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

Abstract

This invention provides a crystalline form of tubulin-SRC dual-target inhibitor, a method for producing the same, and its use. Specifically, it discloses two free crystalline forms and 13 crystalline forms of 10 salts of a compound represented by formula I, a method for producing the same, and its use. The compound, salt forms, and crystalline forms can be used as a dual-target inhibitor of tubulin and Src kinase, or as a single tubulin or Src kinase inhibitor; the compound, salt forms, and crystalline forms can significantly inhibit the polymerization of tubulin monomers and inhibit cell proliferation; and they have the advantages of good pharmacokinetic properties for topical administration to the skin, excellent drug formulation, suitability for use in the production of topical skin formulations, rapid metabolism, and few side effects. [Formula 1] TIFF2026529489000074.tif40147

Description

Detailed description of the invention

[0001] This application claims priority to Chinese patent application 2023108740075, filed on 14 July 2023. This application incorporates the full text of the aforementioned Chinese patent application. [Technical field] This invention relates to a crystalline tubulin-SRC dual-target inhibitor, a method for producing the same, and its use.

[0002] [Background technology] Microtubules are essential components of the cytoskeleton in eukaryotic cells and play a vital role in various cellular functions, including maintaining cell morphology, signal transduction, organelle transport, cell movement, cell division, and mitosis.

[0003] Microtubules are composed of two types of tubulin subunits, α-tubulin and β-tubulin, which form tubulin heterodimers, the basic units of microtubule assembly. Microtubule-targeting agents (MTAs) disrupt the dynamic stability and structure of microtubules, inhibiting the formation of the mitotic spindle, inducing cell cycle arrest in the G2 / M phase, and promoting apoptosis.

[0004] Microtubules are involved in many important cellular processes and are one of the most important drug targets in the treatment of hyperproliferative diseases. Several microtubule-targeted drugs, such as vinblastine and taxane compounds approved by the US FDA, are widely used to treat multiple solid tumors and hematological malignancies. However, their clinical efficacy is limited due to drug resistance and dose-limiting toxicity. Compared to single-target drugs, dual-target inhibitors can overcome drug resistance and improve therapeutic efficacy, and tubulin-SRC dual-target inhibitors, tubulin-receptor tyrosine kinase (RTK) dual-target inhibitors, and tubulin-histone deacetylase (HDAC) dual-target inhibitors are hot spots in research.

[0005] Actinic keratosis (AK) is a skin condition associated with long-term exposure to ultraviolet radiation. It is the second most common disease among dermatologists in the United States, characterized by uncontrolled proliferation of mutated keratinocytes. Considered a precancerous lesion, if not treated promptly, 20% of cases can progress to cutaneous squamous cell carcinoma (SCC). Currently, tirvaniblin, a tubulin-SRC dual-target inhibitor, has shown significant clinical efficacy in the topical treatment of AK (NCT03285477) and has been approved for sale by the FDA. This suggests that developing new tubulin-SRC dual-target inhibitors with superior efficacy in the topical treatment of AK may be a promising direction.

[0006] A Chinese patent application with application number 202211139978.7 describes compound I-2 (the compound represented by formula I in this application) which has a tubulin-SRC dual target inhibitory effect.

[0007] [ka]

[0008] Based on that the said compound has good biological activity, it is necessary to develop a suitable salt form and solid form thereof to improve druggability potential or other properties. [Summary of the Invention] An object of the present invention is to provide a crystalline form of a tubulin-SRC dual-target inhibitor, a preparation method and use thereof, wherein the dual-target inhibitor has the crystalline form or salt form according to the present invention and has advantages such as good stability; said crystalline form or salt form can be used as a dual-target inhibitor of tubulin and SRC kinase, and can also be used as a single inhibitor of tubulin or SRC kinase.

[0009] The present invention provides a Form A crystal in the free state of the compound represented by formula I.

[0010]

Chemical Formula

[0011] Provided that, using Cu-Kα radiation for said Form A crystal in the free state, the powder X-ray expressed in 2θ angles diffraction pattern has diffraction peaks at positions of 14.49±0.2°, 17.02±0.2°, 18.42±0.2°, and 20.53±0.2°.

[0012] In one embodiment, using Cu-Kα radiation for said Form A crystal in the free state, 2θ the powder X-ray diffraction pattern expressed in angles further has diffraction peaks at one or more positions selected from 7.25±0.2°, 9.20±0.2°, 12.39±0.2°, and 13.77±0.2°.

[0013] In one embodiment, using Cu-Kα radiation for said Form A crystal in the free state, 2θ the powder X-ray diffraction pattern expressed in angles has diffraction peaks at positions of 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°.

[0014] In one embodiment, using Cu-Kα radiation of the Form A crystal in free form, 2θ the powder X-ray diffraction pattern expressed in terms of angles has diffraction peaks at positions of 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°.

[0015] In one embodiment, using Cu-Kα radiation of the Form A crystal in free form, 2θ the powder X-ray diffraction pattern expressed in terms of angles has diffraction peaks at positions of 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°.

[0016] In one embodiment, using Cu-Kα radiation of the Form A crystal in free form, 2θ the powder X-ray diffraction pattern expressed in terms of angles has diffraction peaks at positions of 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°.

[0017] In one embodiment, the Form A crystal in free form is an anhydrous crystal form. In one embodiment, using Cu-Kα radiation of the Form A crystal in free form, 2θ the positions and relative intensities of diffraction peaks comprised in the powder X-ray diffraction pattern expressed in terms of angles are basically as shown in Table 1.

[0018] [Table 1]

[0019] In one embodiment, the Cu-Kα line of the free-state type A crystal is used, 2θ The powder X-ray diffraction pattern, represented by angles, is basically as shown in Figure 1. In one embodiment, the differential scanning calorimetry curve of the free-state type A crystal has an endothermic peak starting at 94.7±3°C.

[0020] In one embodiment, the differential scanning calorimetry curve of the free-state type A crystal has one endothermic peak at 96.6±3°C. In one embodiment, the thermogravimetric analysis curve of the free-state type A crystal shows a weight loss of approximately 0.98% at 150°C.

[0021] In one embodiment, the differential scanning calorimetry curve of the free-state type A crystal is basically as shown in Figure 3. In one embodiment, the thermogravimetric analysis curve of the free-state A-type crystal is basically as shown in Figure 2.

[0022] This invention provides a free-state B-type crystal of a compound represented by formula I.

[0023] [ka]

[0024] However, using the Cu-Kα rays from the free-state B-type crystal, and powder X-rays expressed at a 2θ angle. The diffraction pattern has diffraction peaks at the following positions: 16.55±0.2°, 17.77±0.2°, 20.36±0.2°, 21.24±0.2°, and 22.66±0.2°.

[0025] In one embodiment, the Cu-Kα line of the free-state B-type crystal is used, 2θ The powder X-ray diffraction pattern, represented by angles, 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°.

[0026] In one embodiment, the Cu-Kα line of the free-state B-type crystal is used, 2θ The powder X-ray diffraction pattern, represented by angles, has diffraction peaks at the following positions: 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°.

[0027] In one embodiment, the Cu-Kα line of the free-state B-type crystal is used, 2θ The powder X-ray diffraction pattern, represented by angles, has diffraction peaks at the following positions: 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°.

[0028] In one embodiment, the free-state type B crystal is in anhydrous crystalline form. In one embodiment, the Cu-Kα line of the free-state B-type crystal is used, 2θ The positions and relative intensities of the diffraction peaks included in the powder X-ray diffraction pattern, represented by angles, are basically as shown in Table 2.

[0029] [Table 2]

[0030] In one embodiment, the Cu-Kα line of the free-state B-type crystal is used, 2θ The powder X-ray diffraction pattern, represented by angles, is basically as shown in Figure 4. In one embodiment, the differential scanning calorimetry curve of the free-state type B crystal has an endothermic peak starting at 77.2±3°C.

