern of the hydrochloride salt form E1 also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 6.15±0.2°, 7.66±0.2°, 8.41±0.2°, 9.49±0.2°, 9.91±0.2°, 10.88±0.2°, 11.42±0.2°, 13.06±0.2°, 13.66±0.2°, 14.69±0.2°, 15.32±0.2°, 15.52±0.2°, 15.88±0.2°, 16.25±0.2°, 16.81±0.2°, 17.35±0.2 °, 18.37±0.2°, 19.01±0.2°, 19.75±0.2°, 21.15±0.2°, 21.51±0.2°, 21.81±0.2°, 22.50±0.2°, 22.87±0.2°, 23.56±0.2°, 24.95±0.2°, 25.18±0.2°, 25.63±0.2°, 26.71±0.2°, 27.10±0.2°, 27.91±0.2°, 28.47±0.2°, 29.30±0.2°, 29.81±0.2°, 30.12±0.2°, 32.93±0.2°, 34.96±0.2°; b. The differential scanning calorimetry curve of the hydrochloride salt form E1 has two starting points of endothermic peaks at 13.36°C ± 2°C and 174.06°C ± 2°C; c. The thermogravimetric analysis curve of the hydrochloride salt form E1 has three weight loss steps at 25.81°C±2°C, 120.00°C±2°C and 160.00°C±2°C, and begins to decompose at 211.29°C±2°C. In another preferred embodiment, the hydrochloride salt form E1 has an X-ray powder diffraction pattern substantially as shown in Figure 38. In another preferred example, the hydrochloride salt form E1 has a differential scanning calorimetry diagram substantially as shown in Figure 39. In another preferred example, the hydrochloride salt form E1 has a thermogravimetric analysis diagram substantially as shown in FIG. 40 . In another preferred embodiment, the hydrochloride crystal form E1 of the compound of formula (I) is a hydrate crystal form, wherein the water content is 0.5 to 4 equivalents.

24. The crystal form according to claim 4, characterized in that The crystal form is the hydrochloride crystal form E2 of the compound of formula I-1, and the X-ray powder diffraction pattern of the hydrochloride crystal form E2 has a 2θ angle selected from the following group: 7.88±0.2°, 14.14±0.2°, 19.75±0.2°. In another preferred embodiment, the hydrochloride salt form E2 further has one or more characteristics selected from the following group: a. The X-ray powder diffraction pattern of the hydrochloride salt form E2 also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 9.51±0.2°, 10.90±0.2°, 11.49±0.2°, 13.10±0.2°, 13.64±0.2°, 14.76±0.2°, 15.39±0.2°, 15.75±0.2°, 16.30±0.2°, 16.93±0.2°, 19.01±0.2°, 20.69±0.2°, 21.54±0.2°, 2 1.84±0.2°, 22.19±0.2°, 22.57±0.2°, 23.01±0.2°, 23.63±0.2°, 24.96±0.2°, 25.90±0.2°, 26.32±0.2°, 26.78±0.2°, 27.19±0.2°, 27.48±0.2°, 27.94±0.2°, 28.68±0.2°, 29.07±0.2°, 29.50±0.2°, 29.91±0.2°, 31.74±0.2°, 32.96±0.2°, 33.66±0.2°; b. The differential scanning calorimetry curve of the hydrochloride salt form E2 has two starting points of endothermic peaks at 14.99°C ± 2°C and 174.19°C ± 2°C; c. The thermogravimetric analysis curve of the hydrochloride salt form E2 has three weight loss steps at 33.18°C±2°C, 90.00°C±2°C and 140.00°C±2°C, and begins to decompose at 213.17°C±2°C. In another preferred embodiment, the hydrochloride salt form E2 has an X-ray powder diffraction pattern substantially as shown in Figure 41. In another preferred example, the hydrochloride salt form E2 has a differential scanning calorimetry diagram substantially as shown in Figure 42. In another preferred example, the hydrochloride salt form E2 has a thermogravimetric analysis diagram substantially as shown in Figure 43. In another preferred embodiment, the hydrochloride crystal form E2 of the compound of formula (I) is prepared from the hydrochloride crystal form F of the compound of formula (I) in vacuum at 10°C to 70°C. In another preferred embodiment, the hydrochloride crystal form E2 of the compound of formula (I) is prepared by drying the hydrochloride crystal form F of the compound of formula (I) at 80°C to 120°C. In another preferred embodiment, the hydrochloride crystal form E2 of the compound of formula (I) is a hydrate crystal form, wherein the water content is 0.5 to 4 equivalents.

