Crystal form of acid salt of sulfoximine compound, preparation method therefor, and use thereof

Abstract

NOT VISIBLE DUE TO STATUS OF PATENT

Description

A crystalline form of an acid salt of a sulfoximine compound, and its preparation method and use Technical Field

[0001] The present invention belongs to the field of drug development, and in particular relates to a crystal 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) signaling. Its family consists of four members (FGFR1, FGFR2, FGFR3, FGFR4). It is a glycoprotein composed of an extracellular immunoglobulin (Ig)-like domain, a hydrophobic transmembrane region, and an intracellular portion including a tyrosine kinase region. The binding of FGF ligands causes receptor dimerization and conformational changes in the intracellular domain, thereby causing intermolecular transphosphorylation between the kinase domain and the intracellular tail. The phosphorylated residues act as docking sites for attached proteins, which promote downstream signaling cascades, resulting in cell behavior, including proliferation, survival, differentiation, migration, and angiogenesis. Abnormal FGFRs signaling is involved in a variety of cancer types, including liver cancer, intrahepatic bile duct cancer, bladder cancer, endometrial cancer, breast cancer, and lung cancer, and disease progression occurs through overexpression, point mutations, and / or chromosomal translocations.

[0003] With continued research, pan-FGFR1-3 inhibitors have produced clinical responses in a variety of FGFR-altered cancers, but they also exhibit target-restricted toxicities, leading to adverse side effects such as hyperphosphatemia and tissue mineralization. This stems from the fact that phosphate reabsorption is regulated by FGFR1 and FGFR3. Several studies have outlined the presence of FGFR2 translocations in 14% of intrahepatic cholangiocarcinomas; FGFR2 mutations in 12-14% of endometrial cancers and 5% of squamous non-small cell lung cancers; and FGFR2 amplification 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 therapies by indirectly overactivating FGFR2 in tumor-associated fibroblasts.

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

[0005] The purpose of the present invention is to develop a pharmaceutically acceptable salt form, a crystal form and a preparation method of a sulfoximine FGFR inhibitor compound.

[0006] One aspect of the present invention provides a compound of formula (I),

[0007] an amorphous or crystalline form or a solvate thereof;

[0008] wherein m is 1, 2, 3, 4, 5, 6, 7, 8 or 9;

[0009] 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.

[0010] In another preferred embodiment, the structure of the compound of formula I-1 is as follows:

[0011] The present invention provides a crystal form A of a compound of formula I-1, whose X-ray powder diffraction pattern has special 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°, and 28.90±0.2°.

[0012] In some embodiments of the present invention, the crystal form A of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 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°.

[0013] In some embodiments of the present invention, the XRPD pattern of Form A of the compound of Formula I-1 is shown in FIG1 .

[0014] Table 1: XRPD analysis data of Form A of the compound of formula I-1

[0015] In some embodiments of the present invention, the differential scanning calorimetry curve of the crystal form A of the compound of formula I-1 has two starting points of endothermic peaks at 26.10°C±2°C and 223.34°C±2°C.

[0016] In some embodiments of the present invention, the DSC spectrum of Form A of the compound of Formula I-1 is shown in FIG2 .

[0017] In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned crystal form A of the compound of formula I-1 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℃.

[0018] In some embodiments of the present invention, the TGA spectrum of the crystal form A of the compound of formula I-1 is shown in FIG3 .

[0019] The present invention also provides a method for preparing the crystal form A of the above-mentioned compound of formula I-1, comprising 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 beating to obtain the crystal form, wherein the alcohol solvent is selected from methanol, ethanol, isopropyl alcohol, etc., the ester solvent is selected from ethyl acetate, isopropyl acetate, formic acid, 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 the 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 isopropyl alcohol and water, and in the mixed solvent of the alcohol solvent and water, the volume ratio of the alcohol solvent to water is selected from: 1:0.1 to 1.5.

[0020] The present invention also provides a maleate salt crystalline form A of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 5.82±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°, and 26.77±0.2°.

[0021] In some embodiments of the present invention, the maleate salt form A of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 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°. .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°.

[0022] In some embodiments of the present invention, the XRPD pattern of the maleate salt form A of the compound of formula I-1 is shown in FIG4 .

[0023] Table 2 XRPD analysis data of maleate salt form A of the compound of formula I-1

[0024] The present invention also provides a method for preparing the crystal form A of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and maleic acid to acetonitrile and dichloromethane, and recrystallizing or slurrying the obtained compound, wherein the ratio of the compound of formula I-1 to maleic acid is selected from: 0.8 to 1.2.

[0025] The present invention also provides a monomaleate crystalline form B of the compound of formula I-1, which has an X-ray powder diffraction pattern having special 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°.

[0026] In some embodiments of the present invention, the monomaleate crystalline form B of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 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°.

[0027] In some embodiments of the present invention, the XRPD pattern of the monomaleate crystalline form B of the compound of formula I-1 is shown in FIG5 .

[0028] Table 3 XRPD analysis data of the monomaleate salt form B of the compound of formula I-1

[0029] In some embodiments of the present invention, the monomaleate crystalline form B of the compound of formula I-1 has a differential scanning calorimetry curve with an endothermic peak starting point at 213.92°C±2°C.

[0030] In some embodiments of the present invention, the DSC spectrum of the monomaleate crystalline form B of the compound of formula I-1 is shown in FIG6 .

[0031] In some embodiments of the present invention, the monomaleate crystalline form B of the compound of formula I-1 has a thermogravimetric analysis curve with 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.

[0032] In some embodiments of the present invention, the TGA spectrum of the monomaleate crystalline form B of the compound of formula I-1 is shown in FIG7 .

[0033] The present invention also provides a method for preparing the monomaleate crystalline form B of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and maleic acid to tetrahydrofuran, and recrystallizing or slurrying the obtained compound, wherein the ratio of the compound of formula I-1 to maleic acid is selected from: 0.8 to 1.2.

[0034] The present invention also provides a fumarate crystalline 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°, and 29.46±0.2°.

[0035] In some embodiments of the present invention, the fumarate salt form A of the compound of formula I-1 has an X-ray powder diffraction pattern having 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°.

[0036] In some embodiments of the present invention, the XRPD pattern of the fumarate crystalline form A of the compound of formula I-1 is shown in FIG8 .

[0037] Table 4 XRPD analysis data of the fumarate salt form A of the compound of formula I-1

[0038] The present invention also provides a method for preparing the fumarate crystalline form A of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and fumaric acid to acetonitrile and dichloromethane, and then recrystallizing or slurrying the compound, wherein the ratio of the compound of formula I-1 to fumaric acid is selected from: 0.8 to 1.2.

[0039] The present invention also provides a hemi-fumarate crystalline form B of the compound of formula I-1, whose 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°, and 28.754±0.2°.

[0040] In some embodiments of the present invention, the hemi-fumarate crystalline form B of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 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°.

[0041] In some embodiments of the present invention, the XRPD pattern of the hemi-fumarate crystalline form B of the compound of formula I-1 is shown in FIG9 .

[0042] Table 5 XRPD analysis data of hemifumarate salt form B of the compound of formula I-1

[0043] In some embodiments of the present invention, the hemi-fumarate crystalline form B of the compound of formula I-1 has a differential scanning calorimetry curve with endothermic peak starting points at 21.34°C±2°C, 172.21°C±2°C, and 234.34°C±2°C.

[0044] In some embodiments of the present invention, the DSC spectrum of the hemi-fumarate crystalline form B of the compound of formula I-1 is shown in FIG10 .

[0045] In some embodiments of the present invention, the hemi-fumarate crystalline form B of the compound of formula I-1 has a thermogravimetric analysis curve with three weight loss steps at three temperatures: 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.

[0046] In some embodiments of the present invention, the TGA spectrum of the hemi-fumarate crystalline form B of the compound of formula I-1 is shown in FIG11 .

[0047] The present invention also provides a method for preparing the hemi-fumarate crystal form B of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and fumaric acid to tetrahydrofuran, and recrystallizing or slurrying the mixture, wherein the ratio of the compound of formula I-1 to fumaric acid is selected from: 1.6 to 2.4.

[0048] The present invention also provides a monoglycolate crystalline form A of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 6.37±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°, and 30.96±0.2°.

[0049] In some embodiments of the present invention, the monoglycolate crystalline form A of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 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°, 2 0.41±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°.

[0050] In some embodiments of the present invention, the XRPD pattern of the monoglycolate crystalline form A of the compound of formula I-1 is shown in FIG12 .

[0051] Table 6 XRPD analysis data of the monoglycolate salt of the compound of formula I-1, Form A

[0052] In some embodiments of the present invention, the monoglycolate crystalline form A of the compound of formula I-1 has a differential scanning calorimetry curve with two endothermic peak starting points at 109.66°C±2°C and 198.83°C±2°C.

[0053] In some embodiments of the present invention, the DSC spectrum of the monoglycolic acid salt form A of the compound of formula I-1 is shown in FIG13 .

[0054] In some embodiments of the present invention, the monoglycolate crystalline form A of the compound of formula I-1 has a thermogravimetric analysis curve with three weight loss steps at 33.00℃±2℃, 100.00℃±2℃ and 165.00℃±2℃, and begins to decompose after 200.00℃±2℃.

[0055] In some embodiments of the present invention, the TGA spectrum of the monoglycolate crystalline form A of the compound of formula I-1 is shown in FIG14 .

[0056] The present invention also provides a method for preparing the monoglycolate crystalline form A of the compound of formula I-1, comprising adding the compound of formula I-1 and glycolic acid to acetonitrile, and then recrystallizing or slurrying the monoglycolate. The ratio of the compound of formula I-1 to glycolic acid is selected from 0.8 to 1.2.

[0057] The present invention also provides a glycolate crystalline form B of the 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°.

[0058] In some embodiments of the present invention, the glycolate crystalline form B of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 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°. .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°.

[0059] In some embodiments of the present invention, the glycolate crystalline form B of the compound of formula I-1 has an XRPD pattern as shown in FIG15 .

[0060] Table 7 XRPD analysis data of the glycolate crystal form B of the compound of formula I-1

[0061] The present invention also provides a method for preparing the glycolate crystalline form B of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and glycolic acid to tetrahydrofuran or dichloromethane, and then recrystallizing or slurrying the mixture, wherein the ratio of the compound of formula I-1 to glycolic acid is selected from: 0.8 to 1.2.

[0062] The present invention also provides a mono L-malate crystalline form A of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 6.01±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°, and 30.53±0.2°.

[0063] In some embodiments of the present invention, the mono L-malate crystalline form A of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 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°.

[0064] In some embodiments of the present invention, the XRPD pattern of the mono-L-malate crystalline form A of the compound of formula I-1 is shown in FIG16 .

[0065] Table 8 XRPD analysis data of the mono-L-malate crystal form A of the compound of formula I-1

[0066] In some embodiments of the present invention, the mono L-malate crystalline form A of the compound of formula I-1 has a differential scanning calorimetry curve with an endothermic peak starting point at 204.74°C±2°C.

[0067] In some embodiments of the present invention, the DSC spectrum of the mono-L-malate crystalline form A of the compound of formula I-1 is shown in FIG17 .

[0068] In some embodiments of the present invention, the mono L-malate crystalline form A of the compound of formula I-1 has a thermogravimetric analysis curve with 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.

[0069] In some embodiments of the present invention, the TGA spectrum of the mono-L-malate crystalline form A of the compound of formula I-1 is shown in FIG18 .

[0070] The present invention also provides a method for preparing the mono L-malate crystalline form A of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and L-malic acid to acetonitrile, tetrahydrofuran, or dichloromethane, and then recrystallizing or slurrying the obtained compound. The ratio of the compound of formula I-1 to L-malic acid is selected from the range of 0.8 to 1.2.

[0071] The present invention also provides a monosuccinate crystalline form A of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 6.15±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°, and 25.17±0.2°.

[0072] In some embodiments of the present invention, the monosuccinate salt form A of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks 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°. .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°.

[0073] In some embodiments of the present invention, the XRPD pattern of the monosuccinate salt form A of the compound of formula I-1 is shown in FIG19 .

[0074] Table 9 XRPD analysis data of the monosuccinate salt of the compound of formula I-1, Form A

[0075] In some embodiments of the present invention, the monosuccinate salt form A of the compound of formula I-1 has a differential scanning calorimetry curve with endothermic peak starting points at 72.75°C±2°C, 146.41°C±2°C, and 175.72°C±2°C.

[0076] In some embodiments of the present invention, the DSC spectrum of the monosuccinate salt form A of the compound of formula I-1 is shown in FIG20 .

[0077] In some embodiments of the present invention, the monosuccinate crystalline form A of the compound of formula I-1 has a thermogravimetric analysis curve with three weight loss steps at 33.00℃±2℃, 90.00℃±2℃ and 160.00℃±2℃, and begins to decompose after 260.00℃±2℃.

[0078] In some embodiments of the present invention, the TGA spectrum of the monosuccinate salt form A of the compound of formula I-1 is shown in Figure 21.

[0079] The present invention also provides a method for preparing the monosuccinate salt form A of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and succinic acid to acetonitrile, tetrahydrofuran, or dichloromethane, and then recrystallizing or slurrying the obtained product, wherein the ratio of the compound of formula I-1 to succinic acid is selected from the range of 0.8 to 1.2.

[0080] The present invention also provides a sulfate crystalline form A of the compound of formula I-1, which has an X-ray powder diffraction pattern with 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°.

[0081] In some embodiments of the present invention, the sulfate crystalline form A of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 6.74±0.2°, 9.56±0.2°, 12.89±0.2°, 13.78±0.2°, 14.68±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°.

[0082] In some embodiments of the present invention, the XRPD pattern of the sulfate salt form A of the compound of formula I-1 is shown in Figure 22.

[0083] Table 10 XRPD analysis data of the sulfate salt of the compound of formula I-1, Form A

[0084] The present invention also provides a method for preparing the sulfate crystal form A of the compound of formula I-1, comprising adding the compound of formula I-1 and sulfuric acid to acetonitrile, and then recrystallizing or slurrying the sulfate crystal form A. The ratio of the compound of formula I-1 to sulfuric acid is selected from 0.8 to 1.2.

[0085] The present invention also provides a crystalline form A of the L-tartrate salt of the compound of formula I-1, which has an X-ray powder diffraction pattern having 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°.

[0086] In some embodiments of the present invention, the L-tartrate salt form A of the compound of formula I-1 has an X-ray powder diffraction pattern having 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°.

[0087] In some embodiments of the present invention, the XRPD pattern of the L-tartrate salt form A of the compound of formula I-1 is shown in Figure 23.

[0088] Table 11 XRPD analysis data of L-tartrate salt form A of the compound of formula I-1

[0089] The present invention also provides a method for preparing the L-tartrate salt form A of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and L-tartaric acid to acetonitrile, and recrystallizing or slurrying the mixture, wherein the ratio of the compound of formula I-1 to L-tartaric acid is selected from: 0.8 to 1.2.

[0090] The present invention also provides the hippurate crystalline form A of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 6.17±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°, and 26.45±0.2°.

[0091] In some embodiments of the present invention, the hippurate crystalline form A of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 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°. 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°.

[0092] In some embodiments of the present invention, the XRPD pattern of the hippurate salt form A of the compound of formula I-1 is shown in Figure 24.

[0093] Table 12 XRPD analysis data of hippurate salt form A of compound of formula I-1

[0094] The present invention also provides a method for preparing the hippurate crystalline form A of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and hippuric acid to tetrahydrofuran, and recrystallizing or slurrying the obtained compound, wherein the ratio of the compound of formula I-1 to hippuric acid is selected from: 0.8 to 1.2.

[0095] The present invention also provides the above-mentioned glutaric acid salt form A of the 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°, and 29.92±0.2°.

[0096] In some embodiments of the present invention, the glutaric acid salt form A of the compound of formula I-1 has an X-ray powder diffraction pattern with special diffraction peaks at the following 2θ angles: 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°.

[0097] In some embodiments of the present invention, the XRPD pattern of the glutaric acid salt form A of the compound of formula I-1 is shown in Figure 25.