[0031] In one embodiment, the differential scanning calorimetry curve of the free-state type B crystal has one endothermic peak at 84.5±3°C. In one embodiment, the differential scanning calorimetry curve of the free-state type B crystal has one endothermic peak at 92.4±3°C.

[0032] In one embodiment, the thermogravimetric analysis curve of the free-state type B crystal shows a weight loss of approximately 0.48% at 150°C. In one embodiment, the differential scanning calorimetry curve of the free-state B-type crystal is basically as shown in Figure 6.

[0033] In one embodiment, the thermogravimetric analysis curve of the free-state B-type crystal is basically as shown in Figure 5. The present invention further provides a method for producing free form A crystals of a compound represented by formula I, comprising dissolving the compound represented by formula I in a solvent and volatilizing it at room temperature, 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, and 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.

[0034] The present invention further provides a method for producing free form B crystals of a compound represented by formula I, comprising concentrating a solution of the compound represented by formula I under reduced pressure and drying it at 40-60°C, wherein the solution is an alcohol-based solution or a halogenated hydrocarbon solution.

[0035] Preferably, the compound represented by formula I is dissolved in MeOH or dichloromethane, then rotated and evaporated under reduced pressure, and the resulting gel-like sample is vacuum-dried at 50°C.

[0036] The present invention further provides a phosphate of a compound represented by formula I. In one embodiment, the phosphate of the compound represented by formula I is a type A crystal of the phosphate of the compound represented by formula I, and the powder X-ray diffraction pattern of the type A crystal of the phosphate, using Cu-Kα rays and expressed at a 2θ angle, is 6.74. Diffraction peaks are found at the following positions: ±0.2°, 13.47±0.2°, 15.69±0.2°, 16.86±0.2°, and 18.09±0.2°.

[0037] In one embodiment, the Cu-Kα line of the A-type crystal of the phosphate is used, 2θ The powder X-ray diffraction pattern, expressed as angles, has diffraction peaks at the following positions: 6.74±0.2°, 13.47±0.2°, 15.69±0.2°, 18.09±0.2°, and 20.26±0.2°.

[0038] In one embodiment, the Cu-Kα line of the A-type crystal of the phosphate is used, 2θ The powder X-ray diffraction pattern, represented by angles, further 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°.

[0039] In one embodiment, the Cu-Kα line of the A-type crystal of the phosphate is used, 2θ The powder X-ray diffraction pattern, represented by angles, has diffraction peaks at the following positions: 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°.

[0040] In one embodiment, the Cu-Kα line of the A-type crystal of the phosphate is used, 2θ The powder X-ray diffraction pattern, represented by angles, has diffraction peaks at the following positions: 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°.

[0041] In one embodiment, the Cu-Kα line of the A-type crystal of the phosphate is used, 2θ The positions and relative intensities of the diffraction peaks included in the powder X-ray diffraction pattern, represented by angles, are basically as shown in Table 3.

[0042] [Table 3]

[0043] In one embodiment, the Cu-Kα line of the A-type crystal of the phosphate is used, 2θ The powder X-ray diffraction pattern, represented by angles, is basically as shown in Figure 7. In one embodiment, in the A-type crystal of the phosphate, the molar ratio of the compound represented by formula I to phosphoric acid is 1:1.

[0044] In one embodiment, the differential scanning calorimetry curve of the type A crystal of the phosphate has an endothermic peak starting at 172.8 ± 3°C. In one embodiment, the differential scanning calorimetry curve of the type A crystal of the phosphate has one endothermic peak at 174.5±3℃.

[0045] In one embodiment, the thermogravimetric analysis curve of the A-type crystal of the phosphate shows a weight loss of approximately 4.40% at 150°C. In one embodiment, the differential scanning calorimetry curve of the A-type crystal of the phosphate is basically as shown in Figure 9.

[0046] In one embodiment, the thermogravimetric analysis curve of the A-type crystal of the phosphate is basically shown in Figure As shown in 8. The present invention further provides a method for producing type A crystals of the phosphate of the compound represented by formula I, comprising mixing the compound represented by formula I, phosphoric acid, and a solvent, and forming a slurry at room temperature; The aforementioned solvents include ester-based solvents, ether-based solvents, mixed solvents of alcohol-based solvents and water, and mixed solvents of ketone-based solvents and saturated alkane-based solvents.

[0047] In one embodiment, the molar ratio of phosphoric acid to the compound represented by formula I is 1.0 to 1.7, preferably 1.2. In one embodiment, the molar ratio of phosphoric acid to the compound represented by formula I is (1.0 to 1.7):1, preferably 1.2:1.

[0048] In one embodiment, the molar volume ratio of the compound represented by formula I to the solvent is 0.11 to 0.21 mol / L, preferably 0.16 mol / L. In one embodiment, the mixed solvent of the alcohol-based solvent and water has a volume ratio of (14-24):1, preferably 19:1.

[0049] In one embodiment, the mixed solvent is a ketone solvent and a saturated alkane solvent, where the volume ratio of the ketone solvent to the saturated alkane solvent is (0.5-2):1. In one embodiment, 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.

[0050] In one embodiment, the phosphate of the compound represented by formula I is a B-type crystal of the phosphate of the compound represented by formula I, and the powder X-ray diffraction pattern expressed at a 2θ angle using Cu-Kα rays from the B-type crystal of the phosphate is 6.68 ± Diffraction peaks are observed at the following positions: 0.2°, 13.37±0.2°, 14.16±0.2°, 15.30±0.2°, 16.74±0.2°, and 20.12±0.2°.

[0051] In one embodiment, the B-type crystal of the phosphate is in an anhydrous crystalline form. In one embodiment, the molar ratio of the compound represented by formula I to phosphoric acid in the type B crystal of the phosphate is 1:1.

[0052] In one embodiment, the Cu-Kα line of the B-type crystal of the phosphate is used, 2θ The powder X-ray diffraction pattern, represented by angles, 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°.

[0053] In one embodiment, the Cu-Kα line of the B-type crystal of the phosphate is used, 2θ The powder X-ray diffraction pattern, represented by angles, 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°.

[0054] In one embodiment, the Cu-Kα line of the B-type crystal of the phosphate is used, 2θ The powder X-ray diffraction pattern, represented by angles, has diffraction peaks at the following positions: 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°.

[0055] In one embodiment, the Cu-Kα line of the B-type crystal of the phosphate is used, 2θ The powder X-ray diffraction patterns, expressed as angles, are 3.35±0.2°, 6.68±0.2°, and 13. Diffraction peaks are found at the following positions: 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°.

[0056] In one embodiment, the Cu-Kα line of the B-type crystal of the phosphate is used, 2θ The positions and relative intensities of the diffraction peaks included in the powder X-ray diffraction pattern, represented by angles, are basically as shown in Table 4.

[0057] [Table 4]

[0058] In one embodiment, the Cu-Kα line of the B-type crystal of the phosphate is used, 2θ The powder X-ray diffraction pattern, represented by angles, is basically as shown in Figure 11. The present invention further provides a method for producing type B crystals of a phosphate of a compound represented by formula I, wherein the type A crystals of the phosphate are heated to 150 ± 10°C to obtain type B crystals of the phosphate.

[0059] In one embodiment, the type A crystals of the phosphate are heated under the protection of nitrogen gas. In one embodiment, the heating temperature is 145 to 155°C, preferably 150°C.

[0060] The present invention further provides a fumarate of the compound represented by formula I. In one embodiment, the fumarate of the compound represented by formula I is a type A crystal of the fumarate of the compound represented by formula I, and the powder X-ray diffraction patterns, expressed as 2θ angles using Cu-Kα rays from the type A crystal of the fumarate, are 13.51±0.2° and 15.41±0. Diffraction peaks are found at 0.2°, 17.57±0.2°, 19.48±0.2°, and 20.11±0.2°.