25. The crystal form according to claim 4, characterized in that The crystal form is the hydrochloride crystal form F of the compound of formula I-1, and the X-ray powder diffraction pattern of the hydrochloride crystal form F has a 2θ angle selected from the following group: 7.65±0.2°, 11.47±0.2°, 13.93±0.2°. In another preferred embodiment, the hydrochloride salt form F further has one or more characteristics selected from the following group: a. The X-ray powder diffraction pattern of the hydrochloride salt form F also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the group consisting of 6.85±0.2°, 10.21±0.2°, 10.70±0.2°, 14.80±0.2°, 15.25±0.2°, 16.60±0.2°, 16.88±0.2°, 17.84±0.2°, 19.00±0.2°, 19.16±0.2°, 19. .84±0.2°, 20.09±0.2°, 20.34±0.2°, 21.51±0.2°, 22.35±0.2°, 23.22±0.2°, 23.86±0.2°, 25.06±0.2°, 25.31±0.2°, 25.63±0.2°, 26.68±0.2°, 28.10±0.2°, 28.87±0.2°, 30.53±0.2°, 32.45±0.2°, 33.59±0.2°; b. The differential scanning calorimetry curve of the hydrochloride salt form F has two starting points of endothermic peaks at 36.03°C ± 2°C and 172.45°C ± 2°C; c. The thermogravimetric analysis curve of the hydrochloride salt form F has three weight loss steps at 33.35°C±2°C, 100.00°C±2°C and 150.00°C±2°C, and begins to decompose at 212.66°C±2°C. In another preferred example, the hydrochloride salt form F has an X-ray powder diffraction pattern substantially as shown in Figure 44. In another preferred example, the hydrochloride salt form F has a differential scanning calorimetry diagram substantially as shown in Figure 45. In another preferred example, the hydrochloride salt form F has a thermogravimetric analysis diagram substantially as shown in Figure 46. In another preferred embodiment, the hydrochloride crystal form F of the compound of formula (I) is a hydrate crystal form, wherein the water content is 1 to 4 equivalents.

26. The crystalline form according to claim 4, characterized in that The crystal form is the hydrochloride crystal form G of the compound of formula I-1, and the X-ray powder diffraction pattern of the hydrochloride crystal form G has a 2θ angle selected from the following group: 15.52±0.2°, 16.77±0.2°, 23.04±0.2°. In another preferred embodiment, the hydrochloride salt form G further has one or more characteristics selected from the following group: a. The X-ray powder diffraction pattern of the hydrochloride crystalline form G also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the group consisting of 5.83±0.2°, 7.18±0.2°, 9.97±0.2°, 11.63±0.2°, 12.00±0.2°, 12.35±0.2°, 13.26±0.2°, 13.58±0.2°, 14.17±0.2°, 14.60±0.2°, 17.64±0.2°, 18.37±0.2°, 18. 81±0.2°, 19.14±0.2°, 19.80±0.2°, 20.27±0.2°, 20.48±0.2°, 21.35±0.2°, 21.82±0.2°, 22.65±0.2°, 23.35±0.2°, 24.43±0.2°, 25.47±0.2°, 26.24±0.2°, 26.54±0.2°, 26.84±0.2°, 27.92±0.2°, 28.94±0.2°, 29.31±0.2°, 30.18±0.2°; b. The differential scanning calorimetry curve of the hydrochloride form G has three starting points of endothermic peaks at 59.42°C ± 2°C, 151.02°C ± 2°C and 166.01°C ± 2°C; c. The thermogravimetric analysis curve of the hydrochloride salt form G has three weight loss steps at 26.28°C±2°C, 120.00°C±2°C and 150.00°C±2°C. In another preferred example, the hydrochloride salt form G has an X-ray powder diffraction pattern substantially as shown in Figure 47. In another preferred example, the hydrochloride salt form G has a differential scanning calorimetry diagram substantially as shown in Figure 48. In another preferred example, the hydrochloride salt form G has a thermogravimetric analysis diagram substantially as shown in Figure 49. In another preferred embodiment, the hydrochloride crystal form G of the compound of formula (I) is a hydrate crystal form, wherein the water content is 1.0 to 6 equivalents.