[0098] Table 13 XRPD analysis data of the glutaric acid salt of the compound of formula I-1, Form A

[0099] The present invention also provides a method for preparing the above-mentioned glutaric acid salt form A of the compound of formula I-1, comprising adding the compound of formula I-1 and glutaric acid to acetonitrile and dichloromethane, and recrystallizing or slurrying the compound, wherein the ratio of the compound of formula I-1 to glutaric acid is selected from: 0.8 to 1.2.

[0100] The present invention also provides the p-toluenesulfonate crystalline form A of the compound of formula I-1, which has an X-ray powder diffraction pattern having 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°, and 35.22±0.2°.

[0101] In some embodiments of the present invention, the p-toluenesulfonate crystalline form A of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 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°. .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°.

[0102] In some embodiments of the present invention, the XRPD pattern of the p-toluenesulfonate crystalline form A of the compound of formula I-1 is shown in FIG26 .

[0103] Table 14 XRPD analysis data of p-toluenesulfonate salt of formula I-1 compound Form A

[0104] The present invention also provides a method for preparing the p-toluenesulfonate crystalline form A of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and p-toluenesulfonic acid to acetonitrile, and recrystallizing or slurrying the compound, wherein the ratio of the compound of formula I-1 to p-toluenesulfonic acid is selected from: 0.8 to 1.2.

[0105] The present invention also provides the p-toluenesulfonate crystalline form B of the compound of formula I-1, whose 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°, and 29.25±0.2°.

[0106] In some embodiments of the present invention, the p-toluenesulfonate salt form B of the above-mentioned formula I-1 compound has an X-ray powder diffraction pattern having 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°, and 29.25±0.2°.

[0107] In some embodiments of the present invention, the XRPD pattern of the p-toluenesulfonate crystalline form B of the compound of formula I-1 is shown in FIG27 .

[0108] Table 15 XRPD analysis data of p-toluenesulfonate salt of formula I-1 compound Form B

[0109] The present invention also provides a method for preparing the p-toluenesulfonate crystalline form B of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and p-toluenesulfonic acid to tetrahydrofuran, and recrystallizing or slurrying the obtained compound, wherein the ratio of the compound of formula I-1 to p-toluenesulfonic acid is selected from: 0.8 to 1.2.

[0110] The present invention also provides the above-mentioned mesylate crystalline form A of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 6.70±0.2°, 9.10±0.2°, 9.81±0.2°, 10.160.2°, 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°, and 27.18±0.2°.

[0111] In some embodiments of the present invention, the above-mentioned mesylate salt form A of the compound of formula I-1 has an X-ray powder diffraction pattern with 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°.

[0112] In some embodiments of the present invention, the XRPD pattern of the mesylate salt form A of the compound of formula I-1 is shown in FIG28 .

[0113] Table 16 XRPD analysis data of the mesylate salt of the compound of formula I-1, Form A

[0114] The present invention also provides a method for preparing the above-mentioned methanesulfonate crystal form A of the compound of formula I-1, comprising adding the compound of formula I-1 and methanesulfonic acid to tetrahydrofuran, and recrystallizing or slurrying the obtained compound, wherein the ratio of the compound of formula I-1 to methanesulfonic acid is selected from: 0.8 to 1.2.

[0115] The present invention also provides the hydrochloride form C1 of the 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°, 12.2500.2°, 13.1800.2°, 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°, and 27.51±0.2°.

[0116] In some embodiments of the present invention, the hydrochloride crystalline form C1 of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 7.47±0.2°, 7.73±0.2°, 9.63±0.2°, 11.4600.2°, 12.2500.2°, 13.1800.2°, 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°.

[0117] In some embodiments of the present invention, the XRPD pattern of the hydrochloride crystal form C1 of the compound of formula I-1 is shown in Figure 29.

[0118] Table 17 XRPD analysis data of the hydrochloride crystal form C1 of the compound of formula I-1

[0119] In some embodiments of the present invention, the hydrochloride crystal form C1 of the above-mentioned compound of formula I-1 has a differential scanning calorimetry curve with two starting points of endothermic peaks at 39.76℃±2℃ and 153.80℃±2℃, and the sample decomposes at 214.75℃±2℃.

[0120] In some embodiments of the present invention, the DSC spectrum of the hydrochloride crystal form C1 of the compound of formula I-1 is shown in Figure 30.

[0121] In some embodiments of the present invention, the hydrochloride crystal form C1 of the above-mentioned compound of formula I-1 has three weight loss steps at 26.03℃±2℃, 100.00℃±2℃, and 150.00℃±2℃ in its thermogravimetric analysis curve.

[0122] In some embodiments of the present invention, the hydrochloride crystal form C1 of the compound of formula I-1 has a TGA spectrum as shown in FIG31 .

[0123] The present invention also provides a method for preparing the hydrochloride crystal form C1 of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and hydrochloric acid to ethyl acetate, and recrystallizing or beating to obtain the compound, wherein the ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2, and the hydrochloride crystal form C1 of the compound of formula I-1 is an ethyl acetate solvent and a hydrate crystal form, the ethyl acetate content is 0.62 equivalents, and the water content is 3.0 equivalents.

[0124] The present invention also provides the hydrochloride 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°, and 30.74±0.2°.

[0125] In some embodiments of the present invention, the hydrochloride form C2 of the compound of formula I-1 has an X-ray powder diffraction pattern having 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°.

[0126] In some embodiments of the present invention, the XRPD pattern of the hydrochloride crystal form C2 of the compound of formula I-1 is shown in Figure 32.

[0127] Table 18 XRPD analysis data of the hydrochloride salt form C2 of the compound of formula I-1

[0128] In some embodiments of the present invention, the hydrochloride crystal form C2 of the above-mentioned formula I-1 compound has a differential scanning calorimetry curve with two starting points of endothermic peaks at 33.27℃±2℃ and 155.72℃±2℃, and the sample begins to decompose at 212.45℃±2℃.

[0129] In some embodiments of the present invention, the hydrochloride crystal form C2 of the compound of formula I-1 has a DSC spectrum as shown in FIG33 .

[0130] In some embodiments of the present invention, the hydrochloride crystal form C2 of the above-mentioned compound of formula I-1 has three weight loss steps at 28.19℃±2℃, 115.00℃±2℃, and 150.00℃±2℃ in its thermogravimetric analysis curve.

[0131] In some embodiments of the present invention, the hydrochloride crystal form C2 of the compound of formula I-1 has a TGA spectrum as shown in FIG34 .

[0132] The present invention also provides a method for preparing the hydrochloride crystal form C2 of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and hydrochloric acid to 2-methyltetrahydrofuran, and recrystallizing or beating to obtain the compound, wherein the ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2, the hydrochloride crystal form C2 of the compound of formula I-1 is a 2-methyltetrahydrofuran solvent and a hydrate crystal form, the 2-methyltetrahydrofuran content is 0.21 equivalents, and the water content is 2.8 equivalents.

[0133] The present invention also provides the hydrochloride form D of the 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°, and 21.80±0.2°.

[0134] In some embodiments of the present invention, the hydrochloride form D of the compound of formula I-1 has an X-ray powder diffraction pattern with special diffraction peaks at the following 2θ angles: 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°, 14.9 8±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°.

[0135] In some embodiments of the present invention, the XRPD pattern of the hydrochloride crystal form D of the compound of formula I-1 is shown in Figure 35.

[0136] Table 19 XRPD analysis data of the hydrochloride salt form D of the compound of formula I-1

[0137] In some embodiments of the present invention, the hydrochloride form D of the compound of formula I-1 has a differential scanning calorimetry curve with two endothermic peak starting points at 55.20℃±2℃ and 164.37℃±2℃, and the sample begins to decompose at 211.35℃±2℃.

[0138] In some embodiments of the present invention, the DSC spectrum of the hydrochloride crystal form D of the compound of formula I-1 is shown in Figure 36.

[0139] In some embodiments of the present invention, the hydrochloride crystal form D of the compound of formula I-1 has two weight loss steps at 36.24°C±2°C and 110.00°C±2°C in its thermogravimetric analysis curve.

[0140] In some embodiments of the present invention, the TGA spectrum of the hydrochloride crystal form D of the compound of formula I-1 is shown in Figure 37.

[0141] The present invention also provides a method for preparing the hydrochloride crystal form D of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and hydrochloric acid to butanone, and recrystallizing or beating to obtain the compound. The ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2, and the hydrochloride crystal form D of the compound of formula I-1 is an anhydrous crystal form.

[0142] The present invention also provides the hydrochloride crystalline 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°.

[0143] In some embodiments of the present invention, the hydrochloride form E1 of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 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°.

[0144] In some embodiments of the present invention, the XRPD pattern of the hydrochloride form E1 of the compound of formula I-1 is shown in Figure 38.

[0145] Table 20 XRPD analysis data of the hydrochloride salt form E1 of the compound of formula I-1

[0146] In some embodiments of the present invention, the hydrochloride form E1 of the compound of formula I-1 has a differential scanning calorimetry curve with two endothermic peak starting points at 13.36°C±2°C and 174.06°C±2°C, and the sample begins to decompose at 211.29°C±2°C.

[0147] In some embodiments of the present invention, the hydrochloride crystal form E1 of the compound of formula I-1 has a DSC spectrum as shown in FIG39 .

[0148] 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.

[0149] In some embodiments of the present invention, the hydrochloride crystal form E1 of the compound of formula I-1 has a TGA spectrum as shown in FIG40 .

[0150] The present invention also provides a method for preparing the hydrochloride crystal form E1 of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and hydrochloric acid to ethanol, and recrystallizing or beating to obtain the compound, wherein the ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2, and 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.

[0151] The present invention also provides the hydrochloride 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°, and 29.91±0.2°.

[0152] In some embodiments of the present invention, the hydrochloride form E2 of the compound of formula I-1 has an X-ray powder diffraction pattern having 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°.

[0153] In some embodiments of the present invention, the XRPD pattern of the hydrochloride crystal form E2 of the compound of formula I-1 is shown in Figure 41.

[0154] Table 21 XRPD analysis data of the hydrochloride salt form E2 of the compound of formula I-1

[0155] In some embodiments of the present invention, the hydrochloride form E2 of the above-mentioned compound of formula I-1 has a differential scanning calorimetry curve with two starting points of endothermic peaks at 14.99℃±2℃ and 174.19℃±2℃, and the sample begins to decompose at 213.17℃±2℃.

[0156] In some embodiments of the present invention, the hydrochloride crystal form E2 of the compound of formula I-1 has a DSC spectrum as shown in FIG42 .

[0157] In some embodiments of the present invention, the hydrochloride crystal form E2 of the above-mentioned compound of formula I-1 has three weight loss steps at 33.18℃±2℃, 90.00℃±2℃ and 140.00℃±2℃ in its thermogravimetric analysis curve.

[0158] In some embodiments of the present invention, the hydrochloride crystal form E2 of the compound of formula I-1 has a TGA spectrum as shown in FIG43 .

[0159] The present invention also provides a method for preparing the hydrochloride crystal form E2 of the above-mentioned compound of formula I-1, which is prepared by drying the hydrochloride crystal form F of the compound of formula I-1 under vacuum at 25°C, 50°C or 100°C, wherein the ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2, and the hydrochloride crystal form E2 of the compound of formula I-1 is a hydrate crystal form with a water content of 1.8 equivalents.

[0160] The present invention also provides the hydrochloride form F of the compound of formula 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°, and 33.59±0.2°.

[0161] In some embodiments of the present invention, the hydrochloride form F of the compound of formula I-1 has an X-ray powder diffraction pattern having 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°.

[0162] In some embodiments of the present invention, the XRPD pattern of the hydrochloride form F of the compound of formula I-1 is shown in Figure 44.

[0163] Table 22 XRPD analysis data of the hydrochloride salt form F of the compound of formula I-1

[0164] In some embodiments of the present invention, the hydrochloride form F of the compound of formula I-1 has a differential scanning calorimetry curve with two starting points of endothermic peaks at 36.03°C±2°C and 172.45°C±2°C, and the sample begins to decompose at 212.66°C±2°C.

[0165] In some embodiments of the present invention, the DSC spectrum of the hydrochloride form F of the compound of formula I-1 is shown in Figure 45.

[0166] In some embodiments of the present invention, the hydrochloride form F of the compound of formula I-1 has three weight loss steps at 33.35°C±2°C, 100.00°C±2°C and 150.00°C±2°C in its thermogravimetric analysis curve.

[0167] In some embodiments of the present invention, the TGA spectrum of the hydrochloride crystal form F of the compound of formula I-1 is shown in Figure 46.

[0168] The present invention also provides a method for preparing the hydrochloride crystal form F of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and hydrochloric acid to ethanol, acetone, ethyl acetate, acetonitrile, tetrahydrofuran or a methyl isobutyl ketone / trifluoroethanol mixed solvent, and recrystallizing or beating at 50°C to obtain the compound. 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.

[0169] The present invention also provides the hydrochloride form G of the compound of formula I-1, which has an X-ray powder diffraction pattern having 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°, and 30.18±0.2°.

[0170] In some embodiments of the present invention, the hydrochloride form G of the compound of formula I-1 has an X-ray powder diffraction pattern with special diffraction peaks at the following 2θ angles: 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°.

[0171] In some embodiments of the present invention, the XRPD pattern of the hydrochloride crystal form G of the compound of formula I-1 is shown in Figure 47.

[0172] Table 23 XRPD analysis data of the hydrochloride salt of the compound of formula I-1, Form G

[0173] In some embodiments of the present invention, the hydrochloride form G of the compound of formula I-1 has a differential scanning calorimetry curve with endothermic peak starting points at 59.42°C±2°C, 151.02°C±2°C and 166.01°C±2°C.

[0174] In some embodiments of the present invention, the DSC spectrum of the hydrochloride crystal form G of the compound of formula I-1 is shown in Figure 48.

[0175] In some embodiments of the present invention, the hydrochloride crystal form G of the above-mentioned compound of formula I-1 has three weight loss steps at 26.28℃±2℃, 120.00℃±2℃ and 150.00℃±2℃ in its thermogravimetric analysis curve.

[0176] In some embodiments of the present invention, the TGA spectrum of the hydrochloride crystal form G of the compound of formula I-1 is shown in Figure 49.

[0177] The present invention also provides a preparation method of the hydrochloride crystal form G of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and hydrochloric acid to water, suspending and recrystallizing or beating at 25°C, 50°C or raising or lowering the temperature to obtain the obtained compound, wherein the ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2, and 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.

[0178] The present invention also provides the hydrochloride crystalline form H of the compound of formula I-1, which has an X-ray powder diffraction pattern with 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°, 18.6 2±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°.

[0179] In some embodiments of the present invention, the hydrochloride form H of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks 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°.

[0180] In some embodiments of the present invention, the XRPD pattern of the hydrochloride crystal form H of the compound of formula I-1 is shown in Figure 50.

[0181] Table 24 XRPD analysis data of the hydrochloride salt form H of the compound of formula I-1

[0182] In some embodiments of the present invention, the hydrochloride form H of the above-mentioned compound of formula I-1 has a differential scanning calorimetry curve with two endothermic peak starting points at 51.49℃±2℃ and 153.61℃±2℃, and the sample begins to decompose at 211.73℃±2℃.

[0183] In some embodiments of the present invention, the DSC spectrum of the hydrochloride crystal form H of the compound of formula I-1 is shown in Figure 51.

[0184] In some embodiments of the present invention, the hydrochloride 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 its thermogravimetric analysis curve.

[0185] In some embodiments of the present invention, the hydrochloride crystal form H of the compound of formula I-1 has a TGA spectrum as shown in Figure 52.

[0186] The present invention also provides a method for preparing the hydrochloride form H of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and hydrochloric acid to a methanol / water mixed solvent and suspending and recrystallizing or beating at 25% or 50% of the solvent to obtain the obtained compound. The ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2. The hydrochloride form H of the compound of formula I-1 is a hydrated form and has a water content of 3.9 equivalents.

[0187] The present invention also provides the hydrochloride crystalline form I of the 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°.

[0188] In some embodiments of the present invention, the hydrochloride crystalline form I of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 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°.

