Crystal forms of tubulin-SRC dual-targeting inhibitor, preparation method therefor and use thereof

Abstract

The present invention provides a crystal forms of a tubulin-SRC dual-targeting inhibitor, a preparation method therefor and a use thereof. Specifically disclosed are 2 free crystal forms of the compound shown in Formula I and 13 crystal forms of 10 salts, a preparation method therefor and a use thereof. The compound and the salt forms and crystal forms thereof can be used as tubulin and Src kinase dual-targeting inhibitors, or as tubulin inhibotors or Src kinase inhibitors alone. The compound, and the salt forms and crystal forms thereof, can also significantly inhibit the polymerization of tubulin monomers and inhibit cell proliferation, have good pharmacokinetic properties for topical administration to the skin, have good druggability, can be used to prepare skin topical preparations, and have the advantages of fast metabolism and low side effects.

Description

Crystalline tubulin-SRC dual-target inhibitor, preparation method and use thereof

[0001] This application claims priority to Chinese patent application No. 2023108740075, filed on July 14, 2023. This application incorporates the entirety of the aforementioned Chinese patent application. Technical Field

[0002] The present invention relates to a crystalline tubulin-SRC dual-target inhibitor, a preparation method and use thereof. Background Art

[0003] Microtubules are an important component of the cytoskeleton in eukaryotic cells and play an important role in maintaining cell morphology, signal transduction, organelle transport, cell motility, cell division and mitosis, and other cellular functions.

[0004] Microtubules are composed of two types of tubulin subunits: α-tubulin and β-tubulin. α-Tubulin and β-tubulin form tubulin heterodimers, the basic units of microtubule assembly. Microtubule-targeting agents (MTAs) can disrupt the dynamic stability and structure of microtubules, interfering with mitotic spindle formation, inducing cell cycle arrest at the G2 / M phase, and promoting apoptosis.

[0005] Microtubules are involved in many important cellular processes and have become one of the most important drug targets for the treatment of hyperproliferative diseases. Several FDA-approved microtubule-targeting agents, such as vinblastine and taxanes, are widely used to treat multiple solid tumors and hematologic malignancies. However, drug resistance and dose-limiting toxicities limit their clinical efficacy. Compared with single-target drugs, dual-target inhibitors overcome drug resistance and can improve therapeutic efficacy, becoming a research hotspot. These include tubulin-SRC dual-target inhibitors, tubulin-receptor tyrosine kinase (RTK) dual-target inhibitors, and tubulin-histone deacetylase (HDAC) dual-target inhibitors.

[0006] Actinic keratosis (AK) is a skin disease associated with prolonged exposure to ultraviolet light. It is the second most common disease seen by dermatologists in the United States. Characterized by the uncontrolled proliferation of mutated keratinocytes, AK is considered a precancerous lesion. If left untreated, 20% of cases may progress to squamous cell carcinoma (SCC) of the skin. Currently, the tubulin-SRC dual-target inhibitor Tirbanibulin has shown significant clinical efficacy in the topical treatment of AK (NCT03285477) and has been approved by the FDA for marketing. This suggests that developing new, more effective tubulin-SRC dual-target inhibitors for the topical treatment of AK may be a promising approach.

[0007] Chinese invention patent application number 202211139978.7 describes compound I-2 (the compound represented by formula I of the present application) with tubulin-SRC dual-target inhibitory effect:

[0008] On the basis of the good biological activity of the compound, it is necessary to develop a suitable salt form and its solid form to obtain improved drugability or other properties.

[0009] Summary of the Invention

[0010] The present invention aims to provide a crystalline tubulin-SRC dual-target inhibitor, a preparation method, and its use. The dual-target inhibitor has a crystal form or salt form as described in the present invention, which has advantages such as better stability. The crystal form or salt form can be used as a tubulin and SRC kinase dual-target inhibitor, and can also be used as a single tubulin or SRC kinase inhibitor.

[0011] The present invention provides a free crystalline form A of a compound represented by formula I,

[0012] The free crystalline form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, with diffraction peaks at 14.49±0.2°, 17.02±0.2°, 18.42±0.2°, and 20.53±0.2°.

[0013] In one embodiment, the free crystalline form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and has diffraction peaks at one or more of the following positions: 7.25±0.2°, 9.20±0.2°, 12.39±0.2°, and 13.77±0.2°.

[0014] In one embodiment, the free crystalline form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, with diffraction peaks at 3.66±0.2°, 7.25±0.2°, 9.20±0.2°, 11.13±0.2°, 12.39±0.2°, 13.77±0.2°, and 14.49±0.2°.

[0015] In one embodiment, the free crystalline form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, with diffraction peaks at 7.25±0.2°, 9.20±0.2°, 12.39±0.2°, 13.77±0.2°, 14.49±0.2°, 17.02±0.2°, 17.78±0.2°, 18.42±0.2°, and 20.53±0.2°.

[0016] In one embodiment, the free crystalline form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, with diffraction peaks at 3.66±0.2°, 7.25±0.2°, 9.20±0.2°, 11.13±0.2°, 12.39±0.2°, 13.77±0.2°, 14.49±0.2°, 17.02±0.2°, 17.78±0.2°, 18.42±0.2°, and 20.53±0.2°.

[0017] In one embodiment, the free crystalline form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and has diffraction peaks at 3.66±0.2°, 7.25±0.2°, 9.20±0.2°, 11.13±0.2°, 12.39±0.2°, 13.77±0.2°, 14.49±0.2°, 17.02±0.2°, 17.78±0.2°, 18.42±0.2°, 20.53±0.2°, and 20.92±0.2°.

[0018] In one embodiment, the free crystalline form A is an anhydrous crystalline form.

[0019] In one embodiment, the free crystalline form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and the diffraction peak positions and relative intensities thereof are substantially as shown in Table 1:

[0020] Table 1

[0021] In one embodiment, the X-ray powder diffraction pattern of the free crystalline form A using Cu-Kα radiation and expressed in 2θ angles is substantially as shown in FIG1 .

[0022] In one embodiment, the free crystalline form A has a differential scanning calorimetry analysis chart with an endothermic peak starting point at 94.7±3°C.

[0023] In one embodiment, the free crystalline form A has an endothermic peak at 96.6±3° C. in its differential scanning calorimetry analysis chart.

[0024] In one embodiment, the free crystalline form A has a weight loss of about 0.98% at 150° C. in a thermogravimetric analysis diagram.

[0025] In one embodiment, the differential scanning calorimetry analysis diagram of the free-state crystalline form A is substantially as shown in FIG3 .

[0026] In one embodiment, the thermogravimetric analysis diagram of the free-state crystalline form A is substantially as shown in FIG2 .

[0027] The present invention also provides a free crystalline form B of the compound shown in formula I,

[0028] The free crystalline form B has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, with diffraction peaks at 16.55±0.2°, 17.77±0.2°, 20.36±0.2°, 21.24±0.2°, and 22.66±0.2°.

[0029] In one embodiment, the free crystalline form B has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and further has diffraction peaks at one or more of the following positions: 8.89±0.2°, 10.99±0.2°, 13.81±0.2°, 16.10±0.2°, and 19.65±0.2°.

[0030] In one embodiment, the free crystalline form B has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, with diffraction peaks at 8.89±0.2°, 10.99±0.2°, 13.81±0.2°, 16.10±0.2°, 16.55±0.2°, 17.77±0.2°, 19.65±0.2°, 20.36±0.2°, 21.24±0.2°, and 22.66±0.2°.

[0031] In one embodiment, the free crystalline form B has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and has diffraction peaks at 8.89±0.2°, 10.99±0.2°, 13.81±0.2°, 14.97±0.2°, 16.10±0.2°, 16.55±0.2°, 17.77±0.2°, 19.65±0.2°, 20.36±0.2°, 21.24±0.2°, 22.66±0.2°, 23.92±0.2°, 24.80±0.2°, 25.41±0.2°, and 26.65±0.2°.

[0032] In one embodiment, the free crystalline form B is an anhydrous crystalline form.

[0033] In one embodiment, the free crystalline form B has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and the diffraction peak positions and relative intensities thereof are substantially as shown in Table 2:

[0034] Table 2

[0035] In one embodiment, the X-ray powder diffraction pattern of the free crystalline form B using Cu-Kα radiation and expressed in 2θ angles is substantially as shown in FIG. 4 .

[0036] In one embodiment, the differential scanning calorimetry analysis diagram of the free crystalline form B shows an endothermic peak starting point at 77.2±3°C.

[0037] In one embodiment, the free-state crystalline form B has an endothermic peak at 84.5±3° C. in its differential scanning calorimetry analysis chart.

[0038] In one embodiment, the free crystalline form B has an endothermic peak at 92.4±3°C in its differential scanning calorimetry analysis chart.

[0039] In one embodiment, the free crystalline form B has a weight loss of about 0.48% at 150° C. in a thermogravimetric analysis diagram.

[0040] In one embodiment, the differential scanning calorimetry analysis diagram of the free-state crystalline Form B is substantially as shown in FIG6 .

[0041] In one embodiment, the thermogravimetric analysis diagram of the free-state crystalline form B is substantially as shown in FIG5 .

[0042] The present invention also provides a method for preparing the free crystalline form A of the compound shown in Formula I, comprising dissolving the compound shown in Formula I in a solvent and volatilizing the solvent at room temperature to obtain the free crystalline form A, wherein the solvent is an organic solvent or a mixed solvent, and the organic solvent includes but is not limited to: CHCl3, THF, acetone, toluene, cyclopentyl methyl ether, 2-methyltetrahydrofuran, isopropanol, IPAc, 2-butanone; and the mixed solvent is a mixed solvent of an organic solvent and water, and the mixed solvent includes but is not limited to: a mixed solvent of MeOH and H2O, and a mixed solvent of acetonitrile and H2O.

[0043] The present invention also provides a method for preparing the free crystalline form B of the compound represented by formula I, comprising concentrating a solution of the compound represented by formula I under reduced pressure and drying at 40-60° C. to obtain the free crystalline form B; the solution is an alcohol solution or a halogenated hydrocarbon solution.

[0044] Preferably, the compound represented by formula I is dissolved in MeOH or dichloromethane and then rotary evaporated under reduced pressure, and the obtained colloidal sample is transferred to 50° C. and dried under vacuum to obtain the product.

[0045] The present invention also provides a phosphate of the compound shown in formula I.

[0046] In one embodiment, the phosphate of the compound shown in Formula I is the phosphate crystal form A of the compound shown in Formula I. In the phosphate crystal form A, the phosphate crystal form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and has diffraction peaks at 6.74±0.2°, 13.47±0.2°, 15.69±0.2°, 16.86±0.2°, and 18.09±0.2°.

[0047] In one embodiment, the phosphate crystal form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, with diffraction peaks at 6.74±0.2°, 13.47±0.2°, 15.69±0.2°, 18.09±0.2°, and 20.26±0.2°.

[0048] In one embodiment, the X-ray powder diffraction pattern of the phosphate crystal form A using Cu-Kα radiation and expressed in 2θ angles also has diffraction peaks at one or more of the following positions: 11.87±0.2°, 12.56±0.2°, 13.75±0.2°, 18.60±0.2°, 20.26±0.2°, and 25.26±0.2°.

[0049] In one embodiment, the phosphate crystal form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and has diffraction peaks at 6.74±0.2°, 11.87±0.2°, 12.56±0.2°, 13.47±0.2°, 13.75±0.2°, 15.69±0.2°, 16.86±0.2°, 18.09±0.2°, and 20.26±0.2°.

[0050] In one embodiment, the phosphate crystalline form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and has diffraction peaks at 3.40±0.2°, 6.74±0.2°, 7.47±0.2°, 11.87±0.2°, 12.56±0.2°, 13.47±0.2°, 13.75±0.2°, 14.94±0.2°, 15.69±0.2°, 16.86±0.2°, 18.09±0.2°, 18.61±0.2°, 20.26±0.2°, and 25.26±0.2°.

[0051] In one embodiment, the X-ray powder diffraction pattern of the phosphate crystal form A using Cu-Kα radiation and expressed in 2θ angles comprises diffraction peak positions and relative intensities substantially as shown in Table 3:

[0052] Table 3

[0053] In one embodiment, the X-ray powder diffraction pattern of the phosphate crystal form A using Cu-Kα radiation and expressed in 2θ angles is substantially as shown in FIG. 7 .

[0054] In one embodiment, in the phosphate crystal form A, the molar ratio of the compound represented by formula I to phosphoric acid is 1:1.

[0055] In one embodiment, the differential scanning calorimetry analysis diagram of the phosphate crystal form A shows an endothermic peak starting point at 172.8±3°C.

[0056] In one embodiment, the phosphate crystal form A has an endothermic peak at 174.5±3°C in its differential scanning calorimetry analysis chart.

[0057] In one embodiment, the phosphate crystal form A has a weight loss of about 4.40% at 150° C. in a thermogravimetric analysis diagram.

[0058] In one embodiment, the differential scanning calorimetry analysis diagram of the phosphate crystal form A is substantially as shown in FIG9 .

[0059] In one embodiment, the thermogravimetric analysis diagram of the phosphate crystal form A is substantially as shown in FIG8 .

[0060] The present invention also provides a method for preparing the phosphate crystal form A of the compound shown in Formula I, comprising mixing the compound shown in Formula I, phosphoric acid, and a solvent, and slurrying at room temperature to obtain the phosphate crystal form A of the compound shown in Formula I;

[0061] The solvent is an ester solvent, an ether solvent, a mixed solvent of an alcohol solvent and water, or a mixed solvent of a ketone solvent and a saturated alkane solvent.

[0062] In one embodiment, the molar ratio of the phosphoric acid to the compound of formula I is 1.0-1.7, preferably 1.2.

[0063] In one embodiment, the molar ratio of the phosphoric acid to the compound of formula I is (1.0-1.7):1; preferably 1.2:1.

[0064] In one embodiment, the molar volume ratio of the compound represented by formula I to the solvent is 0.11-0.21 mol / L, preferably 0.16 mol / L.

[0065] In one embodiment, in the mixed solvent of the alcohol solvent and water, the volume ratio of the alcohol solvent to the water is (14-24):1, preferably 19:1.

[0066] In one embodiment, in the mixed solvent of the ketone solvent and the saturated alkane solvent, the volume ratio of the ketone solvent to the saturated alkane solvent is (0.5-2):1.

[0067] In one embodiment, the solvent is an IPA / H2O (19:1, v / v) mixed solvent, an acetone / n-heptane (1:1, v / v) mixed solvent, isopropyl acetate or methyl tert-butyl ether.

[0068] In one embodiment, the phosphate of the compound represented by Formula I is a phosphate crystal form B of the compound represented by Formula I. In the phosphate crystal form B, the phosphate crystal form B has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and has diffraction peaks at 6.68±0.2°, 13.37±0.2°, 14.16±0.2°, 15.30±0.2°, 16.74±0.2°, and 20.12±0.2°.

[0069] In one embodiment, the phosphate crystal form B is an anhydrous crystal form.

[0070] In one embodiment, in the phosphate crystal form B, the molar ratio of the compound represented by formula I to phosphoric acid is 1:1.

[0071] In one embodiment, the phosphate crystal form B uses Cu-Kα radiation and an X-ray powder diffraction pattern expressed in 2θ angles, and further has diffraction peaks at one or more of the following positions: 3.35±0.2°, 14.53±0.2°, 21.26±0.2°, 22.53±0.2°, 24.42±0.2°, and 25.24±0.2°.

[0072] In one embodiment, the phosphate crystal form B uses Cu-Kα radiation and an X-ray powder diffraction pattern expressed in 2θ angles, and further has diffraction peaks at one or more of the following positions: 3.35±0.2°, 14.53±0.2°, 21.27±0.2°, 22.53±0.2°, 24.43±0.2°, and 25.24±0.2°.

[0073] In one embodiment, the phosphate crystal form B has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, with diffraction peaks at 6.68±0.2°, 13.37±0.2°, 14.16±0.2°, 14.53±0.2°, 15.30±0.2°, 16.74±0.2°, 20.12±0.2°, and 21.26±0.2°.

[0074] In one embodiment, the phosphate form B has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and has diffraction peaks at 3.35±0.2°, 6.68±0.2°, 13.37±0.2°, 14.16±0.2°, 14.53±0.2°, 15.30±0.2°, 16.74±0.2°, 20.12±0.2°, 21.26±0.2°, 22.53±0.2°, 24.42±0.2°, and 25.24±0.2°.

[0075] In one embodiment, the X-ray powder diffraction pattern of the phosphate crystal form B using Cu-Kα radiation and expressed in 2θ angles comprises diffraction peak positions and relative intensities substantially as shown in Table 4:

[0076] Table 4

[0077] In one embodiment, the X-ray powder diffraction pattern of the phosphate crystal form B using Cu-Kα radiation and expressed in 2θ angles is substantially as shown in FIG. 11 .

[0078] The present invention also provides a method for preparing the phosphate crystal form B of the compound shown in Formula I, wherein the phosphate crystal form A is heated to 150±10° C. to obtain the phosphate crystal form B.

[0079] In one embodiment, the phosphate crystal form A is heated under nitrogen protection.

[0080] In one embodiment, the heating temperature is 145-155°C, preferably 150°C.

[0081] The present invention also provides a fumarate salt of the compound shown in Formula I.

[0082] In one embodiment, the fumarate salt of the compound represented by Formula I is a fumarate salt crystalline form A of the compound represented by Formula I, and the fumarate salt crystalline form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and has diffraction peaks at 13.51±0.2°, 15.41±0.2°, 17.57±0.2°, 19.48±0.2°, and 20.11±0.2°.

[0083] In one embodiment, the fumarate salt form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and further has diffraction peaks at one or more of the following positions: 9.03±0.2°, 9.78±0.2°, 16.89±0.2°, 22.04±0.2°, 23.71±0.2°, 24.24±0.2°, and 25.72±0.2°.

[0084] In one embodiment, the fumarate salt form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, with diffraction peaks at 9.03±0.2°, 9.78±0.2°, 13.51±0.2°, 15.41±0.2°, 16.89±0.2°, 17.57±0.2°, 19.48±0.2°, 20.11±0.2°, and 22.04±0.2°.

[0085] In one embodiment, the fumarate salt form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and has diffraction peaks at 9.03±0.2°, 9.78±0.2°, 13.51±0.2°, 15.41±0.2°, 16.89±0.2°, 17.57±0.2°, 19.48±0.2°, 20.11±0.2°, 22.04±0.2°, 23.71±0.2°, 24.24±0.2°, and 25.72±0.2°.

[0086] In one embodiment, the fumarate salt crystalline form A is an anhydrous crystalline form.