[0061] In one embodiment, using Cu-Kα rays from the type A crystal of the fumarate, the powder X-ray diffraction pattern, expressed as a 2θ angle, is further 9.03±0.2° and 9.78±0. Diffraction peaks are present at one or more of the following positions: 2°, 16.89±0.2°, 22.04±0.2°, 23.71±0.2°, 24.24±0.2°, and 25.72±0.2°.

[0062] In one embodiment, using Cu-Kα radiation from the type A crystal of the fumarate, the powder X-ray diffraction patterns expressed as 2θ angles were 9.03±0.2°, 9.78±0.2°, and 13 Diffraction peaks are found at the following positions: 0.51±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°.

[0063] In one embodiment, using Cu-Kα radiation from the type A crystal of the fumarate, the powder X-ray diffraction patterns expressed as 2θ angles were 9.03±0.2°, 9.78±0.2°, and 13 Diffraction peaks are found at the following positions: 0.51±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°.

[0064] In one embodiment, the type A crystal of the fumarate is in an anhydrous crystalline form. In one embodiment, in the type A crystal of the fumarate, the molar ratio of the compound represented by formula I to fumaric acid is 1:1.

[0065] In one embodiment, using Cu-Kα rays from the type A crystal of the fumarate, the position and relative intensity of the diffraction peaks included in the powder X-ray diffraction pattern represented by a 2θ angle are fundamental. As shown in Table 5.

[0066] [Table 5]

[0067] In one embodiment, using the Cu-Kα line of the fumarate type A crystal, the powder X-ray diffraction pattern, represented by a 2θ angle, is basically as shown in Figure 12. In one embodiment, the differential scanning calorimetry curve of the fumarate type A crystal has an endothermic peak starting at 128.2 ± 3°C.

[0068] In one embodiment, the differential scanning calorimetry curve of the fumarate type A crystal has one endothermic peak at 130.3 ± 3°C. In one embodiment, the thermogravimetric analysis curve of the fumarate type A crystal shows a weight loss of approximately 1.17% at 150°C.

[0069] In one embodiment, the differential scanning calorimetry curve of the fumarate type A crystal is basically as shown in Figure 14. In one embodiment, the thermogravimetric analysis curve of the fumarate type A crystal is basically as shown in Figure 13.

[0070] The present invention further provides a method for producing type A crystals of a fumarate of a compound represented by formula I, comprising mixing a compound represented by formula I, fumaric acid, and a solvent, and forming a slurry at room temperature, wherein the solvent is an ester-based solvent, an ether-based solvent, a mixed solvent of an alcohol-based solvent and water, or a mixed solvent of a ketone-based solvent and a saturated alkane-based solvent.

[0071] In one embodiment, the molar ratio of fumaric acid to the compound represented by formula I is 1.0 It is approximately 1.5, and preferably 1.0. In one embodiment, the molar ratio of fumaric acid to the compound represented by formula I is (1.0 to 1.5):1, preferably 1.0:1.

[0072] In one embodiment, the molar volume ratio of the compound represented by formula I to the solvent is 0.06 to 0.16 mol / L, preferably 0.11 mol / L; In one embodiment, the mixed solvent of the alcohol-based solvent and water has a volume ratio of (14-24):1, preferably 19:1.

[0073] In one embodiment, the mixed solvent is a ketone solvent and a saturated alkane solvent, where the volume ratio of the ketone solvent to the saturated alkane solvent is (0.5-2):1. In one embodiment, 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.

[0074] The present invention further provides p-toluenesulfonate salts of the compound represented by formula I. In one embodiment, the p-toluenesulfonate of the compound represented by formula I is a type A crystal of the p-toluenesulfonate of the compound represented by formula I, and the powder X-ray diffraction pattern of the type A crystal of the p-toluenesulfonate, using Cu-Kα rays and expressed at a 2θ angle, is 5.41±0.2°, 8.10 Diffraction peaks are found at the following positions: ±0.2°, 14.74±0.2°, 17.13±0.2°, 18.10±0.2°, and 19.98±0.2°.

[0075] In one embodiment, using Cu-Kα rays from the type A crystal of the p-toluenesulfonate, the powder X-ray diffraction pattern, expressed at a 2θ angle, is further 10.81±0.2° It has diffraction peaks at one or more positions: 18.83±0.2°, 21.83±0.2°, and 24.37±0.2°.

[0076] In one embodiment, using Cu-Kα radiation from the p-toluenesulfonate type A crystal, the powder X-ray diffraction patterns expressed at a 2θ angle were 5.41±0.2° and 7.74± Diffraction peaks are found at the following positions: 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°.

[0077] In one embodiment, using Cu-Kα radiation from the p-toluenesulfonate type A crystal, the powder X-ray diffraction patterns expressed at a 2θ angle were 5.41±0.2° and 7.74± Diffraction peaks are found at the following positions: 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°.

[0078] In one embodiment, in the type A crystal of the p-toluenesulfonate, the molar ratio of the compound represented by formula I to p-toluenesulfonic acid is 1:1. In one embodiment, using Cu-Kα rays from the p-toluenesulfonate type A crystal, the position and phase of the diffraction peaks included in the powder X-ray diffraction pattern represented by a 2θ angle are determined. The strength-to-strength ratios are basically as shown in Table 6.

[0079] [Table 6]

[0080] In one embodiment, using the Cu-Kα line of the p-toluenesulfonate type A crystal, the powder X-ray diffraction pattern represented by a 2θ angle is basically as shown in Figure 16. be.

[0081] In one embodiment, the differential scanning calorimetry curve of the p-toluenesulfonate type A crystal has an endothermic peak starting at 149.9 ± 3°C. In one embodiment, the differential scanning calorimetry curve of the type A crystal of the p-toluenesulfonate has one endothermic peak at 152.1±3°C.

[0082] In one embodiment, the thermogravimetric analysis curve of the p-toluenesulfonate type A crystal shows a weight loss of approximately 0.94% at 150°C. In one embodiment, the differential scanning calorimetry curve of the p-toluenesulfonate type A crystal is basically as shown in Figure 18.

[0083] In one embodiment, the thermogravimetric analysis curve of the p-toluenesulfonate type A crystal is basically as shown in Figure 17. The present invention further provides a method for producing type A crystals of p-toluenesulfonate of the compound represented by formula I, comprising mixing the compound represented by formula I, p-toluenesulfonic acid, and a solvent, and forming a slurry at room temperature; The aforementioned solvent is an ester-based solvent or an ether-based solvent.

[0084] In one embodiment, the molar ratio of p-toluenesulfonic acid to the compound represented by formula I is 1.0 to 1.5, preferably 1.0. In one embodiment, the p-toluenesulfonic acid and a compound represented by formula I The molar ratio is (1.0 to 1.5):1, preferably 1.0:1.

[0085] In one embodiment, the molar volume ratio of the compound represented by formula I to the solvent is 0.06 to 0.16 mol / L, preferably 0.11 mol / L; In one embodiment, the solvent is isopropyl acetate or methyl tert-butyl ether.

[0086] The present invention further provides a benzenesulfonate salt of the compound represented by formula I. In one embodiment, the benzenesulfonate of the compound represented by formula I is a type A crystal of the benzenesulfonate of the compound represented by formula I, and the powder X-ray diffraction pattern of the type A crystal of the benzenesulfonate using Cu-Kα rays and expressed at a 2θ angle is 4.2 Diffraction peaks are found at the following positions: 9±0.2°, 8.49±0.2°, 10.02±0.2°, 13.81±0.2°, and 15.26±0.2°.

[0087] In one embodiment, using Cu-Kα rays from the A-type crystal of the benzenesulfonate, the powder X-ray diffraction pattern, represented by a 2θ angle, is further 10.68±0.2°, 1 Diffraction peaks are present at one or more of the following positions: 6.80±0.2°, 18.80±0.2°, 19.73±0.2°, 20.53±0.2°, and 20.99±0.2°.

[0088] In one embodiment, using Cu-Kα radiation from the A-type crystal of the benzenesulfonate, the powder X-ray diffraction patterns, expressed as 2θ angles, were 4.29±0.2° and 8.49±0. Diffraction peaks are found at the following positions: 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°.