[0189] In some embodiments of the present invention, the XRPD pattern of the hydrochloride form I of the compound of formula I-1 is shown in Figure 53.

[0190] Table 25 XRPD analysis data of the hydrochloride salt form I of the compound of formula I-1

[0191] In some embodiments of the present invention, the hydrochloride crystal form I of the compound of formula I-1 has two endothermic peak starting points at 18.15°C ± 2°C and 194.49°C ± 2°C, and the sample begins to decompose at 215.51°C ± 2°C.

[0192] In some embodiments of the present invention, the DSC spectrum of the hydrochloride crystal form I of the compound of formula I-1 is shown in Figure 54.

[0193] In some embodiments of the present invention, the hydrochloride form I of the compound of formula I-1 has three weight loss steps in its thermogravimetric analysis curve at 28.31°C±2°C, 70.00°C±2°C and 173.00°C±2°C.

[0194] In some embodiments of the present invention, the TGA spectrum of the hydrochloride crystal form I of the compound of formula I-1 is shown in Figure 55.

[0195] The present invention also provides a method for preparing the hydrochloride crystal form I of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and hydrochloric acid to methanol or a methanol / methyl tert-butyl ether mixed solvent, suspending and recrystallizing or beating at 25% tert-butyl, wherein the ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2, and the hydrochloride crystal form I of the compound of formula I-1 is an anhydrous crystal form.

[0196] The present invention also provides the hydrochloride form J1 of the compound of formula I-1, which has an X-ray powder diffraction pattern having 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°, and 30.16±0.2°.

[0197] In some embodiments of the present invention, the hydrochloride form J1 of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 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°. 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°.

[0198] In some embodiments of the present invention, the XRPD pattern of the hydrochloride crystal form J1 of the compound of formula I-1 is shown in Figure 56.

[0199] Table 26 XRPD analysis data of the hydrochloride salt form J1 of the compound of formula I-1

[0200] In some embodiments of the present invention, the hydrochloride form J1 of the compound of formula I-1 has a differential scanning calorimetry curve with two endothermic peak starting points at 70.82°C±2°C and 165.48°C±2°C, and the sample begins to decompose at 212.96°C±2°C.

[0201] In some embodiments of the present invention, the hydrochloride crystal form J1 of the compound of formula I-1 has a DSC spectrum as shown in FIG57 .

[0202] 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.

[0203] In some embodiments of the present invention, the hydrochloride crystal form J1 of the compound of formula I-1 has a TGA spectrum as shown in Figure 58.

[0204] The present invention also provides a method for preparing the hydrochloride form J1 of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and hydrochloric acid to 2-methyltetrahydrofuran, suspending at 50°C or heating and cooling to recrystallize or slurry to obtain the compound, wherein the ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2, and the hydrochloride form J1 of the compound of formula I-1 is a solvate of 2-methyltetrahydrofuran and water, the 2-methyltetrahydrofuran content is 0.75 equivalents, and the water content is 0.98 equivalents.

[0205] The present invention also provides the hydrochloride form J2 of the compound of formula I-1, which has an X-ray powder diffraction pattern having 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°, and 29.00±0.2°.

[0206] In some embodiments of the present invention, the hydrochloride form J2 of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 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°. 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°.

[0207] In some embodiments of the present invention, the XRPD pattern of the hydrochloride crystal form J2 of the compound of formula I-1 is shown in Figure 59.

[0208] Table 27 XRPD analysis data of the hydrochloride salt form J2 of the compound of formula I-1

[0209] In some embodiments of the present invention, the hydrochloride form J2 of the above-mentioned compound of formula I-1 has a differential scanning calorimetry curve with two endothermic peak starting points at 77.60℃±2℃ and 163.47℃±2℃, and the sample begins to decompose at 211.78℃±2℃.

[0210] In some embodiments of the present invention, the hydrochloride crystal form J2 of the compound of formula I-1 has a DSC spectrum as shown in Figure 60.

[0211] In some embodiments of the present invention, the hydrochloride crystal form J2 of the compound of formula I-1 has two weight loss steps at 28.73°C±2°C and 120.00°C±2°C in its thermogravimetric analysis curve.

[0212] In some embodiments of the present invention, the hydrochloride crystal form J2 of the compound of formula I-1 has a TGA spectrum as shown in Figure 61.

[0213] The present invention also provides a method for preparing the hydrochloride crystal form J2 of the above-mentioned compound of formula I-1, comprising heating the hydrochloride crystal form J1 of the compound of formula I-1 to 110°C to obtain the compound, wherein the ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2, and the hydrochloride crystal form J2 of the compound of formula I-1 is a solvate of 2-methyltetrahydrofuran and water, the 2-methyltetrahydrofuran content is 0.39 equivalents, and the water content is 0.94 equivalents.

[0214] The present invention also provides the hydrochloride form K of the compound of formula I-1, 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°, and 32.56±0.2°.

[0215] In some embodiments of the present invention, the hydrochloride form K of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks 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°.

[0216] In some embodiments of the present invention, the XRPD pattern of the hydrochloride form K of the compound of formula I-1 is shown in Figure 62.

[0217] Table 28 XRPD analysis data of the hydrochloride salt form K of the compound of formula I-1

[0218] In some embodiments of the present invention, the hydrochloride form K of the compound of formula I-1 has a differential scanning calorimetry curve with two endothermic peak starting points at 80.73°C±2°C and 171.74°C±2°C, and the sample begins to decompose at 211.42°C±2°C.

[0219] In some embodiments of the present invention, the DSC spectrum of the hydrochloride form K of the compound of formula I-1 is shown in Figure 63.

[0220] In some embodiments of the present invention, the hydrochloride 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 in its thermogravimetric analysis curve.

[0221] In some embodiments of the present invention, the TGA spectrum of the hydrochloride form K of the compound of formula I-1 is shown in Figure 64.

[0222] The present invention also provides a preparation method of the hydrochloride crystal form K of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and hydrochloric acid to methyl tert-butyl ether, suspending at 50°C or heating and cooling to recrystallize or slurry to obtain the obtained product, wherein the ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2, and the hydrochloride crystal form K of the compound of formula I-1 is a solvate of methyl tert-butyl ether and water, the methyl tert-butyl ether content is 0.5 equivalents, and the water content is 0.93 equivalents.

[0223] The present invention also provides the hydrochloride form L of the 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°, and 29.80±0.2°.

[0224] In some embodiments of the present invention, the hydrochloride form L of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 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°.

[0225] In some embodiments of the present invention, the XRPD pattern of the hydrochloride form L of the compound of formula I-1 is shown in Figure 65.

[0226] Table 29 XRPD analysis data of the hydrochloride salt form L of the compound of formula I-1

[0227] In some embodiments of the present invention, the hydrochloride form L of the compound of formula I-1 has a differential scanning calorimetry curve with an endothermic peak starting point at 180.17°C±2°C, and the sample begins to decompose at 212.43°C±2°C.

[0228] In some embodiments of the present invention, the DSC spectrum of the hydrochloride crystal form L of the above-mentioned compound of formula I-1 is shown in Figure 66.

[0229] In some embodiments of the present invention, the hydrochloride crystal form L of the compound of formula I-1 has two weight loss steps at 33.53°C±2°C and 140.00°C±2°C in its thermogravimetric analysis curve.

[0230] In some embodiments of the present invention, the TGA spectrum of the hydrochloride form L of the compound of formula I-1 is shown in Figure 67.

[0231] The present invention also provides a preparation method of the hydrochloride crystal form L of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and hydrochloric acid to toluene, suspending or heating and cooling to recrystallize or slurry at 25°C or 50°C, wherein 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 equivalents.

[0232] The present invention also provides the hydrochloride 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°, and 28.88±0.2°.

[0233] In some embodiments of the present invention, the hydrochloride form M of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks 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°.

[0234] In some embodiments of the present invention, the XRPD pattern of the hydrochloride form M of the compound of formula I-1 is shown in Figure 68.

[0235] Table 30 XRPD analysis data of the hydrochloride salt form M of the compound of formula I-1

[0236] In some embodiments of the present invention, the hydrochloride form M of the compound of formula I-1 has a differential scanning calorimetry curve with endothermic peak starting points at 31.74°C±2°C and 150.05°C±2°C, and the sample begins to decompose at 215.09°C±2°C.

[0237] In some embodiments of the present invention, the DSC spectrum of the hydrochloride form M of the compound of formula I-1 is shown in Figure 69.

[0238] In some embodiments of the present invention, the hydrochloride 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 its thermogravimetric analysis curve.

[0239] In some embodiments of the present invention, the hydrochloride crystal form M of the compound of formula I-1 has a TGA spectrum as shown in Figure 70.

[0240] The present invention also provides a method for preparing the hydrochloride crystal form M of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and hydrochloric acid to a mixed solvent of isopropyl alcohol / dimethyl sulfoxide, isopropyl acetate / dimethyl sulfoxide, and water / dimethyl sulfoxide, and suspending, recrystallizing, or slurrying at 25°C or 50°C to obtain the obtained product, wherein the ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2, and the hydrochloride crystal form M of the compound of formula I-1 is a solvate of dimethyl sulfoxide and water, wherein the dimethyl sulfoxide content is 3.4 equivalents and the water content is 13.7 equivalents.

[0241] The present invention also provides the hydrochloride form N of the 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°, and 28.42±0.2°.

[0242] In some embodiments of the present invention, the hydrochloride form N of the compound of formula I-1 has an X-ray powder diffraction pattern with special diffraction peaks at the following 2θ angles: 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°.

[0243] In some embodiments of the present invention, the XRPD spectrum of the hydrochloride form N of the compound of formula I-1 is shown in Figure 71.

[0244] Table 31 XRPD analysis data of the hydrochloride salt form N of the compound of formula I-1

[0245] In some embodiments of the present invention, the hydrochloride form N of the compound of formula I-1 has a differential scanning calorimetry curve with endothermic peak starting points at 47.38°C±2°C and 167.91°C±2°C, and the sample begins to decompose at 212.57°C±2°C.

[0246] In some embodiments of the present invention, the DSC spectrum of the hydrochloride crystal form N of the above-mentioned compound of formula I-1 is shown in Figure 72.

[0247] In some embodiments of the present invention, the hydrochloride form N of the compound of formula I-1 has three weight loss steps at 33.22°C±2°C, 75.00°C±2°C and 150.00°C±2°C in its thermogravimetric analysis curve.

[0248] In some embodiments of the present invention, the TGA spectrum of the hydrochloride form N of the compound of formula I-1 is shown in Figure 73.

[0249] The present invention also provides a method for preparing the hydrochloride form N of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and hydrochloric acid to methanol, and preparing the salt by suspension recrystallization or slurrying at 25°, wherein the ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2, the hydrochloride form N of the compound of formula I-1 is a hydrate form, and the water content is 3.0 equivalents.

[0250] The present invention also provides the hydrochloride form O of the compound of formula I-1, which has an X-ray powder diffraction pattern having 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°, and 27.93±0.2°.

[0251] In some embodiments of the present invention, the hydrochloride form O of the compound of formula I-1 has an X-ray powder diffraction pattern having special 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°.

[0252] In some embodiments of the present invention, the hydrochloride crystal form O of the compound of formula I-1 has an XRPD pattern as shown in Figure 74.

[0253] Table 32 XRPD analysis data of the hydrochloride salt form O of the compound of formula I-1

[0254] In some embodiments of the present invention, the hydrochloride form O of the compound of formula I-1 has a differential scanning calorimetry curve with endothermic peak starting points at 12.36°C±2°C and 174.87°C±2°C, and the sample begins to decompose at 212.00°C±2°C.

[0255] In some embodiments of the present invention, the hydrochloride crystal form O of the above-mentioned compound of formula I-1 has a DSC spectrum as shown in Figure 75.

[0256] In some embodiments of the present invention, the hydrochloride crystal form O of the compound of formula I-1 has three weight loss steps at 27.70℃±2℃, 115.00℃±2℃ and 160.00℃±2℃ in its thermogravimetric analysis curve.

[0257] In some embodiments of the present invention, the hydrochloride crystal form O of the compound of formula I-1 has a TGA spectrum as shown in Figure 76.

[0258] The present invention also provides a preparation method of the hydrochloride crystal form O of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and hydrochloric acid to dichloromethane, and suspending the salt for recrystallization or slurrying at 25°, wherein the ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2, and the hydrochloride crystal form O of the compound of formula I-1 is a hydrate crystal form, and the water content is 0.9 equivalents.

[0259] Another aspect of the present invention provides a method for preparing a crystalline form of a pharmaceutically acceptable salt of the compound of formula (I), characterized in that it comprises the following steps:

[0260] a. The compound of formula (I) and the acid are dissolved or dispersed in a 1 to 20-fold volume of solvent A in a molar ratio of 1: (0.8-3);

[0261] b. Suspension, recrystallization or slurrying;

[0262] 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);

[0263] The solvent A is selected from the group consisting of acetonitrile, dichloromethane, tetrahydrofuran, or a combination thereof;

[0264] 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.

[0265] In another preferred embodiment, the solvent A is selected from the following group: methyl isobutyl ketone / trifluoroethanol, methanol / water, methanol / methyl tert-butyl ether, isopropyl alcohol / dimethyl sulfoxide, isopropyl acetate / dimethyl sulfoxide, and water / dimethyl sulfoxide.

[0266] In another preferred embodiment, the suspending comprises the following steps:

[0267] a. Suspending the compound of formula (I), the acid and the solvent at 45 to 65 ° C for 1 to 3 hours;

[0268] b. Cool naturally to 20-30°C and continue to suspend for at least 48 hours;

[0269] c. The resulting suspension was centrifuged through a 0.4-0.5 μm filter at 12,000-16,000 rpm;

[0270] d. The obtained solid was dried under vacuum at 45-65°C.

[0271] Another aspect of the present invention provides a method for obtaining a crystalline form of a pharmaceutically acceptable salt of the compound of formula (I), characterized in that the method is a method of converting one crystalline form of the pharmaceutically acceptable salt of the compound of formula (I) into another crystalline form of the salt by a crystalline form conversion method;

[0272] Wherein, the method for crystal form conversion comprises the following steps:

[0273] 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;

[0274] b. Suspension;

[0275] c. The resulting suspension was centrifuged through a 0.4-0.5 μm filter membrane at 12,000-16,000 rpm;

[0276] 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.

[0277] In another preferred embodiment, the solvent A is selected from the group consisting of methyl isobutyl ketone / trifluoroethanol, methanol / water, isopropyl alcohol / dimethyl sulfoxide, isopropyl acetate / dimethyl sulfoxide, and dimethyl sulfoxide / water.

[0278] In another preferred embodiment, the suspending comprises the steps of: stirring at a speed of 300-400 rpm at 20-30°C.

[0279] In another preferred embodiment, the suspending comprises the steps of: stirring at 40-60°C and a speed of 300-400 rpm.

[0280] In another preferred embodiment, the suspension comprises the steps of performing 8 to 12 temperature rise and fall cycles between 5 and 50°C at a rate of 0.05 to 0.2°C / min while stirring at a rate of 300-400 rpm, and the final temperature of the suspension is 10 to 15°C.

[0281] In another preferred embodiment, the suspending comprises the steps of: filtering through 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.

[0282] Another aspect of the present invention provides a pharmaceutical composition comprising the compound of formula (I), the crystalline form A, or a crystalline form of the compound of formula (I);

[0283] and

[0284] One or more pharmaceutically acceptable carriers, excipients, adjuvants, excipients and / or diluents.

[0285] In another preferred embodiment, the pharmaceutical composition further comprises other therapeutic agents.

[0286] 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, and diethylstilbestrol.

[0287] 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, and B-Raf inhibitors. 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-HER2 antibody, anti-VEGFR antibody, anti-EGFR antibody, anti-c-MET antibody, and anti-CD20 antibody.

[0288] 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.

[0289] Another aspect of the present invention provides the use of the compound of formula (I), the crystalline form A, the crystalline form of the compound of formula (I), and the pharmaceutical composition in the preparation of a drug for preventing and / or treating diseases related to increased activity or expression of FGFR2.

[0290] 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.