[0087] In one embodiment, in the fumarate salt crystalline form A, the molar ratio of the compound represented by formula I to fumaric acid is 1:1.

[0088] In one embodiment, the fumarate salt crystalline form A uses Cu-Kα radiation and an X-ray powder diffraction pattern expressed in 2θ angles, and the diffraction peak positions and relative intensities thereof are substantially as shown in Table 5:

[0089] Table 5

[0090] In one embodiment, the fumarate salt form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles as shown in FIG12 .

[0091] In one embodiment, the fumarate salt crystalline form A has a differential scanning calorimetry analysis chart showing an endothermic peak starting point at 128.2±3°C.

[0092] In one embodiment, the fumarate salt form A has an endothermic peak at 130.3±3° C. in its differential scanning calorimetry analysis chart.

[0093] In one embodiment, the fumarate salt crystalline form A has a weight loss of about 1.17% at 150° C. in a thermogravimetric analysis diagram.

[0094] In one embodiment, the differential scanning calorimetry analysis diagram of the fumarate salt form A is substantially as shown in FIG14 .

[0095] In one embodiment, the thermogravimetric analysis diagram of the fumarate salt form A is substantially as shown in FIG13 .

[0096] The present invention also provides a method for preparing a fumarate crystalline form A of a compound as shown in Formula I, comprising mixing the compound as shown in Formula I, fumaric acid, and a solvent, and slurrying at room temperature to obtain the fumarate crystalline form A; the solvent is an ester solvent, an ether solvent, a mixed solvent of an alcohol solvent and water, or a mixed solvent of a ketone solvent and a saturated alkane solvent.

[0097] In one embodiment, the molar ratio of the fumaric acid to the compound of formula I is 1.0-1.5, preferably 1.0.

[0098] In one embodiment, the molar ratio of the fumaric acid to the compound represented by formula I is (1.0-1.5):1; preferably 1.0:1.

[0099] In one embodiment, the molar volume ratio of the compound represented by formula I to the solvent is 0.06-0.16 mol / L, preferably 0.11 mol / L.

[0100] In one embodiment, in the mixed solvent of the alcohol solvent and water, the volume ratio of the alcohol solvent to the water is (14-24):1, preferably 19:1.

[0101] In one embodiment, in the mixed solvent of the ketone solvent and the saturated alkane solvent, the volume ratio of the ketone solvent to the saturated alkane solvent is (0.5-2):1.

[0102] In one embodiment, the solvent is an IPA / H2O (19:1, v / v) mixed solvent, an acetone / n-heptane (1:1, v / v) mixed solvent, isopropyl acetate or methyl tert-butyl ether.

[0103] The present invention also provides a p-toluenesulfonate salt of the compound represented by formula I.

[0104] In one embodiment, the p-toluenesulfonate salt of the compound represented by Formula I is the p-toluenesulfonate salt crystalline form A of the compound represented by Formula I. In the p-toluenesulfonate salt crystalline form A, the p-toluenesulfonate salt crystalline form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and has diffraction peaks at 5.41±0.2°, 8.10±0.2°, 14.74±0.2°, 17.13±0.2°, 18.10±0.2°, and 19.98±0.2°.

[0105] In one embodiment, the p-toluenesulfonate salt form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and further has diffraction peaks at one or more of the following positions: 10.81±0.2°, 18.83±0.2°, 21.83±0.2°, and 24.37±0.2°.

[0106] In one embodiment, the p-toluenesulfonate salt form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, with diffraction peaks at 5.41±0.2°, 7.74±0.2°, 8.10±0.2°, 10.81±0.2°, 14.74±0.2°, 17.13±0.2°, 18.10±0.2°, 18.83±0.2°, and 19.98±0.2°.

[0107] In one embodiment, the p-toluenesulfonate salt form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and has diffraction peaks at 5.41±0.2°, 7.74±0.2°, 8.10±0.2°, 10.81±0.2°, 14.74±0.2°, 17.13±0.2°, 18.10±0.2°, 18.83±0.2°, 19.98±0.2°, 21.01±0.2°, 21.83±0.2°, 22.85±0.2°, 23.41±0.2°, 24.37±0.2°, 26.18±0.2°, and 28.58±0.2°.

[0108] In one embodiment, in the p-toluenesulfonate crystalline form A, the molar ratio of the compound represented by Formula I to p-toluenesulfonic acid is 1:1.

[0109] In one embodiment, the p-toluenesulfonate salt form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and the diffraction peak positions and relative intensities thereof are substantially as shown in Table 6:

[0110] Table 6

[0111] In one embodiment, the p-toluenesulfonate crystalline form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles as shown in FIG16 .

[0112] In one embodiment, the p-toluenesulfonate crystalline form A has a differential scanning calorimetry analysis chart showing an endothermic peak starting point at 149.9±3°C.

[0113] In one embodiment, the p-toluenesulfonate crystalline form A has an endothermic peak at 152.1±3° C. in its differential scanning calorimetry analysis chart.

[0114] In one embodiment, the p-toluenesulfonate crystalline form A shows a weight loss of approximately 0.94% at 150° C. in a thermogravimetric analysis diagram.

[0115] In one embodiment, the differential scanning calorimetry analysis diagram of the p-toluenesulfonate crystalline form A is substantially as shown in FIG18 .

[0116] In one embodiment, the thermogravimetric analysis diagram of the p-toluenesulfonate crystalline form A is substantially as shown in FIG17 .

[0117] The present invention also provides a method for preparing the p-toluenesulfonate crystalline form A of the compound represented by formula I, comprising mixing the compound represented by formula I, p-toluenesulfonic acid, and a solvent, and slurrying at room temperature to obtain the p-toluenesulfonate crystalline form A;

[0118] The solvent is an ester solvent or an ether solvent.

[0119] In one embodiment, the molar ratio of p-toluenesulfonic acid to the compound of formula I is 1.0-1.5, preferably 1.0.

[0120] In one embodiment, the molar ratio of p-toluenesulfonic acid to the compound represented by Formula I is (1.0-1.5):1; preferably 1.0:1.

[0121] In one embodiment, the molar volume ratio of the compound represented by formula I to the solvent is 0.06-0.16 mol / L, preferably 0.11 mol / L.

[0122] In one embodiment, the solvent is isopropyl acetate or methyl tert-butyl ether.

[0123] The present invention also provides a benzenesulfonate salt of the compound shown in formula I.

[0124] In one embodiment, the benzenesulfonate salt of the compound represented by Formula I is a benzenesulfonate salt crystalline form A of the compound represented by Formula I. In the benzenesulfonate salt crystalline form A, the benzenesulfonate salt crystalline form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and has diffraction peaks at 4.29±0.2°, 8.49±0.2°, 10.02±0.2°, 13.81±0.2°, and 15.26±0.2°.

[0125] In one embodiment, the benzenesulfonate salt form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and further has diffraction peaks at one or more of the following positions: 10.68±0.2°, 16.80±0.2°, 18.80±0.2°, 19.73±0.2°, 20.53±0.2°, and 20.99±0.2°.

[0126] In one embodiment, the benzenesulfonate salt form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and has diffraction peaks at 4.29±0.2°, 8.49±0.2°, 10.02±0.2°, 10.68±0.2°, 13.81±0.2°, 15.26±0.2°, 16.80±0.2°, 18.80±0.2°, 19.73±0.2°, 20.53±0.2°, and 20.99±0.2°.

[0127] In one embodiment, the benzenesulfonate salt form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and has diffraction peaks at 4.29±0.2°, 5.75±0.2°, 8.49±0.2°, 10.02±0.2°, 10.68±0.2°, 11.18±0.2°, 11.48±0.2°, 12.70±0.2°, 13.81±0.2°, 15.26±0.2°, 16.80±0.2°, 18.80±0.2°, 19.73±0.2°, 20.53±0.2°, 20.99±0.2°, 21.95±0.2°, and 23.90±0.2°.

[0128] In one embodiment, in the benzenesulfonate salt crystalline form A, the molar ratio of the compound represented by formula I to benzenesulfonic acid is 1:1.

[0129] In one embodiment, the benzenesulfonate salt form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and the diffraction peak positions and relative intensities thereof are substantially as shown in Table 7:

[0130] Table 7

[0131] In one embodiment, the X-ray powder diffraction pattern of the benzenesulfonate salt form A using Cu-Kα radiation and expressed in 2θ angles is substantially as shown in Figure 19.

[0132] In one embodiment, the benzenesulfonate salt form A has a differential scanning calorimetry analysis chart showing an endothermic peak starting point at 144.5±3°C.

[0133] In one embodiment, the benzenesulfonate salt form A has an endothermic peak at 146.4±3° C. in its differential scanning calorimetry analysis chart.

[0134] In one embodiment, the benzenesulfonate salt crystal form A has a weight loss of about 1.28% at 140° C. in a thermogravimetric analysis diagram.

[0135] In one embodiment, the differential scanning calorimetry analysis diagram of the benzenesulfonate salt form A is substantially as shown in FIG21 .

[0136] In one embodiment, the thermogravimetric analysis diagram of the benzenesulfonate salt form A is substantially as shown in FIG20 .

[0137] The present invention also provides a method for preparing the benzenesulfonate crystalline form A of the compound represented by formula I, comprising mixing the compound represented by formula I, benzenesulfonic acid, and a solvent, and slurrying the mixture at room temperature to obtain the benzenesulfonate crystalline form A;

[0138] The solvent is a mixed solvent of an ester solvent, an alcohol solvent and water.

[0139] In one embodiment, the molar ratio of the benzenesulfonic acid to the compound of formula I is 1.0-1.5, preferably 1.0.

[0140] In one embodiment, the molar ratio of the benzenesulfonic acid to the compound of Formula I is (1.0-1.5); preferably 1.0:1.

[0141] In one embodiment, the molar volume ratio of the compound represented by formula I to the solvent is 0.06-0.16 mol / L, preferably 0.11 mol / L.

[0142] In one embodiment, in the mixed solvent of the alcohol solvent and water, the volume ratio of the alcohol solvent to the water is (14-24):1, preferably 19:1.

[0143] In one embodiment, the solvent is an IPA / H2O (19:1, v / v) mixed solvent or isopropyl acetate.

[0144] The present invention also provides an oxalate of the compound shown in Formula I.

[0145] In one embodiment, the oxalate of the compound of Formula I is oxalate crystal form A of the compound of Formula I, and the oxalate crystal form A comprises the compound of Formula I and oxalic acid;

[0146] The oxalate crystalline form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, with diffraction peaks at 7.32±0.2°, 8.47±0.2°, 14.62±0.2°, 17.00±0.2°, 18.58±0.2°, and 19.44±0.2°.

[0147] In one embodiment, the oxalate salt form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and has diffraction peaks at one or more of the following positions: 12.93±0.2°, 13.47±0.2°, 15.23±0.2°, 22.38±0.2°, and 26.00±0.2°.

[0148] In one embodiment, the oxalate salt form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and has diffraction peaks at 7.32±0.2°, 8.47±0.2°, 12.93±0.2°, 13.47±0.2°, 14.62±0.2°, 15.23±0.2°, 17.00±0.2°, 18.58±0.2°, 19.44±0.2°, 22.38±0.2°, and 26.00±0.2°.

[0149] In one embodiment, the oxalate salt form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and has diffraction peaks at 4.64±0.2°, 7.32±0.2°, 8.47±0.2°, 12.93±0.2°, 13.47±0.2°, 14.62±0.2°, 15.23±0.2°, 17.00±0.2°, 18.05±0.2°, 18.58±0.2°, 19.44±0.2°, 20.57±0.2°, 21.49±0.2°, 22.38±0.2°, 23.26±0.2°, 23.59±0.2°, and 26.00±0.2°.

[0150] In one embodiment, the X-ray powder diffraction pattern of the oxalate salt form A using Cu-Kα radiation and expressed in 2θ angles comprises diffraction peak positions and relative intensities substantially as shown in Table 8:

[0151] Table 8

[0152] In one embodiment, the X-ray powder diffraction pattern of the oxalate salt form A using Cu-Kα radiation and expressed in 2θ angles is substantially as shown in Figure 38.

[0153] In one embodiment, the oxalate crystal form A may have a differential scanning calorimetry analysis chart showing an endothermic peak starting point at 151.3±3°C.

[0154] In one embodiment, the oxalate salt form A has an endothermic peak at 153.6±3°C in its differential scanning calorimetry analysis chart.

[0155] In one embodiment, the oxalate crystal form A has an endothermic peak at 162.8±3°C in its differential scanning calorimetry analysis chart.

[0156] In one embodiment, the oxalate salt form A has an endothermic peak at 218.8±3°C in its differential scanning calorimetry analysis chart.

[0157] In one embodiment, the oxalate salt form A has a weight loss of about 4.10% at 150° C. in a thermogravimetric analysis diagram.

[0158] In one embodiment, the differential scanning calorimetry analysis diagram of the oxalate crystal form A is substantially as shown in FIG40 .

[0159] In one embodiment, the thermogravimetric analysis diagram of the oxalate crystal form A is basically as shown in Figure 39.

[0160] In one embodiment, the oxalate of the compound represented by Formula I is the oxalate crystal form B of the compound represented by Formula I, wherein the molar ratio of the compound represented by Formula I to oxalic acid in the oxalate crystal form B is 1:1;

[0161] Among them, the oxalate crystal form B uses Cu-Kα radiation and an X-ray powder diffraction pattern expressed in 2θ angles, with diffraction peaks at 7.63±0.2°, 8.32±0.2°, 15.25±0.2°, 16.29±0.2°, 22.05±0.2°, and 23.84±0.2°.

[0162] In one embodiment, the oxalate salt form B has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and has diffraction peaks at one or more of the following positions: 12.47±0.2°, 17.66±0.2°, 18.26±0.2°, 18.77±0.2°, and 19.16±0.2°.

[0163] In one embodiment, the oxalate salt form B has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and has diffraction peaks at 7.63±0.2°, 8.32±0.2°, 12.47±0.2°, 15.25±0.2°, 16.29±0.2°, 17.66±0.2°, 18.26±0.2°, 18.77±0.2°, 19.16±0.2°, 22.05±0.2°, and 23.84±0.2°.

[0164] In one embodiment, the oxalate salt form B has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and has diffraction peaks at 7.63±0.2°, 8.32±0.2°, 12.47±0.2°, 15.25±0.2°, 16.29±0.2°, 17.66±0.2°, 18.26±0.2°, 18.77±0.2°, 19.16±0.2°, 19.92±0.2°, 20.83±0.2°, 21.28±0.2°, 22.05±0.2°, 23.84±0.2°, 25.05±0.2°, 26.40±0.2°, 27.41±0.2°, and 29.25±0.2°.

[0165] In one embodiment, in the oxalate salt form B, the molar ratio of the compound represented by formula I to oxalic acid is 1:1.

[0166] In one embodiment, the X-ray powder diffraction pattern of the oxalate crystalline form B using Cu-Kα radiation and expressed in 2θ angles comprises diffraction peak positions and relative intensities substantially as shown in Table 9:

[0167] Table 9

[0168] In one embodiment, the X-ray powder diffraction pattern of the oxalate salt form B using Cu-Kα radiation and expressed in 2θ angles is substantially as shown in Figure 22.

[0169] In one embodiment, the oxalate crystal form B has a differential scanning calorimetry analysis chart showing an endothermic peak starting point at 155.5±3°C.

[0170] In one embodiment, the oxalate crystal form B has an endothermic peak at 158.2±3°C in its differential scanning calorimetry analysis chart.

[0171] In one embodiment, the oxalate crystal form B has an endothermic peak at 218.7±3°C in its differential scanning calorimetry analysis chart.

[0172] In one embodiment, the oxalate salt form B has a weight loss of about 1.21% at 150° C. in a thermogravimetric analysis diagram.

[0173] In one embodiment, the differential scanning calorimetry analysis diagram of the oxalate crystal form B is substantially as shown in FIG24 .

[0174] In one embodiment, the thermogravimetric analysis diagram of the oxalate crystal form B is substantially as shown in FIG23 .

[0175] The present invention also provides a method for preparing the oxalate crystal form A of the compound represented by formula I, comprising mixing the compound represented by formula I, oxalic acid, and a solvent, and slurrying at room temperature to obtain the oxalate crystal form A;

[0176] The solvent is a mixed solvent of an alcohol solvent and water.

[0177] In one embodiment, the molar ratio of oxalic acid to the compound of formula I is 1.0-1.5, preferably 1.0.

[0178] In one embodiment, the molar ratio of oxalic acid to the compound represented by Formula I is (1.0-1.5):1; preferably 1.0:1.

[0179] In a certain embodiment, in the mixed solvent of the alcohol solvent and water, the volume ratio of the alcohol solvent to the water is (14-24):1, preferably 19:1.

[0180] In one embodiment, the solvent is a mixed solvent of IPA / H2O (19:1, v / v).

[0181] The present invention also provides a method for preparing the oxalate crystal form B of the compound represented by formula I, comprising mixing the compound represented by formula I, oxalic acid, and a solvent, and slurrying the mixture at room temperature to obtain the oxalate crystal form B;

[0182] The solvent is a mixed solvent of ester solvents, ether solvents, ketone solvents and saturated alkane solvents.

[0183] In one embodiment, the molar ratio of oxalic acid to the compound represented by formula I is 1.0-1.5, preferably 1.0.

[0184] In one embodiment, the molar ratio of oxalic acid to the compound represented by Formula I is (1.0-1.5):1; preferably 1.0:1.

[0185] In one embodiment, the molar volume ratio of the compound represented by formula I to the solvent is 0.02-0.08 mol / L, preferably 0.05 mol / L.

[0186] In one embodiment, in the mixed solvent of the ketone solvent and the saturated alkane solvent, the volume ratio of the ketone solvent to the saturated alkane solvent is (0.5-2):1.

[0187] In one embodiment, the solvent is an acetone / n-heptane (1:1, v / v) mixed solvent, isopropyl acetate or methyl tert-butyl ether.

[0188] The present invention also provides a maleate salt of the compound shown in Formula I.

[0189] In one embodiment, the maleate salt of the compound represented by Formula I is a maleate salt crystalline form A of the compound represented by Formula I. In the maleate salt crystalline form A, the maleate salt crystalline form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and has diffraction peaks at 13.54±0.2°, 16.92±0.2°, 17.64±0.2°, 19.61±0.2°, and 23.77±0.2°.

[0190] In one embodiment, the maleate salt form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and further has diffraction peaks at one or more of the following positions: 3.44±0.2°, 9.64±0.2°, 18.08±0.2°, 20.82±0.2°, and 27.20±0.2°.