[0089] In one embodiment, using Cu-Kα radiation from the A-type crystal of the benzenesulfonate, the powder X-ray diffraction patterns, expressed as 2θ angles, were 4.29±0.2° and 5.75±0. Diffraction peaks are found at the following positions: 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°.

[0090] In one embodiment, in the A-type crystal of the benzenesulfonate, the molar ratio of the compound represented by formula I to benzenesulfonic acid is 1:1. In one embodiment, using Cu-Kα rays from the type A crystal of the benzenesulfonate, the position and relative intensity of the diffraction peaks included in the powder X-ray diffraction pattern, represented by a 2θ angle, are determined. The degrees are basically as shown in Table 7.

[0091] [Table 7]

[0092] In one embodiment, using the Cu-Kα line of the benzenesulfonate type A crystal, the powder X-ray diffraction pattern, represented by a 2θ angle, is basically as shown in Figure 19. .

[0093] In one embodiment, the differential scanning calorimetry curve of the type A crystal of the benzenesulfonate has an endothermic peak starting at 144.5 ± 3°C. In one embodiment, the differential scanning calorimetry curve of the A-type crystal of the benzenesulfonate has one endothermic curve at 146.4 ± 3°C.

[0094] In one embodiment, the thermogravimetric analysis curve of the A-type crystal of the benzenesulfonate shows a weight loss of approximately 1.28% at 140°C. In one embodiment, the differential scanning calorimetry curve of the A-type crystal of the benzenesulfonate is basically as shown in Figure 21.

[0095] In one embodiment, the thermogravimetric analysis curve of the A-type crystal of the benzenesulfonate is basically as shown in Figure 20. The present invention further provides a method for producing type A crystals of a benzenesulfonate of a compound represented by formula I, comprising mixing the compound represented by formula I, benzenesulfonic acid, and a solvent, and forming a slurry at room temperature to obtain type A crystals of a benzenesulfonate; The aforementioned solvent is a mixed solvent of an ester-based solvent, an alcohol-based solvent, and water.

[0096] In one embodiment, the molar ratio of benzenesulfonic acid to the compound represented by formula I is 1.0 to 1.5, preferably 1.0. In one embodiment, the molar ratio of benzenesulfonic acid to the compound represented by formula I is (1.0 to 1.5), preferably 1.0:1.

[0097] In one embodiment, the molar volume ratio of the compound represented by formula I to the solvent is 0.06 to 0.16 mol / L, preferably 0.11 mol / L; In one embodiment, the mixed solvent of the alcohol-based solvent and water has a volume ratio of (14-24):1, preferably 19:1.

[0098] In one embodiment, the solvent is a mixed solvent of IPA / H2O (19:1, v / v) or isopropyl acetate. The present invention further provides an oxalate salt of the compound represented by formula I.

[0099] In one embodiment, the oxalate of the compound represented by formula I is a type A crystal of the oxalate of the compound represented by formula I, and the type A crystal of the oxalate contains the compound represented by formula I and oxalic acid; Here, using the Cu-Kα line of the A-type crystal of the oxalate, the powder X represented by a 2θ angle is used. The linear diffraction pattern has diffraction peaks at the following positions: 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°.

[0100] In one embodiment, using Cu-Kα rays from the A-type crystal of the oxalate, the powder X-ray diffraction pattern, expressed as a 2θ angle, is further 12.93±0.2°, 13.47± Diffraction peaks are present at one or more of the following positions: 0.2°, 15.23±0.2°, 22.38±0.2°, and 26.00±0.2°.

[0101] In one embodiment, using Cu-Kα rays from the A-type crystal of the oxalate, the powder X-ray diffraction patterns, expressed as 2θ angles, were 7.32±0.2°, 8.47±0.2°, and 12 Diffraction peaks are found at the following positions: 0.93±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°.

[0102] In one embodiment, using Cu-Kα rays from the A-type crystal of the oxalate, the powder X-ray diffraction patterns, expressed as 2θ angles, are 4.64±0.2°, 7.32±0.2°, and 8. Diffraction peaks are found at the following positions: 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°.

[0103] In one embodiment, using Cu-Kα rays from the A-type crystal of the oxalate, the position and relative intensity of the diffraction peaks included in the powder X-ray diffraction pattern represented by a 2θ angle are fundamental. As shown in Table 8.

[0104] [Table 8]

[0105] In one embodiment, using the Cu-Kα line of the A-type crystal of the oxalate, the powder X-ray diffraction pattern represented by a 2θ angle is basically as shown in Figure 38. In one embodiment, the differential scanning calorimetry curve of the type A crystal of the oxalate has an endothermic peak starting at 151.3 ± 3°C.

[0106] In one embodiment, the differential scanning calorimetry curve of the A-type crystal of the oxalate has one endothermic curve at 153.6 ± 3°C. In one embodiment, the differential scanning calorimetry curve of the A-type crystal of the oxalate has one endothermic curve at 162.8 ± 3°C.

[0107] In one embodiment, the differential scanning calorimetry curve of the type A crystal of the oxalate has one endothermic curve at 218.8 ± 3°C. In one embodiment, the thermogravimetric analysis curve of the A-type crystal of the oxalate shows a weight loss of approximately 4.10% at 150°C.

[0108] In one embodiment, the differential scanning calorimetry curve of the A-type crystal of the oxalate is basically as shown in Figure 40. In one embodiment, the thermogravimetric analysis curve of the A-type crystal of the oxalate is basically as shown in Figure 39.

[0109] In one embodiment, the oxalate of the compound represented by formula I is a B-type crystal of the oxalate of the compound represented by formula I, and the B-type crystal of the oxalate is represented by formula I The molar ratio of the compound to oxalic acid is 1:1; Here, using the Cu-Kα rays of the B-type crystal of the oxalate, the powder X-ray diffraction pattern, expressed as a 2θ angle, has diffraction peaks at the following positions: 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°.

[0110] In one embodiment, using Cu-Kα rays from the B-type crystal of the oxalate, the powder X-ray diffraction pattern, expressed as a 2θ angle, is further 12.47±0.2°, 17.66± Diffraction peaks are present at one or more of the following positions: 0.2°, 18.26±0.2°, 18.77±0.2°, and 19.16±0.2°.

[0111] In one embodiment, using Cu-Kα rays from the B-type crystal of the oxalate, the powder X-ray diffraction pattern, expressed as a 2θ angle, has diffraction peaks at the following positions: 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°.

[0112] In one embodiment, using Cu-Kα rays from the B-type crystal of the oxalate, the powder X-ray diffraction pattern, expressed as a 2θ angle, has diffraction peaks at the following positions: 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°.

[0113] In one embodiment, the molar ratio of the compound represented by formula I to oxalic acid in the B-type crystal of the oxalate is 1:1. In one embodiment, using Cu-Kα rays from the B-type crystal of the oxalate, the position and relative intensity of the diffraction peaks included in the powder X-ray diffraction pattern represented by a 2θ angle are fundamental. As shown in Table 9,

[0114] [Table 9]

[0115] In one embodiment, using the Cu-Kα line of the B-type crystal of the oxalate, the powder X-ray diffraction pattern, represented by a 2θ angle, is basically as shown in Figure 22. In one embodiment, the differential scanning calorimetry curve of the B-type crystal of the oxalate has an endothermic peak starting at 155.5 ± 3°C.

[0116] In one embodiment, the differential scanning calorimetry curve of the B-type crystal of the oxalate has one endothermic curve at 158.2 ± 3°C. In one embodiment, the differential scanning calorimetry curve of the B-type crystal of the oxalate has one endothermic curve at 218.7 ± 3°C.

[0117] In one embodiment, the thermogravimetric analysis curve of the B-type crystal of the oxalate shows a weight loss of approximately 1.21% at 150°C. In one embodiment, the differential scanning calorimetry curve of the B-type crystal of the oxalate is basically as shown in Figure 24.