27. The crystalline form according to claim 4, characterized in that The crystal form is the hydrochloride crystal form H of the compound of formula I-1, and the X-ray powder diffraction pattern of the hydrochloride crystal form H has a 2θ angle selected from the following group: 5.83±0.2°, 16.67±0.2°, 18.40±0.2°. In another preferred embodiment, the hydrochloride salt form H further has one or more characteristics selected from the following group: a. The X-ray powder diffraction pattern of the hydrochloride salt form H also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the group consisting of: 7.16±0.2°, 10.02±0.2°, 11.64±0.2°, 12.35±0.2°, 13.23±0.2°, 13.59±0.2°, 14.58±0.2°, 15.51±0.2°, 15.97±0.2°, 17.63±0.2°, 18.62±0.2°, 19.11±0.2°, 20.23±0.2°, 20. .54±0.2°, 21.40±0.2°, 22.07±0.2°, 22.62±0.2°, 22.78±0.2°, 23.36±0.2°, 24.73±0.2°, 24.98±0.2°, 26.23±0.2°, 26.57±0.2°, 26.91±0.2°, 27.88±0.2°, 29.01±0.2°, 29.30±0.2°, 29.61±0.2°, 30.21±0.2°, 31.21±0.2°, 32.12±0.2°, 34.66±0.2°; b. The differential scanning calorimetry curve of the hydrochloride salt form H has two starting points of endothermic peaks at 51.49°C ± 2°C and 153.61°C ± 2°C; c. The thermogravimetric analysis curve of the hydrochloride salt form H has three weight loss steps at 26.12°C±2°C, 110.00°C±2°C and 150.00°C±2°C, and begins to decompose at 211.73°C±2°C. In another preferred example, the hydrochloride salt form H has an X-ray powder diffraction pattern substantially as shown in Figure 50. In another preferred example, the hydrochloride salt form H has a differential scanning calorimetry diagram substantially as shown in Figure 51. In another preferred example, the hydrochloride salt form H has a thermogravimetric analysis diagram substantially as shown in Figure 52. In another preferred embodiment, the hydrochloride crystal form H of the compound of formula (I) is a hydrate crystal form, wherein the water content is 2 to 8 equivalents.

28. The crystalline form according to claim 4, characterized in that The crystal form is hydrochloride crystal form I, and the X-ray powder diffraction pattern of the hydrochloride crystal form I has a 2θ angle selected from the following group: 6.68±0.2°, 13.34±0.2°, 21.42±0.2°. In another preferred embodiment, the hydrochloride salt form I further has one or more characteristics selected from the following group: a. The X-ray powder diffraction pattern of the hydrochloride salt form I also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 9.50±0.2°, 12.31±0.2°, 12.54±0.2°, 14.05±0.2°, 14.96±0.2°, 15.38±0.2°, 17.18±0.2°, 17.92±0.2°, 19.03±0.2°, 19.74±0.2°, 19.99±0.2°, 20.96±0.2°, 21. .62±0.2°, 21.99±0.2°, 22.98±0.2°, 23.52±0.2°, 23.80±0.2°, 24.38±0.2°, 25.92±0.2°, 26.81±0.2°, 27.21±0.2°, 27.60±0.2°, 27.78±0.2°, 28.26±0.2°, 28.74±0.2°, 30.07±0.2°, 31.00±0.2°, 32.69±0.2°, 34.02±0.2°, 34.83±0.2°; b. The differential scanning calorimetry curve of the hydrochloride salt form I has two starting points of endothermic peaks at 18.15°C ± 2°C and 194.49°C ± 2°C; c. The thermogravimetric analysis curve of the hydrochloride salt form I has three weight loss steps at 28.31°C±2°C, 70.00°C±2°C and 173.00°C±2°C, and begins to decompose at 215.51°C±2°C. In another preferred embodiment, the hydrochloride salt form I has an X-ray powder diffraction pattern substantially as shown in Figure 53. In another preferred embodiment, the hydrochloride salt form I has a differential scanning calorimetry diagram substantially as shown in Figure 54. In another preferred embodiment, the hydrochloride salt form I has a thermogravimetric analysis diagram substantially as shown in Figure 55. In another preferred embodiment, the hydrochloride crystalline form I of the compound of formula (I) is an anhydrous crystalline form.