[0191] In one embodiment, the maleate salt form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, with diffraction peaks at 3.44±0.2°, 9.64±0.2°, 13.54±0.2°, 16.92±0.2°, 17.64±0.2°, 18.08±0.2°, 19.61±0.2°, 20.82±0.2°, 23.77±0.2°, and 27.20±0.2°.

[0192] In one embodiment, the maleate salt form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and has diffraction peaks at 3.44±0.2°, 9.64±0.2°, 13.54±0.2°, 16.92±0.2°, 17.64±0.2°, 18.08±0.2°, 19.61±0.2°, 20.82±0.2°, 22.36±0.2°, 22.71±0.2°, 23.77±0.2°, 27.20±0.2°, 28.90±0.2°, and 30.67±0.2°.

[0193] In one embodiment, in the maleate salt crystalline form A, the molar ratio of the compound represented by formula I to maleic acid is 1:1.

[0194] In one embodiment, the maleate salt crystalline form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and the diffraction peak positions and relative intensities thereof are substantially as shown in Table 10:

[0195] Table 10

[0196] In one embodiment, the maleate salt form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles as shown in Figure 25.

[0197] In one embodiment, the maleate salt crystalline form A has a differential scanning calorimetry analysis chart showing an endothermic peak starting point at 123.4±3°C.

[0198] In one embodiment, the maleate salt form A has an endothermic peak at 125.2±3°C in its differential scanning calorimetry analysis chart.

[0199] In one embodiment, the maleate salt crystalline form A has a weight loss of about 2.56% at 120° C. in a thermogravimetric analysis diagram.

[0200] In one embodiment, the differential scanning calorimetry analysis diagram of the maleate salt form A is substantially as shown in FIG27 .

[0201] In one embodiment, the thermogravimetric analysis diagram of the maleate salt form A is substantially as shown in FIG26 .

[0202] The present invention also provides a method for preparing the maleate crystalline form A of the compound represented by formula I, comprising mixing the compound represented by formula I, maleic acid, and a solvent, and slurrying the mixture at room temperature to obtain the maleate crystalline form A;

[0203] The solvent is a mixed solvent of ester solvents, ether solvents, ketone solvents and saturated alkane solvents.

[0204] In one embodiment, the molar ratio of maleic acid to the compound of formula I is 1.0-1.5, preferably 1.0.

[0205] In one embodiment, the molar ratio of maleic acid to the compound of formula I is (1.0-1.5):1; preferably 1.0:1.

[0206] In one embodiment, in the mixed solvent of the ketone solvent and the saturated alkane solvent, the volume ratio of the ketone solvent to the saturated alkane solvent is (0.5-2):1.

[0207] In one embodiment, the solvent is an acetone / n-heptane (1:1, v / v) mixed solvent, isopropyl acetate or methyl tert-butyl ether.

[0208] The present invention also provides a malate salt of the compound represented by formula I.

[0209] In one embodiment, the malate salt of the compound represented by Formula I is malate crystalline form A of the compound represented by Formula I. In the malate crystalline form A, the malate crystalline form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and has diffraction peaks at 8.95±0.2°, 9.89±0.2°, 13.21±0.2°, 16.53±0.2°, and 18.93±0.2°.

[0210] In one embodiment, the malate salt form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, with diffraction peaks at 8.95±0.2°, 9.89±0.2°, 13.21±0.2°, 16.17±0.2°, 16.53±0.2°, 18.93±0.2°, and 24.77±0.2°.

[0211] In one embodiment, the malate salt form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and has diffraction peaks at 6.63±0.2°, 8.95±0.2°, 9.89±0.2°, 13.21±0.2°, 16.17±0.2°, 16.53±0.2°, 18.93±0.2°, 21.62±0.2°, 23.20±0.2°, 23.80±0.2°, and 24.77±0.2°.

[0212] In one embodiment, in the malate crystalline form A, the molar ratio of the compound represented by formula I to malic acid is 1:1.

[0213] In one embodiment, the malate crystalline form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and the diffraction peak positions and relative intensities thereof are substantially as shown in Table 11:

[0214] Table 11

[0215] In one embodiment, the malate crystalline form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles as shown in Figure 28.

[0216] In one embodiment, the malate crystalline form A has a differential scanning calorimetry analysis chart showing an endothermic peak starting point at 86.3±3°C.

[0217] In one embodiment, the malate crystalline form A has an endothermic peak at 96.3±3° C. in its differential scanning calorimetry analysis chart.

[0218] In one embodiment, the malate crystalline form A shows a weight loss of about 2.26% at 150° C. in a thermogravimetric analysis diagram.

[0219] In one embodiment, the differential scanning calorimetry analysis diagram of the malate salt form A is substantially as shown in FIG30 .

[0220] In one embodiment, the thermogravimetric analysis diagram of the malate crystalline form A is substantially as shown in FIG29 .

[0221] The present invention also provides a method for preparing the malate crystalline form A of the compound represented by formula I, comprising mixing the compound represented by formula I, malic acid, and a solvent, and slurrying the mixture at room temperature to obtain the malate crystalline form A;

[0222] The solvent is a mixed solvent of a ketone solvent and a saturated alkane solvent.

[0223] In one embodiment, the molar ratio of malic acid to the compound represented by formula I is 1.0-1.5, preferably 1.0.

[0224] In one embodiment, the molar ratio of malic acid to the compound represented by formula I is (1.0-1.5):1; preferably 1.0:1.

[0225] In one embodiment, in the mixed solvent of the ketone solvent and the saturated alkane solvent, the volume ratio of the ketone solvent to the saturated alkane solvent is (0.5-2):1, preferably 1:1.

[0226] In one embodiment, the solvent is a mixed solvent of acetone / n-heptane (1:1, v / v).

[0227] The present invention also provides a succinate salt of the compound shown in formula I.

[0228] In one embodiment, the succinate salt of the compound represented by Formula I is a succinate salt crystal form A of the compound represented by Formula I, wherein the succinate salt crystal form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and has diffraction peaks at 6.94±0.2°, 9.20±0.2°, 13.87±0.2°, 16.29±0.2°, 17.94±0.2°, and 20.21±0.2°.

[0229] In one embodiment, the succinate salt form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and further has diffraction peaks at one or more of the following positions: 14.70±0.2°, 17.40±0.2°, 19.48±0.2°, 20.96±0.2°, 22.18±0.2°, 23.04±0.2°, 23.92±0.2°, and 26.18±0.2°.

[0230] In one embodiment, the succinate salt form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and has diffraction peaks at 6.94±0.2°, 9.20±0.2°, 13.87±0.2°, 16.29±0.2°, 17.94±0.2°, 20.21±0.2°, 20.96±0.2°, 22.18±0.2°, and 26.18±0.2°.

[0231] In one embodiment, the succinate salt form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and has diffraction peaks at 6.94±0.2°, 9.20±0.2°, 13.87±0.2°, 14.70±0.2°, 16.29±0.2°, 17.40±0.2°, 17.94±0.2°, 19.48±0.2°, 20.21±0.2°, 20.96±0.2°, 22.18±0.2°, 23.04±0.2°, 23.92±0.2°, and 26.18±0.2°.

[0232] In one embodiment, in the succinate salt crystal form A, the molar ratio of the compound represented by formula I to succinic acid is 1:1.

[0233] In one embodiment, the X-ray powder diffraction pattern of the succinate salt form A using Cu-Kα radiation and expressed in 2θ angles comprises diffraction peak positions and relative intensities substantially as shown in Table 12:

[0234] Table 12

[0235] In one embodiment, in the succinate salt crystalline form A, the molar ratio of the compound represented by formula I to succinic acid is 1:1.2, 1:1.1 or 1:1.

[0236] In one embodiment, the X-ray powder diffraction pattern of the succinate salt form A using Cu-Kα radiation and expressed in 2θ angles is substantially as shown in Figure 31.

[0237] In one embodiment, the differential scanning calorimetry analysis diagram of the succinate salt form A shows an endothermic peak starting point at 75.9±3°C.

[0238] In one embodiment, the succinate salt form A has an endothermic peak at 85.4±3° C. in its differential scanning calorimetry analysis chart.

[0239] In one embodiment, the succinate salt crystal form A has a weight loss of about 4.49% at 150° C. in a thermogravimetric analysis diagram.

[0240] In one embodiment, the differential scanning calorimetry analysis diagram of the succinate salt form A is substantially as shown in FIG33 .

[0241] In one embodiment, the thermogravimetric analysis diagram of the succinate salt form A is substantially as shown in FIG32 .

[0242] The present invention also provides a method for preparing the succinate salt crystal form A of the compound represented by formula I, comprising mixing the compound represented by formula I, succinic acid, and a solvent, and slurrying the mixture at room temperature to obtain the succinate salt crystal form A;

[0243] The solvent is an ether solvent.

[0244] In one embodiment, the molar ratio of succinic acid to the compound represented by formula I is 1.0-1.5, preferably 1.0.

[0245] In one embodiment, the molar ratio of succinic acid to the compound represented by Formula I is (1.0-1.5):1; preferably 1.0:1.

[0246] In one embodiment, the solvent is methyl tert-butyl ether.

[0247] The present invention also provides a methanesulfonate salt of the compound shown in Formula I.

[0248] In one embodiment, the mesylate salt of the compound represented by Formula I is a mesylate salt crystalline form A of the compound represented by Formula I, wherein the mesylate salt crystalline form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and has diffraction peaks at 5.03±0.2°, 17.03±0.2°, 18.11±0.2°, 20.60±0.2°, and 23.40±0.2°.

[0249] In one embodiment, the X-ray powder diffraction pattern of the mesylate salt form A using Cu-Kα radiation and expressed in 2θ angles comprises diffraction peak positions and relative intensities substantially as shown in Table 13:

[0250] Table 13

[0251] In one embodiment, the X-ray powder diffraction pattern of the mesylate salt form A using Cu-Kα radiation and expressed in 2θ angles is substantially as shown in Figure 34.

[0252] In one embodiment, the mesylate salt of the compound represented by Formula I is a mesylate salt crystalline form B of the compound represented by Formula I, and the mesylate salt crystalline form B has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and has diffraction peaks at 18.89±0.2°, 20.43±0.2°, 21.07±0.2°, 23.44±0.2°, and 24.46±0.2°.

[0253] In one embodiment, the mesylate salt form B has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and further has diffraction peaks at one or more of the following positions: 9.76±0.2°, 11.32±0.2°, 15.46±0.2°, and 17.26±0.2°.

[0254] In one embodiment, the mesylate salt form B has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and further has diffraction peaks at one or more of the following positions: 9.83±0.2°, 11.32±0.2°, 15.46±0.2°, and 17.26±0.2°.

[0255] In one embodiment, the mesylate salt form B has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, with diffraction peaks at 9.76±0.2°, 11.32±0.2°, 15.46±0.2°, 17.26±0.2°, 18.89±0.2°, 20.43±0.2°, 21.07±0.2°, 23.44±0.2°, and 24.46±0.2°.

[0256] In one embodiment, the mesylate salt form B has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, with diffraction peaks at 9.83±0.2°, 11.32±0.2°, 15.46±0.2°, 17.26±0.2°, 18.89±0.2°, 20.43±0.2°, 21.07±0.2°, 23.44±0.2°, and 24.46±0.2°.

[0257] In one embodiment, the mesylate salt form B has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and has diffraction peaks at 9.76±0.2°, 11.32±0.2°, 15.46±0.2°, 16.98±0.2°, 17.26±0.2°, 17.63±0.2°, 18.89±0.2°, 19.68±0.2°, 20.43±0.2°, 21.07±0.2°, 21.58±0.2°, 22.09±0.2°, 22.69±0.2°, 23.44±0.2°, and 24.46±0.2°.

[0258] In one embodiment, the mesylate salt form B has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and has diffraction peaks at 9.83±0.2°, 11.32±0.2°, 15.46±0.2°, 16.98±0.2°, 17.26±0.2°, 17.63±0.2°, 18.89±0.2°, 19.68±0.2°, 20.43±0.2°, 21.07±0.2°, 21.58±0.2°, 22.09±0.2°, 22.69±0.2°, 23.44±0.2°, and 24.46±0.2°.

[0259] In one embodiment, in the mesylate salt crystalline form B, the molar ratio of the compound represented by formula I to methanesulfonic acid is 1:2.

[0260] In one embodiment, the mesylate salt form B has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and the diffraction peak positions and relative intensities thereof are substantially as shown in Table 14:

[0261] Table 14

[0262] In one embodiment, in the mesylate salt crystalline form B, the molar ratio of the compound represented by formula I to methanesulfonic acid is 1:2.1 or 1:2.

[0263] In one embodiment, the mesylate salt form B has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles as shown in Figure 35.

[0264] In one embodiment, the mesylate salt form B has a differential scanning calorimetry analysis chart showing an endothermic peak starting point at 97.3±3°C.

[0265] In one embodiment, the mesylate salt form B has an endothermic peak at 109.4±3° C. in its differential scanning calorimetry analysis chart.

[0266] In one embodiment, the mesylate salt form B has a weight loss of about 0.91% at 80°C and a weight loss of about 2.40% at 80-130°C according to a thermogravimetric analysis.

[0267] In one embodiment, the differential scanning calorimetry analysis diagram of the mesylate salt form B is substantially as shown in FIG37 .

[0268] In one embodiment, the thermogravimetric analysis diagram of the mesylate salt form B is substantially as shown in FIG36 .

[0269] The present invention also provides a method for preparing the mesylate crystalline form A of the compound represented by formula I, comprising mixing the compound represented by formula I, methanesulfonic acid, and a solvent, and slurrying at room temperature to obtain the mesylate crystalline form A;

[0270] The solvent is a mixed solvent of a ketone solvent and a saturated alkane solvent.

[0271] In one embodiment, the molar ratio of the methanesulfonic acid to the compound represented by formula I is (1.0-1.2):1; preferably 1:1.

[0272] In one embodiment, in the mixed solvent of the ketone solvent and the saturated alkane solvent, the volume ratio of the ketone solvent to the saturated alkane solvent is (0.5-2):1, preferably 1:1.

[0273] In one embodiment, the solvent is a mixed solvent of acetone / n-heptane (1:1, v / v).

[0274] The present invention also provides a method for preparing the mesylate crystal form B of the compound shown in Formula I, comprising mixing the compound shown in Formula I, methanesulfonic acid, and a solvent, and slurrying at room temperature to obtain the mesylate crystal form B;

[0275] The solvent is a mixed solvent of ester solvents, ether solvents, ketone solvents and saturated alkane solvents.

[0276] In one embodiment, the molar ratio of methanesulfonic acid to the compound represented by formula I is (1.5-2.5):1; preferably 2:1.

[0277] In one embodiment, in the mixed solvent of the ketone solvent and the saturated alkane solvent, the volume ratio of the ketone solvent to the saturated alkane solvent is (0.5-2):1.

[0278] In one embodiment, the solvent is an acetone / n-heptane (1:1, v / v) mixed solvent, isopropyl acetate or methyl tert-butyl ether.

[0279] The present invention also provides a 2-hydroxyethanesulfonate salt of the compound shown in Formula I.

[0280] In one embodiment, the 2-hydroxyethanesulfonate salt of the compound represented by Formula I is a 2-hydroxyethanesulfonate salt form A of the compound represented by Formula I, and the 2-hydroxyethanesulfonate salt form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and has diffraction peaks at 4.85±0.2°, 9.85±0.2°, 10.98±0.2°, 18.09±0.2°, 19.35±0.2°, and 20.33±0.2°.

[0281] In one embodiment, the 2-hydroxyethanesulfonate salt form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and further has diffraction peaks at one or more of the following positions: 15.54±0.2°, 15.94±0.2°, 21.83±0.2°, 22.33±0.2°, and 22.87±0.2°.

[0282] In one embodiment, the 2-hydroxyethanesulfonate salt form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and has diffraction peaks at 4.85±0.2°, 9.85±0.2°, 10.98±0.2°, 15.54±0.2°, 15.94±0.2°, 18.09±0.2°, 19.35±0.2°, 20.33±0.2°, 21.83±0.2°, 22.33±0.2°, and 22.87±0.2°.

[0283] In one embodiment, the 2-hydroxyethanesulfonate salt form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, and has diffraction peaks at 4.85±0.2°, 9.85±0.2°, 10.98±0.2°, 12.83±0.2°, 15.54±0.2°, 15.94±0.2°, 16.66±0.2°, 18.09±0.2°, 19.35±0.2°, 20.33±0.2°, 21.83±0.2°, 22.33±0.2°, and 22.87±0.2°.

[0284] In one embodiment, in the 2-hydroxyethanesulfonate salt form A, the molar ratio of the compound represented by formula I to 2-hydroxyethanesulfonic acid is 1:1.

[0285] In one embodiment, the X-ray powder diffraction pattern of the 2-hydroxyethanesulfonate salt form A using Cu-Kα radiation and expressed in 2θ angles comprises diffraction peak positions and relative intensities substantially as shown in Table 15:

[0286] Table 15

[0287] In one embodiment, the X-ray powder diffraction pattern of the 2-hydroxyethanesulfonate salt form A using Cu-Kα radiation and expressed in 2θ angles is substantially as shown in Figure 41.

[0288] In one embodiment, the differential scanning calorimetry analysis diagram of the 2-hydroxyethanesulfonate salt form A shows an endothermic peak starting point at 109.5±3°C.

[0289] In one embodiment, the 2-hydroxyethanesulfonate salt form A has an endothermic peak at 118.4±3° C. in its differential scanning calorimetry analysis chart.

[0290] In one embodiment, the 2-hydroxyethanesulfonate salt form A has a weight loss of about 1.28% at 110° C. in a thermogravimetric analysis diagram.

[0291] In one embodiment, the differential scanning calorimetry analysis diagram of the 2-hydroxyethanesulfonate salt form A is substantially as shown in FIG43 .

[0292] In one embodiment, the thermogravimetric analysis diagram of the 2-hydroxyethanesulfonate salt form A is substantially as shown in FIG42 .

[0293] The present invention also provides a method for preparing the crystalline form A of the 2-hydroxyethanesulfonate of the compound represented by Formula I, comprising mixing the compound represented by Formula I, 2-hydroxyethanesulfonic acid, and a solvent, and slurrying the mixture at room temperature to obtain the crystalline form A of the 2-hydroxyethanesulfonate;

[0294] The solvent is a mixed solvent of an ester solvent, a ketone solvent and a saturated alkane solvent.

[0295] In one embodiment, the molar ratio of the 2-hydroxyethanesulfonic acid to the compound represented by Formula I is (1.5-2.5):1; preferably 2:1.

[0296] In one embodiment, in the mixed solvent of the ketone solvent and the saturated alkane solvent, the volume ratio of the ketone solvent to the saturated alkane solvent is (0.5-2):1.

[0297] In one embodiment, the solvent is a mixed solvent of acetone / n-heptane (1:1, v / v) or isopropyl acetate.