[0118] In one embodiment, the thermogravimetric analysis curve of the B-type crystal of the oxalate is basically as shown in Figure 23. The present invention further provides a method for producing type A crystals of the oxalate of the compound represented by formula I, comprising mixing the compound represented by formula I, oxalic acid, and a solvent, and forming a slurry at room temperature; The aforementioned solvent is a mixed solvent of an alcohol-based solvent and water.

[0119] In one embodiment, the molar ratio of oxalic acid to the compound represented by formula I is 1.0 to 1.5, preferably 1.0. In one embodiment, the molar ratio of oxalic acid to the compound represented by formula I is (1. The ratio is 0-1.5):1, preferably 1.0:1.

[0120] In one embodiment, the mixed solvent of the alcohol-based solvent and water has a volume ratio of (14-24):1, preferably 19:1.

[0121] In one embodiment, the solvent is a mixed solvent of IPA / H2O (19:1, v / v). The present invention further provides a method for producing B-type crystals of an oxalate of a compound represented by formula I, comprising mixing the compound represented by formula I, oxalic acid, and a solvent, and forming a slurry at room temperature to obtain B-type crystals of the oxalate; The aforementioned solvent is a mixed solvent of ester-based solvents, ether-based solvents, ketone-based solvents, and saturated alkane-based solvents.

[0122] In one embodiment, the molar ratio of oxalic acid to the compound represented by formula I is 1.0 to 1.5, preferably 1.0. In one embodiment, the molar ratio of oxalic acid to the compound represented by formula I is (1.0 to 1.5):1, preferably 1.0:1.

[0123] In one embodiment, the molar volume ratio of the compound represented by formula I to the solvent is 0.02 to 0.08 mol / L, preferably 0.05 mol / L; In one embodiment, the mixed solvent is a ketone solvent and a saturated alkane solvent, where the volume ratio of the ketone solvent to the saturated alkane solvent is (0.5-2):1.

[0124] In one embodiment, the solvent is a mixed solvent of acetone / n-heptane (1:1, v / v), isopropyl acetate, or methyl tert-butyl ether. The present invention further provides a maleate of the compound represented by formula I.

[0125] In one embodiment, the maleate of the compound represented by formula I is a type A crystal of the maleate of the compound represented by formula I, and the powder X-ray diffraction pattern of the type A crystal of the maleate, using Cu-Kα rays and represented by a 2θ angle, is Diffraction peaks are found at the following positions: 13.54±0.2°, 16.92±0.2°, 17.64±0.2°, 19.61±0.2°, and 23.77±0.2°.

[0126] In one embodiment, using Cu-Kα rays from the maleate type A crystal, the powder X-ray diffraction pattern, represented by a 2θ angle, is further 3.44±0.2°, 9.64±0. It has diffraction peaks at one or more positions: 0.2°, 18.08±0.2°, 20.82±0.2°, and 27.20±0.2°.

[0127] In one embodiment, using Cu-Kα rays from the maleate type A crystal, the powder X-ray diffraction patterns expressed as 2θ angles were 3.44±0.2°, 9.64±0.2°, 1 Diffraction peaks are found at the following positions: 3.54±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°.

[0128] In one embodiment, using Cu-Kα rays from the maleate type A crystal, the powder X-ray diffraction patterns expressed as 2θ angles were 3.44±0.2°, 9.64±0.2°, 1 Diffraction peaks are found at the following positions: 3.54±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°.

[0129] In one embodiment, in the maleate type A crystal, the molar ratio of the compound represented by formula I to maleic acid is 1:1. In one embodiment, using Cu-Kα rays from the maleate type A crystal, the position and relative intensity of the diffraction peaks included in the powder X-ray diffraction pattern represented by a 2θ angle are as follows: Essentially, this is as shown in Table 10.

[0130] [Table 10]

[0131] In one embodiment, using the Cu-Kα line of the maleate type A crystal, the powder X-ray diffraction pattern, represented by a 2θ angle, is basically as shown in Figure 25. In one embodiment, the differential scanning calorimetry curve of the maleate type A crystal has an endothermic peak starting at 123.4 ± 3°C.

[0132] In one embodiment, the differential scanning calorimetry curve of the maleate type A crystal has one endothermic curve at 125.2 ± 3°C. In one embodiment, the thermogravimetric analysis curve of the maleate type A crystal shows a weight loss of approximately 2.56% at 120°C.

[0133] In one embodiment, the differential scanning calorimetry curve of the maleate type A crystal is basically as shown in Figure 27. In one embodiment, the thermogravimetric analysis curve of the maleate type A crystal is basically as shown in Figure 26.

[0134] The present invention further involves mixing a compound represented by formula I, maleic acid, and a solvent, forming a slurry at room temperature, and obtaining a type A crystal of maleate, the maleate of the compound represented by formula I. Provides a method for producing type A crystals; The aforementioned solvent is a mixed solvent of ester-based solvents, ether-based solvents, ketone-based solvents, and saturated alkane-based solvents.

[0135] In one embodiment, the molar ratio of maleic acid to the compound represented by formula I is 1.0 to 1.5, preferably 1.0. In one embodiment, the molar ratio of maleic acid to the compound represented by formula I is (1.0 to 1.5):1, preferably 1.0:1.

[0136] In one embodiment, the mixed solvent is a ketone solvent and a saturated alkane solvent, where the volume ratio of the ketone solvent to the saturated alkane solvent is (0.5-2):1. In one embodiment, the solvent is a mixed solvent of acetone / n-heptane (1:1, v / v), isopropyl acetate, or methyl tert-butyl ether.

[0137] The present invention further provides a malate salt of the compound represented by formula I. In one embodiment, the malate of the compound represented by formula I is a type A crystal of the malate of the compound represented by formula I, and the powder X-ray diffraction pattern of the type A crystal of the malate, using Cu-Kα rays and expressed at a 2θ angle, is 8.95. Diffraction peaks are found at the following positions: ±0.2°, 9.89±0.2°, 13.21±0.2°, 16.53±0.2°, and 18.93±0.2°.

[0138] In one embodiment, using Cu-Kα radiation from the type A crystal of the malate, the powder X-ray diffraction patterns, expressed as 2θ angles, were 8.95±0.2°, 9.89±0.2°, and 13. Diffraction peaks are found at the following positions: 0.21±0.2°, 16.17±0.2°, 16.53±0.2°, 18.93±0.2°, and 24.77±0.2°.

[0139] In one embodiment, using Cu-Kα radiation from the type A crystal of the malate, the powder X-ray diffraction patterns, expressed as 2θ angles, are 6.63±0.2°, 8.95±0.2°, and 9. Diffraction peaks are found at the following positions: 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°.

[0140] In one embodiment, in the A-type crystal of the malate salt, the molar ratio of the compound represented by formula I to malic acid is 1:1. In one embodiment, using Cu-Kα rays from the type A crystal of the malate, the position and relative intensity of the diffraction peaks included in the powder X-ray diffraction pattern represented by a 2θ angle are fundamental. As shown in Table 11.

[0141] [Table 11]

[0142] In one embodiment, using the Cu-Kα line of the A-type crystal of the malate, the powder X-ray diffraction pattern, represented by a 2θ angle, is basically as shown in Figure 28. In one embodiment, the differential scanning calorimetry curve of the type A crystal of the malate has an endothermic peak starting at 86.3±3°C.

[0143] In one embodiment, the differential scanning calorimetry curve of the type A crystal of the malate has one endothermic curve at 96.3 ± 3°C. In one embodiment, the thermogravimetric analysis curve of the A-type crystal of the malate shows a weight loss of approximately 2.26% at 150°C.

[0144] In one embodiment, the differential scanning calorimetry curve of the A-type crystal of the malate is basically as shown in Figure 30. In one embodiment, the thermogravimetric analysis curve of the A-type crystal of the malate is basically as shown in Figure 29.