29. The crystalline form according to claim 4, characterized in that The crystal form is hydrochloride crystal form J1, and the X-ray powder diffraction pattern of the hydrochloride crystal form J1 has a 2θ angle selected from the following group: 6.80±0.2°, 14.87±0.2°, 20.41±0.2°. In another preferred embodiment, the hydrochloride salt form J1 further has one or more characteristics selected from the following group: a. The X-ray powder diffraction pattern of the hydrochloride salt form J1 also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 7.82±0.2°, 7.95±0.2°, 10.08±0.2°, 11.69±0.2°, 12.30±0.2°, 12.60±0.2°, 13.60±0.2°, 15.98±0.2°, 16.25±0.2°, 18.05±0.2°, 18.60±0.2° .2°, 18.79±0.2°, 19.49±0.2°, 20.82±0.2°, 21.55±0.2°, 21.70±0.2°, 22.06±0.2°, 22.88±0.2°, 23.69±0.2°, 24.92±0.2°, 25.13±0.2°, 26.19±0.2°, 26.57±0.2°, 29.07±0.2°, 30.16±0.2°, 31.85±0.2°, 32.80±0.2°; b. The differential scanning calorimetry curve of the hydrochloride salt form J1 has two starting points of endothermic peaks at 70.82°C ± 2°C and 165.48°C ± 2°C; c. The thermogravimetric analysis curve of the hydrochloride salt form J1 has two weight loss steps at 33.94°C±2°C and 110.00°C±2°C, and starts to decompose at 212.96°C±2°C. In another preferred embodiment, the hydrochloride salt form J1 has an X-ray powder diffraction pattern substantially as shown in Figure 56. In another preferred example, the hydrochloride salt form J1 has a differential scanning calorimetry diagram substantially as shown in Figure 57. In another preferred example, the hydrochloride salt form J1 has a thermogravimetric analysis diagram substantially as shown in Figure 58. In another preferred embodiment, the hydrochloride salt form J1 of the compound of formula (I) is a solvate of 2-methyltetrahydrofuran and water, wherein the content of 2-methyltetrahydrofuran is 0.1 to 2 equivalents, and the content of water is 0.1 to 2 equivalents.

30. The crystalline form according to claim 4, characterized in that The crystal form is hydrochloride crystal form J2, and the X-ray powder diffraction pattern of the hydrochloride crystal form J2 has a 2θ angle selected from the following group: 14.69±0.2°, 18.89±0.2°, 22.23±0.2°. In another preferred embodiment, the hydrochloride salt form J2 further has one or more characteristics selected from the following group: a. The X-ray powder diffraction pattern of the hydrochloride salt form J2 also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 6.78±0.2°, 7.96±0.2°, 8.31±0.2°, 11.59±0.2°, 12.24±0.2°, 13.56±0.2°, 16.44±0.2°, 16.63±0.2°, 17.45±0.2°, 18.12±0.2°, 19.51±0.2°, 20.12±0.2°, 20.35±0. 2°, 20.49±0.2°, 21.28±0.2°, 21.46±0.2°, 22.75±0.2°, 23.27±0.2°, 24.09±0.2°, 24.86±0.2°, 24.99±0.2°, 25.37±0.2°, 25.65±0.2°, 26.54±0.2°, 27.62±0.2°, 28.61±0.2°, 29.00±0.2°, 30.43±0.2°, 32.10±0.2°, 33.01±0.2°, 36.96±0.2°; b. The differential scanning calorimetry curve of the hydrochloride salt form J2 has two starting points of endothermic peaks at 77.60°C ± 2°C and 163.47°C ± 2°C; c. The thermogravimetric analysis curve of the hydrochloride salt form J2 has two weight loss steps at 28.73°C±2°C and 120.00°C±2°C, and starts to decompose at 211.78°C±2°C. In another preferred example, the hydrochloride salt form J2 has an X-ray powder diffraction pattern substantially as shown in Figure 59. In another preferred example, the hydrochloride salt form J2 has a differential scanning calorimetry diagram substantially as shown in Figure 60. In another preferred example, the hydrochloride salt form J2 has a thermogravimetric analysis diagram substantially as shown in Figure 61. In another preferred embodiment, the hydrochloride crystalline form J2 of the compound of formula (I) is prepared by heating the hydrochloride crystalline form J1 of the compound of formula (I) to 90°C to 130°C. In another preferred embodiment, the hydrochloride salt form J2 of the compound of formula (I) is a solvate of 2-methyltetrahydrofuran and water, wherein the content of 2-methyltetrahydrofuran is 0.2 to 0.8 equivalents, and the content of water is 0.5 to 2 equivalents.