[0291] In another preferred embodiment, the disease associated with increased FGFR2 activity or expression is selected from the group consisting of 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.

[0292] In another preferred embodiment, the bile duct cancer is intrahepatic bile duct cancer.

[0293] In another preferred embodiment, the liver cancer is hepatocellular carcinoma.

[0294] In another preferred embodiment, the lung cancer is squamous cell lung carcinoma or non-small cell lung cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0295] FIG1 is an XRPD pattern of Compound I-1 Form A.

[0296] Figure 2 is the DSC spectrum of Compound I-1 Form A.

[0297] Figure 3 is the TGA spectrum of Compound I-1 Form A.

[0298] FIG4 is an XRPD pattern of Compound I-1 maleate salt Form A.

[0299] FIG5 is an XRPD pattern of Compound I-1 monomaleate salt Form B.

[0300] FIG6 is a DSC spectrum of Compound I-1 monomaleate crystal form B.

[0301] FIG7 is a TGA spectrum of Compound I-1 monomaleate salt Form B.

[0302] FIG8 is an XRPD pattern of Compound I-1 fumarate salt Form A.

[0303] FIG9 is an XRPD pattern of Compound I-1 hemifumarate Form B.

[0304] FIG10 is a DSC spectrum of Compound I-1 hemifumarate Form B.

[0305] FIG11 is a TGA spectrum of Compound I-1 hemifumarate Form B.

[0306] FIG12 is an XRPD pattern of Compound I-1 monoglycolate Form A.

[0307] FIG13 is a DSC spectrum of Compound I-1 monoglycolate Form A.

[0308] FIG14 is a TGA spectrum of Compound I-1 monoglycolate Form A.

[0309] FIG15 is an XRPD pattern of Compound I-1 glycolate Form B.

[0310] FIG16 is an XRPD pattern of Compound I-1 mono-L-malate Form A.

[0311] FIG17 is a DSC spectrum of Compound I-1 mono-L-malate Form A.

[0312] FIG18 is a TGA spectrum of Compound I-1 mono-L-malate Form A.

[0313] FIG19 is an XRPD pattern of Compound I-1 monosuccinate Form A.

[0314] FIG20 is a DSC spectrum of Compound I-1 monosuccinate Form A.

[0315] Figure 21 is the TGA spectrum of Compound I-1 monosuccinate Form A.

[0316] FIG22 is an XRPD pattern of Compound I-1 sulfate salt Form A.

[0317] FIG23 is an XRPD pattern of Compound I-1 L-tartrate Form A.

[0318] FIG24 is an XRPD pattern of Compound I-1 hippurate salt Form A.

[0319] FIG25 is an XRPD pattern of Compound I-1 glutarate salt Form A.

[0320] FIG26 is an XRPD pattern of Compound I-1 p-toluenesulfonate Form A.

[0321] FIG27 is an XRPD pattern of Compound I-1 p-toluenesulfonate Form B.

[0322] FIG28 is an XRPD pattern of Compound I-1 mesylate salt Form A.

[0323] FIG29 is an XRPD pattern of Compound I-1 hydrochloride Form C1.

[0324] FIG30 is a DSC spectrum of Compound I-1 hydrochloride salt form C1.

[0325] FIG31 is a TGA spectrum of Compound I-1 hydrochloride salt form C1.

[0326] Figure 32 is the XRPD pattern of Compound I-1 hydrochloride Form C2.

[0327] FIG33 is a DSC spectrum of Compound I-1 hydrochloride salt form C2.

[0328] Figure 34 is the TGA spectrum of Compound I-1 hydrochloride form C2.

[0329] FIG35 is an XRPD pattern of Compound I-1 hydrochloride Form D.

[0330] FIG36 is a DSC spectrum of Compound I-1 hydrochloride Form D.

[0331] FIG37 is a TGA spectrum of Compound I-1 hydrochloride Form D.

[0332] FIG38 is an XRPD pattern of Compound I-1 hydrochloride Form E1.

[0333] FIG39 is a DSC spectrum of Compound I-1 hydrochloride Form E1.

[0334] FIG40 is a TGA spectrum of Compound I-1 hydrochloride form E1.

[0335] Figure 41 is the XRPD pattern of Compound I-1 hydrochloride Form E2.

[0336] FIG42 is a DSC spectrum of Compound I-1 hydrochloride Form E2.

[0337] Figure 43 is the TGA spectrum of Compound I-1 hydrochloride form E2.

[0338] Figure 44 is the XRPD pattern of Compound I-1 hydrochloride Form F.

[0339] Figure 45 is the DSC spectrum of Compound I-1 hydrochloride Form F.

[0340] Figure 46 is the TGA spectrum of Compound I-1 hydrochloride Form F.

[0341] Figure 47 is the XRPD pattern of Compound I-1 hydrochloride Form G.

[0342] FIG48 is a DSC spectrum of Compound I-1 hydrochloride Form G.

[0343] Figure 49 is the TGA spectrum of Compound I-1 hydrochloride Form G.

[0344] Figure 50 is the XRPD pattern of Compound I-1 hydrochloride Form H.

[0345] Figure 51 is the DSC spectrum of Compound I-1 hydrochloride Form H.

[0346] Figure 52 is the TGA spectrum of Compound I-1 hydrochloride Form H.

[0347] Figure 53 is the XRPD pattern of Compound I-1 hydrochloride Form I.

[0348] Figure 54 is the DSC spectrum of Compound I-1 hydrochloride Form I.

[0349] Figure 55 is the TGA spectrum of Compound I-1 hydrochloride Form I.

[0350] Figure 56 is the XRPD pattern of Compound I-1 hydrochloride Form J1.

[0351] Figure 57 is the DSC spectrum of Compound I-1 hydrochloride Form J1.

[0352] Figure 58 is the TGA spectrum of Compound I-1 hydrochloride Form J1.

[0353] Figure 59 is the XRPD pattern of Compound I-1 hydrochloride Form J2.

[0354] Figure 60 is the DSC spectrum of Compound I-1 hydrochloride Form J2.

[0355] Figure 61 is the TGA spectrum of Compound I-1 hydrochloride Form J2.

[0356] Figure 62 is the XRPD pattern of Compound I-1 hydrochloride Form K.

[0357] Figure 63 is the DSC spectrum of Compound I-1 hydrochloride Form K.

[0358] Figure 64 is the TGA spectrum of Compound I-1 hydrochloride Form K.

[0359] Figure 65 is the XRPD pattern of Compound I-1 hydrochloride Form L.

[0360] Figure 66 is the DSC spectrum of Compound I-1 hydrochloride Form L.

[0361] Figure 67 is the TGA spectrum of Compound I-1 hydrochloride Form L.

[0362] Figure 68 is the XRPD pattern of Compound I-1 hydrochloride Form M.

[0363] Figure 69 is the DSC spectrum of Compound I-1 hydrochloride Form M.

[0364] Figure 70 is the TGA spectrum of Compound I-1 hydrochloride Form M.

[0365] Figure 71 is the XRPD pattern of Compound I-1 hydrochloride Form N.

[0366] Figure 72 is the DSC spectrum of Compound I-1 hydrochloride Form N.

[0367] Figure 73 is the TGA spectrum of Compound I-1 hydrochloride Form N.

[0368] Figure 74 is the XRPD pattern of Compound I-1 hydrochloride Form O.

[0369] Figure 75 is the DSC spectrum of Compound I-1 hydrochloride Form O.

[0370] Figure 76 is the TGA spectrum of Compound I-1 hydrochloride Form O. DETAILED DESCRIPTION

[0371] To address the problems of the prior art, the inventors conducted in-depth research on the different forms of the compound of formula (I) and developed multiple crystal forms and acid salt forms of the compound of formula (I), particularly the hydrochloride salt. These crystal forms significantly improve the physicochemical properties of the compound of formula (I), including solubility, hygroscopicity, and chemical stability. The raw materials for the crystalline acid salt compound meet industrial production requirements and can meet the needs of clinical pharmaceutical formulation development. They possess significant clinical application value and are expected to accelerate the development of a new generation of FGFR2 inhibitors. Based on this, the present invention was completed.

[0372] definition

[0373] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term should not be construed as ambiguous or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears herein, it is intended to refer to the corresponding commercial product or its active ingredient.

[0374] As used herein, the term "n or more 2θ values ​​selected from the following group" refers to any positive integer including n and greater than n (e.g., n, n+1, ...), wherein the upper limit Nup is the number of all 2θ peaks in the group. For example, "1 or more" includes not only 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, ..., each positive integer of the upper limit Nup, but also includes "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", etc. For example, "3 or more" not only includes 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, ... the upper limit Nup, each positive integer, but also includes "4 or more", "5 or more", "6 or more", "7 or more", "8 or more", "9 or more", "10 or more" and other ranges.

[0375] 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, wherein the solvent includes but is not limited to acetonitrile, an alcohol solvent, an ester solvent, an ether solvent, or a mixed solvent of an alcohol solvent and water.

[0376] The intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0377] The chemical reactions of the present invention are carried out in suitable solvents that are compatible with the chemical transformations of the present invention and the reagents and materials required. To obtain the compounds of the present invention, it may sometimes be necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0378] The present invention will be described in detail below through examples, which are not intended to limit the present invention in any way.

[0379] All solvents used in the present invention were commercially available and used without further purification.

[0380] Common abbreviations used in the present invention are as follows:

[0381] The test items and methods used in the present invention are as follows:

[0382] In order to better understand the content of the present invention, further description is given below in conjunction with specific embodiments, but the specific implementation methods are not intended to limit the content of the present invention.

[0383] Example 1: Preparation of the compound of formula (I-1)

[0384] first step:

[0385] Compound a (5.0 g, 26.3 mmol) and triethylamine (8.0 g, 11 ml) were dissolved in DCM (50 ml). 2-Methacryloyl chloride (3.03 g, 2.8 ml) was added dropwise to the reaction mixture at 0°C and stirred for 1 hour. The reaction mixture 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 resulting crude product was purified by silica gel column chromatography (EA / PE = 1 / 4) to afford compound b (4.9 g, 72%) as a pale yellowish-white solid.

[0386] MS (ESI) m / z 258,260 [M+H] + .

[0387] Step 2:

[0388] 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 the atmosphere was replaced 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 crude product was purified by silica gel column chromatography (EA / PE = 1 / 8 to 1 / 4) to afford compound c (1.52 g, 64%) as a yellow solid.

[0389] MS (ESI) m / z 306 [M+H] + .

[0390] 1 H NMR (500MHz, CDCl3) δ7.70-7.65(m,2H),7.53(dd,J=11.5,1.9Hz,1H),7.20(dd,J =8.2,1.9Hz,1H),5.78(s,1H),5.48(d,J=1.7Hz,1H),2.04(s,3H),1.34(s,12H).

[0391] Step 3:

[0392] Compound d (2.00 g, 19.6 mmol) and ammonium carbamate (2.29 g, 29.4 mmol) were added to a flask in sequence, followed by MeOH (40 mL) and diethyl iodophenyl (13.24 g, 41.1 mmol). The reaction solution was stirred open 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) as a white solid.

[0393] MS (ESI) m / z 120 [M+H] + .

[0394] Step 4:

[0395] 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 for 13 h. The reaction mixture was filtered through celite, and the filter cake was washed with ethyl acetate (50 mL) and saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE / EtOAc = 4 / 1 to 1 / 1) to obtain compound f (410 mg) as a yellow oil.

[0396] MS (ESI) m / z 274 [M+H] + .

[0397] Step 5:

[0398] To a 100 mL round-bottom flask were added compound f (1.02 g, 3.10 mmol), bis(pinacol) borate (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) in sequence. The temperature was raised to 100°C and the reaction was allowed to react for 4 h. After monitoring the reaction completion, the mixture was cooled to room temperature, filtered through celite, and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (PE / EtOAc = 1 / 1) to give compound g (0.80 g) as a yellow solid.

[0399] 1 H NMR (400MHz, CDCl3) δ7.62(d,J=8.3Hz,2H),6.98(d,J=8.3Hz,2H),3.37–3.30(m,1H),3.15–3.08(m,1H),2.20(dd,J=29.3,6.9Hz,2H),1.26(s,6H).

[0400] Step 6:

[0401] Compound h (10.6 g 0.0466 mol) was dissolved in dichloromethane (100 mL) and trifluoroacetic acid (26.7 g 0.2334 mol), stirred at 10°C, and N-iodosuccinimide (10.5 g 0.0466 mol) was added in batches. The reaction was allowed to proceed for 4 h. After the reaction was completed, 150 mL of saturated aqueous sodium bicarbonate solution was slowly added dropwise at 10°C. A solid precipitated and was filtered and dried to obtain compound i (13.4 g) as a purple solid.

[0402] 1 H NMR (400MHz, CDCl3) δ8.22(s,1H),5.61(s,2H),3.80(s,3H).

[0403] Step 7:

[0404] 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) were added to a reaction flask, the atmosphere was purged with nitrogen three times, and DMF (35 mL) and water (5 mL) were added. The mixture was stirred at 50°C for 16 h. After completion of the reaction, water (150 mL) and dichloromethane (200 mL) were added, and the mixture was extracted. The organic phase was washed with saturated brine and concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain compound j (1.1 g) as a light yellow solid.

[0405] ESI-MS m / z 404.2[M+H] +

[0406] 1H NMR(400MHz, CDCl3)δ8.35(s,1H),7.82(dd,J=11.7,2.1Hz,1H),7.69(s,1H),7.44–7.33(m,2H),5 .87(s,1H),5.66(s,2H),5.58(q,J=1.5Hz,1H),3.66(d,J=1.1Hz,3H),2.12(dd,J=1.6,0.9Hz,3H).

[0407] Step 8:

[0408] To a 25 mL round-bottom flask were 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 for 0.5 h. After monitoring the reaction completion, the mixture was cooled to room temperature, filtered through celite, and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (DCM / MeOH = 6 / 1) to give the compound of formula I-1 (22 mg) as a white solid.

[0409] MS (ESI) m / z 519.4 [M+H] +

[0410] 1 H NMR(400MHz, CDCl3)δ8.28(s,1H),7.65–7.61(m,1H),7.48(s,1H),7.05(d,J =7.7Hz,2H),7.00(t,J=4.1Hz,2H),6.91(d,J=8.5Hz,2H),5.73(s,1H),5.45( d,J=1.3Hz,1H),4.98(s,2H),3.59(d,J=0.9Hz,3H),3.36(dd,J=12.6,6.0Hz, 2H), 3.13 (dd, J=12.8, 6.6Hz, 2H), 2.29–2.19 (m, 3H), 1.99 (d, J=10.1Hz, 3H).

[0411] Example 2: Preparation of Form A of the Compound of Formula I-1

[0412] The above-mentioned 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 Form A of the compound of formula I-1 (58.2 g) as a white solid.

[0413] Example 3: Preparation of Maleate Crystal Form A of the Compound of Formula I-1

[0414] 3.1: Approximately 20 mg of the compound of Formula I-1 and 1.0 equivalent of maleic acid were weighed into a 2 mL glass vial and placed in 0.15 mL of acetonitrile for suspension screening. The resulting sample was suspended at 50°C for 2 hours, then naturally cooled to 25°C and suspended at 25°C for at least 48 hours. The resulting suspension was centrifuged through a 0.45 μm nylon filter at 14,000 rpm. The resulting solid was vacuum dried at 50°C for 2 hours to obtain a sample of the maleate salt of the compound of Formula I-1, Form A.

[0415] 3.2: Approximately 20 mg of the compound of Formula I-1 and 1.0 equivalent of the counterion were weighed into a 2 mL glass vial and placed in 0.15 mL of dichloromethane for suspension screening. The resulting sample was suspended at 50°C for 2 hours, then naturally cooled to 25°C and suspended at 25°C for at least 48 hours. The resulting suspension was centrifuged through a 0.45 μm nylon filter at 14,000 rpm. The resulting solid was vacuum dried at 50°C for 2 hours to obtain a sample of the maleate salt of the compound of Formula I-1, Form A.