[0145] The present invention further provides a method for producing type A crystals of malate of a compound represented by formula I, comprising mixing a compound represented by formula I, malic acid, and a solvent, and forming a slurry at room temperature; The aforementioned solvent is a mixed solvent of a ketone-based solvent and a saturated alkane-based solvent.

[0146] In one embodiment, the molar ratio of malic acid to the compound represented by formula I is 1.0 to 1.5, preferably 1.0. In one embodiment, the molar ratio of malic acid to the compound represented by formula I is (1.0 to 1.5):1, preferably 1.0:1.

[0147] In one embodiment, the mixed solvent of the ketone solvent and the saturated alkane solvent has a volume ratio of (0.5-2):1, preferably 1:1.

[0148] In one embodiment, the solvent is acetone / n-heptane (1:1, v / v) It is a mixed solvent. The present invention further provides succinate salts of the compound represented by formula I.

[0149] In one embodiment, the succinate of the compound represented by formula I is a type A crystal of the succinate of the compound represented by formula I, where the powder X-ray diffraction pattern, expressed as 2θ angle using Cu-Kα rays from the type A crystal of the succinate, is 6.94±0.2°, 9.20 Diffraction peaks are found at the following positions: ±0.2°, 13.87±0.2°, 16.29±0.2°, 17.94±0.2°, and 20.21±0.2°.

[0150] In one embodiment, using Cu-Kα rays from the succinate type A crystal, the powder X-ray diffraction pattern, expressed at a 2θ angle, is further 14.70±0.2°, 17.40± Diffraction peaks are present at one or more of the following positions: 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°.

[0151] In one embodiment, using Cu-Kα rays from the succinate type A crystal, the powder X-ray diffraction patterns expressed as 2θ angles were 6.94±0.2°, 9.20±0.2°, and 13. Diffraction peaks are found at the following positions: 0.87±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°.

[0152] In one embodiment, using Cu-Kα rays from the succinate type A crystal, the powder X-ray diffraction patterns expressed as 2θ angles were 6.94±0.2°, 9.20±0.2°, and 13. Diffraction peaks are found at the following positions: 0.87±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°.

[0153] In one embodiment, the A-type crystal of the succinate has a molar ratio of 1:1 between the compound represented by formula I and succinic acid. In one embodiment, using Cu-Kα rays from the succinate type A crystal, the position and relative intensity of the diffraction peaks included in the powder X-ray diffraction pattern represented by a 2θ angle are fundamental. As shown in Table 12.

[0154] [Table 12]

[0155] In one embodiment, the A-type crystal of the succinate has a molar ratio of the compound represented by formula I to succinic acid of 1:1.2, 1:1.1, or 1:1. In one embodiment, using the Cu-Kα line of the succinate type A crystal, the powder X-ray diffraction pattern, represented by a 2θ angle, is basically as shown in Figure 31.

[0156] In one embodiment, the differential scanning calorimetry curve of the succinate type A crystal has an endothermic peak starting at 75.9 ± 3°C. In one embodiment, the differential scanning calorimetry curve of the succinate type A crystal has one endothermic peak at 85.4 ± 3°C.

[0157] In one embodiment, the thermogravimetric analysis curve of the succinate type A crystal shows a weight loss of approximately 4.49% at 150°C. In one embodiment, the differential scanning calorimetry curve of the succinate type A crystal is basically as shown in Figure 33.

[0158] In one embodiment, the thermogravimetric analysis curve of the succinate type A crystal is basically as shown in Figure 32. The present invention further provides a method for producing type A crystals of succinate of a compound represented by formula I, comprising mixing a compound represented by formula I, succinic acid, and a solvent, and forming a slurry at room temperature to obtain type A crystals of succinate; The aforementioned solvent is an ether-based solvent.

[0159] In one embodiment, the molar ratio of succinic acid to the compound represented by formula I is 1.0 to 1.5, preferably 1.0. In one embodiment, the molar ratio of succinic acid to the compound represented by formula I is (1.0 to 1.5):1, preferably 1.0:1.

[0160] In one embodiment, the solvent is methyl tert-butyl ether. The present invention further provides a methanesulfonate of the compound represented by formula I. In one embodiment, the methanesulfonate of the compound represented by formula I is a type A crystal of the methanesulfonate of the compound represented by formula I, where the powder X-ray diffraction pattern, expressed at a 2θ angle using Cu-Kα rays from the type A crystal of the methanesulfonate, is 5. Diffraction peaks are found at the following positions: 03±0.2°, 17.03±0.2°, 18.11±0.2°, 20.60±0.2°, and 23.40±0.2°.

[0161] In one embodiment, the Cu-Kα rays of the type A crystal of the methanesulfonate are used to determine the position and relative intensity of the diffraction peaks included in the powder X-ray diffraction pattern represented by a 2θ angle. This is basically as shown in Table 13.

[0162] [Table 13]

[0163] In one embodiment, using the Cu-Kα line of the A-type crystal of the methanesulfonate, the powder X-ray diffraction pattern, represented by a 2θ angle, is basically as shown in Figure 34.

[0164] In one embodiment, the methanesulfonate of the compound represented by formula I is a B-type crystal of the methanesulfonate of the compound represented by formula I, and the powder X-ray diffraction pattern, expressed at a 2θ angle using Cu-Kα rays from the B-type crystal of the methanesulfonate, is 18.89 ± Diffraction peaks are found at the following positions: 0.2°, 20.43±0.2°, 21.07±0.2°, 23.44±0.2°, and 24.46±0.2°.

[0165] In one embodiment, using Cu-Kα rays from the type B crystal of the methanesulfonate, the powder X-ray diffraction pattern, represented by a 2θ angle, is further 9.76±0.2°, 11. Diffraction peaks are present at one or more positions: 32±0.2°, 15.46±0.2°, and 17.26±0.2°.

[0166] In one embodiment, using Cu-Kα rays from the B-type crystal of the methanesulfonate, the powder X-ray diffraction pattern, expressed at a 2θ angle, is further 9.83±0.2°, 11. Diffraction peaks are present at one or more positions: 32±0.2°, 15.46±0.2°, and 17.26±0.2°.

[0167] In one embodiment, using Cu-Kα radiation from the B-type crystal of the methanesulfonate, the powder X-ray diffraction patterns, expressed as 2θ angles, were 9.76±0.2° and 11.32±0. Diffraction peaks are found at the following positions: 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°.

[0168] In one embodiment, using Cu-Kα radiation from the B-type crystal of the methanesulfonate, the powder X-ray diffraction patterns, expressed as 2θ angles, were 9.83±0.2° and 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°, 24.46±0.2° It has a diffraction peak at that position.

[0169] In one embodiment, using Cu-Kα radiation from the B-type crystal of the methanesulfonate, the powder X-ray diffraction patterns, expressed as 2θ angles, were 9.76±0.2° and 11.32±0. Diffraction peaks are found at the following positions: 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°.

[0170] In one embodiment, using Cu-Kα radiation from the B-type crystal of the methanesulfonate, the powder X-ray diffraction patterns, expressed as 2θ angles, were 9.83±0.2° and 11.32±0. Diffraction peaks are found at the following positions: 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°.

[0171] In one embodiment, the molar ratio of the compound represented by formula I to methanesulfonic acid in the type B crystal of the methanesulfonate is 1:2. In one embodiment, the Cu-Kα radiation from the B-type crystal of the methanesulfonate is used to determine the position and relative intensity of the diffraction peaks included in the powder X-ray diffraction pattern represented by a 2θ angle. This is basically as shown in Table 14.

[0172] [Table 14]

[0173] In one embodiment, the molar ratio of the compound represented by formula I to methanesulfonic acid in the type B crystal of the methanesulfonate is 1:2.1 or 1:2. In one embodiment, using the Cu-Kα line of the B-type crystal of the methanesulfonate, the powder X-ray diffraction pattern, represented by a 2θ angle, is basically as shown in Figure 35.