31. The crystalline form according to claim 4, characterized in that The crystal form is hydrochloride crystal form K, and the X-ray powder diffraction pattern of the hydrochloride crystal form K has a 2θ angle selected from the following group: 14.93±0.2°, 16.08±0.2°, 23.68±0.2°. In another preferred embodiment, the hydrochloride salt form K further has one or more characteristics selected from the following group: a. The X-ray powder diffraction pattern of the hydrochloride salt form K also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the group consisting of 6.79±0.2°, 7.83±0.2°, 8.04±0.2°, 10.00±0.2°, 10.74±0.2°, 11.61±0.2°, 12.25±0.2°, 12.64±0.2°, 13.57±0.2°, 18.05±0.2°, 18.63±0.2°, 19.43±0. 2°, 20.15±0.2°, 20.49±0.2°, 20.64±0.2°, 21.52±0.2°, 21.72±0.2°, 21.93±0.2°, 23.27±0.2°, 24.73±0.2°, 25.19±0.2°, 26.25±0.2°, 26.57±0.2°, 27.42±0.2°, 28.02±0.2°, 28.67±0.2°, 29.13±0.2°, 29.91±0.2°, 32.56±0.2°; b. The differential scanning calorimetry curve of the hydrochloride salt form K has two starting points of endothermic peaks at 80.73°C ± 2°C and 171.74°C ± 2°C; c. The thermogravimetric analysis curve of the hydrochloride salt form K has three weight loss steps at 33.39°C±2°C, 125.00°C±2°C and 155.00°C±2°C, and starts to decompose at 211.42°C±2°C. In another preferred example, the hydrochloride salt form K has an X-ray powder diffraction pattern substantially as shown in Figure 62. In another preferred example, the hydrochloride salt form K has a differential scanning calorimetry diagram substantially as shown in Figure 63. In another preferred example, the hydrochloride salt form K has a thermogravimetric analysis diagram substantially as shown in Figure 64. In another preferred embodiment, the hydrochloride crystal form K of the compound of formula (I) is a solvate of methyl tert-butyl ether and water, wherein the content of methyl tert-butyl ether is 0.1 to 1 equivalents, and the content of water is 0.5 to 2 equivalents.

32. The crystalline form according to claim 4, characterized in that The crystal form is hydrochloride crystal form L, and the X-ray powder diffraction pattern of the hydrochloride crystal form L has a 2θ angle selected from the following group: 16.89±0.2°, 21.69±0.2°, 22.60±0.2°. In another preferred embodiment, the hydrochloride salt form L further has one or more characteristics selected from the following group: a. The X-ray powder diffraction pattern of the hydrochloride salt form L also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 7.70±0.2°, 8.15±0.2°, 8.82±0.2°, 9.85±0.2°, 11.25±0.2°, 12.72±0.2°, 13.59±0.2°, 14.68±0.2°, 15.07±0.2°, 15.56±0.2°, 16.60±0.2°, 17.56±0.2°, 18.53±0.2 °, 18.98±0.2°, 19.74±0.2°, 20.29±0.2°, 20.52±0.2°, 21.30±0.2°, 22.79±0.2°, 24.38±0.2°, 25.57±0.2°, 26.21±0.2°, 26.50±0.2°, 26.97±0.2°, 27.48±0.2°, 28.17±0.2°, 28.60±0.2°, 29.54±0.2°, 29.80±0.2°, 31.17±0.2°, 33.28±0.2°; b. The differential scanning calorimetry curve of the hydrochloride salt form L has a starting point of an endothermic peak at 180.17°C ± 2°C; c. The thermogravimetric analysis curve of the hydrochloride crystal form L has two weight loss steps at 33.53°C±2°C and 140.00°C±2°C, and starts to decompose at 212.43°C±2°C. In another preferred example, the hydrochloride salt form L has an X-ray powder diffraction pattern substantially as shown in Figure 65. In another preferred example, the hydrochloride salt form L has a differential scanning calorimetry diagram substantially as shown in Figure 66. In another preferred example, the hydrochloride salt form L has a thermogravimetric analysis diagram substantially as shown in Figure 67. In another preferred embodiment, the hydrochloride crystal form L of the compound of formula (I) is a toluene solvate, wherein the toluene content is 0.2 to 1 equivalent.