[0416] Example 4: Preparation of Monomaleate Crystal Form B of the Compound of Formula I-1

[0417] Approximately 20 mg of the compound of Formula I-1 and 1.0 equivalent of maleic acid were weighed into a 2 mL glass vial and placed in 0.15 mL of tetrahydrofuran for suspension screening. The resulting sample was suspended at 50°C for 2 hours, then naturally cooled to 25°C and suspended at 25°C for at least 48 hours. The resulting suspension was centrifuged through a 0.45 μm nylon filter at 14,000 rpm. The resulting solid was vacuum dried at 50°C for 2 hours to obtain a monomaleate salt, Form B, of the compound of Formula I-1.

[0418] Example 5: Preparation of Fumarate Form A of the Compound of Formula I-1

[0419] 5.1: Approximately 20 mg of the compound of Formula I-1 and 1.0 equivalent of fumaric acid were weighed into a 2 mL glass vial and placed in 0.15 mL of acetonitrile for suspension screening. The resulting sample was suspended at 50°C for 2 hours, then naturally cooled to 25°C and suspended at 25°C for at least 48 hours. The resulting suspension was centrifuged through a 0.45 μm nylon filter at 14,000 rpm. The resulting solid was vacuum dried at 50°C for 2 hours to obtain a sample of the fumarate salt, Form A, of the compound of Formula I-1.

[0420] 5.2: Approximately 20 mg of the compound of Formula I-1 and 1.0 equivalent of fumaric acid were weighed into a 2 mL glass vial and placed in 0.15 mL of dichloromethane for suspension screening. The resulting sample was suspended at 50°C for 2 hours, then naturally cooled to 25°C and suspended at 25°C for at least 48 hours. The resulting suspension was centrifuged through a 0.45 μm nylon filter at 14,000 rpm. The resulting solid was vacuum dried at 50°C for 2 hours to obtain a sample of the fumarate salt, Form A, of the compound of Formula I-1.

[0421] Example 6: Preparation of Hemifumarate Form B of the Compound of Formula I-1

[0422] Approximately 20 mg of the compound of Formula I-1 and 1.0 equivalent of fumaric acid were weighed into a 2 mL glass vial and placed in 0.15 mL of tetrahydrofuran for suspension screening. The resulting sample was suspended at 50°C for 2 hours, then naturally cooled to 25°C and suspended at 25°C for at least 48 hours. The resulting suspension was centrifuged at 14,000 rpm through a 0.45 μm nylon filter. The resulting solid was vacuum dried at 50°C for 2 hours to obtain a sample of the hemi-fumarate crystalline Form B of the compound of Formula I-1.

[0423] Example 7: Preparation of Form A of the Monoglycolate Salt of the Compound of Formula I-1

[0424] Approximately 20 mg of the compound of Formula I-1 and 1.0 equivalent of glycolic acid were weighed into a 2 mL glass vial and placed in 0.15 mL of acetonitrile for suspension screening. The resulting sample was suspended at 50°C for 2 hours, then naturally cooled to 25°C and suspended at 25°C for at least 48 hours. The resulting suspension was centrifuged at 14,000 rpm through a 0.45 μm nylon filter. The resulting solid was vacuum dried at 50°C for 2 hours to obtain a sample of Form A, the monoglycolic acid salt of the compound of Formula I-1.

[0425] Example 8: Preparation of Glycolate Form B of the Compound of Formula I-1

[0426] 8.1: Approximately 20 mg of the compound of Formula I-1 and 1.0 equivalent of glycolic acid were weighed into a 2 mL glass vial and placed in 0.15 mL of tetrahydrofuran for suspension screening. The resulting sample was suspended at 50°C for 2 hours, then naturally cooled to 25°C and suspended at 25°C for at least 48 hours. The resulting suspension was centrifuged through a 0.45 μm nylon filter at 14,000 rpm. The resulting solid was vacuum dried at 50°C for 2 hours to obtain a sample of Form B of the glycolate salt of the compound of Formula I-1.

[0427] 8.2: Approximately 20 mg of the compound of Formula I-1 and 1.0 equivalent of glycolic acid were weighed into a 2 mL glass vial and placed in 0.15 mL of dichloromethane for suspension screening. The resulting sample was suspended at 50°C for 2 hours, then naturally cooled to 25°C and suspended at 25°C for at least 48 hours. The resulting suspension was centrifuged through a 0.45 μm nylon filter at 14,000 rpm. The resulting solid was vacuum dried at 50°C for 2 hours to obtain a sample of Form B of the glycolate salt of the compound of Formula I-1.

[0428] Example 9: Preparation of Mono L-Malate Form A of the Compound of Formula I-1

[0429] 9.1: Approximately 20 mg of the compound of Formula I-1 and 1.0 equivalent of L-malic acid were weighed into a 2 mL glass vial and placed in 0.15 mL of tetrahydrofuran for suspension screening. The resulting sample was suspended at 50°C for 2 hours, then naturally cooled to 25°C and suspended at 25°C for at least 48 hours. The resulting suspension was centrifuged through a 0.45 μm nylon filter at 14,000 rpm. The resulting solid was vacuum dried at 50°C for 2 hours to obtain a sample of the mono-L-malate salt, Form A, of the compound of Formula I-1.

[0430] 9.2: Approximately 20 mg of the compound of Formula I-1 and 1.0 equivalent of glycolic acid were weighed into a 2 mL glass vial and placed in 0.15 mL of dichloromethane for suspension screening. The resulting sample was suspended at 50°C for 2 hours, then naturally cooled to 25°C and suspended at 25°C for at least 48 hours. The resulting suspension was centrifuged through a 0.45 μm nylon filter at 14,000 rpm. The resulting solid was vacuum dried at 50°C for 2 hours to obtain a sample of the mono-L-malate salt, Form A, of the compound of Formula I-1.

[0431] 9.3: Approximately 20 mg of the compound of Formula I-1 and 1.0 equivalent of glycolic acid were weighed into a 2 mL glass vial and placed in 0.15 mL of acetonitrile for suspension screening. The resulting sample was suspended at 50°C for 2 hours, then naturally cooled to 25°C and suspended at 25°C for at least 48 hours. The resulting suspension was centrifuged through a 0.45 μm nylon filter at 14,000 rpm. The resulting solid was vacuum dried at 50°C for 2 hours to obtain a sample of the mono-L-malate salt, Form A, of the compound of Formula I-1.

[0432] Example 10: Preparation of Monosuccinate Form A of the Compound of Formula I-1

[0433] 10.1: Approximately 20 mg of the compound of Formula I-1 and 1.0 equivalent of succinic acid were weighed into a 2 mL glass vial and placed in 0.15 mL of acetonitrile for suspension screening. The resulting sample was suspended at 50°C for 2 hours, then naturally cooled to 25°C and suspended at 25°C for at least 48 hours. The resulting suspension was centrifuged through a 0.45 μm nylon filter at 14,000 rpm. The resulting solid was vacuum dried at 50°C for 2 hours to obtain a sample of the monosuccinate salt, Form A, of the compound of Formula I-1.

[0434] 10.2: Approximately 20 mg of the compound of Formula I-1 and 1.0 equivalent of succinic acid were weighed into a 2 mL glass vial and placed in 0.15 mL of dichloromethane for suspension screening. The resulting sample was suspended at 50°C for 2 hours, then naturally cooled to 25°C and suspended at 25°C for at least 48 hours. The resulting suspension was centrifuged through a 0.45 μm nylon filter at 14,000 rpm. The resulting solid was vacuum dried at 50°C for 2 hours to obtain a sample of the monosuccinate salt, Form A, of the compound of Formula I-1.

[0435] Example 11: Preparation of Sulfate Crystalline Form A of the Compound of Formula I-1

[0436] Approximately 20 mg of the compound of Formula I-1 and 1.0 equivalent of sulfuric acid were weighed into a 2 mL glass vial and placed in 0.15 mL of acetonitrile for suspension screening. The resulting sample was suspended at 50°C for 2 hours, then naturally cooled to 25°C and suspended at 25°C for at least 48 hours. The resulting suspension was centrifuged through a 0.45 μm nylon filter at 14,000 rpm. The resulting solid was vacuum dried at 50°C for 2 hours to obtain a sample of the sulfate salt of the compound of Formula I-1, Form A.

[0437] Example 12: Preparation of L-tartrate Form A of the Compound of Formula I-1

[0438] Approximately 20 mg of the compound of Formula I-1 and 1.0 equivalent of L-tartaric acid were weighed into a 2 mL glass vial and placed in 0.15 mL of acetonitrile for suspension screening. The resulting sample was suspended at 50°C for 2 hours, then naturally cooled to 25°C and suspended at 25°C for at least 48 hours. The resulting suspension was centrifuged through a 0.45 μm nylon filter at 14,000 rpm. The resulting solid was vacuum dried at 50°C for 2 hours to obtain a sample of the L-tartrate salt, Form A, of the compound of Formula I-1.

[0439] Example 13: Preparation of Form A of the Hippurate Salt of the Compound of Formula I-1

[0440] Approximately 20 mg of the compound of Formula I-1 and 1.0 equivalent of hippuric acid were weighed into a 2 mL glass vial and placed in 0.15 mL of tetrahydrofuran for suspension screening. The resulting sample was suspended at 50°C for 2 hours, then naturally cooled to 25°C and suspended at 25°C for at least 48 hours. The resulting suspension was centrifuged at 14,000 rpm through a 0.45 μm nylon filter. The resulting solid was vacuum dried at 50°C for 2 hours to obtain a hippurate salt Form A sample of the compound of Formula I-1.

[0441] Example 14: Preparation of Form A of the Glutarate Salt of the Compound of Formula I-1

[0442] 14.1: Approximately 20 mg of the compound of Formula I-1 and 1.0 equivalent of glutaric acid were weighed into a 2 mL glass vial and placed in 0.15 mL of acetonitrile for suspension screening. The resulting sample was suspended at 50°C for 2 hours, then naturally cooled to 25°C and suspended at 25°C for at least 48 hours. The resulting suspension was centrifuged through a 0.45 μm nylon filter at 14,000 rpm. The resulting solid was vacuum dried at 50°C for 2 hours to obtain a sample of the glutaric acid salt, Form A, of the compound of Formula I-1.

[0443] 14.2: Approximately 20 mg of the compound of Formula I-1 and 1.0 equivalent of glutaric acid were weighed into a 2 mL glass vial and placed in 0.15 mL of dichloromethane for suspension screening. The resulting sample was suspended at 50°C for 2 hours, then naturally cooled to 25°C and suspended at 25°C for at least 48 hours. The resulting suspension was centrifuged through a 0.45 μm nylon filter at 14,000 rpm. The resulting solid was vacuum dried at 50°C for 2 hours to obtain a sample of Form A of the glutaric acid salt of the compound of Formula I-1.

[0444] Example 15: Preparation of p-toluenesulfonate Form A of the compound of formula I-1

[0445] Approximately 20 mg of the compound of Formula I-1 and 1.0 equivalent of p-toluenesulfonic acid were weighed into a 2 mL glass vial and placed in 0.15 mL of acetonitrile for suspension screening. The resulting sample was suspended at 50°C for 2 hours, then naturally cooled to 25°C and suspended at 25°C for at least 48 hours. The resulting suspension was centrifuged through a 0.45 μm nylon filter at 14,000 rpm. The resulting solid was vacuum dried at 50°C for 2 hours to obtain a sample of the p-toluenesulfonate salt of the compound of Formula I-1, Form A.

[0446] Example 16: Preparation of p-toluenesulfonate Form B of the compound of formula I-1

[0447] Approximately 20 mg of the compound of Formula I-1 and 1.0 equivalent of p-toluenesulfonic acid were weighed into a 2 mL glass vial and placed in 0.15 mL of tetrahydrofuran for suspension screening. The resulting sample was suspended at 50°C for 2 hours, then naturally cooled to 25°C and suspended at 25°C for at least 48 hours. The resulting suspension was centrifuged through a 0.45 μm nylon filter at 14,000 rpm. The resulting solid was vacuum dried at 50°C for 2 hours to obtain a p-toluenesulfonate salt of the compound of Formula I-1, Form B.

[0448] Example 17: Preparation of Methanesulfonate Form A of the Compound of Formula I-1

[0449] Approximately 20 mg of the compound of Formula I-1 and 1.0 equivalent of methanesulfonic acid were weighed into a 2 mL glass vial and placed in 0.15 mL of tetrahydrofuran for suspension screening. The resulting sample was suspended at 50°C for 2 hours, then naturally cooled to 25°C and suspended at 25°C for at least 48 hours. The resulting suspension was centrifuged through a 0.45 μm nylon filter at 14,000 rpm. The resulting solid was vacuum dried at 50°C for 2 hours to obtain a sample of the mesylate salt Form A of the compound of Formula I-1.

[0450] Example 18: Preparation of Hydrochloride Form C1 of Compound I-1

[0451] 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 4M hydrogen chloride dioxane solution was added dropwise. After addition, the mixture was returned to room temperature and stirred overnight. The mixture was filtered and dried to obtain a sample of the hydrochloride form C1 of the compound of formula I-1 (18.3 g) as a white solid.

[0452] Example 19: Preparation of Hydrochloride Form C2 of the Compound of Formula I-1

[0453] Weigh approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 and add 0.2-0.5 mL of 2-methyltetrahydrofuran. Suspend the mixture at 25°C at 300-400 rpm under magnetic stirring. Filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm. The resulting solid portion is the hydrochloride Form C2 sample of the compound of Formula I-1.

[0454] Example 20: Preparation of Hydrochloride Form D of the Compound of Formula I-1

[0455] Weigh approximately 40 mg of the compound of Formula I-1 and 1.05 equivalents of hydrochloric acid (diluted 10-fold with butanone) into a 2 mL glass vial. Add the screening solvent and perform the screening experiment using the suspension method. The resulting sample is suspended at 50°C (35°C, dichloromethane) for 2 hours, then naturally cooled to 25°C and suspended at 25°C for at least 48 hours. The resulting suspension is centrifuged through a 0.45 μm nylon filter at 14,000 rpm. The resulting solid is vacuum dried at 50°C for 2 hours to obtain the hydrochloride Form D sample of the compound of Formula I-1.

[0456] Example 21: Preparation of Hydrochloride Form E1 of Compound I-1

[0457] 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 ~1.2 equivalents of HCl (12N 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 crystals of the compound of formula I-1 to the above system, stir at 50°C for 2 h, then cool the solution naturally to 25°C and stir at 25°C for 3 days. Add ~0.1 equivalents of HCl (12N HCl aqueous solution diluted to 1.2 N with ethanol) to the above system and continue stirring at 25°C for 1 day. Collect the solid portion by suction filtration and dry the resulting solid under vacuum at 25°C for approximately 17 h. The obtained solid is then dried under vacuum at 50°C for another 2 h to obtain a sample of the hydrochloride crystal form E1 of the compound of formula I-1 (2.8 g) as an off-white solid.

[0458] Example 22: Preparation of Hydrochloride Form E2 of the Compound of Formula I-1

[0459] Weigh approximately 40 mg of the compound of Formula I-1 and 1.05 equivalents of hydrochloric acid (diluted 10-fold with ethanol) into a 2 mL glass vial. Add the screening solvent and perform the screening experiment using the suspension method. The resulting sample is suspended at 50°C (35°C, dichloromethane) for 2 hours, then naturally cooled to 25°C and suspended at 25°C for at least 48 hours. The resulting suspension is centrifuged at 14,000 rpm through a 0.45 μm nylon filter to obtain a solid, Form F hydrochloride of the compound of Formula I-1. This solid is then vacuum-dried at 50°C for 2 hours to obtain Form E2 hydrochloride of the compound of Formula I-1.

[0460] Example 23: Preparation of Form F of Hydrochloride Salt of Compound of Formula I-1

[0461] 23.1: Weigh approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 and add 0.2-0.5 mL of ethanol. Suspend the mixture at 25°C at 300-400 rpm under magnetic stirring. Filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm to obtain a solid sample of the hydrochloride Form F of the compound of Formula I-1.