[0298] The present invention also provides a pharmaceutical composition comprising any of the above-mentioned crystal forms or salt forms of the compound represented by Formula I, and at least one pharmaceutical excipient.

[0299] The selection of the pharmaceutical excipients varies depending on the route of administration and the characteristics of the action, and can generally be fillers, diluents, binders, wetting agents, disintegrants, lubricants, emulsifiers, suspending agents, etc. conventional in the art.

[0300] The present invention also provides a use of a substance M, wherein the substance M is any of the above-mentioned crystal forms, salt forms or pharmaceutical compositions of the compound represented by formula I.

[0301] The uses include:

[0302] 1) Inhibit tubulin polymerization and / or Src kinase;

[0303] 2) preventing and / or treating diseases related to tubulin polymerization and / or Src kinase;

[0304] 3) Preparation of tubulin polymerization and / or Src kinase inhibitors;

[0305] 4) Preparation of drugs or preparations for preventing and / or treating diseases related to tubulin polymerization and / or Src kinase.

[0306] Preferably, the use includes: inhibiting tubulin polymerization; and / or preventing and / or treating diseases mediated by tubulin polymerization; and / or preparing tubulin polymerization inhibitors, and / or preventing and / or treating drugs, pharmaceutical compositions or preparations for diseases mediated by tubulin polymerization.

[0307] Preferably, the use includes: inhibiting Src kinase; and / or preventing and / or treating diseases mediated by Src kinase; and / or preparing Src kinase inhibitors; and / or preparing drugs, pharmaceutical compositions or preparations for preventing and / or treating diseases mediated by Src kinase.

[0308] Preferably, the drug is an external preparation.

[0309] Preferably, the drug is a transdermal drug.

[0310] Preferably, the diseases related to tubulin polymerization and / or Src kinase include tumors and skin diseases.

[0311] The present invention also provides a use of a substance M, wherein the substance M is any of the above-mentioned crystal forms, salt forms or pharmaceutical compositions of the compound represented by formula I.

[0312] The use is in the preparation of medicines for treating or preventing tumors and / or skin diseases.

[0313] Preferably, the tumor includes: solid tumor, sarcoma, hematological cancer;

[0314] More preferably, the tumor comprises: breast cancer, ovarian cancer, prostate cancer, cervical cancer, testicular cancer, colon cancer, colorectal cancer, liver cancer, non-small cell lung cancer, squamous cell carcinoma (e.g., squamous cell carcinoma of the skin), small cell lung cancer, gastric cancer, gastrointestinal stromal tumor, pancreatic cancer, bladder cancer, germ cell tumor, mast cell tumor, mastocytosis, glioblastoma, neuroblastoma, astrocytoma, melanoma, B cell lymphoma, T cell lymphoma, slowly progressive lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, myeloma and / or myelodysplastic syndrome.

[0315] Preferably, the skin disease includes actinic keratosis, psoriasis, atopic dermatitis, psoriasis, vitiligo, roseola and / or systemic lupus erythematosus.

[0316] Preferably, the drug is an external preparation.

[0317] Preferably, the drug is a transdermal drug.

[0318] The present invention also provides a use of at least one of the crystal forms or salt forms of the compound represented by Formula I for treating or preventing tumors and / or skin diseases.

[0319] Preferably, the tumor includes: solid tumor, sarcoma, hematological cancer;

[0320] More preferably, the tumor comprises: breast cancer, ovarian cancer, prostate cancer, cervical cancer, testicular cancer, colon cancer, colorectal cancer, liver cancer, non-small cell lung cancer, squamous cell carcinoma (e.g., cutaneous squamous cell carcinoma), small cell lung cancer, gastric cancer, gastrointestinal stromal tumor, pancreatic cancer, bladder cancer, germ cell tumor, mast cell tumor, mastocytosis, glioblastoma, neuroblastoma, astrocytoma, melanoma, B cell lymphoma, T cell lymphoma, slowly progressive lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, myeloma and / or myelodysplastic syndrome.

[0321] Preferably, the skin disease includes actinic keratosis, psoriasis, atopic dermatitis, psoriasis, vitiligo, roseola and / or systemic lupus erythematosus.

[0322] The present invention also provides a method for inhibiting Src kinase, or preventing and / or treating Src kinase-related (or mediated) diseases, comprising the steps of administering the above-mentioned crystal form and / or salt form to a subject in need thereof.

[0323] The present invention also provides a method for inhibiting tubulin, or preventing and / or treating diseases associated with (or mediated by) tubulin, comprising the steps of administering the crystal form and / or salt form of the present invention to a subject in need thereof.

[0324] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0325] the term

[0326] When the terms "about" and "approximately" are used in reference to XRPD peaks, these terms mean that the error of the referenced X-ray powder diffraction peak position [°2θ] is: ±0.3, ±0.2 or ±0.1, preferably ±0.2, more preferably ±0.1.

[0327] When referring to XRPD peak positions, 2θ angles may be rounded to 2 or 4 significant figures after the decimal point.

[0328] When the terms "about" and "approximately" are used in reference to a temperature or a temperature range, these terms mean that the error of the referenced temperature or temperature range is: ±5°C, ±3°C, ±2°C, or ±1°C, preferably ±3°C.

[0329] The reagents and raw materials used in the present invention are commercially available.

[0330] The present invention provides a compound, salt form, and crystal form for use as a dual-target tubulin-Src kinase inhibitor. The compound has the structure of Formula I as described herein. The compound, salt form, and crystal form can be used as a dual-target tubulin and Src kinase inhibitor, or as a single tubulin or Src kinase inhibitor. The compound can significantly inhibit the polymerization of tubulin monomers and cell proliferation. It exhibits excellent pharmacokinetic properties for topical skin administration and good drugability. It can be used to prepare topical skin preparations, exhibiting rapid metabolism and minimal side effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0331] Figure 1 XRPD pattern of free form A;

[0332] Figure 2 TGA diagram of free form A;

[0333] FIG3 is a DSC diagram of free form A;

[0334] FIG4 is an XRPD pattern of free form B;

[0335] FIG5 is a TGA diagram of free form B;

[0336] FIG6 is a DSC diagram of free form B;

[0337] Figure 7 XRPD pattern of phosphate crystal form A;

[0338] Figure 8 TGA diagram of phosphate crystal form A;

[0339] Figure 9 DSC diagram of phosphate crystal form A;

[0340] Figure 10 VT-XRPD pattern of phosphate crystal form A;

[0341] Figure 11 is an XRPD pattern of phosphate crystal form B;

[0342] Figure 12 XRPD pattern of fumarate salt Form A;

[0343] Figure 13 is a TGA diagram of the fumarate salt form A;

[0344] Figure 14 is a DSC diagram of the fumarate salt form A;

[0345] Figure 15 VH-XRPD pattern of fumarate salt Form A;

[0346] Figure 16 XRPD pattern of p-toluenesulfonate salt Form A;

[0347] Figure 17 is a TGA diagram of p-toluenesulfonate Form A;

[0348] Figure 18 DSC diagram of p-toluenesulfonate Form A;

[0349] Figure 19 is an XRPD pattern of benzenesulfonate salt Form A;

[0350] Figure 20 is a TGA diagram of benzenesulfonate salt Form A;

[0351] Figure 21 DSC diagram of benzenesulfonate salt Form A;

[0352] Figure 22 XRPD pattern of oxalate salt Form B;

[0353] Figure 23 is a TGA diagram of oxalate salt Form B;

[0354] Figure 24 is a DSC diagram of oxalate salt Form B;

[0355] Figure 25 XRPD pattern of maleate salt Form A;

[0356] Figure 26 TGA diagram of maleate salt Form A;

[0357] Figure 27 DSC diagram of maleate salt Form A;

[0358] Figure 28 XRPD pattern of malate salt Form A;

[0359] Figure 29 is a TGA diagram of malate crystal form A;

[0360] Figure 30 DSC diagram of malate crystal form A;

[0361] Figure 31 is an XRPD pattern of succinate salt Form A;

[0362] Figure 32 is a TGA diagram of succinate salt Form A;

[0363] Figure 33 is a DSC diagram of succinate salt Form A;

[0364] Figure 34 XRPD pattern of mesylate salt Form A;

[0365] Figure 35 is an XRPD pattern of mesylate salt Form B;

[0366] Figure 36 is a TGA diagram of mesylate salt Form B;

[0367] Figure 37 DSC diagram of mesylate salt Form B;

[0368] Figure 38 XRPD pattern of oxalate salt Form A;

[0369] Figure 39 is a TGA diagram of oxalate salt form A;

[0370] Figure 40 is a DSC diagram of oxalate salt Form A;

[0371] Figure 41 is an XRPD pattern of 2-hydroxyethanesulfonate Form A;

[0372] Figure 42 is a TGA diagram of 2-hydroxyethanesulfonate Form A;

[0373] Figure 43 DSC diagram of 2-hydroxyethanesulfonate Form A;

[0374] Figure 44 Dynamic solubility curve in water at 37°C;

[0375] Figure 45 Dynamic solubility curve in SGF at 37°C;

[0376] Figure 46 Dynamic solubility curve in FaSSIF at 37°C;

[0377] Figure 47 Dynamic solubility curve in FeSSIF at 37°C;

[0378] Figure 48 is a DVS image of the free form A;

[0379] Figure 49: XRPD stacked images of free form A before and after DVS testing;

[0380] Figure 50 is a DVS image of phosphate crystal form A;

[0381] Figure 51 XRPD overlay of phosphate crystal form A before and after DVS testing;

[0382] Figure 52 DVS image of fumarate salt Form A;

[0383] Figure 53 XRPD overlay of fumarate salt Form A before and after DVS testing;

[0384] Figure 54 is a DVS diagram of p-toluenesulfonate Form A;

[0385] Figure 55 is an XRPD overlay of p-toluenesulfonate Form A before and after DVS testing;

[0386] Figure 56 DVS diagram of benzenesulfonate salt Form A;

[0387] Figure 57 XRPD overlay of benzenesulfonate salt Form A before and after DVS testing;

[0388] Figure 58 DVS image of oxalate salt form B;

[0389] Figure 59 is an XRPD overlay of oxalate Form B before and after DVS testing;

[0390] Figure 60 is an XRPD overlay of the stability evaluation sample of free form A;

[0391] Figure 61 is an XRPD overlay of a stability evaluation sample of the phosphate crystal form A;

[0392] Figure 62 is an XRPD overlay of the stability evaluation sample of the fumarate salt Form A;

[0393] Figure 63 is an XRPD overlay of the p-toluenesulfonate Form A stability evaluation sample;

[0394] Figure 64 is an XRPD overlay of the stability evaluation sample of the besylate salt Form A;

[0395] Figure 65 is an XRPD overlay of the stability evaluation sample of the oxalate salt Form B;

[0396] Figure 66 shows the results of the tubulin polymerization inhibition test of the compound represented by Formula I;

[0397] Figure 67 shows the experimental results of p-SRC inhibitory activity. DETAILED DESCRIPTION

[0398] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0399] Instrument information and methods

[0400] 1. X-ray powder diffraction (XRPD)

[0401] The XRPD pattern was collected on an X-ray powder diffraction analyzer produced by PANalytacal, and the scanning parameters are shown in Table 16.

[0402] Table 16 XRPD test parameters

[0403] 2. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC)

[0404] The TGA and DSC patterns were collected on a TA 5500 thermogravimetric analyzer and a TA 2500 differential scanning calorimeter, respectively. Table 17 lists the test parameters.

[0405] Table 17 TGA and DSC test parameters

[0406] 3. Dynamic moisture sorption (DVS)

[0407] Dynamic moisture sorption (DVS) curves were collected on a DVS IntrInsic from SMS (Surface Measurement Systems). Relative humidity at 25°C was calibrated using the deliquescent temperatures of LiCl, Mg(NO₃)₂, and KCl. DVS test parameters are listed in Table 18.

[0408] Table 18 DVS test parameters

[0409] 4. Polarized Light Microscopy (PLM)

[0410] Polarizing microscopy images were taken at room temperature using a Zeiss Axio Scope.A1 microscope.

[0411] 5. Liquid NMR ( 1 H NMR)

[0412] Liquid-state NMR spectra were collected on a Bruker 400M NMR spectrometer using DMSO-d6 or CD3OD as solvent.

[0413] 6. High Performance Liquid Chromatography and Ion Chromatography (HPLC / IC)

[0414] In the experiment, the purity test, dynamic solubility and stability test were performed by Agilent 1260 high performance liquid chromatograph, and the ion salt formation molar ratio test was performed by ion chromatography. The analysis conditions are shown in Tables 19 and 20.

[0415] Table 19 HPLC test conditions

[0416] Table 20 Ion chromatography test conditions

[0417] Solvent Chinese-English comparison table

[0418] The abbreviations of the solvents and their corresponding Chinese names are shown in Table 21.

[0419] Table 21 Comparison table of Chinese and English names of solvents used in the experiment

[0420] Preparation of the compound represented by formula I

[0421] The synthetic route is as follows:

[0422] Step 1: Synthesis of 1-bromo-4-(2-bromoethoxy)-2-methylbenzene

[0423] 4-Bromo-3-methylphenol (1 g, 5.37 mmol), 1,2-dibromoethane (5.99 g, 32.2 mmol), and potassium carbonate (4.45 g, 32.2 mmol) were dissolved in acetone (30 mL) and refluxed at 80°C for 18 hours. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was separated by column chromatography (petroleum ether:ethyl acetate (v / v) = 30:1) to afford 1-bromo-4-(2-bromoethoxy)-2-methylbenzene (1.3 g, colorless oil, 82.8% yield).

[0424] Step 2: (3aR,6aS)-5-(2-(4-bromo-3-methylphenoxy)ethyl)hexahydro-1H-furo[3,4-c]pyrrole

[0425] 1-Bromo-4-(2-bromoethoxy)-2-methylbenzene (1.3 g, 4.45 mmol) was dissolved in dry acetonitrile (30 mL), and (3aR,6aS)-hexahydro-1H-furo[3,4-c]pyrrole hydrochloride (730 mg, 4.90 mmol) and potassium carbonate (1.844 g, 13.36 mmol) were added. The mixture was heated to 80°C and reacted for 20 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified on a silica gel column (petroleum ether:ethyl acetate (v / v) = 1:1) to obtain (3aR,6aS)-5-(2-(4-bromo-3-methylphenoxy)ethyl)hexahydro-1H-furo[3,4-c]pyrrole (1.0 g, yellow oil, yield 69.1%).

[0426] LC-MS, M / Z (ESI): 326.0 [M+H] + .

[0427] Step 3: N-benzyl-2-(5-(2-methyl-4-(2-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)ethoxy)phenyl)pyridin-2-yl)acetamide (I)

[0428] (3aR,6aS)-5-(2-(4-bromo-3-methylphenoxy)ethyl)hexahydro-1H-furo[3,4-c]pyrrole (150 mg, 0.460 mmol) was dissolved in dry 1,4-dioxane (5 mL), and N-benzyl-2-(5-(tributylstannyl)pyridin-2-yl)acetamide (355 mg, 0.690 mmol) and bis(triphenylphosphino)palladium dichloride (32.3 mg, 0.046 mmol) were added. The atmosphere was replaced with argon three times, and the temperature was raised to 100°C under argon protection for 4 hours. The reaction solution was cooled to room temperature, diluted with water (50 mL), extracted with dichloromethane (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was separated on a silica gel plate (ethyl acetate:methanol (V / V) = 20:1, NH3·H2O) to give N-benzyl-2-(5-(2-methyl-4-(2-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)ethoxy)phenyl)pyridin-2-yl)acetamide (compound shown in Formula I) (20 mg, yield 9.22%), i.e., an amorphous solid of the compound of Formula I.

[0429] 1 H NMR (400MHz, DMSO-d6): δ8.62(t, 1H), 8.41(d, 1H), 7.70~6.83(m, 10H), 4.30(d, 2H), 4.07(t, 2H), 3.78~3.62(m, 4H), 3.39~3.37(m, 2H), 2.75~2.61(m, 6H), 2.39~2.37(m, 2H), 2.21(s, 3H).

[0430] LC-MS, M / Z (ESI): 472.2 [M+H] + .

[0431] Example 1 Free Form A

[0432] Preparation of free crystal form A:

[0433] The compound represented by Formula I was stirred and dissolved in THF solution at room temperature, filtered after dissolution, and slowly evaporated at room temperature to obtain free crystalline Form A. The solid was vacuum dried at room temperature and characterized by XRPD and TGA / DSC.

[0434] The XRPD and TGA / DSC characterization results of the free-state Form A sample are shown in Figures 1-3, and the XRPD diffraction peak data for the free-state Form A are shown in Table 22. TGA results show a 0.98% weight loss upon heating the sample to 150°C. DSC results reveal an endothermic peak at 96.6°C with an onset temperature of 94.7°C. The TGA weight loss of the free-state Form A is low, and the DSC shows only a single melting signal, indicating that the free-state Form A is an anhydrous form. 1 H NMR was collected using CD3OD as solvent, and the specific data are shown below.

[0435] 1 H NMR (400MHz, CD3OD): δ8.40(1H,d),7.74(1H,dd),7.44(1H,d),7.33~7.28(4H,m),7.26~7.23(1H,m),7.15(1H,d),6.91(1H,d) ,6.86(1H,dd),4.42(2H,s),4.15(2H,t),3.82(2H,s),3.71~3.64(4H,m),3.02(2H,t),2.86(4H,t),2.33(2H,dd),2.25(3H,s).

[0436] Table 22 XRPD diffraction peak data of free form A

[0437] Example 2 Free Form B

[0438] A free-state Form B sample was obtained by dissolving the compound represented by Formula I in MeOH, removing the solvent by rotary evaporation under reduced pressure, and then drying the resulting colloidal sample at 50°C in vacuo. XRPD and TGA / DSC characterization results are shown in Figures 4-6 , and the XRPD diffraction peak data for the free-state Form B are shown in Table 23. TGA results showed a 0.48% weight loss upon heating the sample to 150°C, while DSC results revealed two endothermic peaks at 84.5°C and 92.4°C (peak temperatures). 1 The H NMR results are shown below. No residual MeOH was observed in the Form B sample. The TGA weight loss of the free Form B was low, indicating that the free Form B was anhydrous. The free Form B was heated to 86°C, cooled to room temperature, and exposed to air, resulting in the sample converting to the free Form A.

[0439] 1H NMR (400MHz, CD3OD): δ8.66(1H,t),8.44(1H,d),7.71(1H,d),7.41~7.14(7H,m),6.92(1H,s),6.87(1H,d ),4.32(2H,d),4.09(2H,t),3.73(4H,m),3.41~3.39(2H,m),2.77~2.63(6H,m),2.39(2H,m),2.23(3H,s).