33. The crystalline form according to claim 4, characterized in that The crystal form is hydrochloride crystal form M, and the X-ray powder diffraction pattern of the hydrochloride crystal form M has a 2θ angle selected from the following group: 14.17±0.2°, 20.82±0.2°, 22.60±0.2°. In another preferred embodiment, the hydrochloride salt form M further has one or more characteristics selected from the following group: a. The X-ray powder diffraction pattern of the hydrochloride salt form M also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the group consisting of 6.84±0.2°, 7.21±0.2°, 8.92±0.2°, 10.07±0.2°, 10.69±0.2°, 10.89±0.2°, 11.24±0.2°, 13.23±0.2°, 14.90±0.2°, 15.59±0.2°, 16.74±0.2°, 17.67±0.2°, 18.29±0.2°, 18.94±0. 2°, 19.46±0.2°, 19.71±0.2°, 19.96±0.2°, 21.49±0.2°, 21.83±0.2°, 23.14±0.2°, 23.54±0.2°, 24.17±0.2°, 25.17±0.2°, 25.45±0.2°, 26.10±0.2°, 27.17±0.2°, 27.61±0.2°, 28.09±0.2°, 28.88±0.2°, 29.42±0.2°, 30.12±0.2°, 32.48±0.2°, 35.22±0.2°; b. The differential scanning calorimetry curve of the hydrochloride salt form M has the starting points of the endothermic peaks at 31.74°C ± 2°C and 150.05°C ± 2°C; c. The thermogravimetric analysis curve of the hydrochloride salt form M has two weight loss steps at 32.98°C±2°C and 115.00°C±2°C, and starts to decompose at 215.09°C±2°C. In another preferred example, the hydrochloride salt form M has an X-ray powder diffraction pattern substantially as shown in Figure 68. In another preferred example, the hydrochloride salt form M has a differential scanning calorimetry diagram substantially as shown in Figure 69. In another preferred example, the hydrochloride salt form M has a thermogravimetric analysis diagram substantially as shown in Figure 70. In another preferred embodiment, the hydrochloride crystal form M of the compound of formula (I) is a solvate of dimethyl sulfoxide and water, wherein the content of dimethyl sulfoxide is 1 to 7 equivalents, and the content of water is 5 to 25 equivalents.

34. The crystalline form according to claim 4, characterized in that The crystal form is hydrochloride crystal form N, and the X-ray powder diffraction pattern of the hydrochloride crystal form N has a 2θ angle selected from the following group: 16.19±0.2°, 20.10±0.2°, 28.42±0.2°. In another preferred embodiment, the hydrochloride salt form N further has one or more characteristics selected from the following group: a. The X-ray powder diffraction pattern of the hydrochloride salt form N also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the group consisting of 6.61±0.2°, 7.80±0.2°, 9.75±0.2°, 11.19±0.2°, 12.53±0.2°, 13.17±0.2°, 14.61±0.2°, 15.24±0.2°, 16.02±0.2°, 18.51±0.2°, 19.36±0.2°, 21.57±0.2°, 21.95±0.2°, 23.47±0.2°, 25.60±0.2°, 27.32±0.2°, 29.12±0.2°; b. The differential scanning calorimetry curve of the hydrochloride salt form N has the starting points of the endothermic peaks at 47.38°C ± 2°C and 167.91°C ± 2°C; c. The thermogravimetric analysis curve of the hydrochloride salt form N has three weight loss steps at 33.22°C±2°C, 75.00°C±2°C and 150.00°C±2°C, and begins to decompose at 212.57°C±2°C. In another preferred example, the hydrochloride salt form N has an X-ray powder diffraction pattern substantially as shown in Figure 71. In another preferred example, the hydrochloride salt form N has a differential scanning calorimetry diagram substantially as shown in Figure 72. In another preferred example, the hydrochloride salt form N has a thermogravimetric analysis diagram substantially as shown in Figure 73. In another preferred embodiment, the hydrochloride crystal form N of the compound of formula (I) is a hydrate crystal form, wherein the water content is 1 to 6 equivalents.