[0462] 23.2: Weigh approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 and add 0.2-0.5 mL of acetone. Suspend the mixture at 25°C at 300-400 rpm under magnetic stirring. Filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm to obtain a solid sample of the hydrochloride Form F of the compound of Formula I-1.

[0463] 23.3: Weigh approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 and add 0.2-0.5 mL of acetonitrile. Suspend the mixture at 25°C at 300-400 rpm under magnetic stirring. Filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm to obtain a solid sample of the hydrochloride Form F of the compound of Formula I-1.

[0464] 23.4: Approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 was weighed and added to 0.2-0.5 mL of tetrahydrofuran. The suspension was suspended at 300-400 rpm under magnetic stirring at 25°C. The resulting suspension was centrifuged at 14,000 rpm using a 0.45 μm nylon membrane centrifuge tube. The resulting solid was a sample of the hydrochloride Form F of the compound of Formula I-1.

[0465] 23.5: Approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 was weighed and added to 0.2-0.5 mL of methyl isobutyl ketone / trifluoroethanol (9 / 1, v / v). The suspension was suspended at 300-400 rpm under magnetic stirring at 25°C. The resulting suspension was centrifuged at 14,000 rpm using a 0.45 μm nylon membrane centrifuge tube. The resulting solid was the hydrochloride Form F sample of the compound of Formula I-1.

[0466] 23.6: Weigh approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 and add 0.1-0.5 mL of ethanol. Suspend the mixture at 50°C at 300-400 rpm under magnetic stirring. Filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm to obtain a solid sample of the hydrochloride Form F of the compound of Formula I-1.

[0467] 23.7: Weigh approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 and add 0.1-0.5 mL of acetone. Suspend the mixture at 50°C at 300-400 rpm under magnetic stirring. Filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm to obtain a solid sample of the hydrochloride Form F of the compound of Formula I-1.

[0468] 23.8: Weigh approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 and add 0.1-0.5 mL of ethyl acetate. Suspend the mixture at 50°C at 300-400 rpm under magnetic stirring. Filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm to obtain a solid sample of the hydrochloride Form F of the compound of Formula I-1.

[0469] 23.9: Weigh approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 and add 0.1-0.5 mL of acetonitrile. Suspend the mixture at 50°C at 300-400 rpm under magnetic stirring. Filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm to obtain a solid sample of the hydrochloride Form F of the compound of Formula I-1.

[0470] 23.10: Approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 was weighed and added to 0.1-0.5 mL of tetrahydrofuran. The suspension was suspended at 50°C at 300-400 rpm under magnetic stirring. The resulting suspension was centrifuged at 14,000 rpm using a 0.45 μm nylon membrane centrifuge tube. The resulting solid was a sample of the hydrochloride Form F of the compound of Formula I-1.

[0471] 23.11: Approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 was weighed and added to 0.1-0.5 mL of methyl isobutyl ketone / trifluoroethanol (9 / 1, v / v). The suspension was suspended at 50°C at 300-400 rpm under magnetic stirring. The resulting suspension was centrifuged at 14,000 rpm using a 0.45 μm nylon membrane centrifuge tube. The resulting solid was the hydrochloride Form F sample of the compound of Formula I-1.

[0472] 23.12: Approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 was weighed and added with 0.1-0.5 mL of ethanol. The mixture was subjected to 10 heating and cooling cycles between 5°C and 50°C at a rate of 0.1°C / min while being suspended under magnetic stirring at 300-400 rpm. The temperature was maintained at 10°C during sampling. The resulting suspension was centrifuged through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm at 10°C to obtain a solid sample of the hydrochloride Form F of the compound of Formula I-1.

[0473] 23.13: Approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 was weighed and added with 0.1-0.5 mL of acetone. The mixture was subjected to 10 heating and cooling cycles between 5°C and 50°C at a rate of 0.1°C / min while being suspended under magnetic stirring at 300-400 rpm. The temperature was maintained at 10°C during sampling. The resulting suspension was centrifuged through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm at 10°C to obtain a solid sample of the hydrochloride Form F of the compound of Formula I-1.

[0474] 23.14: Approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 was weighed and added with 0.1-0.5 mL of ethyl acetate. The mixture was subjected to 10 heating and cooling cycles between 5°C and 50°C at a rate of 0.1°C / min while magnetically stirring at 300-400 rpm. The temperature was maintained at 10°C during sampling. The resulting suspension was centrifuged through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm at 10°C to obtain a solid sample of the hydrochloride Form F of the compound of Formula I-1.

[0475] 23.15: Approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 was weighed and added with 0.1-0.5 mL of acetonitrile. The mixture was subjected to 10 heating and cooling cycles between 5°C and 50°C at a rate of 0.1°C / min while being suspended under magnetic stirring at 300-400 rpm. The temperature was maintained at 10°C during sampling. The resulting suspension was centrifuged and filtered through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm at 10°C to obtain a solid sample of the hydrochloride Form F of the compound of Formula I-1.

[0476] 23.16: Approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 was weighed and added with 0.1-0.5 mL of tetrahydrofuran. The mixture was subjected to 10 heating and cooling cycles between 5°C and 50°C at a rate of 0.1°C / min while being suspended under magnetic stirring at 300-400 rpm. The temperature was maintained at 10°C during sampling. The resulting suspension was centrifuged through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm at 10°C to obtain a solid sample of the hydrochloride Form F of the compound of Formula I-1.

[0477] 23.17: Approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 was weighed and 0.1-0.5 mL of methyl isobutyl ketone / trifluoroethanol (9 / 1, v / v) was added. The mixture was subjected to 10 heating and cooling cycles between 5°C and 50°C at a rate of 0.1°C / min while being magnetically stirred at 300-400 rpm. The temperature was maintained at 10°C during sampling. The resulting suspension was centrifuged through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm at 10°C to obtain a solid sample of the hydrochloride Form F of the compound of Formula I-1.

[0478] Example 24: Preparation of Hydrochloride Form G of the Compound of Formula I-1

[0479] 24.1: Weigh approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 and add 0.2-0.5 mL of water. Suspend the mixture at 25°C with magnetic stirring at 300-400 rpm. Filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm to obtain a solid sample of the hydrochloride Form G of the compound of Formula I-1.

[0480] 24.2: Weigh approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 and add 0.1-0.5 mL of methanol. Suspend the mixture at 50°C at 300-400 rpm under magnetic stirring. Filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm to obtain a solid sample of the hydrochloride Form G of the compound of Formula I-1.

[0481] 24.3: Approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 was weighed and 0.1-0.5 mL of methyl isobutyl ketone / trifluoroethanol (9 / 1, v / v) was added. The mixture was subjected to 10 heating and cooling cycles between 5°C and 50°C at a rate of 0.1°C / min while being magnetically stirred at 300-400 rpm. The temperature was maintained at 10°C during sampling. The resulting suspension was centrifuged at 14,000 rpm at 10°C using a 0.45 μm nylon membrane centrifuge tube. The resulting solid was a sample of the hydrochloride Form G of the compound of Formula I-1.

[0482] Example 25: Preparation of Hydrochloride Form H of the Compound of Formula I-1

[0483] 25.1: Weigh approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 and add 0.2-0.5 mL of methanol / water (1 / 1, v / v). Suspend the mixture at 25°C at 300-400 rpm under magnetic stirring. Filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm to obtain a solid sample of the hydrochloride Form H of the compound of Formula I-1.

[0484] 25.2: Approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 was weighed and added to 0.1-0.5 mL of methanol / water (1 / 1, v / v). The suspension was suspended at 50°C at 300-400 rpm under magnetic stirring. The resulting suspension was centrifuged at 14,000 rpm using a 0.45 μm nylon membrane centrifuge tube. The resulting solid was the hydrochloride Form H sample of the compound of Formula I-1.

[0485] Example 26: Preparation of Hydrochloride Form I of Compound I-1

[0486] 26.1: Weigh approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 and add 0.1-0.5 mL of methanol. Suspend the mixture at 50°C at 300-400 rpm under magnetic stirring. Filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm to obtain a solid sample of the hydrochloride Form I of the compound of Formula I-1.

[0487] 26.2: Weigh approximately 40 mg of Form E1 hydrochloride of the compound of Formula I-1 and dissolve thoroughly in a minimum volume of methanol at 25°C. Pass the resulting thin suspension through a 0.45 μm nylon membrane syringe filter to obtain a clear solution. Slowly add 8 mL of methyl tert-butyl ether to each portion of the clear solution (0.8 mL). Filter the resulting suspension by centrifugation at 14,000 rpm using a 0.45 μm nylon membrane centrifuge tube. The resulting solid is a sample of Form I hydrochloride of the compound of Formula I-1.

[0488] Example 27: Preparation of the hydrochloride salt of the compound of formula I-1, Form J1

[0489] 27.1: Weigh approximately 40 mg of the hydrochloride salt of the compound of Formula I-1, Form E1, and add 0.1-0.5 mL of 2-methyltetrahydrofuran. Suspend the mixture at 50°C at 300-400 rpm under magnetic stirring. Filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm to obtain a solid sample of the hydrochloride salt of the compound of Formula I-1, Form J1.

[0490] 27.2: Approximately 40 mg of the hydrochloride salt of the compound of Formula I-1, Form E1, was weighed and added with 0.1-0.5 mL of 2-methyltetrahydrofuran. The mixture was subjected to 10 heating and cooling cycles between 5°C and 50°C at a rate of 0.1°C / min while being suspended under magnetic stirring at 300-400 rpm. The temperature was maintained at 10°C during sampling. The resulting suspension was centrifuged through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm at 10°C to obtain a solid sample of the hydrochloride salt of the compound of Formula I-1, Form J1.

[0491] Example 28: Preparation of the hydrochloride salt of the compound of formula I-1, Form J2

[0492] The above-mentioned hydrochloride crystal form J1 sample of the compound of formula I-1 is heated to 110° C. to obtain a solid which is the hydrochloride crystal form J2 sample of the compound of formula I-1.

[0493] Example 29: Preparation of Form K of Hydrochloride Salt of Compound of Formula I-1

[0494] 29.1: Weigh approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 and add 0.1-0.5 mL of methyl tert-butyl ether. Suspend the mixture at 50°C at 300-400 rpm under magnetic stirring. Filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm to obtain a solid sample of the hydrochloride Form K of the compound of Formula I-1.

[0495] 29.2: Approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 was weighed and added with 0.1-0.5 mL of methyl tert-butyl ether. The mixture was subjected to 10 heating and cooling cycles between 5°C and 50°C at a rate of 0.1°C / min while being suspended under magnetic stirring at 300-400 rpm. The temperature was maintained at 10°C during sampling. The resulting suspension was centrifuged and filtered through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm at 10°C to obtain a solid sample of the hydrochloride Form K of the compound of Formula I-1.

[0496] 29.3: Approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 was weighed and added with 0.1-0.5 mL of toluene. The mixture was subjected to 10 heating and cooling cycles between 5°C and 50°C at a rate of 0.1°C / min while being suspended under magnetic stirring at 300-400 rpm. The temperature was maintained at 10°C during sampling. The resulting suspension was centrifuged and filtered through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm at 10°C to obtain a solid sample of the hydrochloride Form K of the compound of Formula I-1.

[0497] Example 30: Preparation of Form L of Hydrochloride Salt of Compound I-1

[0498] 30.1: Weigh approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 and add 0.1-0.5 mL of toluene. Suspend the mixture at 25°C at 300-400 rpm under magnetic stirring. Filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm to obtain a solid sample of the hydrochloride Form L of the compound of Formula I-1.

[0499] 30.2: Approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 was weighed and added with 0.1-0.5 mL of toluene. The suspension was suspended at 50°C at 300-400 rpm under magnetic stirring. The resulting suspension was centrifuged at 14,000 rpm using a 0.45 μm nylon membrane centrifuge tube. The resulting solid was the hydrochloride Form L sample of the compound of Formula I-1.

[0500] Example 31: Preparation of Hydrochloride Form M of the Compound of Formula I-1

[0501] 31.1: Approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 was weighed and added to 0.1-0.5 mL of isopropyl alcohol / dimethyl sulfoxide (9 / 1, v / v). The suspension was suspended at 300-400 rpm under magnetic stirring at 25°C. The resulting suspension was centrifuged at 14,000 rpm using a 0.45 μm nylon membrane centrifuge tube. The resulting solid was the hydrochloride Form M sample of the compound of Formula I-1.

[0502] 31.2: Approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 was weighed and added with 0.1-0.5 mL of isopropyl acetate / dimethyl sulfoxide (9 / 1, v / v). The suspension was suspended at 300-400 rpm under magnetic stirring at 25°C. The resulting suspension was centrifuged at 14,000 rpm using a 0.45 μm nylon membrane centrifuge tube. The resulting solid was the hydrochloride Form M sample of the compound of Formula I-1.

[0503] 31.3: Approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 was weighed and added to 0.1-0.5 mL of dimethyl sulfoxide / water (1 / 1, v / v). The suspension was suspended at 300-400 rpm under magnetic stirring at 25°C. The resulting suspension was centrifuged at 14,000 rpm using a 0.45 μm nylon membrane centrifuge tube. The resulting solid was the hydrochloride Form M sample of the compound of Formula I-1.

[0504] 31.4: Approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 was weighed and added with 0.1-0.5 mL of isopropyl alcohol / dimethyl sulfoxide (9 / 1, v / v). The suspension was suspended at 50°C at 300-400 rpm under magnetic stirring. The resulting suspension was centrifuged at 14,000 rpm using a 0.45 μm nylon membrane centrifuge tube. The resulting solid was the hydrochloride Form M sample of the compound of Formula I-1.

[0505] 31.5: Approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 was weighed and 0.1-0.5 mL of isopropyl acetate / dimethyl sulfoxide (9 / 1, v / v) was added. The mixture was suspended at 50°C with magnetic stirring at 300-400 rpm. The resulting suspension was centrifuged at 14,000 rpm using a 0.45 μm nylon membrane centrifuge tube. The resulting solid was the hydrochloride Form M sample of the compound of Formula I-1.

[0506] 31.6: Approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 was weighed and added to 0.1-0.5 mL of dimethyl sulfoxide / water (1 / 1, v / v). The suspension was suspended at 50°C at 300-400 rpm under magnetic stirring. The resulting suspension was centrifuged at 14,000 rpm using a 0.45 μm nylon membrane centrifuge tube. The resulting solid was the hydrochloride Form M sample of the compound of Formula I-1.

[0507] 31.7: Approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 was weighed and added with 0.1-0.5 mL of isopropanol / dimethyl sulfoxide (9 / 1, v / v). The mixture was subjected to 10 heating and cooling cycles between 5°C and 50°C at a rate of 0.1°C / min while being magnetically stirred at 300-400 rpm. The temperature was maintained at 10°C during sampling. The resulting suspension was centrifuged through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm at 10°C to obtain a solid sample of the hydrochloride Form M of the compound of Formula I-1.

[0508] 31.8: Approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 was weighed and 0.1-0.5 mL of isopropyl acetate / dimethyl sulfoxide (9 / 1, v / v) was added. The mixture was subjected to 10 heating and cooling cycles between 5°C and 50°C at a rate of 0.1°C / min while being magnetically stirred at 300-400 rpm. The temperature was maintained at 10°C during sampling. The resulting suspension was centrifuged and filtered through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm at 10°C to obtain a solid sample of the hydrochloride Form M of the compound of Formula I-1.

[0509] 31.9: Approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 was weighed and added with 0.1-0.5 mL of dimethyl sulfoxide / water (1 / 1, v / v). The mixture was subjected to 10 heating and cooling cycles between 5°C and 50°C at a rate of 0.1°C / min while being magnetically stirred at 300-400 rpm. The temperature was maintained at 10°C during sampling. The resulting suspension was centrifuged through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm at 10°C to obtain a solid sample of the hydrochloride Form M of the compound of Formula I-1.

[0510] Example 32: Preparation of Form N of Hydrochloride Salt of Compound of Formula I-1

[0511] 32.1: Weigh approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 and add 0.2-0.5 mL of methanol. Suspend the mixture at 25°C at 300-400 rpm under magnetic stirring. Filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm to obtain a solid sample of the hydrochloride Form N of the compound of Formula I-1.