[0440] Table 23 XRPD diffraction peak data of free form B

[0441] Example 3 Study on the transformation relationship between free state crystal forms

[0442] In order to further study the transformation relationship between free form A and free form B, suspension competition experiments between free form A and free form B were set up in CPME and IPAc systems at room temperature and 50°C.

[0443] The specific steps are as follows:

[0444] 1) Saturated solutions of free Form A samples in different solvent systems at corresponding temperatures were prepared; 2) Equal masses of free Form A and free Form B samples were added to the saturated solutions to form suspensions; 3) magnetic stirring was performed at room temperature; 4) after stirring for two days, the solid was isolated and analyzed by XRPD. The results are shown in Table 24. Free Form A was obtained in all experiments. The experiments demonstrated that free Form A is thermodynamically more stable than free Form B at room temperature and 50°C.

[0445] Table 24 Suspension competition test results between free crystal forms A and B

[0446] Example 4

[0447] Phosphate crystal form A

[0448] 300 mg of the compound of Formula I and 73.5 mg of phosphoric acid were slurried in 4 mL of IPA / H₂O (19:1, v / v) solution at room temperature for 2 days to obtain phosphate Form A. The XRPD of the phosphate Form A sample is shown in Figure 7 , and the XRPD data are shown in Table 25 below. TGA / DSC results are shown in Figures 8 and 9 . TGA results showed a 4.40% weight loss when the sample was heated to 150°C; DSC results showed two endothermic peaks at 103.6°C and 174.5°C (peak temperatures). 1The H NMR results are shown below. The results showed that the molar ratio of IPA to the compound of Formula I in the sample was 0.04 (-0.4 wt%). HPLC / IC results showed that the molar ratio of phosphoric acid to the compound of Formula I was 1:1.

[0449] The crystal form of phosphate crystal form A was identified by VT-XRPD. The results showed (Figure 10): after purging phosphate crystal form A under N2 conditions for 20 minutes, the crystal form remained unchanged; when heated to 150°C under nitrogen protection, cooled to 30°C, and then exposed to air, it was observed to transform into free crystal form B. 1 H NMR results indicate that Form A of the phosphate salt is a hydrate, which dehydrates under heating conditions to form the anhydrous Form B of the phosphate salt. The XRPD pattern of Form B is shown in Figure 11, and the XRPD data are shown in Table 26 below.

[0450] 1 H NMR (400MHz, DMSO-d6): δ8.67(1H,t),8.43(1H,d),7.71(1H,dd),7.41~7.15(7H,m),6.93(1H,d),6.8 7(1H,dd),4.31(2H,d),4.12(2H,t),3.72~3.66(4H,m),3.44(2H,m),2.86~2.75(6H,m),2.23(3H,s).

[0451] Table 25 XRPD diffraction peak data of phosphate crystal form A

[0452] Table 26 XRPD diffraction peak data of phosphate crystal form B

[0453] Fumarate Form A

[0454] 300 mg of the compound of Formula I and 73.5 mg of fumaric acid were slurried in 6 mL of MTBE solution at room temperature for 2 days to obtain the fumarate salt Form A. The XRPD of the fumarate salt Form A sample is shown in Figure 12. TGA / DSC results are shown in Figures 13 and 14. TGA results show a 1.17% weight loss when the sample is heated to 150°C; DSC results show an endothermic peak at 130.3°C with an onset temperature of 128.2°C. 1 The H NMR results are shown below. The results show that the molar ratio of fumaric acid to the compound of Formula I in the sample is 1:1, and the molar ratio of the residual solvent MTBE to the compound of Formula I is 0.01 (-0.1 wt%).

[0455] Fumarate Form A was studied by variable humidity XRPD (VH-XRPD). The results showed (Figure 15) that after the fumarate Form A was placed under 85% RH, a diffraction peak shift was observed; after the sample was placed back to 30% RH, the sample converted to fumarate Form A. Combined with the DVS test results of fumarate Form A (as shown in Figure 52), the fumarate sample gained weight significantly under high humidity (>70% RH) conditions, suggesting that fumarate exists in a hydrated state under high humidity conditions, and under low humidity conditions (such as 30% RH), the sample converted back to anhydrous fumarate Form A.

[0456] 1 H NMR (400MHz, DMSO-d6): δ8.67(1H,t),8.44(1H,d),7.71(1H,dd),7.41~7.15(7H,m),6.93(1H,s),6.87(1H,dd),6. 61(2H,s),4.32(2H,d),4.11(2H,t),3.73~3.68(4H,m),3.43(2H,m),2.83~2.73(6H,m),2.44(2H,d),2.23(3H,s).

[0457] Table 27 XRPD diffraction peak data of fumarate salt form A

[0458] p-Toluenesulfonate Form A

[0459] 300 mg of the compound of Formula I and 121.5 mg of p-toluenesulfonic acid monohydrate were slurried in 6 mL of IPAc solution at room temperature for 2 days to obtain p-toluenesulfonate Form A. The XRPD of the p-toluenesulfonate Form A sample is shown in Figure 16. TGA / DSC results are shown in Figures 17 and 18. TGA results show a 0.94% weight loss when the sample is heated to 150°C; DSC results show an endothermic peak at 152.1°C with an onset temperature of 149.9°C. 1 The H NMR results are as follows. The results show that the molar ratio of p-toluenesulfonic acid to the compound represented by Formula I in the sample is 1:1, and the molar ratio of the residual solvent IPAc to the compound represented by Formula I is 0.01 (-0.1 wt%).

[0460] 1H NMR (400MHz, DMSO-d6): δ9.79(1H,s),8.69(1H,t),8.44(1H,d),7.73(1H,dd),7.47(2H,d),7.43(1H,d),7.35~7.21(6H,m),7. 12(2H,d),7.01~6.94(2H,m),4.36~4.29(4H,m),3.93(1H,s),3.81~3.45(8H,m),3.13~2.80(3H,m),2.29(3H,s),2.26(3H,s).

[0461] Table 28 XRPD diffraction peak data of p-toluenesulfonate Form A

[0462] Benzenesulfonate Form A

[0463] 300 mg of the compound of Formula I and 100.5 mg of benzenesulfonic acid were slurried in 6 mL of IPAc solution at room temperature for 2 days to obtain Form A benzenesulfonate. The XRPD pattern of the Form A benzenesulfonate sample is shown in Figure 19. TGA / DSC results are shown in Figures 20 and 21. TGA results show a 1.28% weight loss when the sample is heated to 140°C; DSC results show an endothermic peak at 146.4°C, with an onset temperature of 144.5°C. 1 H NMR was measured in DMSO-d6, and the results are as follows. The results showed that the molar ratio of benzenesulfonic acid to the compound of Formula I in the sample was 1:1, and the molar ratio of the residual solvent IPAc to the compound of Formula I was 0.01 (-0.1 wt%).

[0464] 1 H NMR (400MHz, DMSO-d6): δ9.79(1H,s),8.68(1H,t),8.44(1H,d),7.73(1H,dd),7.61~7.58(2H,m),7.43(1H,d),7. 35~7.21(9H,m),7.01~6.94(2H,m),4.32(4H,m),3.93(1H,s),3.80~3.46(8H,m),3.13~2.81(3H,m),2.25(3H,s).

[0465] Table 29 XRPD diffraction peak data of benzenesulfonate salt form A

[0466] Oxalate Form B

[0467] 300 mg of the compound of Formula I and 79.5 mg of oxalic acid dihydrate were slurried in 12 mL of an acetone / n-heptane (1:1, v / v) solution at room temperature for 7 days and then at 55°C for 1 day to obtain Form B oxalate. The XRPD pattern of the Form B oxalate sample is shown in Figure 22. TGA / DSC results are shown in Figures 23 and 24. TGA results show a 1.21% weight loss when the sample is heated to 150°C; DSC results show two endothermic peaks at 158.2°C and 218.7°C (peak temperatures). 1 The H NMR results are as follows, showing that the molar ratio of the residual solvent Acetone to the compound of Formula I is 0.01 (-0.1 wt%). The HPLC / IC results show that the molar ratio of oxalic acid to the compound of Formula I is 1:1.

[0468] 1 H NMR (400MHz, DMSO-d6): δ8.68(1H,t),8.44(1H,d),7.72(1H,dd),7.41(1H,d),7.35~7.19(6H, m), 6.98~6.91(2H,m), 4.32~4.25(4H,m), 3.74~3.34(10H,m), 2.94~2.85(4H,m), 2.25(3H,s).

[0469] Table 30 XRPD diffraction peak data of oxalate crystal form B

[0470] Maleate salt form A

[0471] The compound of Formula I (828906-01-A) and an equimolar amount of maleic acid were slurried in an acetone / n-heptane (1:1, v / v) solution for three days. The solid sample was isolated and vacuum dried to obtain the maleate salt Form A. XRPD and TGA / DSC results of the maleate salt Form A sample are shown in Figures 25-27. TGA results showed a 2.56% weight loss upon heating to 120°C. DSC results revealed three endothermic peaks at 54.7°C, 125.2°C, and 200.7°C (peak temperatures). 1 The H NMR results are shown below. In the maleate salt crystalline form A, the molar ratio of maleic acid to the compound represented by Formula I was 1.0, the molar ratio of the residual solvent acetone to the compound represented by Formula I was 0.03 (-0.3 wt %), and no residual n-heptane was observed.

[0472] 1H NMR (400MHz, DMSO-d6): δ8.67(1H,t),8.44(1H,d),7.71(1H,dd),7.41~7.20(7H,m),6.99~ 6.93(2H,m),6.04(2H,s),4.33~4.28(4H,m),3.73(3H,s),2.98~2.80(3H,m),2.25(3H,s).

[0473] Table 31 XRPD diffraction peak data of maleate salt form A

[0474] Malate Form A

[0475] The compound of Formula I and an equimolar amount of malic acid were slurried in an acetone / n-heptane (1:1, v / v) solution for 6 days. The solid sample was isolated and vacuum dried to obtain malate Form A. Powder diffraction, TGA, and DSC analyses were performed on the sample. The resulting XRPD is shown in Figure 28, and the TGA / DSC results are presented in Figures 29 and 30. TGA results show a 2.26% weight loss upon heating the sample to 150°C. DSC results revealed three endothermic peaks at 44.6°C, 96.3°C, and 215.8°C (peak temperatures). 1 The H NMR results are shown below. In the malate Form A sample, the molar ratio of malic acid to the compound represented by Formula I was 1:1, the molar ratio of the residual solvent acetone to the compound represented by Formula I was 0.01 (~0.1 wt%), and the molar ratio of n-heptane to the compound represented by Formula I was 0.02 (~0.3 wt%).

[0476] 1 H NMR (400MHz, CD3OD): δ8.40(1H,d),7.74(1H,dd),7.47(1H,d),7.31~7.29(4H,m),7.27~7.22(1H,m),7.19(1H,d),6.97(1H,d),6.93(1H,dd),4 .42(2H,s),4.34~4.31(3H,m),3.81(3H,t),3.67~3.62(4H,m),3.44(2H ,t),3.09(2H,s),2.91(2H,dd),2.77(1H,dd),2.53(1H,q),2.26(3H,s).

[0477] Table 32 XRPD diffraction peak data of malate crystal form A

[0478] Succinate Form A

[0479] Form A succinate salt was obtained by slurrying the compound of Formula I and an equimolar amount of succinic acid in an MTBE solution for 6 days, isolating the solid sample, and vacuum drying it. XRPD and TGA / DSC results of Form A succinate salt are shown in Figures 31-33. TGA results show a 4.49% weight loss when the sample is heated to 150°C. DSC results show two endothermic peaks at 57.3°C and 85.4°C (peak temperatures). 1 The H NMR results shown below show that in the succinate salt form A, the molar ratio of succinic acid to the compound represented by Formula I is 1.2:1, and no residual MTBE solvent is observed.

[0480] 1 H NMR (400MHz, CD3OD): δ8.40(1H,d),7.74(1H,dd),7.47(1H,d),7.32~7.31( 4H,m),7.27~7.22(1H,m),7.16(1H,d),6.95(1H,d),6.91(1H,dd),4.43(2H ,s),4.25(2H,t),3.83(2H,d),3.76(2H,dd),3.69~3.65(2H,m),3.41~3.37 (2H,m),3.21(2H,t),3.00(2H,s),2.69(2H,dd),2.55(5H,s),2.26(3H,s).

[0481] Table 33 XRPD diffraction peak data of succinate salt form A

[0482] Methanesulfonate Form A / B

[0483] Methanesulfonate Form A was obtained by slurrying the compound of Formula I and methanesulfonic acid in an acetone / n-heptane (1:1, v / v) solution at a 1:1 molar ratio for three days, separating the colloidal solid sample, and vacuum drying. Methanesulfonate Form B was obtained by slurrying the compound of Formula I and methanesulfonic acid in an IPAc solution at a 1:2 molar ratio for three days, separating the solid sample, and vacuum drying. The XRPD patterns of the methanesulfonate Forms A and B are shown in Figures 34 and 35, respectively.

[0484] The TGA / DSC results of Form B mesylate are detailed in Figures 36 and 37. TGA results show a 0.91% weight loss when the sample is heated to 80°C and a 2.40% weight loss when heated from 80°C to 130°C. DSC results show an endothermic peak at 109.4°C (peak temperature). 1The H NMR results are as follows: in the mesylate salt form B, the molar ratio of methanesulfonic acid to the compound of Formula I is 2.1, and the molar ratio of the residual solvent IPAc to the compound of Formula I is 0.04 (-0.7 wt %).

[0485] Methanesulfonate Form B: 1 H NMR (400MHz, CD3OD): δ8.80(1H,s),8.52(1H,d),8.01(1H,dd),7.36~7.33(5H,m),7.30~7.27(1H,m),7.09~7.01(2H,m),4.45(2H,s),4.41~4 .40(3H,m),4.17~4.15(2H,m),4.05(2H,t),3.90(2H,d),3.71(2H,s), 3.65~3.57(5H,m),3.16(2H,s),2.93(2H,t),2.69(6H,d),2.35(3H,s).

[0486] Table 34 XRPD diffraction peak data of mesylate salt form A

[0487] Table 35 XRPD diffraction peak data of mesylate salt form B

[0488] Oxalate Form A

[0489] Oxalate Form A was obtained by slurrying the compound of Formula I and oxalic acid in an equimolar ratio in an IPA / H₂O (19:1, v / v) solution for three days, isolating the solid sample, and vacuum drying it. The XRPD pattern of Oxalate Form A is shown in Figure 38.

[0490] The TGA / DSC results of oxalate Form A are shown in Figures 39 and 40. The TGA results show that the sample loses 4.10% weight when heated to 150°C. The DSC results show that the sample has three endothermic peaks at 153.6°C, 162.8°C, and 218.8°C (peak temperatures). 1 The H NMR results shown below show that in the oxalate salt form A, the molar ratio of the residual solvent IPA to the compound represented by Formula I is 0.03 (-0.3 wt %).

[0491] Oxalate Form A: 1H NMR (400MHz, DMSO-d6): δ8.67(1H,t),8.44(1H,d),7.72(1H,dd),7.41(1H,d),7.35~7.18(6H, m), 6.98~6.91(2H,m), 4.33~4.26(4H,m), 3.74~3.35(10H,m), 2.94~2.85(4H,m), 2.25(3H,s).

[0492] Table 36 XRPD diffraction peak data of oxalate crystal form A

[0493] 2-Hydroxyethanesulfonate Form A

[0494] Form A of the 2-hydroxyethanesulfonate salt was obtained by slurrying the compound of Formula I and an equimolar amount of 2-hydroxyethanesulfonic acid in an acetone / n-heptane (1:1, v / v) solution for three days, isolating the solid sample, and vacuum drying. The XRPD pattern of the Form A sample of 2-hydroxyethanesulfonate salt is shown in Figure 41, and the TGA / DSC results are detailed in Figures 42 and 43. TGA results show a 1.28% weight loss when the sample is heated to 110°C. DSC results reveal two endothermic peaks at 57.4°C and 118.4°C (peak temperatures). 1 The H NMR results are shown below. In the 2-hydroxyethanesulfonate salt form A, the molar ratio of 2-hydroxyethanesulfonic acid to the compound represented by Formula I is 1.2, the molar ratio of the residual solvent acetone to the compound represented by Formula I is 0.03 (~0.3 wt %), and the molar ratio of n-heptane to the compound represented by Formula I is 0.01 (~0.2 wt %).

[0495] 1 H NMR (400MHz, DMSO-d6): δ9.78(1H,s),8.67(1H,t),8.44(1H,d),7.73(1H,dd),7.43~7.21(7H,m),7.00~6.9 4(2H,m),4.37~4.30(4H,m),3.93(1H,s),3.77~3.45(10H,m),3.13~2.80(3H,m),2.60(2H,t),2.25(3H,s).

[0496] Table 37 XRPD diffraction peak data of 2-hydroxyethanesulfonate crystal form A

[0497] Example 5 Performance Evaluation Experiment

[0498] Dynamic solubility experiment

[0499] The solid feed concentration was 10 mg / mL (calculated as the compound shown in Formula I) and the mixture was rotated and mixed at 37°C. The solubility of each sample in four systems, water, SGF, FaSSIF and FeSSIF, was measured at different time points (1, 4 and 24 hours). After sampling at each time point, the samples were centrifuged (10000 rpm) and filtered (0.45 μm PTFE filter head). The HPLC concentration and pH value of the filtrate were measured, and the solid sample after centrifugation was tested by XRPD. The solubility test results are summarized in Table 38, and the solubility curves in each system are shown in Figures 44-47. Compared with the free form A, the different salt form samples showed different degrees of solubility improvement in H2O, SGF and FaSSIF. Among them, the solubility of the fumarate form A and the oxalate form B in H2O and FaSSIF was higher than that of other salt forms.

[0500] Preparation of biosolvents

[0501] Preparation of simulated gastric fluid (SGF)

[0502] Weigh 100 mg of NaCl and 50 mg of Trinaton X-100 into a 50 mL volumetric flask and dissolve in purified water. Add 816 μL of 1 M hydrochloric acid and adjust the pH to 1.8 with 1 M hydrochloric acid or 1 M NaOH solution. Bring to volume with purified water.

[0503] Preparation of simulated fasting intestinal fluid (FaSSIF)

[0504] Weigh 340 mg of anhydrous NaH2PO4 and 620 mg of NaCl into a 100 mL volumetric flask. Dissolve with purified water, then add 55.44 μL of 50% NaOH solution. Adjust the pH to 6.5 with 1 M hydrochloric acid or 1 M NaOH solution. Add purified water to bring the mixture to volume. Next, weigh 110 mg of SIF powder into a 50 mL volumetric flask, dissolve with the above solution, and bring the mixture to volume.