35. The crystalline form according to claim 4, characterized in that The crystal form is hydrochloride crystal form O, and the X-ray powder diffraction pattern of the hydrochloride crystal form O has a 2θ angle selected from the following group: 15.51±0.2°, 18.36±0.2°, 20.17±0.2°. In another preferred embodiment, the hydrochloride salt form O further has one or more characteristics selected from the following group: a. The X-ray powder diffraction pattern of the hydrochloride crystal form O also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 6.14±0.2°, 8.39±0.2°, 9.90±0.2°, 11.28±0.2°, 13.19±0.2°, 13.54±0.2°, 14.40±0.2°, 15.33±0.2°, 15.87±0.2°, 16.79±0.2°, 17.32±0.2°, 19.03±0.2°, 19.38±0.2°, 19.84±0.2°, 20.39±0.2°, 21.14±0.2° 2°, 21.82±0.2°, 22.51±0.2°, 22.84±0.2°, 23.77±0.2°, 24.59±0.2°, 25.28±0.2°, 26.21±0.2°, 26.82±0.2°, 27.07±0.2°, 27.93±0.2°, 28.45±0.2°, 29.24±0.2°, 29.70±0.2°, 30.12±0.2°, 30.91±0.2°, 31.32±0.2°, 32.02±0.2°, 32.81±0.2°, 33.99±0.2°, 35.51±0.2°, 37.27±0.2°; b. The differential scanning calorimetry curve of the hydrochloride salt form O has the starting points of the endothermic peaks at 12.36°C ± 2°C and 174.87°C ± 2°C; c. The thermogravimetric analysis curve of the hydrochloride salt form O has three weight loss steps at 27.70°C±2°C, 115.00°C±2°C and 160.00°C±2°C, and begins to decompose at 212.00°C±2°C. In another preferred example, the hydrochloride salt form O has an X-ray powder diffraction pattern substantially as shown in Figure 74. In another preferred example, the hydrochloride salt form O has a differential scanning calorimetry diagram substantially as shown in Figure 75. In another preferred example, the hydrochloride salt form O has a thermogravimetric analysis diagram substantially as shown in Figure 76. In another preferred embodiment, the hydrochloride crystal form O of the compound of formula (I) is a hydrate crystal form, wherein the water content is 0.4 to 2 equivalents.

36. A method for preparing a crystalline form of a pharmaceutically acceptable salt of a compound of formula (I) according to any one of claims 5 to 35, characterized in that: The steps include: a. dissolving or dispersing the compound of formula (I) and the acid in a molar ratio of 1:(0.8-3) into 1 to 20 times the volume of solvent A; b. Suspension, recrystallization or slurrying; wherein the acid is not selected from hydrochloric acid (preferably, the acid is selected from the group consisting of maleic acid, fumaric acid, glycolic acid, L-malic acid, succinic acid, sulfuric acid, L-tartaric acid, hippuric acid, glutaric acid, p-toluenesulfonic acid or methanesulfonic acid); The solvent A is selected from the group consisting of acetonitrile, dichloromethane, tetrahydrofuran, or a combination thereof; Or the acid is hydrochloric acid or hydrochloric acid dioxane; and the solvent A is selected from the following group: ethyl acetate, 2-methyltetrahydrofuran, butanone, ethanol, acetone, ethyl acetate, acetonitrile, tetrahydrofuran, methyl isobutyl ketone, trifluoroethanol, water, methanol, methyl tert-butyl ether, toluene, isopropanol, dimethyl sulfoxide, isopropyl acetate, dichloromethane, or a combination thereof. In another preferred embodiment, the solvent A is selected from the following group: methyl isobutyl ketone / trifluoroethanol, methanol / water, methanol / methyl tert-butyl ether, isopropanol / dimethyl sulfoxide, isopropyl acetate / dimethyl sulfoxide, water / dimethyl sulfoxide. In another preferred embodiment, the suspending comprises the following steps: a. suspending the compound of formula (I), the acid and the solvent at 45 to 65 ° C for 1 to 3 hours; b. Cool naturally to 20-30°C and continue to suspend for at least 48 hours; c. The resulting suspension was centrifuged at 12000-16000 rpm through a 0.4-0.5 μm filter membrane; d. The obtained solid was dried under vacuum at 45-65°C.