[0512] 32.2: Approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 was weighed and added with 0.1-0.5 mL of methanol. The mixture was subjected to 10 heating and cooling cycles between 5°C and 50°C at a rate of 0.1°C / min while being suspended under magnetic stirring at 300-400 rpm. The temperature was maintained at 10°C during sampling. The resulting suspension was centrifuged and filtered through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm at 10°C to obtain a solid sample of the hydrochloride Form N of the compound of Formula I-1.

[0513] Example 33: Preparation of Hydrochloride Form O of Compound I-1

[0514] Weigh approximately 40 mg of the hydrochloride Form E1 of the compound of Formula I-1 and add 0.2-0.5 mL of dichloromethane. Suspend the mixture at 25°C at 300-400 rpm under magnetic stirring. Filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm to obtain a solid sample of the hydrochloride Form O of the compound of Formula I-1.

[0515] Experimental Example 1: Solid Stability and Solubility of Hydrochloride Form I of Compound I-1

[0516] 1.1 Solid Stability of Hydrochloride Form I of Compound I-1

[0517] An open container containing the hydrochloride salt of the compound of Formula I-1, Form I, was placed at 25°C / 60% RH for one week. A sealed container containing the hydrochloride salt of the compound of Formula I-1, Form I, was placed at 60°C for one week. Stability samples under these conditions were subjected to XRPD, HPLC, and stoichiometric testing, and the samples were observed for color change.

[0518] Table 33 Solid Stability of Hydrochloride Form I of Formula I-1

[0519] 1.2 Solubility of Free Form A of the Compound of Formula I-1

[0520] Weigh 10 mg of the free-state crystalline Form A of the compound of Formula I-1 or 10.8 mg (equivalent to 10 mg of the free anhydrate) of the hydrochloride crystalline Form I of the compound of Formula I-1 into an 8 mL glass vial. Add 5 mL of dissolution medium. The resulting suspension / clear solution is stirred at 400 rpm at 37°C for 2 h, 8 h, and 24 h, followed by centrifugation at 14,000 rpm at 37°C for 5 min. The solubility of the supernatant is determined by HPLC, the pH of the supernatant is measured using a pH meter, and the residual solids are analyzed by XRPD.

[0521] Table 34 Solubility test of free crystal form A of compound of formula I-1

[0522] Table 35 Solubility test of the hydrochloride crystal form I of the compound of formula I-1

[0523] Conclusion: The total impurity content and crystalline form of the hydrochloride salt of the compound of Formula I-1, Form I, remained unchanged, demonstrating good physical stability. Furthermore, the hydrochloride salt of the compound of Formula I-1, Form I, exhibited significantly improved solubility in all four media compared to the free crystalline form of the compound of Formula I-1.

[0524] Experimental Example 2: FGFR2 receptor activity inhibition test of hydrochloride crystal form I

[0525] 2.3 Test of the activity of the hydrochloride crystal form I of the compound of formula I-1 on FGFR2 background cells

[0526] 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, MFM223).

[0527] The cell lines were 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 compounds were prepared into 10 mM solutions using DMSO.

[0528] Prepare compound storage plates (tubes): Perform a 4-fold serial dilution with DMSO from the highest concentration to the lowest, for a total of nine concentrations. Also prepare the internal control compound by diluting it 4-fold for a total of nine concentrations. Next, prepare the compound working solution: Add 98 μL of cell culture medium to a flat-bottomed 96-well transparent plate. Pipette 2 μL of compound from the compound storage plate into the cell culture medium in the 96-well transparent plate. Add 2 μL of DMSO to the vehicle control. After adding the compound or DMSO, mix thoroughly by pipetting with a dispenser.

[0529] Cell plating and drug administration: 1) Stain cells with trypan blue and count viable cells, requiring a viability of >90%; 2) Adjust the cell concentration to the appropriate concentration; 3) Add 95 μL of cell suspension (6,000–10,000 cells / well) to each well of the compound assay plate. Add culture medium without cells (containing 0.1%) to the Min control wells; 4) Add drug to the compound assay plate: Add 5 μL of a 20× working solution of compound as indicated in Table 1 to the cell culture plate. Add 5 μL of a DMSO-cell culture medium mixture to the Max control wells. The final DMSO concentration is 0.1%; 5) Incubate the plate in a 37°C, 5% CO2 incubator for 72–96 hours.

[0530] Follow the instructions of the Promega CellTiter-Glo Luminescent Cell Viability 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 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 cell culture medium in each well) of 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.

[0531] The cell proliferation inhibition rate (Inhibition Rate) data were processed using the following formula: Inhibition Rate (Inh%) = 100-(RLU Drug -RLU Min ) / (RLU Max -RLU Min )*100%.

[0532] 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.

[0533] Table 36 Test compound inhibition results on FGFR2 background cell line proliferation

[0534] 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.

[0535] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound of formula (I), its amorphous or crystalline form or its solvate; Among them, 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) as claimed in 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 2θ angles selected from the group consisting of: 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 group consisting of: a. The X-ray powder diffraction pattern of the crystalline form A further has 1 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 the 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 °C ± 2 °C, 110.00 °C ± 2 °C and 200.00 °C ± 2 °C, and starts to decompose after 250.00 °C ± 2 °C. In another preferred embodiment, the crystalline form A has an X-ray powder diffraction pattern substantially as shown in Figure 1. In another preferred embodiment, the crystalline form A has a differential scanning calorimetry pattern substantially as shown in Figure 2. In another preferred embodiment, the crystalline form A has a thermogravimetric analysis pattern substantially as shown in Figure 3.

3. A method for preparing crystalline form A as described in claim 2, characterized in that, The method comprises the following steps: a. Dissolving or dispersing the compound I-1 in 1 to 5 volumes of acetonitrile, an alcohol solvent, an ester solvent, an ether solvent or a mixed solvent of an alcohol solvent and water; b. Recrystallizing or slurrying; 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 formate, 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 the alcohol solvent and water is selected from the group consisting of 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) as claimed in 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 compound I-1 to the acid is 1:(0.8 - 3); more preferably, 1:(0.8 - 2).

5. The crystalline form according to claim 4, characterized in that, The crystal form is the maleate crystal form A of compound I-1, and the X-ray powder diffraction pattern of the maleate crystal form A has 2θ angles selected from the group consisting of: 15.17 ± 0.2°, 23.02 ± 0.2°, 24.42 ± 0.2°. In another preferred example, the X-ray powder diffraction pattern of the maleate crystal 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 group consisting of: 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°, 17.88 ± 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°, 34.09 ± 0.2°. In another preferred example, the maleate crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 4.

6. The crystalline form according to claim 4, characterized in that, The crystal form is the monomaleate crystal form B of compound I-1, and the X-ray powder diffraction pattern of the monomaleate crystal form B has 2θ angles selected from the group consisting of: 16.57 ± 0.2°, 17.38 ± 0.2°, 20.39 ± 0.2°. In another preferred example, the monomaleate crystal form B further has one or more characteristics selected from the following group: a. The X-ray powder diffraction pattern of the monomaleate crystal 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: 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°, 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 crystal form B has the starting point of an endothermic peak at 213.92°C ± 2°C; c. The thermogravimetric analysis curve of the monomaleate crystal form B has two weight loss steps at 24.00°C ± 2°C and 180.00°C ± 2°C, and starts to decompose after 250.00°C ± 2°C. In another preferred example, the maleate crystal form B has an X-ray powder diffraction pattern substantially as shown in Figure 5. In another preferred example, the maleate crystal form B has a differential scanning calorimetry pattern substantially as shown in Figure 6. In another preferred example, the maleate crystal form B has a thermogravimetric analysis pattern substantially as shown in Figure 7.

7. The crystalline 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 2θ angles 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 crystal 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°, 17.90±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°, 29.46±0.2°, 38.24±0.2°. In another preferred embodiment, the fumarate crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 8.

8. The crystalline form according to claim 4, characterized in that, The crystal form is the hemifumarate crystal form B of the compound of formula I-1, and the X-ray powder diffraction pattern of the hemifumarate crystal form B has 2θ angles selected from the following group: 5.12±0.2°, 14.24±0.2°, 10.20±0.2°. In another preferred embodiment, the hemifumarate crystal form B further has one or more characteristics selected from the following group: a. The X-ray powder diffraction pattern of the hemifumarate crystal 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: 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°, 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 hemifumarate crystal form B has the 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 hemifumarate polymorph 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 starts to decompose after 270.00 °C ± 2 °C. In another preferred example, the hemifumarate polymorph B has an X-ray powder diffraction pattern substantially as shown in Figure 9. In another preferred example, the hemifumarate polymorph B has a differential scanning calorimetry pattern substantially as shown in Figure 10. In another preferred example, the hemifumarate polymorph B has a thermogravimetric analysis pattern substantially as shown in Figure 11.

9. The crystalline form according to claim 4, characterized in that, The crystal form is the monoethanolate polymorph A of the compound of formula I-1, and the X-ray powder diffraction pattern of the monoethanolate polymorph A has 2θ angles selected from the following group: 18.22 ± 0.2 °, 22.83 ± 0.2 °, 26.41 ± 0.2 °. In another preferred example, the monoethanolate polymorph A further has one or more characteristics selected from the following group: a. The X-ray powder diffraction pattern of the monoethanolate polymorph A further has 1 or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) 2θ angles selected from the following group: 6.37 ± 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 °, 19.09 ± 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 monoethanolate polymorph A has the starting points of endothermic peaks at 109.66 °C ± 2 °C and 198.83 °C ± 2 °C; c. The thermogravimetric analysis curve of the monoethanolate polymorph A has three weight loss steps at three places of 33.00 °C ± 2 °C, 100.00 °C ± 2 °C, and 165.00 °C ± 2 °C, and starts to decompose after 200.00 °C ± 2 °C. In another preferred example, the monoethanolate polymorph A has an X-ray powder diffraction pattern substantially as shown in Figure 12. In another preferred example, the monoethanolate polymorph A has a differential scanning calorimetry pattern substantially as shown in Figure 13. In another preferred example, the monoethanolate polymorph A has a thermogravimetric analysis pattern substantially as shown in Figure 14.

10. The crystalline form according to claim 4, wherein, The crystal form is 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 2θ angles 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 crystal 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°, 32.27±0.2°. In another preferred embodiment, the glycolate crystal form B has an X-ray powder diffraction pattern substantially as shown in Figure 15.

11. The crystalline form according to claim 4, characterized in that, The crystal form is that of the compound of formula I-1, and the X-ray powder diffraction pattern of the mono-L-malate crystal form A has 2θ angles 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 crystal form A further has one or more of the following characteristics: a. The X-ray powder diffraction pattern of the mono-L-malate crystal 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: 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 single L-malate crystal form A has the starting point of an endothermic peak at 204.74 °C ± 2 °C; c. The thermogravimetric analysis curve of the single L-malate crystal form A 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. In another preferred example, the single L-malate crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 16. In another preferred example, the single L-malate crystal form A has a differential scanning calorimetry pattern substantially as shown in Figure 17. In another preferred example, the single L-malate crystal form A has a thermogravimetric analysis pattern substantially as shown in Figure 18.

12. The crystalline form according to claim 4, characterized in that, The crystal form is the single succinate crystal form A of the compound of formula I-1, characterized in that the X-ray powder diffraction pattern of the single succinate crystal form A has 2θ angles selected from the group consisting of: 18.40 ± 0.2 °, 24.09 ± 0.2 °, 24.62 ± 0.2 °. In another preferred example, the single succinate crystal form A further has one or more characteristics selected from the group consisting of: a. The X-ray powder diffraction pattern of the single succinate crystal form A further has 1 or more (such as 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 °, 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 single succinate crystal form A has the 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 single succinate crystal form A has three weight loss steps at 33.00 °C ± 2 °C, 90.00 °C ± 2 °C and 160.00 °C ± 2 °C, and starts to decompose after 260.00 °C ± 2 °C. In another preferred example, the single succinate crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 19. In another preferred example, the monosuccinate polymorph A has a differential scanning calorimetry chart substantially as shown in Figure 20. In another preferred example, the monosuccinate polymorph A has a thermogravimetric analysis chart substantially as shown in Figure 21.

13. The crystalline form according to claim 4, characterized in that, The polymorph is the sulfate polymorph A of the compound of formula I-1, and the X-ray powder diffraction pattern of the sulfate polymorph A has 2θ angles selected from the group consisting of: 14.97 ± 0.2°, 20.21 ± 0.2°, 22.58 ± 0.2°. In another preferred example, the X-ray powder diffraction pattern of the sulfate polymorph A further 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: 6.74 ± 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 polymorph A has an X-ray powder diffraction chart substantially as shown in Figure 22.

14. The crystalline form according to claim 4, wherein The polymorph is the L-tartrate polymorph A of the compound of formula I-1, and the X-ray powder diffraction pattern of the L-tartrate polymorph A has 2θ angles selected from the group consisting of: 5.53 ± 0.2°, 16.95 ± 0.2°, 20.79 ± 0.2°. In another preferred example, the X-ray powder diffraction pattern of the L-tartrate crystal 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: 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 crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 23.

15. The crystalline form according to claim 4, characterized in that, The crystal form is the 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 2θ angles selected from the following group: 6.17±0.2°, 12.30±0.2°, 18.78±0.2°. In another preferred example, the X-ray powder diffraction pattern of the hippurate crystal 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: 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°, 16.06±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 example, the hippurate crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 24.

16. The crystalline form according to claim 4, wherein The crystal form is the glutarate crystal form A of the compound of formula I-1, and the X-ray powder diffraction pattern of the glutarate crystal form A has 2θ angles 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 glutarate crystal 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 group consisting of: 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 embodiment, the glutarate crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 25.

17. The crystalline form according to claim 4, wherein, The crystal form is the p-toluenesulfonate crystal form A of the compound of formula I-1, and the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form A has 2θ angles selected from the group consisting of: 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 crystal 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 group consisting of: 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°, 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 embodiment, the p-toluenesulfonate crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 26.

18. The crystalline form according to claim 4, wherein The crystal form is the p-toluenesulfonate crystal form B of the compound of formula I-1, and the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form B has 2θ angles selected from the group consisting of: 13.95 ± 0.2°, 19.52 ± 0.2°, 25.40 ± 0.2°. In another preferred example, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal 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: 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 crystal form B has an X-ray powder diffraction pattern substantially as shown in Figure 27.

19. The crystalline form according to claim 4, wherein The crystal form is the methanesulfonate crystal form A of the compound of formula I-1, and the X-ray powder diffraction pattern of the methanesulfonate crystal form A has 2θ angles selected from the following group: 19.57±0.2°, 14.27±0.2°, 24.99±0.2°. In another preferred example, the X-ray powder diffraction pattern of the methanesulfonate crystal 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: 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 methanesulfonate crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 28.

20. The crystalline 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 2θ angles selected from the following group: 7.73±0.2°, 19.57±0.2°, 19.78±0.2°. In another preferred example, the hydrochloride crystal form C1 further has one or more characteristics selected from the following group: a. The X-ray powder diffraction pattern of the hydrochloride crystal form C1 further 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: 7.47±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 crystal form C1 has 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 crystal 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 example, the hydrochloride crystal form C1 has an X-ray powder diffraction pattern substantially as shown in Figure 29. In another preferred example, the hydrochloride crystal form C1 has a differential scanning calorimetry pattern substantially as shown in Figure 30. In another preferred example, the hydrochloride crystal form C1 has a thermogravimetric analysis pattern substantially as shown in Figure 31. In another preferred example, the hydrochloride crystal form C1 is an ethyl acetate solvent and hydrate crystal form, wherein the ethyl acetate content is 0.1 to 1 equivalent, and the water content is 1 to 5 equivalents.