[0505] Preparation of simulated fed state intestinal fluid (FeSSIF)

[0506] Add 0.82 mL of glacial acetic acid and 1.18 g of NaCl to a 100 mL volumetric flask and dissolve in purified water. Add 528 μL of 50% NaOH solution. Adjust the pH to 5.0 with 1 M hydrochloric acid or 1 M NaOH solution. Add purified water to the volume. Then, weigh 560 mg of SIF powder into a 50 mL volumetric flask and dissolve in the above solution. Dose to the volume.

[0507] Table 38 Summary of 37℃ dynamic solubility test results

[0508] S: solubility (mg / mL); --: XRPD not tested.

[0509] Hygroscopicity test

[0510] The hygroscopicity of phosphate Form A, fumarate Form A, p-toluenesulfonate Form A, benzenesulfonate Form A, oxalate Form B, and free Form A was evaluated using a dynamic moisture sorption instrument (DVS). The percentage change in mass of the samples was recorded as the humidity varied (0% RH to 95% RH) at a constant temperature of 25°C. The DVS test results and the XRPD results of the samples before and after the DVS test are shown in Figures 48-59. The results show that the free Form A is almost non-hygroscopic, while the p-toluenesulfonate Form A, benzenesulfonate Form A, and oxalate Form B are slightly hygroscopic. Phosphate Form A is a hydrate that rapidly dehydrates below 10% RH. Fumarate Form A exhibits significant hygroscopicity above 70% RH. All of the above-mentioned forms showed no change in crystalline form after the DVS test, demonstrating their high stability in high-humidity environments.

[0511] Solid-state stability

[0512] Phosphate Form A, fumarate Form A, p-toluenesulfonate Form A, benzenesulfonate Form A, oxalate Form B, and free Form A were exposed to air for one week at 25°C / 60% RH and 40°C / 75% RH, respectively. The physical and chemical stability of the samples was then tested by XRPD and HPLC. The purity data are listed in Table 39, and the XRPD results are shown in Figures 60-65. The results show that no significant change in purity was observed for free Form A and the different salt forms after exposure to air for one week at 25°C / 60% RH and 40°C / 75% RH. The crystalline forms of the different samples remained unchanged after the stability test, indicating that all of the above crystalline forms possess high solid-state stability.

[0513] Table 39 Summary of solid state stability evaluation

[0514] The control compound (trade name Tirbanibulin) used in the test examples of this invention is a dual-action Src kinase and tubulin polymerization inhibitor approved by the FDA and the EU for the topical treatment of actinic keratosis of the face or scalp. The control compound was prepared with reference to patent WO 2008 / 002676 A2. The control compound structure is as follows:

[0515] Test Example 1: Inhibition of Tubulin Monomer Polymerization

[0516] Tubulin Polymerization Assay Kit (cytoskeleton, Cat.# BK011P) was used to conduct the compound inhibition test of tubulin monomer polymerization.

[0517] Before the test, the 96-well plate (Corning Costar, Cat. #3686) provided with the kit was placed in a microplate reader (MD, SpectraMax M5) and heated to 37°C for 10 minutes. The 96-well plate was removed and 5 μL of a 12.5 μM compound solution or blank solution was added. The 96-well plate was then placed in a microplate reader and incubated at 37°C for 1 minute to allow the compound solution to warm to 37°C. The 96-well plate was removed and 50 μL of the reaction mixture prepared according to the supplier's instructions was quickly added to each well. The addition was completed within 1 minute and bubbles were avoided. The 96-well plate was then immediately placed in a microplate reader and shaken for 5 seconds. Kinetic mode was used with excitation at 360 nm and emission at 420 nm at 37°C for 30-60 minutes, with detection every 30 seconds. The tubulin monomer polymerization curve was obtained with the detection time as the X-axis and the fluorescence signal value as the Y-axis. As shown in Figure 66 and Table 40, the larger the Vmax value and the higher the maximum fluorescence signal value of the polymerization curve, the lower the inhibitory efficiency of the compound.

[0518] Table 40

[0519] The results of the compound inhibition test on microtubule polymerization are shown in Figure 66 and Table 40. The results show that the Vmax value and the maximum fluorescence signal value of the polymerization curve corresponding to the compound represented by Formula I of the present invention are significantly smaller, indicating that it can significantly inhibit the polymerization of microtubule monomers and has better inhibitory activity than the control compound.

[0520] Test Example 2: Compound inhibition of cell proliferation test

[0521] The proliferation assays of human skin squamous cell carcinoma cells A-431 (ATCC, CRL-1555) and actinic keratosis patient-derived cells HT 297.T (ATCC, CRL-7782) were used to detect the inhibitory effect of small molecule compounds on cell proliferation.

[0522] A-431 cells and HT 297.T cells were cultured in DMEM medium containing 10% fetal bovine serum and grown in a 37°C, 5% CO2 incubator. Logarithmic phase cells were seeded into 96-well cell culture plates at 1000 cells / well, 100 μL per well, and cultured overnight in a 37°C, 5% CO2 incubator. The next day, 100 μL of a gradient diluted 2× test compound solution was added to each well, DMSO was used as a positive control, and 10 μM staurosporine (Aladdin, S102392) was set as a negative control group. The culture plates with the added compounds were incubated in a 37°C, 5% CO2 incubator for 4 days. After incubation, the cells were used The fluorescence signal was measured using the Envision 2104 Multilabel Reader using the luciferase assay system (Promega, G9243) according to the manufacturer's instructions. The inhibition rate was calculated using the following formula. A curve was then plotted with the Log value of the inhibitor concentration on the X-axis and the inhibition rate on the Y-axis. IC was calculated using Graphpad 8.0. 50 Inhibition% = (positive control group signal - test well signal) / (positive control group signal - negative control group signal) * 100

[0523] Table 41 Inhibition results of test compounds on proliferation of A-431 and HT 297 T cells

[0524] The results of the cell proliferation inhibition test of the compounds are shown in Table 41. The results indicate that the compounds of Formula I of the present invention can significantly inhibit cell proliferation, especially the inhibitory effect on HT297.T cells derived from human actinic keratosis patients is significantly better than that of the control compound, indicating that the compounds of Formula I of the present invention have a better therapeutic effect on actinic keratosis.

[0525] Test Example 3: Thermodynamic Solubility Test

[0526] Prepare phosphate buffered saline (PBS) at pH 7.4, FeSSIF solution at pH 6.5, and FaSSGF solution at pH 1.6. Accurately weigh the compound, add the prepared phosphate buffer at pH 7.4, FeSSIF solution at pH 6.5, and FaSSGF solution at pH 1.6 to a solution concentration of 4 mg / mL, shake at 1000 rpm for 1 hour, and then incubate at room temperature overnight. The incubated solution was centrifuged at 12000 rpm for 10 minutes to remove undissolved particles, and the supernatant was transferred to a new centrifuge tube. After the supernatant was appropriately diluted, an acetonitrile solution containing the internal standard was added and quantified using a standard curve prepared with the same matrix.

[0527] Table 42 Thermodynamic solubility test results

[0528] The results of the thermodynamic solubility test are shown in Table 42. The results indicate that, compared with the control compound, the compound represented by Formula I of the present invention has greater thermodynamic solubility under neutral conditions and better drugability.

[0529] Test Example 4: Pharmacokinetic Test

[0530] For pharmacokinetic studies in mice, three male ICR mice (20-25 g) were fasted overnight and administered with either 1 mg / kg or 5 mg / kg via tail vein injection. Blood samples were collected before and 15, 30 minutes, and 1, 2, 4, 8, and 24 hours after dosing. Three other mice were administered 5 mg / kg orally by gavage, and blood samples were collected before and 15, 30 minutes, and 1, 2, 4, 8, and 24 hours after dosing. Blood samples were centrifuged at 6800 g for 6 minutes at 2-8°C, and plasma was collected and stored at -80°C. Plasma was collected at each time point and mixed with 3-5 times the volume of acetonitrile containing the internal standard. The mixture was vortexed for 1 minute and centrifuged at 13,000 rpm at 4°C for 10 minutes. The supernatant was mixed with 3 times the volume of water, and the appropriate amount of the mixture was analyzed by LC-MS / MS. Key pharmacokinetic parameters were analyzed using a non-compartmental model using WinNonlin 7.0 software.

[0531] Table 43 Mouse pharmacokinetic test results 1

[0532] Table 44 Mouse pharmacokinetic test results 3

[0533] The results of the mouse pharmacokinetic test are shown in Table 43 and Table 44. The results show that compared with the control compound, the compound represented by Formula I of the present invention is rapidly metabolized in mice, has low potential systemic toxicity, and has good drugability.

[0534] Test Example 5: Human liver microsome stability test

[0535] The stability test for human liver microsomes was performed by incubating the compound with human liver microsomes in vitro. The test compound was first prepared as a 10 mM stock solution in DMSO solvent, and then diluted to 0.5 mM with acetonitrile. Human liver microsomes (Corning) were diluted with PBS to form a microsome / buffer solution, and this solution was used to dilute 0.5 mM of the compound to form a working solution. The working solution contained 1.5 μM compound and 0.75 mg / ml human liver microsomes. A deep-well plate was prepared, and 30 μL of the working solution was added to each well. The reaction was then initiated by adding 15 μL of preheated 6 mM NADPH solution and incubated at 37°C. The reaction was terminated by adding 135 μL of acetonitrile to the corresponding wells at 0, 5, 15, 30, and 45 minutes of incubation. After terminating the reaction with acetonitrile at the final 45-minute time point, the deep-well plate was vortexed for 10 minutes (600 rpm / min) and then centrifuged for 15 minutes. After centrifugation, the supernatant was collected and purified water was added in a 1:1 ratio. LC-MS / MS was then performed to obtain the ratio of the peak area of ​​the compound to the peak area of ​​the internal standard at each time point. The peak area ratios of the compound at 5, 15, 30, and 45 minutes were compared with the peak area ratio at 0 minute. The remaining percentage of the compound at each time point was calculated. T was calculated using Graphpad 5 software. 1 / 2 .

[0536] Table 45 Human liver microsome stability test results

[0537] The results of the human liver microsome stability test are shown in Table 45. The results indicate that the compound represented by Formula I of the present invention is rapidly metabolized in human liver microsomes, has low potential systemic toxicity, and has good drugability.

[0538] Test Example 6: Compounds inhibit the Src signaling pathway

[0539] Western Blot was used to detect the inhibition of p-SRC by the compounds on A-431 skin cancer cells (ATCC, CRL-1555) to evaluate the inhibitory effect of the compounds on the SRC signaling pathway.

[0540] A-431 cells were cultured in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% fetal bovine serum in a 37°C, 5% CO2 incubator. 500,000 cells / well were seeded into 12-well cell culture plates and incubated overnight at 37°C, 5% CO2. The next day, the medium was replaced and the cells were treated with various concentrations of the compounds, with DMSO as a control. The plates were then incubated for another 24 hours at 37°C, 5% CO2. The cells were washed once with PBS and lysed with RIPA lysis buffer (R0010, Solebio) at low temperature for 30 minutes. The protein lysate was collected into a centrifuge tube and centrifuged at 14,000 g for 10 minutes at 4°C. The supernatant was transferred to a fresh tube. Protein concentration was determined using a BCA protein assay kit (P0009, Beyotime Biosciences). The protein quantification of each sample was consistent using 5× protein loading buffer, boiled at 100°C for 5 min, and p-SRC levels were detected by western blot. The p-SRC antibody (Ab185617) was purchased from Abcam, and the GAPDH antibody (60004-1-Ig) was purchased from Proteintech.

[0541] The test results are shown in FIG67 , which indicate that the compound represented by formula I of the present invention can significantly inhibit the phosphorylation of SRC at 80 nM. Compared with the control compound, it has better p-SRC inhibitory activity and can block the SRC downstream signaling pathway.

[0542] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims

1. A crystalline form or salt form of a compound as shown in formula I, in, The crystalline form of the compound shown in Formula I is free crystalline form A or free crystalline form B, The free crystalline form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, with diffraction peaks at 14.49±0.2°, 17.02±0.2°, 18.42±0.2°, and 20.53±0.2°; The free crystalline form B has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, with diffraction peaks at 16.55±0.2°, 17.77±0.2°, 20.36±0.2°, 21.24±0.2°, and 22.66±0.2°; The salt form of the compound as shown in formula I is phosphate, fumarate, p-toluenesulfonate, benzenesulfonate, oxalate, maleate, malate, succinate, methanesulfonate or 2-hydroxyethanesulfonate.

2. The crystalline form or salt form of the compound of formula I according to claim 1, characterized in that: The phosphate of the compound as shown in Formula I is the phosphate crystal form A or the phosphate crystal form B of the compound as shown in Formula I; In the phosphate crystal form A, the X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles has diffraction peaks at 6.74±0.2°, 13.47±0.2°, 15.69±0.2°, 18.09±0.2°, and 20.26±0.2°; In the phosphate crystal form B, the X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles has diffraction peaks at 6.68±0.2°, 13.37±0.2°, 14.16±0.2°, 15.30±0.2°, 16.74±0.2°, and 20.12±0.2°; Or, the fumarate of the compound as shown in Formula I is the fumarate crystalline form A of the compound as shown in Formula I; In the fumarate salt form A, the X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles has diffraction peaks at 13.51±0.2°, 15.41±0.2°, 17.57±0.2°, 19.48±0.2°, and 20.11±0.2°; Or, the p-toluenesulfonate of the compound as shown in Formula I is the p-toluenesulfonate crystalline form A of the compound as shown in Formula I; In the p-toluenesulfonate crystalline form A, the X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles has diffraction peaks at 5.41±0.2°, 8.10±0.2°, 14.74±0.2°, 17.13±0.2°, 18.10±0.2°, and 19.98±0.2°; Or, the benzenesulfonate salt of the compound as shown in Formula I is the benzenesulfonate salt crystal form A of the compound as shown in Formula I; In the benzenesulfonate salt form A, the X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles has diffraction peaks at 4.29±0.2°, 8.49±0.2°, 10.02±0.2°, 13.81±0.2°, and 15.26±0.2°; Or, the oxalate of the compound as shown in Formula I is the oxalate crystal form B or the oxalate crystal form A of the compound as shown in Formula I; In the oxalate crystal form B, the X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles has diffraction peaks at 7.63±0.2°, 8.32±0.2°, 15.25±0.2°, 16.29±0.2°, 22.05±0.2°, and 23.84±0.2°; The oxalate crystal form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, with diffraction peaks at 7.32±0.2°, 8.47±0.2°, 14.62±0.2°, 17.00±0.2°, 18.58±0.2°, and 19.44±0.2°; Or, the maleate of the compound as shown in Formula I is the maleate crystalline form A of the compound as shown in Formula I; In the maleate salt form A, the X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles has diffraction peaks at 13.54±0.2°, 16.92±0.2°, 17.64±0.2°, 19.61±0.2°, and 23.77±0.2°; Or, the malate of the compound of formula I is malate crystalline form A of the compound of formula I; In the malate crystalline form A, the X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles has diffraction peaks at 8.95±0.2°, 9.89±0.2°, 13.21±0.2°, 16.53±0.2°, and 18.93±0.2°; Or, the succinate of the compound as shown in Formula I is the succinate crystal form A of the compound as shown in Formula I; The succinate crystal form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, with diffraction peaks at 6.94±0.2°, 9.20±0.2°, 13.87±0.2°, 16.29±0.2°, 17.94±0.2°, and 20.21±0.2°; Or, the mesylate of the compound as shown in Formula I is the mesylate crystalline form A or mesylate B of the compound as shown in Formula I; The mesylate salt form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, with diffraction peaks at 5.03±0.2°, 17.03±0.2°, 18.11±0.2°, 20.60±0.2°, and 23.40±0.2°; The mesylate salt form B has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, with diffraction peaks at 18.89±0.2°, 20.43±0.2°, 21.07±0.2°, 23.44±0.2°, and 24.46±0.2°; Or, the 2-hydroxyethanesulfonate of the compound as shown in Formula I is the 2-hydroxyethanesulfonate crystalline form A of the compound as shown in Formula I; The 2-hydroxyethanesulfonate salt form A has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, with diffraction peaks at 4.85±0.2°, 9.85±0.2°, 10.98±0.2°, 18.09±0.2°, 19.35±0.2°, and 20.33±0.2°.