[0174] In one embodiment, the differential scanning calorimetry curve of the type B crystal of the methanesulfonate has an endothermic peak starting at 97.3±3°C. In one embodiment, the differential scanning calorimetry curve of the type B crystal of the methanesulfonate has one endothermic curve at 109.4 ± 3°C.

[0175] In one embodiment, the thermogravimetric analysis curve of the type B crystal of the methanesulfonate shows a weight loss of approximately 0.91% at 80°C and approximately 2.40% at 80-130°C.

[0176] In one embodiment, the differential scanning calorimetry curve of the B-type crystal of the methanesulfonate is basically as shown in Figure 37. In one embodiment, the thermogravimetric analysis curve of the B-type crystal of the methanesulfonate is basically as shown in Figure 36.

[0177] The present invention further provides a method for producing type A crystals of methanesulfonate of a compound represented by formula I, comprising mixing the compound represented by formula I, methanesulfonic acid, and a solvent, and forming a slurry at room temperature; The aforementioned solvent is a mixed solvent of a ketone-based solvent and a saturated alkane-based solvent.

[0178] In one embodiment, the molar ratio of methanesulfonic acid to the compound represented by formula I is (1.0 to 1.2):1, preferably 1:1. In one embodiment, the mixed solvent of the ketone solvent and the saturated alkane solvent has a volume ratio of (0.5-2):1, preferably 1:1.

[0179] In one embodiment, the solvent is a mixed solvent of acetone / n-heptane (1:1, v / v). The present invention further provides a method for producing B-type crystals of methanesulfonate of a compound represented by formula I, comprising mixing the compound represented by formula I, methanesulfonic acid, and a solvent, and forming a slurry at room temperature to obtain B-type crystals of methanesulfonate; The aforementioned solvent is a mixed solvent of ester-based solvents, ether-based solvents, ketone-based solvents, and saturated alkane-based solvents.

[0180] In one embodiment, the molar ratio of methanesulfonic acid to the compound represented by formula I is (1.5 to 2.5):1, preferably 2:1. In one embodiment, the mixed solvent is a ketone solvent and a saturated alkane solvent, where the volume ratio of the ketone solvent to the saturated alkane solvent is (0.5-2):1.

[0181] In one embodiment, the solvent is a mixed solvent of acetone / n-heptane (1:1, v / v), isopropyl acetate, or methyl tert-butyl ether. The present invention further provides a 2-hydroxyethanesulfonate of the compound represented by formula I.

[0182] In one embodiment, the 2-hydroxyethanesulfonate of the compound represented by formula I is a type A crystal of the 2-hydroxyethanesulfonate of the compound represented by formula I, and the Cu-Kα line of the type A crystal of the 2-hydroxyethanesulfonate is used at a 2Θ angle. The resulting powder X-ray diffraction pattern has diffraction peaks at the following positions: 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°.

[0183] In one embodiment, using Cu-Kα rays from the type A crystal of the 2-hydroxyethanesulfonate, the powder X-ray diffraction pattern, represented by a 2θ angle, is further 15.54 ± Diffraction peaks are present at one or more of the following positions: 0.2°, 15.94±0.2°, 21.83±0.2°, 22.33±0.2°, and 22.87±0.2°.

[0184] In one embodiment, using Cu-Kα rays from the A-type crystal of the 2-hydroxyethanesulfonate, the powder X-ray diffraction pattern, expressed as 2θ angle, is 4.85±0.2°, 9 0.85±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 Diffraction peaks are observed at ±0.2°, 22.33±0.2°, and 22.87±0.2°.

[0185] In one embodiment, using Cu-Kα rays from the A-type crystal of the 2-hydroxyethanesulfonate, the powder X-ray diffraction pattern, expressed as 2θ angle, is 4.85±0.2°, 9 Diffraction peaks are found at the following positions: 0.85±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°.

[0186] In one embodiment, in the type A crystal of the 2-hydroxyethanesulfonate, the molar ratio of the compound represented by formula I to 2-hydroxyethanesulfonic acid is 1:1.

[0187] In one embodiment, the Cu-Kα rays of the A-type crystal of the 2-hydroxyethanesulfonate are used, and the position of the diffraction peaks included in the powder X-ray diffraction pattern represented by a 2θ angle is The position and relative intensity are basically as shown in Table 15.

[0188] [Table 15]

[0189] In one embodiment, using the Cu-Kα line of the type A crystal of the 2-hydroxyethanesulfonate, the powder X-ray diffraction pattern represented by a 2θ angle is basically shown in Figure 41. That is correct.

[0190] In one embodiment, the differential scanning calorimetry curve of the type A crystal of the 2-hydroxyethanesulfonate has an endothermic peak starting at 109.5 ± 3°C. In one embodiment, the differential scanning calorimetry curve of the type A crystal of the 2-hydroxyethanesulfonate has one endothermic curve at 118.4 ± 3°C.

[0191] In one embodiment, the heat of the A-type crystal of the 2-hydroxyethanesulfonate The gravimetric analysis curve shows a weight loss of approximately 1.28% at 110°C. In one embodiment, the differential scanning calorimetry curve of the A-type crystal of the 2-hydroxyethanesulfonate is basically as shown in Figure 43.

[0192] In one embodiment, the thermogravimetric analysis curve of the A-type crystal of the 2-hydroxyethanesulfonate is basically as shown in Figure 42. The present invention further provides a method for preparing Form A crystal of 2-hydroxyethanesulfonate of the compound represented by Formula I, which comprises mixing the compound represented by Formula I, 2-hydroxyethanesulfonic acid and a solvent, and carrying out slurrying at room temperature to obtain Form A crystal of 2-hydroxyethanesulfonate; The solvent is a mixed solvent of an ester solvent, a ketone solvent and a saturated alkane solvent.

[0193] 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. 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.

[0194] In one embodiment, the solvent is a mixed solvent of acetone / n-heptane (1:1, v / v), or isopropyl acetate. The present invention further provides a pharmaceutical composition comprising the crystalline form or salt form of the compound represented by Formula I according to any one of the above items, and at least one pharmaceutical excipient.

[0195] The selection of the pharmaceutical excipients varies depending on the administration route and functional properties, and generally may be conventional fillers, diluents, binders, wetting agents, disintegrants, lubricants, emulsifiers, suspending agents and the like in the art.

[0196] The present invention further provides use of a substance M, wherein the substance M is the crystalline form, the salt form of the compound represented by Formula I according to any one of the above items, or the pharmaceutical composition described above. Said use is for: 1) inhibiting tubulin polymerization and / or Src kinase; 2) preventing and / or treating diseases associated with tubulin polymerization and / or Src kinase; 3) preparing inhibitors of tubulin polymerization and / or Src kinase; 4) Manufacture of a medicament or preparation for preventing and / or treating a disease associated with tubulin polymerization and / or Src kinase .

[0197] Preferably, the use comprises inhibition of tubulin polymerization; and / or prevention and / or treatment of diseases mediated by tubulin polymerization; and / or manufacture of a tubulin polymerization inhibitor, and / or manufacture of a medicament, pharmaceutical composition or preparation for preventing and / or treating diseases mediated by tubulin polymerization.

[0198] Preferably, the use comprises inhibition of Src kinase; and / or prevention and / or treatment of diseases mediated by Src kinase; and / or manufacture of a Src kinase inhibitor; and / or manufacture of a medicament, pharmaceutical composition or preparation for preventing and / or treating diseases mediated by Src kinase.

[0199] Preferably, the medicament is an external preparation. Preferably, the medicament is a medicament administered transdermally. Preferably, the diseases associated with tubulin polymerization and / or Src kinase include tum ors and skin diseases.

[0200] The present invention further provides use of a substance M, wherein the substance M is a crystalline form, a salt form of the compound represented by formula I according to any one of the above items, or the pharmaceutical composition described above,[ the use is use in the manufacture of a medicament for treating or preventing tumors and / or skin diseases.