37. A method for preparing a crystalline form of a pharmaceutically acceptable salt of a compound of formula (I) according to any one of claims 5 to 36, characterized in that: The method is a method of converting a crystal form of a pharmaceutically acceptable salt of the compound of formula (I) into another crystal form of the salt by crystal form conversion; Wherein, the method for crystal form transformation comprises the following steps: a. dissolving or dispersing a crystalline form of a pharmaceutically acceptable salt of a compound of formula (I) into 1 to 20 times the volume of solvent A; b. Suspension; c. The resulting suspension was centrifuged through a 0.4-0.5 μm filter membrane at a speed of 12000-16000 rpm; Wherein, solvent A is selected from the following group: ethanol, acetone, ethyl acetate, acetonitrile, tetrahydrofuran, methyl isobutyl ketone, trifluoroethanol, methanol, 2-methyltetrahydrofuran, methyl tert-butyl ether, toluene, isopropanol, dimethyl sulfoxide, isopropyl acetate, dimethyl sulfoxide, methanol, dichloromethane, water or a combination thereof. In another preferred embodiment, the solvent A is selected from the following group: methyl isobutyl ketone / trifluoroethanol, methanol / water, isopropanol / dimethyl sulfoxide, isopropyl acetate / dimethyl sulfoxide, and dimethyl sulfoxide / water. In another preferred embodiment, the suspending comprises the steps of: stirring at a rate of 300-400 rpm at 20-30°C. In another preferred embodiment, the suspending comprises the steps of: stirring at 40-60°C and at a rate of 300-400 rpm. In another preferred embodiment, the suspension comprises the steps of: performing 8 to 12 temperature rise and fall cycles at a rate of 0.05 to 0.2°C / min between 5 and 50°C, while stirring at a rate of 300-400 rpm, and the final temperature of the suspension is 10 to 15°C. In another preferred embodiment, the suspending comprises the steps of: filtering with a 0.4-0.5 μm filter membrane to obtain a clear solution, adding methyl tert-butyl ether in a ratio of 1:(8-12) and then suspending.

38. A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1-2, the crystalline form A according to any one of claims 3-4, or the crystalline form of the compound of formula (I) according to any one of claims 5-36; and One or more pharmaceutically acceptable carriers, excipients, adjuvants, auxiliary materials and / or diluents. In another preferred embodiment, the pharmaceutical composition further comprises other therapeutic agents. In another preferred embodiment, the other therapeutic agent is selected from the group consisting of chemotherapeutic drugs, kinase inhibitors, targeted epigenetic regulators, antibody drugs, immune checkpoint inhibitors, or combinations thereof. In another preferred embodiment, the chemotherapeutic drug is selected from the group consisting of cisplatin, doxorubicin, paclitaxel, etoposide, irinotecan, cyclophosphamide, gemcitabine, ifosfamide, tamoxifen, toremifene, fulvestrant, anastrozole, exemestane, goserelin, leuprorelin, melphalan, chlorambucil, busulfan, floxuridine, cytarabine, oxaliplatin, folinic acid, pentostatin, diethylstilbestrol. In another preferred embodiment, the kinase inhibitor is selected from the group consisting of Akt, TGF-βR, Pim, PKA, PKG, PKC, CaM kinase, CDK2, CDK4, CDK4 / 6, MEK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, PDGFαR, PDGFβR, CSFIR, KIT, c-Met, TRKA, TRKB, TRKC, FLT3, VEGFR, BTK, FAK, SYK, FRK, JAK, HPK1, AXL, ALK, B-Raf inhibitor. In another preferred embodiment, the targeted epigenetic regulator is selected from the group consisting of bromodomain inhibitors, histone lysine methyltransferases, histone arginine methyltransferases, histone demethylases, histone deacetylases, histone acetylases, and DNA methyltransferases. In another preferred embodiment, the antibody drug is selected from the following group: anti-HER 2 antibody, anti-VEGFR antibody, anti-EGFR antibody, anti-c-MET antibody, anti-CD20 antibody. In another preferred embodiment, the immune checkpoint inhibitor is selected from the following group: CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1, PD-L1, and PD-L2.

39. Use of a compound of formula (I) as described in any one of claims 1-2, the crystalline form A as described in any one of claims 3-4, the crystalline form of the compound of formula (I) as described in any one of claims 5-36, and the pharmaceutical composition as described in claim 38 in the preparation of a medicament for preventing and / or treating a disease associated with increased activity or expression of FGFR2. In another preferred embodiment, the increased activity or expression of FGFR2 is selected from the group consisting of: FGFR2 amplification, FGFR2 gene mutation, FGFR2 gene fusion / rearrangement, FGFR2 gene translocation, and FGFR2 gene activation. In another preferred embodiment, the disease associated with increased activity or expression of FGFR2 is selected from the following group: bile duct cancer, liver cancer, breast cancer, prostate cancer, lung cancer, thyroid cancer, gastric cancer, ovarian cancer, esophageal cancer, pancreatic cancer, cervical cancer, colorectal cancer, salivary gland cancer, endometrial cancer and urothelial cancer, etc. In another preferred embodiment, the bile duct cancer is intrahepatic bile duct cancer. In another preferred embodiment, the liver cancer is hepatocellular carcinoma. In another preferred embodiment, the lung cancer is squamous cell lung carcinoma or non-small cell lung cancer.

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