21. The crystalline 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 2θ angles selected from the group consisting of: 7.79±0.2°, 19.66±0.2°, 19.82±0.2°. In another preferred example, the hydrochloride crystal form C2 further has one or more characteristics selected from the group consisting of: a. The X-ray powder diffraction pattern of the hydrochloride crystal form C2 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: 7.56±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 crystal form C2 has the 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 crystal 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 starts to decompose at 212.45°C ± 2°C. In another preferred example, the hydrochloride crystal form C2 has an X-ray powder diffraction pattern substantially as shown in Figure 32. In another preferred example, the hydrochloride crystal form C2 has a differential scanning calorimetry pattern substantially as shown in Figure 33. In another preferred example, the hydrochloride crystal form C2 has a thermogravimetric analysis pattern substantially as shown in Figure 34. In another preferred example, the hydrochloride crystal form C2 is a 2-methyltetrahydrofuran solvent and hydrate crystal form, wherein the content of 2-methyltetrahydrofuran is 0.05 to 0.5 equivalents, and the water content is 1 to 5 equivalents.

22. The crystalline 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 2θ angles selected from the following group: 15.93±0.2°, 20.09±0.2°, 20.41±0.2°. In another preferred example, the hydrochloride crystal form D further has one or more characteristics selected from the following group: a. The X-ray powder diffraction pattern of the hydrochloride crystal form D further 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: 6.60±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°, 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 crystal form D has 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 crystal 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 crystal form D has an X-ray powder diffraction pattern substantially as shown in Figure 35. In another preferred example, the hydrochloride crystal form D has a differential scanning calorimetry pattern substantially as shown in Figure 36. In another preferred example, the hydrochloride crystal form D has a thermogravimetric analysis pattern substantially as shown in Figure 37.

23. The crystalline 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 2θ angles selected from the group consisting of: 7.90±0.2°, 14.06±0.2°, 20.19±0.2°. In another preferred example, the hydrochloride crystal form E1 further has one or more characteristics selected from the group consisting of: a. The X-ray powder diffraction pattern of the hydrochloride crystal form E1 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: 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 crystal form E1 has the 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 crystal 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 starts to decompose at 211.29 °C ± 2 °C. In another preferred example, the hydrochloride crystal form E1 has an X-ray powder diffraction pattern substantially as shown in Figure 38. In another preferred example, the hydrochloride crystal form E1 has a differential scanning calorimetry pattern substantially as shown in Figure 39. In another preferred example, the hydrochloride crystal form E1 has a thermogravimetric analysis pattern substantially as shown in Figure 40. In another preferred example, 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 crystalline form according to claim 4, wherein, 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 2θ angles selected from the following group: 7.88 ± 0.2°, 14.14 ± 0.2°, 19.75 ± 0.2°. In another preferred example, the hydrochloride crystal form E2 further has one or more characteristics selected from the following group: a. The X-ray powder diffraction pattern of the hydrochloride crystal form E2 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: 9.51±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°, 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°; b. The differential scanning calorimetry curve of the hydrochloride crystal form E2 has the 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 crystal 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 starts to decompose at 213.17°C±2°C. In another preferred example, the hydrochloride crystal form E2 has an X-ray powder diffraction pattern substantially as shown in Figure 41. In another preferred example, the hydrochloride crystal form E2 has a differential scanning calorimetry pattern substantially as shown in Figure 42. In another preferred example, the hydrochloride crystal form E2 has a thermogravimetric analysis pattern substantially as shown in Figure 43. In another preferred example, 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) under vacuum at 10°C to 70°C. In another preferred example, 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 example, 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 crystalline form according to claim 4, wherein, 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 2θ angles selected from the following group: 7.65±0.2°, 11.47±0.2°, 13.93±0.2°. In another preferred example, the hydrochloride crystal form F further has one or more characteristics selected from the following group: a. The X-ray powder diffraction pattern of the hydrochloride crystal form F further 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 crystal form F has 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 crystal 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 starts to decompose at 212.66°C ± 2°C. In another preferred example, the hydrochloride crystal form F has an X-ray powder diffraction pattern substantially as shown in Figure 44. In another preferred example, the hydrochloride crystal form F has a differential scanning calorimetry pattern substantially as shown in Figure 45. In another preferred example, the hydrochloride crystal form F has a thermogravimetric analysis pattern substantially as shown in Figure 46. In another preferred example, 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 2θ angles selected from the group consisting of: 15.52 ± 0.2°, 16.77 ± 0.2°, 23.04 ± 0.2°. In another preferred example, the hydrochloride crystal form G further has one or more characteristics selected from the group consisting of: a. The X-ray powder diffraction pattern of the hydrochloride crystal form G 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: 5.83±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 crystal form G has the 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 crystal 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 crystal form G has an X-ray powder diffraction pattern substantially as shown in Figure 47. In another preferred example, the hydrochloride crystal form G has a differential scanning calorimetry pattern substantially as shown in Figure 48. In another preferred example, the hydrochloride crystal form G has a thermogravimetric analysis pattern substantially as shown in Figure 49. In another preferred example, 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 2θ angles selected from the following group: 5.83±0.2°, 16.67±0.2°, 18.40±0.2°. In another preferred example, the hydrochloride crystal form H further has one or more characteristics selected from the following group: a. The X-ray powder diffraction pattern of the hydrochloride crystal form H further 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 crystal form H has the 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 crystal 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 starts to decompose at 211.73°C ± 2°C. In another preferred example, the hydrochloride crystal form H has an X-ray powder diffraction pattern substantially as shown in Figure 50. In another preferred example, the hydrochloride crystal form H has a differential scanning calorimetry pattern substantially as shown in Figure 51. In another preferred example, the hydrochloride crystal form H has a thermogravimetric analysis pattern substantially as shown in Figure 52. In another preferred example, 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, wherein The crystal form is hydrochloride crystal form I, and the X-ray powder diffraction pattern of the hydrochloride crystal form I has 2θ angles selected from the group consisting of: 6.68±0.2°, 13.34±0.2°, 21.42±0.2°. In another preferred example, the hydrochloride crystal form I further has one or more characteristics selected from the group consisting of: a. The X-ray powder diffraction pattern of the hydrochloride crystal form I further 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: 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 crystal form I has the 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 crystal 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 starts to decompose at 215.51°C ± 2°C. In another preferred example, the hydrochloride crystal form I has an X-ray powder diffraction pattern substantially as shown in Figure 53. In another preferred example, the hydrochloride crystal form I has a differential scanning calorimetry pattern substantially as shown in Figure 54. In another preferred example, the hydrochloride crystal form I has a thermogravimetric analysis pattern substantially as shown in Figure 55. In another preferred example, the hydrochloride crystal form I of the compound of formula (I) is an anhydrous crystal form.

29. The crystalline form according to claim 4, wherein, The crystal form is hydrochloride crystal form J1, and the X-ray powder diffraction pattern of the hydrochloride crystal form J1 has 2θ angles selected from the group consisting of: 6.80±0.2°, 14.87±0.2°, 20.41±0.2°. In another preferred example, the hydrochloride crystal form J1 further has one or more characteristics selected from the group consisting of: a. The X-ray powder diffraction pattern of the hydrochloride crystal form J1 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: 7.82±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°, 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 crystal form J1 has the 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 crystal 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 example, the hydrochloride crystal form J1 has an X-ray powder diffraction pattern substantially as shown in Figure 56. In another preferred example, the hydrochloride crystal form J1 has a differential scanning calorimetry pattern substantially as shown in Figure 57. In another preferred example, the hydrochloride crystal form J1 has a thermogravimetric analysis pattern substantially as shown in Figure 58. In another preferred example, the hydrochloride crystal 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 the hydrochloride crystal form J2, and the X-ray powder diffraction pattern of the hydrochloride crystal form J2 has 2θ angles selected from the following group: 14.69±0.2°, 18.89±0.2°, 22.23±0.2°. In another preferred example, the hydrochloride crystal form J2 further has one or more characteristics selected from the following group: a. The X-ray powder diffraction pattern of the hydrochloride crystal form J2 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: 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 crystal form J2 has the 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 crystal 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 crystal form J2 has an X-ray powder diffraction pattern substantially as shown in Figure 59. In another preferred example, the hydrochloride crystal form J2 has a differential scanning calorimetry pattern substantially as shown in Figure 60. In another preferred example, the hydrochloride crystal form J2 has a thermogravimetric analysis pattern substantially as shown in Figure 61. In another preferred example, the hydrochloride crystal form J2 of the compound of formula (I) is prepared by heating the hydrochloride crystal form J1 of the compound of formula (I) to 90°C to 130°C. In another preferred example, the hydrochloride crystal 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, wherein The crystal form is hydrochloride crystal form K, and the X-ray powder diffraction pattern of the hydrochloride crystal form K has 2θ angles selected from the following group: 14.93±0.2°, 16.08±0.2°, 23.68±0.2°. In another preferred example, the hydrochloride crystal form K further has one or more characteristics selected from the following group: a. The X-ray powder diffraction pattern of the hydrochloride crystal form K 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: 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 crystal form K has 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 crystal 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 crystal form K has an X-ray powder diffraction pattern substantially as shown in Figure 62. In another preferred example, the hydrochloride crystal form K has a differential scanning calorimetry pattern substantially as shown in Figure 63. In another preferred example, the hydrochloride crystal form K has a thermogravimetric analysis pattern substantially as shown in Figure 64. In another preferred example, 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 equivalent, and the content of water is 0.5 to 2 equivalents.

32. The crystalline form according to claim 4, wherein The crystal form is hydrochloride crystal form L, and the X-ray powder diffraction pattern of the hydrochloride crystal form L has 2θ angles selected from the following group: 16.89 ± 0.2°, 21.69 ± 0.2°, 22.60 ± 0.2°. In another preferred example, the hydrochloride crystal form L further has one or more characteristics selected from the following group: a. The X-ray powder diffraction pattern of the hydrochloride crystal form L 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: 7.70±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 crystal form L has the 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 crystal form L has an X-ray powder diffraction pattern substantially as shown in Figure 65. In another preferred example, the hydrochloride crystal form L has a differential scanning calorimetry pattern substantially as shown in Figure 66. In another preferred example, the hydrochloride crystal form L has a thermogravimetric analysis pattern substantially as shown in Figure 67. In another preferred example, the hydrochloride crystal form L of the compound of formula (I) is a solvate of toluene, wherein the toluene content is 0.2 to 1 equivalent.

33. The crystalline form according to claim 4, wherein The crystal form is hydrochloride crystal form M, and the X-ray powder diffraction pattern of the hydrochloride crystal form M has 2θ angles selected from the following group: 14.17±0.2°, 20.82±0.2°, 22.60±0.2°. In another preferred example, the hydrochloride crystal form M further has one or more characteristics selected from the following group: a. The X-ray powder diffraction pattern of the hydrochloride crystal form M 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: 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 crystal form M has the starting points of endothermic peaks at 31.74°C±2°C and 150.05°C±2°C; c. The thermogravimetric analysis curve of the hydrochloride crystal 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 crystal form M has an X-ray powder diffraction pattern substantially as shown in Figure 68. In another preferred example, the hydrochloride crystal form M has a differential scanning calorimetry pattern substantially as shown in Figure 69. In another preferred example, the hydrochloride crystal form M has a thermogravimetric analysis pattern substantially as shown in Figure 70. In another preferred example, 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, wherein The crystal form is hydrochloride crystal form N, and the X-ray powder diffraction pattern of the hydrochloride crystal form N has 2θ angles selected from the following group: 16.19±0.2°, 20.10±0.2°, 28.42±0.2°. In another preferred example, the hydrochloride crystal form N further has one or more characteristics selected from the following group: a. The X-ray powder diffraction pattern of the hydrochloride crystal form N further 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 crystal form N has the starting points of endothermic peaks at 47.38°C ± 2°C and 167.91°C ± 2°C; c. The thermogravimetric analysis curve of the hydrochloride crystal 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 starts to decompose at 212.57°C ± 2°C. In another preferred example, the hydrochloride crystal form N has an X-ray powder diffraction pattern substantially as shown in Figure 71. In another preferred example, the hydrochloride crystal form N has a differential scanning calorimetry pattern substantially as shown in Figure 72. In another preferred example, the hydrochloride crystal form N has a thermogravimetric analysis pattern substantially as shown in Figure 73. In another preferred example, 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 2θ angles selected from the group consisting of: 15.51±0.2°, 18.36±0.2°, 20.17±0.2°. In another preferred example, the hydrochloride crystal form O further has one or more characteristics selected from the group consisting of: a. The X-ray powder diffraction pattern of the hydrochloride crystal form O 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: 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°, 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 crystal form O has the starting points of endothermic peaks at 12.36°C ± 2°C and 174.87°C ± 2°C; c. The thermogravimetric analysis curve of the hydrochloride crystal 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 starts to decompose at 212.00°C ± 2°C. In another preferred example, the hydrochloride crystal form O has an X-ray powder diffraction pattern substantially as shown in Figure 74. In another preferred example, the hydrochloride crystal form O has a differential scanning calorimetry pattern substantially as shown in Figure 75. In another preferred example, the hydrochloride crystal form O has a thermogravimetric analysis pattern substantially as shown in Figure 76. In another preferred example, 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 5-35, characterized in that, Comprising the following steps: a. Dissolve or disperse the compound of formula (I) and an acid in a molar ratio of 1:(0.8 - 3) in 1 to 20 times the volume of solvent A; b. Suspend, recrystallize or slurry; wherein, the acid is not selected from 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); The solvent A is selected from the following group: acetonitrile, dichloromethane, tetrahydrofuran, or a combination thereof; or the acid is hydrochloric acid or dioxane hydrochloride; and the solvent A is selected from the group consisting of 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. In another preferred embodiment, the solvent A is selected from the group consisting of 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 suspension comprises the following steps: a. Suspending the compound of formula (I), the acid and the solvent at 45 - 65 °C for 1 - 3 h; b. Naturally cooling to 20 - 30 °C and continuing to suspend for at least 48 h; c. Centrifuging the resulting suspension through a 0.4 - 0.5 μm filter membrane at a speed of 12000 - 16000 rpm; d. Vacuum drying the resulting solid 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 - 36, characterized in that, The method is a method of crystal form transformation, which transforms one crystal form of the pharmaceutically acceptable salt of the compound of formula (I) into another crystal form of the salt; wherein the method of crystal form transformation comprises the following steps: a. Dissolving or dispersing one crystal form of the pharmaceutically acceptable salt of the compound of formula (I) in 1 - 20 volumes of solvent A; b. Suspending; c. Centrifuging and filtering the resulting suspension through a 0.4 - 0.5 μm filter membrane at a speed of 12000 - 16000 rpm; wherein the solvent A is selected from the group consisting of 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 group consisting of methyl isobutyl ketone / trifluoroethanol, methanol / water, isopropanol / dimethyl sulfoxide, isopropyl acetate / dimethyl sulfoxide, dimethyl sulfoxide / water. In another preferred embodiment, the suspension comprises the step of stirring at a rate of 300 - 400 rpm at 20 - 30 °C. In another preferred embodiment, the suspension comprises the step of stirring at a rate of 300 - 400 rpm at 40 - 60 °C. In another preferred embodiment, the suspension comprises the step of performing 8 - 12 temperature rising and falling 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. In another preferred embodiment, the suspension comprises the step 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).

38. A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1 - 2, the crystal form A according to any one of claims 3 - 4, or the crystal 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 example, the pharmaceutical composition further comprises other therapeutic agents. In another preferred example, 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 example, 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. In another preferred example, 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 example, 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 example, 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. In another preferred example, 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.

39. Use of a compound of formula (I) as claimed in any one of claims 1-2, polymorph A as claimed in any one of claims 3-4, a polymorph of a compound of formula (I) as claimed in any one of claims 5-36, and the pharmaceutical composition as claimed in claim 38 in the preparation of a medicament for preventing and / or treating a disease associated with an increase in the activity or expression level of FGFR2. In another preferred example, 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, FGFR2 gene activation. In another preferred example, the diseases associated with increased activity or expression level of FGFR2 are selected from the following group: 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, urothelial carcinoma, etc. In another preferred example, the cholangiocarcinoma is intrahepatic cholangiocarcinoma. In another preferred example, the liver cancer is hepatocellular carcinoma. In another preferred example, the lung cancer is squamous cell lung cancer or non-small cell lung cancer.