3. The crystalline form or salt form of the compound as shown in formula I according to claim 2, characterized in that: The free crystalline form A has an X-ray powder diffraction pattern expressed in 2θ angles using Cu-Kα radiation that satisfies any one of the following conditions: (1) It has diffraction peaks at one or more of the following locations: 7.25±0.2°, 9.20±0.2°, 12.39±0.2°, 13.77±0.2°; (2) It has diffraction peaks at 3.66±0.2°, 7.25±0.2°, 9.20±0.2°, 11.13±0.2°, 12.39±0.2°, 13.77±0.2°, and 14.49±0.2°; (3) It has diffraction peaks at 7.25±0.2°, 9.20±0.2°, 12.39±0.2°, 13.77±0.2°, 14.49±0.2°, 17.02±0.2°, 17.78±0.2°, 18.42±0.2°, and 20.53±0.2°; (4) It has diffraction peaks at 3.66±0.2°, 7.25±0.2°, 9.20±0.2°, 11.13±0.2°, 12.39±0.2°, 13.77±0.2°, 14.49±0.2°, 17.02±0.2°, 17.78±0.2°, 18.42±0.2°, and 20.53±0.2°; (5) It has diffraction peaks at 3.66±0.2°, 7.25±0.2°, 9.20±0.2°, 11.13±0.2°, 12.39±0.2°, 13.77±0.2°, 14.49±0.2°, 17.02±0.2°, 17.78±0.2°, 18.42±0.2°, 20.53±0.2°, and 20.92±0.2°; (6) The diffraction peak positions and relative intensities thereof are shown in the following table: Or, the X-ray powder diffraction pattern of the free crystalline form B using Cu-Kα radiation and expressed in 2θ angles satisfies any one of the following conditions: (1) It has diffraction peaks at one or more of the following locations: 8.89±0.2°, 10.99±0.2°, 13.81±0.2°, 16.10±0.2°, 19.65±0.2°; (2) It has diffraction peaks at 8.89±0.2°, 10.99±0.2°, 13.81±0.2°, 16.10±0.2°, 16.55±0.2°, 17.77±0.2°, 19.65±0.2°, 20.36±0.2°, 21.24±0.2°, and 22.66±0.2°; (3) it has diffraction peaks at 8.89±0.2°, 10.99±0.2°, 13.81±0.2°, 14.97±0.2°, 16.10±0.2°, 16.55±0.2°, 17.77±0.2°, 19.65±0.2°, 20.36±0.2°, 21.24±0.2°, 22.66±0.2°, 23.92±0.2°, 24.80±0.2°, 25.41±0.2°, and 26.65±0.2°; (4) The diffraction peak positions and relative intensities thereof are shown in the following table: Or, the X-ray powder diffraction pattern of the phosphate crystal form A using Cu-Kα radiation and expressed in 2θ angles satisfies any one of the following conditions: (1) It has diffraction peaks at one or more of the following locations: 11.87±0.2°, 12.56±0.2°, 13.75±0.2°, 18.60±0.2°, 20.26±0.2°, 25.26±0.2°; (2) It has diffraction peaks at 6.74±0.2°, 11.87±0.2°, 12.56±0.2°, 13.47±0.2°, 13.75±0.2°, 15.69±0.2°, 16.86±0.2°, 18.09±0.2°, and 20.26±0.2°; (3) it has diffraction peaks at 3.40±0.2°, 6.74±0.2°, 7.47±0.2°, 11.87±0.2°, 12.56±0.2°, 13.47±0.2°, 13.75±0.2°, 14.94±0.2°, 15.69±0.2°, 16.86±0.2°, 18.09±0.2°, 18.61±0.2°, 20.26±0.2°, and 25.26±0.2°; (4) The diffraction peak positions and relative intensities thereof are shown in the following table: Or, the X-ray powder diffraction pattern of the phosphate crystal form B using Cu-Kα radiation and expressed in 2θ angles satisfies any one of the following conditions: (1) It has diffraction peaks at one or more of the following locations: 3.35±0.2°, 14.53±0.2°, 21.27±0.2°, 22.53±0.2°, 24.43±0.2°, 25.24±0.2°; (2) It has diffraction peaks at 6.68±0.2°, 13.37±0.2°, 14.16±0.2°, 14.53±0.2°, 15.30±0.2°, 16.74±0.2°, 20.12±0.2°, and 21.26±0.2°; (3) It has diffraction peaks at 3.35±0.2°, 6.68±0.2°, 13.37±0.2°, 14.16±0.2°, 14.53±0.2°, 15.30±0.2°, 16.74±0.2°, 20.12±0.2°, 21.26±0.2°, 22.53±0.2°, 24.42±0.2°, and 25.24±0.2°; (4) The diffraction peak positions and relative intensities thereof are shown in the following table: Or, the fumarate salt form A uses Cu-Kα radiation and the X-ray powder diffraction pattern expressed in 2θ angles satisfies any one of the following conditions: (1) It has diffraction peaks at one or more of the following locations: 9.03±0.2°, 9.78±0.2°, 16.89±0.2°, 22.04±0.2°, 23.71±0.2°, 24.24±0.2°, 25.72±0.2°; (2) Its relative humidity is 9.03±0.2°, 9.78±0.2°, 13.51±0.2°, 15.41±0.2°, 16.89±0.2°, 17.57±0.2°, 19.48±0.2°, There are diffraction peaks at 20.11±0.2° and 22.04±0.2°; (3) It has diffraction peaks at 9.03±0.2°, 9.78±0.2°, 13.51±0.2°, 15.41±0.2°, 16.89±0.2°, 17.57±0.2°, 19.48±0.2°, 20.11±0.2°, 22.04±0.2°, 23.71±0.2°, 24.24±0.2°, and 25.72±0.2°; (4) The diffraction peak positions and relative intensities thereof are shown in the following table: Or, the p-toluenesulfonate crystalline form A uses Cu-Kα radiation and the X-ray powder diffraction pattern expressed in 2θ angles satisfies any one of the following conditions: (1) It has diffraction peaks at one or more of the following locations: 10.81±0.2°, 18.83±0.2°, 21.83±0.2°, 24.37±0.2°; (2) It has diffraction peaks at 5.41±0.2°, 7.74±0.2°, 8.10±0.2°, 10.81±0.2°, 14.74±0.2°, 17.13±0.2°, 18.10±0.2°, 18.83±0.2°, and 19.98±0.2°; (3) it has diffraction peaks at 5.41±0.2°, 7.74±0.2°, 8.10±0.2°, 10.81±0.2°, 14.74±0.2°, 17.13±0.2°, 18.10±0.2°, 18.83±0.2°, 19.98±0.2°, 21.01±0.2°, 21.83±0.2°, 22.85±0.2°, 23.41±0.2°, 24.37±0.2°, 26.18±0.2°, and 28.58±0.2°; (4) The diffraction peak positions and relative intensities thereof are shown in the following table: Or, the benzenesulfonate salt form A uses Cu-Kα radiation and the X-ray powder diffraction pattern expressed in 2θ angles satisfies any one of the following conditions: (1) It has diffraction peaks at one or more of the following locations: 10.68±0.2°, 16.80±0.2°, 18.80±0.2°, 19.73±0.2°, 20.53±0.2°, 20.99±0.2°; (2) It has diffraction peaks at 4.29±0.2°, 8.49±0.2°, 10.02±0.2°, 10.68±0.2°, 13.81±0.2°, 15.26±0.2°, 16.80±0.2°, 18.80±0.2°, 19.73±0.2°, 20.53±0.2°, and 20.99±0.2°; (3) it has diffraction peaks at 4.29±0.2°, 5.75±0.2°, 8.49±0.2°, 10.02±0.2°, 10.68±0.2°, 11.18±0.2°, 11.48±0.2°, 12.70±0.2°, 13.81±0.2°, 15.26±0.2°, 16.80±0.2°, 18.80±0.2°, 19.73±0.2°, 20.53±0.2°, 20.99±0.2°, 21.95±0.2°, and 23.90±0.2°; (4) The diffraction peak positions and relative intensities thereof are shown in the following table: Or, the X-ray powder diffraction pattern of the oxalate crystal form B using Cu-Kα radiation and expressed in 2θ angles satisfies any one of the following conditions: (1) It has diffraction peaks at one or more of the following locations: 12.47±0.2°, 17.66±0.2°, 18.26±0.2°, 18.77±0.2°, 19.16±0.2°; (2) It has diffraction peaks at 7.63±0.2°, 8.32±0.2°, 12.47±0.2°, 15.25±0.2°, 16.29±0.2°, 17.66±0.2°, 18.26±0.2°, 18.77±0.2°, 19.16±0.2°, 22.05±0.2°, and 23.84±0.2°; (3) it has diffraction peaks at 7.63±0.2°, 8.32±0.2°, 12.47±0.2°, 15.25±0.2°, 16.29±0.2°, 17.66±0.2°, 18.26±0.2°, 18.77±0.2°, 19.16±0.2°, 19.92±0.2°, 20.83±0.2°, 21.28±0.2°, 22.05±0.2°, 23.84±0.2°, 25.05±0.2°, 26.40±0.2°, 27.41±0.2°, and 29.25±0.2°; (4) The diffraction peak positions and relative intensities thereof are shown in the following table: Or, the X-ray powder diffraction pattern of the oxalate crystal form A using Cu-Kα radiation and expressed in 2θ angles satisfies any one of the following conditions: (1) It has diffraction peaks at one or more of the following locations: 12.93±0.2°, 13.47±0.2°, 15.23±0.2°, 22.38±0.2°, 26.00±0.2°; (2) It has diffraction peaks at 7.32±0.2°, 8.47±0.2°, 12.93±0.2°, 13.47±0.2°, 14.62±0.2°, 15.23±0.2°, 17.00±0.2°, 18.58±0.2°, 19.44±0.2°, 22.38±0.2°, and 26.00±0.2°; (3) Its relative humidity is 4.64±0.2°, 7.32±0.2°, 8.47±0.2°, 12.93±0.2°, 13.47±0.2°, 14.62±0.2°, 15.23±0.2°, There are diffraction peaks at 17.00±0.2°, 18.05±0.2°, 18.58±0.2°, 19.44±0.2°, 20.57±0.2°, 21.49±0.2°, 22.38±0.2°, 23.26±0.2°, 23.59±0.2°, and 26.00±0.2°; (4) The diffraction peak positions and relative intensities thereof are shown in the following table: Or, the maleate salt form A uses Cu-Kα radiation and the X-ray powder diffraction pattern expressed in 2θ angles satisfies any one of the following conditions: (1) It has diffraction peaks at one or more of the following locations: 3.44±0.2°, 9.64±0.2°, 18.08±0.2°, 20.82±0.2°, 27.20±0.2°; (2) It has diffraction peaks at 3.44±0.2°, 9.64±0.2°, 13.54±0.2°, 16.92±0.2°, 17.64±0.2°, 18.08±0.2°, 19.61±0.2°, 20.82±0.2°, 23.77±0.2°, and 27.20±0.2°; (3) it has diffraction peaks at 3.44±0.2°, 9.64±0.2°, 13.54±0.2°, 16.92±0.2°, 17.64±0.2°, 18.08±0.2°, 19.61±0.2°, 20.82±0.2°, 22.36±0.2°, 22.71±0.2°, 23.77±0.2°, 27.20±0.2°, 28.90±0.2°, and 30.67±0.2°; (4) The diffraction peak positions and relative intensities thereof are shown in the following table: Or, the X-ray powder diffraction pattern of the malate crystalline form A using Cu-Kα radiation and expressed in 2θ angles satisfies any one of the following conditions: (1) It has diffraction peaks at 8.95±0.2°, 9.89±0.2°, 13.21±0.2°, 16.17±0.2°, 16.53±0.2°, 18.93±0.2°, and 24.77±0.2°; (2) an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles, with diffraction peaks at 6.63±0.2°, 8.95±0.2°, 9.89±0.2°, 13.21±0.2°, 16.17±0.2°, 16.53±0.2°, 18.93±0.2°, 21.62±0.2°, 23.20±0.2°, 23.80±0.2°, and 24.77±0.2°; (3) The diffraction peak positions and relative intensities thereof are shown in the following table: Or, the X-ray powder diffraction pattern of the succinate salt form A using Cu-Kα radiation and expressed in 2θ angles satisfies any one of the following conditions: (1) It has diffraction peaks at one or more of the following locations: 14.70±0.2°, 17.40±0.2°, 19.48±0.2°, 20.96±0.2°, 22.18±0.2°, 23.04±0.2°, 23.92±0.2°, 26.18±0.2°; (2) It has diffraction peaks at 6.94±0.2°, 9.20±0.2°, 13.87±0.2°, 16.29±0.2°, 17.94±0.2°, 20.21±0.2°, 20.96±0.2°, 22.18±0.2°, and 26.18±0.2°; (3) it has diffraction peaks at 6.94±0.2°, 9.20±0.2°, 13.87±0.2°, 14.70±0.2°, 16.29±0.2°, 17.40±0.2°, 17.94±0.2°, 19.48±0.2°, 20.21±0.2°, 20.96±0.2°, 22.18±0.2°, 23.04±0.2°, 23.92±0.2°, and 26.18±0.2°; (4) The diffraction peak positions and relative intensities thereof are shown in the following table: Or, the mesylate salt form A uses Cu-Kα radiation and the X-ray powder diffraction pattern expressed in 2θ angles contains diffraction peak positions and relative intensities as shown in the following table: Or, the mesylate salt form B uses Cu-Kα radiation and the X-ray powder diffraction pattern expressed in 2θ angles satisfies any one of the following conditions: (1) It has diffraction peaks at one or more of the following locations: 9.83±0.2°, 11.32±0.2°, 15.46±0.2°, 17.26±0.2°; (2) It has diffraction peaks at 9.83±0.2°, 11.32±0.2°, 15.46±0.2°, 17.26±0.2°, 18.89±0.2°, 20.43±0.2°, 21.07±0.2°, 23.44±0.2°, and 24.46±0.2°; (3) it has diffraction peaks at 9.83±0.2°, 11.32±0.2°, 15.46±0.2°, 16.98±0.2°, 17.26±0.2°, 17.63±0.2°, 18.89±0.2°, 19.68±0.2°, 20.43±0.2°, 21.07±0.2°, 21.58±0.2°, 22.09±0.2°, 22.69±0.2°, 23.44±0.2°, and 24.46±0.2°; (4) The diffraction peak positions and relative intensities thereof are shown in the following table: Or, the X-ray powder diffraction pattern of the 2-hydroxyethanesulfonate salt form A using Cu-Kα radiation and expressed in 2θ angles satisfies any one of the following conditions: (1) It has diffraction peaks at one or more of the following locations: 15.54±0.2°, 15.94±0.2°, 21.83±0.2°, 22.33±0.2°, 22.87±0.2°; (2) It has diffraction peaks at 4.85±0.2°, 9.85±0.2°, 10.98±0.2°, 15.54±0.2°, 15.94±0.2°, 18.09±0.2°, 19.35±0.2°, 20.33±0.2°, 21.83±0.2°, 22.33±0.2°, and 22.87±0.2°; (3) It has diffraction peaks at 4.85±0.2°, 9.85±0.2°, 10.98±0.2°, 12.83±0.2°, 15.54±0.2°, 15.94±0.2°, 16.66±0.2°, 18.09±0.2°, 19.35±0.2°, 20.33±0.2°, 21.83±0.2°, 22.33±0.2°, and 22.87±0.2°; (4) The diffraction peak positions and relative intensities thereof are shown in the following table:

4. The crystalline form or salt form of the compound of formula I according to claim 3, characterized in that: The free crystalline form A of the compound shown in formula I satisfies one or more of the following conditions: (1) It is anhydrous crystalline; (2) Its X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles is shown in FIG1 ; (3) Its differential scanning calorimetry analysis chart has an endothermic peak starting point at 94.7±3°C; (4) Its differential scanning calorimetry analysis chart has an endothermic peak at 96.6±3°C; (5) Its thermogravimetric analysis shows a weight loss of approximately 0.98% at 150°C; (6) Its differential scanning calorimetry analysis diagram is shown in FIG3 ; (7) Its thermogravimetric analysis diagram is shown in Figure 2; Or, the free crystalline form B satisfies one or more of the following conditions: (1) It is anhydrous crystal type; (2) Its X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles is shown in FIG4 ; (3) Its differential scanning calorimetry analysis chart shows an endothermic peak starting point at 77.2±3°C; (4) Its differential scanning calorimetry analysis chart has an endothermic peak at 84.5±3°C; (5) Its differential scanning calorimetry analysis chart has an endothermic peak at 92.4±3°C; (6) Its thermogravimetric analysis shows a weight loss of approximately 0.48% at 150°C; (7) Its differential scanning calorimetry analysis diagram is shown in FIG6 ; (8) Its thermogravimetric analysis diagram is shown in Figure 5; Or, the phosphate crystal form A satisfies one or more of the following conditions: (1) Its X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles is shown in FIG7 ; (2) Its differential scanning calorimetry analysis chart shows an endothermic peak starting point at 172.8±3°C; (3) Its differential scanning calorimetry analysis chart has an endothermic peak at 174.5±3°C; (4) Its thermogravimetric analysis shows a weight loss of approximately 4.40% at 150°C; (5) Its differential scanning calorimetry analysis diagram is shown in FIG9 ; (6) Its thermogravimetric analysis diagram is shown in FIG8 ; (7) In the phosphate crystal form A, the molar ratio of the compound represented by formula I to phosphoric acid is 1:1; Or, the phosphate crystal form B satisfies one or more of the following conditions: (1) It is anhydrous crystal type; (2) Its X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles is shown in FIG11 ; (3) In the phosphate crystal form B, the molar ratio of the compound represented by formula I to phosphoric acid is 1:1; Or, the fumarate salt crystal form A satisfies one or more of the following conditions: (1) It is anhydrous crystal type; (2) Its X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles is shown in FIG12 ; (3) Its differential scanning calorimetry analysis chart shows an endothermic peak starting point at 128.2±3°C; (4) Its differential scanning calorimetry analysis chart has an endothermic peak at 130.3±3°C; (5) Its thermogravimetric analysis shows a weight loss of approximately 1.17% at 150°C; (6) Its differential scanning calorimetry analysis diagram is shown in FIG14 ; (7) Its thermogravimetric analysis diagram is shown in FIG13 ; (8) In the fumarate salt crystalline form A, the molar ratio of the compound represented by formula I to fumaric acid is 1:1; Or, the p-toluenesulfonate crystalline form A satisfies one or more of the following conditions: (1) Its X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles is shown in FIG16 ; (2) Its differential scanning calorimetry analysis chart shows an endothermic peak starting point at 149.9±3°C; (3) Its differential scanning calorimetry analysis chart has an endothermic peak at 152.1±3°C; (4) Its thermogravimetric analysis shows a weight loss of approximately 0.94% at 150°C; (5) Its differential scanning calorimetry analysis diagram is shown in FIG18 ; (6) Its thermogravimetric analysis diagram is shown in FIG17 ; (7) In the p-toluenesulfonate crystalline form A, the molar ratio of the compound represented by formula I to p-toluenesulfonic acid is 1:1; Or, the benzenesulfonate salt form A satisfies one or more of the following conditions: (1) Its X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles is shown in FIG19 ; (2) Its differential scanning calorimetry analysis chart shows an endothermic peak starting point at 144.5±3°C; (3) Its differential scanning calorimetry analysis chart has an endothermic peak at 146.4±3°C; (4) Its thermogravimetric analysis shows a weight loss of approximately 1.28% at 140°C; (5) Its differential scanning calorimetry analysis diagram is shown in FIG21 ; (6) Its thermogravimetric analysis diagram is shown in FIG20 ; (7) In the benzenesulfonate salt form A, the molar ratio of the compound represented by formula I to benzenesulfonic acid is 1:1; Or, the oxalate crystal form B satisfies one or more of the following conditions: (1) Its X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles is shown in FIG22 ; (2) Its differential scanning calorimetry analysis chart shows an endothermic peak starting point at 155.5±3°C; (3) Its differential scanning calorimetry analysis chart has an endothermic peak at 158.2±3°C; (4) Its differential scanning calorimetry analysis chart has an endothermic peak at 218.7±3°C; (5) Its thermogravimetric analysis shows a weight loss of approximately 1.21% at 150°C; (6) Its differential scanning calorimetry analysis diagram is shown in FIG24 ; (7) Its thermogravimetric analysis diagram is shown in FIG23 ; (8) In the oxalate salt form B, the molar ratio of the compound represented by formula I to oxalic acid is 1:1; Or, the oxalate crystal form A satisfies one or more of the following conditions: (1) Its X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles is shown in FIG38 ; (2) Its differential scanning calorimetry analysis chart shows an endothermic peak starting point at 151.3±3°C; (3) Its differential scanning calorimetry analysis chart has an endothermic peak at 153.6±3°C; (4) Its differential scanning calorimetry analysis chart has an endothermic peak at 162.8±3°C; (5) Its differential scanning calorimetry analysis chart has an endothermic peak at 218.8±3°C; (6) Its thermogravimetric analysis shows a weight loss of approximately 4.10% at 150°C; (7) Its differential scanning calorimetry analysis diagram is shown in FIG40 ; (8) Its thermogravimetric analysis diagram is shown in FIG39 ; Or, the maleate salt form A satisfies one or more of the following conditions: (1) Its X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles is shown in FIG25 ; (2) Its differential scanning calorimetry analysis chart shows an endothermic peak starting point at 123.4±3°C; (3) Its differential scanning calorimetry analysis chart has an endothermic peak at 125.2±3°C; (4) Its thermogravimetric analysis shows a weight loss of approximately 2.56% at 120°C; (5) Its differential scanning calorimetry analysis diagram is shown in FIG27 ; (6) Its thermogravimetric analysis diagram is shown in FIG26 ; (7) In the maleate salt form A, the molar ratio of the compound of formula I to maleic acid is 1:1; Or, the malate crystal form A satisfies one or more of the following conditions: (1) Its X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles is shown in FIG28 ; (2) Its differential scanning calorimetry analysis chart shows an endothermic peak starting point at 86.3±3°C; (3) Its differential scanning calorimetry analysis chart has an endothermic peak at 96.3±3°C; (4) Its thermogravimetric analysis shows a weight loss of approximately 2.26% at 150°C; (5) Its differential scanning calorimetry analysis diagram is shown in FIG30 ; (6) Its thermogravimetric analysis diagram is shown in FIG29 ; (7) In the malate crystalline form A, the molar ratio of the compound represented by formula I to malic acid is 1:1; Or, the succinate salt form A satisfies one or more of the following conditions: (1) In the succinate salt form A, the molar ratio of the compound of formula I to succinic acid is 1:1.2, 1:1.1 or 1:1; (2) Its X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles is shown in FIG31 ; (3) Its differential scanning calorimetry analysis chart shows an endothermic peak starting point at 75.9±3°C; (4) Its differential scanning calorimetry analysis chart has an endothermic peak at 85.4±3°C; (5) Its thermogravimetric analysis shows a weight loss of approximately 4.49% at 150°C; (6) Its differential scanning calorimetry analysis diagram is shown in FIG33 ; (7) Its thermogravimetric analysis diagram is shown in FIG32 ; (8) In the succinate salt crystal form A, the molar ratio of the compound represented by formula I to succinic acid is 1:1; Or, the X-ray powder diffraction pattern of the mesylate salt form A using Cu-Kα radiation and expressed in 2θ angles is shown in Figure 34; Or, the mesylate salt form B satisfies one or more of the following conditions: (1) In the mesylate salt form B, the molar ratio of the compound of formula I to methanesulfonic acid is 1:2.1 or 1:2; (2) Its X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles is shown in FIG35 ; (3) Its differential scanning calorimetry analysis chart shows an endothermic peak starting point at 97.3±3°C; (4) Its differential scanning calorimetry analysis chart has an endothermic peak at 109.4±3°C; (5) Its thermogravimetric analysis shows a weight loss of about 0.91% at 80°C and a weight loss of about 2.40% at 80-130°C; (6) Its differential scanning calorimetry analysis diagram is shown in FIG37 ; (7) Its thermogravimetric analysis diagram is shown in FIG36 ; (8) In the mesylate salt form B, the molar ratio of the compound represented by formula I to methanesulfonic acid is 1:2; Or, the 2-hydroxyethanesulfonate salt form A satisfies one or more of the following conditions: (1) Its X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles is shown in FIG41 ; (2) Its differential scanning calorimetry analysis chart shows an endothermic peak starting point at 109.5±3°C; (3) Its differential scanning calorimetry analysis chart has an endothermic peak at 118.4±3°C; (4) Its thermogravimetric analysis shows a weight loss of approximately 1.28% at 110°C; (5) Its differential scanning calorimetry analysis diagram is shown in FIG43 ; (6) Its thermogravimetric analysis diagram is shown in FIG42 ; (7) In the 2-hydroxyethanesulfonate salt form A, the molar ratio of the compound represented by formula I to 2-hydroxyethanesulfonic acid is 1:

1.

5. A method for preparing a crystalline form or salt form of a compound as shown in formula I, characterized in that: The crystalline form of the compound shown in Formula I is the free crystalline form A or the free crystalline form B as described in any one of claims 1 to 4; The salt form of the compound of formula I is the phosphate crystal form A, phosphate crystal form B, fumarate crystal form A, p-toluenesulfonate crystal form A, benzenesulfonate crystal form A, oxalate crystal form B, oxalate crystal form A, maleate crystal form A, malate crystal form A, succinate crystal form A, methanesulfonate crystal form A, methanesulfonate crystal form B, or 2-hydroxyethanesulfonate crystal form A of the compound of formula I as claimed in any one of claims 2 to 4; in, The preparation method of the free-state crystalline form A comprises the following steps: dissolving the compound represented by formula I in a solvent, volatilizing at room temperature, and obtaining the free-state crystalline form A; the solvent is an organic solvent or a mixed solvent, and the organic solvent is preferably CHCl3, THF, acetone, toluene, cyclopentyl methyl ether, 2-methyltetrahydrofuran, isopropanol, IPAc or 2-butanone; the mixed solvent is a mixed solvent of an organic solvent and water, and the mixed solvent is preferably a mixed solvent of MeOH and H2O, or a mixed solvent of acetonitrile and H2O; The preparation method of the free-state crystal form B comprises the following steps: concentrating the compound solution as shown in formula I under reduced pressure, and drying at 40-60° C. to obtain the free-state crystal form B; the solution is an alcohol solution or a halogenated hydrocarbon solution; The preparation method of the phosphate crystal form A comprises the following steps: mixing the compound represented by formula I, phosphoric acid and a solvent, and slurrying at room temperature to obtain the phosphate crystal form A of the compound represented by formula I; the solvent is an ester solvent, an ether solvent, a mixed solvent of an alcohol solvent and water, or a mixed solvent of a ketone solvent and a saturated alkane solvent; The preparation method of the phosphate crystal form B comprises the following steps: heating the phosphate crystal form A to 150±10° C. to obtain the phosphate crystal form B; The preparation method of the fumarate salt crystal form A comprises the following steps: mixing the compound represented by formula I, fumaric acid and a solvent, and slurrying at room temperature to obtain the fumarate salt crystal form A; the solvent is an ester solvent, an ether solvent, a mixed solvent of an alcohol solvent and water, a ketone solvent and A mixed solvent of saturated alkane solvents; The preparation method of the p-toluenesulfonate crystalline form A comprises the following steps: mixing the compound represented by formula I, p-toluenesulfonic acid and a solvent, and slurrying at room temperature to obtain the p-toluenesulfonate crystalline form A; the solvent is an ester solvent or an ether solvent; The preparation method of the benzenesulfonate salt crystal form A comprises the following steps: mixing the compound represented by formula I, benzenesulfonic acid and a solvent, and beating at room temperature to obtain the benzenesulfonate salt crystal form A; the solvent is a mixed solvent of an ester solvent, an alcohol solvent and water; The preparation method of the oxalate crystal form B comprises the following steps: mixing the compound represented by formula I, oxalic acid and a solvent, and slurrying at room temperature to obtain the oxalate crystal form B; the solvent is a mixed solvent of an ester solvent, an ether solvent, a ketone solvent and a saturated alkane solvent; The preparation method of the oxalate crystal form A comprises the following steps: mixing the compound represented by formula I, oxalic acid and a solvent, and slurrying at room temperature to obtain the oxalate crystal form A; the solvent is a mixed solvent of an alcohol solvent and water; The preparation method of the maleate salt crystal form A comprises the following steps: mixing the compound represented by formula I, maleic acid and a solvent, and slurrying at room temperature to obtain the maleate salt crystal form A; the solvent is a mixed solvent of an ester solvent, an ether solvent, a ketone solvent and a saturated alkane solvent; The preparation method of the malate crystal form A comprises the following steps: mixing the compound represented by formula I, malic acid and a solvent, and slurrying at room temperature to obtain the malate crystal form A; the solvent is a mixed solvent of a ketone solvent and a saturated alkane solvent; The preparation method of the succinate salt crystal form A comprises the following steps: mixing the compound shown in formula I, succinic acid and a solvent, and slurrying at room temperature to obtain the succinate salt crystal form A; the solvent is an ether solvent; The preparation method of the mesylate salt crystal form A comprises the following steps: mixing the compound shown in formula I, methanesulfonic acid and a solvent, and beating at room temperature to obtain the mesylate salt crystal form A; the solvent is a mixed solvent of a ketone solvent and a saturated alkane solvent; The preparation method of the mesylate salt crystal form B comprises the following steps: mixing the compound shown in formula I, methanesulfonic acid and a solvent, and beating at room temperature to obtain the mesylate salt crystal form B; the solvent is a mixed solvent of an ester solvent, an ether solvent, a ketone solvent and a saturated alkane solvent; The preparation method of the 2-hydroxyethanesulfonate salt form A comprises the following steps: mixing the compound shown in formula I, 2-hydroxyethanesulfonic acid and a solvent, and slurrying at room temperature to obtain the 2-hydroxyethanesulfonate salt form A; the solvent is a mixed solvent of an ester solvent, a ketone solvent and a saturated alkane solvent.

6. The preparation method according to claim 5, characterized in that: In the preparation method of the free crystalline form B, the compound represented by formula I is dissolved in MeOH or dichloromethane and then rotary evaporated under reduced pressure, and the obtained colloidal sample is transferred to 50° C. and dried under vacuum to obtain; Or, in the method for preparing the phosphate crystal form A, the method for preparing the phosphate crystal form A satisfies one or more of the following conditions: (1) The molar ratio of the phosphoric acid to the compound of formula I is (1.0-1.7):1; preferably 1.2:1; (2) The molar volume ratio of the compound represented by Formula I to the solvent is 0.11-0.21 mol / L; preferably 0.16 mol / L; (3) In the mixed solvent of the alcohol solvent and water, the volume ratio of the alcohol solvent to the water is (14-24):1, preferably 19:1; (4) In the mixed solvent of the ketone solvent and the saturated alkane solvent, the volume ratio of the ketone solvent to the saturated alkane solvent is (0.5-2):1; (5) The solvent is IPA / H2O (19:1, v / v) mixed solvent, acetone / n-heptane (1:1, v / v) mixed solvent, isopropyl acetate or Methyl tert-butyl ether; Or, in the preparation method of the phosphate crystal form B, the preparation method of the phosphate crystal form B satisfies one or two of the following conditions: (1) the phosphate crystal form A is heated under nitrogen protection; (2) The heating temperature is 145-155° C., preferably 150° C.; Or, in the preparation method of the fumarate salt crystal form A, the preparation method of the fumarate salt crystal form A satisfies one or more of the following conditions: (1) The molar ratio of the fumaric acid to the compound of formula I is (1.0-1.5):1; preferably 1.0:1; (2) The molar volume ratio of the compound represented by Formula I to the solvent is 0.06-0.16 mol / L; preferably 0.11 mol / L; (3) In the mixed solvent of the alcohol solvent and water, the volume ratio of the alcohol solvent to the water is (14-24):1, preferably 19:1; (4) In the mixed solvent of the ketone solvent and the saturated alkane solvent, the volume ratio of the ketone solvent to the saturated alkane solvent is (0.5-2):1; (5) The solvent is a mixed solvent of IPA / H2O (19:1, v / v), a mixed solvent of acetone / n-heptane (1:1, v / v), isopropyl acetate or methyl tert-butyl ether; Or, in the method for preparing the p-toluenesulfonate crystalline form A, the method for preparing the p-toluenesulfonate crystalline form A satisfies one or more of the following conditions: (1) The molar ratio of p-toluenesulfonic acid to the compound of formula I is (1.0-1.5):1; preferably 1.0:1; (2) The molar volume ratio of the compound represented by Formula I to the solvent is 0.06-0.16 mol / L; preferably 0.11 mol / L; (3) The solvent is isopropyl acetate or methyl tert-butyl ether; Or, in the preparation method of the benzenesulfonate salt form A, the preparation method of the benzenesulfonate salt form A satisfies one or more of the following conditions: (1) The molar ratio of the benzenesulfonic acid to the compound of formula I is (1.0-1.5):1; preferably 1.0:1; (2) The molar volume ratio of the compound represented by Formula I to the solvent is 0.06-0.16 mol / L; preferably 0.11 mol / L; (3) In the mixed solvent of the alcohol solvent and water, the volume ratio of the alcohol solvent to the water is (14-24):1, preferably 19:1; (4) The solvent is a mixed solvent of IPA / H2O (19:1, v / v) or isopropyl acetate; Or, in the preparation method of the oxalate crystal form B, the preparation method of the oxalate crystal form B satisfies one or more of the following conditions: (1) The molar ratio of the oxalic acid to the compound represented by Formula I is (1.0-1.5):1; preferably 1.0:1; (2) The molar volume ratio of the compound represented by Formula I to the solvent is 0.02-0.08 mol / L, preferably 0.05 mol / L; (3) In the mixed solvent of the ketone solvent and the saturated alkane solvent, the volume ratio of the ketone solvent to the saturated alkane solvent is (0.5-2):1; (4) The solvent is a mixed solvent of acetone / n-heptane (1:1, v / v), isopropyl acetate or methyl tert-butyl ether; Or, in the method for preparing the oxalate crystal form A, the method for preparing the oxalate crystal form A satisfies one or more of the following conditions: (1) The molar ratio of the oxalic acid to the compound represented by Formula I is (1.0-1.5):1; preferably 1.0:1; (2) In the method for preparing the oxalate crystal form A, in the mixed solvent of the alcohol solvent and water, the volume ratio of the alcohol solvent to the water is (14-24):1, preferably 19:1; (3) In the preparation method of the oxalate salt form A, the solvent is a mixed solvent of IPA / H2O (19:1, v / v); Or, in the preparation method of the maleate salt crystalline form A, the preparation method of the maleate salt crystalline form A satisfies one or more of the following conditions: (1) The molar ratio of the maleic acid to the compound of formula I is (1.0-1.5):1; preferably 1.0:1; (2) In the mixed solvent of the ketone solvent and the saturated alkane solvent, the volume ratio of the ketone solvent to the saturated alkane solvent is (0.5-2):1; (3) The solvent is a mixed solvent of acetone / n-heptane (1:1, v / v), isopropyl acetate or methyl tert-butyl ether; Or, in the method for preparing the malate crystalline form A, the method for preparing the malate crystalline form A satisfies one or more of the following conditions: (1) The molar ratio of malic acid to the compound of formula I is (1.0-1.5):1; preferably 1.0:1; (2) In the preparation method of the malate crystalline form A, in the mixed solvent of the ketone solvent and the saturated alkane solvent, the volume ratio of the ketone solvent to the saturated alkane solvent is (0.5-2):1, preferably 1:1; (3) The solvent is a mixed solvent of acetone / n-heptane (1:1, v / v); Or, in the preparation method of the succinate salt crystal form A, the preparation method of the succinate salt crystal form A satisfies one or two of the following conditions: (1) The molar ratio of succinic acid to the compound of formula I is (1.0-1.5):1; preferably 1.0:1; (2) The solvent is methyl tert-butyl ether; Or, in the method for preparing the mesylate salt form A, the method for preparing the mesylate salt form A satisfies one or more of the following conditions: (1) The molar ratio of the methanesulfonic acid to the compound of formula I is (1.0-1.2):1; preferably 1:1; (2) In the mixed solvent of the ketone solvent and the saturated alkane solvent, the volume ratio of the ketone solvent to the saturated alkane solvent is (0.5-2):1, preferably 1:1; (3) The solvent is a mixed solvent of acetone / n-heptane (1:1, v / v); Or, in the preparation method of the mesylate salt crystal form B, the preparation method of the mesylate salt crystal form B satisfies one or more of the following conditions: (1) The molar ratio of the methanesulfonic acid to the compound of formula I is (1.5-2.5):1; preferably 2:1; (2) In the mixed solvent of the ketone solvent and the saturated alkane solvent, the volume ratio of the ketone solvent to the saturated alkane solvent is (0.5-2):1; (3) The solvent is a mixed solvent of acetone / n-heptane (1:1, v / v), isopropyl acetate or methyl tert-butyl ether; Or, the preparation method of the 2-hydroxyethanesulfonate salt form A satisfies one or more of the following conditions: (1) The molar ratio of the 2-hydroxyethanesulfonic acid to the compound of formula I is (1.5-2.5):1; preferably 2:1; (2) In the mixed solvent of the ketone solvent and the saturated alkane solvent, the volume ratio of the ketone solvent to the saturated alkane solvent is (0.5-2):1; (3) The solvent is a mixed solvent of acetone / n-heptane (1:1, v / v) or isopropyl acetate.

7. A pharmaceutical composition, characterized in that It comprises a crystalline form or a salt form of the compound shown in formula I as described in any one of claims 1 to 6, and at least one pharmaceutical excipient.

8. A use of a substance M, characterized in that: The substance M is a crystalline form or salt form of a compound of formula I as described in any one of claims 1 to 6, or a pharmaceutical composition as described in claim 7, The uses include: 1) Inhibit tubulin polymerization and / or Src kinase; 2) Preventing and / or treating diseases related to tubulin polymerization and / or Src kinase; 3) Preparation of tubulin polymerization and / or Src kinase inhibitors; 4) Preparation of drugs or preparations for preventing and / or treating diseases related to tubulin polymerization and / or Src kinase.

9. Use of a substance M in preparing a drug for treating tumors and / or skin diseases, characterized in that: The substance M is a crystalline form or a salt form of the compound of formula I as described in any one of claims 1 to 6, or a pharmaceutical composition as described in claim 7.

10. The use according to claim 9, characterized in that The tumor includes: solid tumors, sarcomas, and hematological cancers; preferably, the tumor includes: breast cancer, ovarian cancer, prostate cancer, cervical cancer, testicular cancer, colon cancer, colorectal cancer, liver cancer, non-small cell lung cancer, squamous cell carcinoma (e.g., squamous cell carcinoma of the skin), small cell lung cancer, gastric cancer, gastrointestinal stromal tumors, pancreatic cancer, bladder cancer, germ cell tumors, mast cell tumors, mastocytosis, glioblastoma, neuroblastoma, astrocytoma, melanoma, B cell lymphoma, T cell lymphoma, slowly progressive lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, myeloma and / or myelodysplastic syndrome; The skin diseases include actinic keratosis, psoriasis, atopic dermatitis, psoriasis, vitiligo, roseola and / or systemic lupus erythematosus.

Images