[0201] Preferably, the tumor includes solid tumor, sarcoma and hematological cancer; More preferably, the tumors include 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 lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, myeloma, and / or myelodysplastic syndromes.

[0202] Preferably, the skin diseases include actinic keratosis, psoriasis, atopic dermatitis, vitiligo, roseola, and / or systemic lupus erythematosus. Preferably, the pharmaceutical is a topical preparation.

[0203] Preferably, the pharmaceutical is administered transdermally. The present invention further provides the use of at least one of the crystalline or salt forms of the compound represented by Formula I above in the treatment or prevention of tumors and / or skin diseases.

[0204] Preferably, the tumors include solid tumors, sarcomas, and hematological carcinomas; More preferably, the tumors include 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 lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, myeloma, and / or myelodysplastic syndromes.

[0205] Preferably, the skin diseases include actinic keratosis, psoriasis, atopic dermatitis, vitiligo, roseola, and / or systemic lupus erythematosus. The present invention further provides a method for inhibiting Src kinase or preventing and / or treating diseases related to (or mediated by) Src kinase, comprising the step of administering the above-mentioned crystalline and / or salt forms to a subject of interest.

[0206] The present invention further provides a method for preventing and / or treating diseases that inhibit tubulin or are related to (or mediated by tubulin), comprising the step of administering the crystalline and / or salt forms described in the present invention to a subject of interest.

[0207] As long as it does not violate common sense in the art, the above preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention. term When the terms "approximately" and "about" are used with respect to XRPD peaks, these terms indicate that the error in the mentioned powder X-ray diffraction peak position [°2θ] is ±0.3, ±0.2, or ±0.1, preferably ±0.2, and more preferably ±0.1.

[0208] When XRPD peak positions are mentioned, the 2θ angle may be rounded to retain two or four significant digits. When the terms “approximately” and “about” are used in relation to temperature or temperature range, these terms indicate that the error in the temperature or temperature range mentioned is ±5°C, ±3°C, ±2°C, or ±1°C, preferably ±3°C.

[0209] All reagents and raw materials used in this invention are commercially available. Positive and progressive effects of the present invention: The present invention relates to compounds, salt forms and crystal forms for use in tubulin-SRC dual-target inhibitors, wherein said compound has the structure of formula I as described in the present invention. Said compound, salt form and crystal form can be used as dual-target inhibitors of tubulin and Src kinase, and can also be used as a single tubulin or Src kinase inhibitor. The compound of the present invention can significantly inhibit the polymerization of tubulin monomers and inhibit cell proliferation. It has favorable pharmacokinetic properties for topical administration to the skin and favorable pharmaceutical properties. It can be used in the preparation of external skin preparations, and has the advantages of rapid metabolism and few side effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0210] [Figure 1] is an XRPD pattern of form A crystal in free state. [Figure 2] is a TGA curve of form A crystal in free state. [Figure 3] is a DSC curve of form A crystal in free state. [Figure 4] is an XRPD pattern of form B crystal in free state. [Figure 5] is a TGA curve of form B crystal in free state. [Figure 6] is a DSC curve of form B crystal in free state. [Figure 7] is an XRPD pattern of form A crystal of phosphate. [Figure 8] is a TGA curve of form A crystal of phosphate. [Figure 9] is a DSC curve of form A crystal of phosphate. [Figure 10] is a VT-XRPD pattern of form A crystal of phosphate. [Figure 11] is an XRPD pattern of form B crystal of phosphate. [Figure 12] is an XRPD pattern of form A crystal of fumarate. [Figure 13] is a TGA curve of form A crystal of fumarate. [Figure 14] is a DSC curve of form A crystal of fumarate. [Figure 15] This is the VH-XRPD pattern of type A crystals of fumarate. [Figure 16] This is the XRPD pattern of type A crystals of p-toluenesulfonate. [Figure 17] This is the TGA curve for type A crystals of p-toluenesulfonate. [Figure 18] This is the DSC curve for type A crystals of p-toluenesulfonate. [Figure 19] This is the XRPD pattern of type A crystals of benzenesulfonate. [Figure 20] This is the TGA curve for type A crystals of benzenesulfonate. [Figure 21] This is the DSC curve for type A crystals of benzenesulfonate. [Figure 22] This is the XRPD pattern of oxalate type B crystals. [Figure 23] This is the TGA curve for type B crystals of oxalate. [Figure 24] This is the DSC curve for type B crystals of oxalate. [Figure 25] This is the XRPD pattern of maleate type A crystals. [Figure 26] This is the TGA curve for type A crystals of maleate. [Figure 27] This is the DSC curve for type A crystals of maleate. [Figure 28] This is the XRPD pattern of type A crystals of malate. [Figure 29] This is the TGA curve for type A crystals of malate. [Figure 30] This is the DSC curve for type A crystals of malate. [Figure 31] This is the XRPD pattern of succinate type A crystals. [Figure 32] This is the TGA curve for succinate type A crystals. [Figure 33] This is the DSC curve for succinate type A crystals. [Figure 34] This is the XRPD pattern of type A crystals of methanesulfonate. [Figure 35]This is the XRPD pattern of type B crystals of methanesulfonate. [Figure 36] This is the TGA curve for type B crystals of methanesulfonate. [Figure 37] This is the DSC curve for type B crystals of methanesulfonate. [Figure 38] This is the XRPD pattern of type A oxalate crystals. [Figure 39] This is the TGA curve for type A crystals of oxalate. [Figure 40] This is the DSC curve for type A crystals of oxalate. [Figure 41] This is the XRPD pattern of type A crystals of 2-hydroxyethanesulfonate. [Figure 42] This is the TGA curve for type A crystals of 2-hydroxyethanesulfonate. [Figure 43] This is the DSC curve for type A crystals of 2-hydroxyethanesulfonate. [Figure 44] This is the dynamic solubility curve in water at 37°C. [Figure 45] This is the dynamic solubility curve in SGF at 37°C. [Figure 46] This is the dynamic solubility curve for FaSSIF at 37°C. [Figure 47] This is the dynamic solubility curve for FeSSIF at 37°C. [Figure 48] This is the DVS curve for a free-state A-type crystal. [Figure 49] This shows XRPD overlays of free-state type A crystals before and after DVS testing. [Figure 50] This is the DVS curve for type A crystals of phosphate. [Figure 51] This image shows XRPD overlays of type A phosphate crystals before and after DVS testing. [Figure 52] This is the DVS curve for type A crystals of fumarate. [Figure 53] This image shows XRPD overlays of type A fumarate crystals before and after DVS testing. [Figure 54] This is the DVS curve for type A crystals of p-toluenesulfonate. [Figure 55] XRPD overlays of p-toluenesulfonate type A crystals before and after DVS testing. [Figure 56] This is the DVS curve for type A crystals of benzenesulfonate. [Figure 57] This image shows XRPD overlays of type A benzenesulfonate crystals before and after DVS testing. [Figure 58] This is the DVS curve for type B crystals of oxalate. [Figure 59] This image shows XRPD overlays of type B oxalate crystals before and after DVS testing. [Figure 60] This is an XRPD overlay of a sample used to evaluate the stability of free-state type A crystals. [Figure 61] This is an XRPD overlay of a stability evaluation sample of type A phosphate crystals. [Figure 62] This is an XRPD overlay of a stability evaluation sample of type A crystals of fumarate. [Figure 63] This is an XRPD overlay of a stability evaluation sample of type A crystals of p-toluenesulfonate. [Figure 64] This is an XRPD overlay of a stability evaluation sample of type A benzenesulfonate crystals. [Figure 65] This is an XRPD overlay of a stability evaluation sample of type B oxalate crystals. [Figure 66] This is the result of an inhibition test of the compound represented by formula I against tubulin polymerization. [Figure 67] These are the results of experiments on p-SRC inhibitory activity. [Modes for carrying out the invention]

[0211] The present invention will be further described below with reference to examples, but the present invention is not limited to the scope of the examples described herein. In the following examples, experimental methods for which specific conditions are not explicitly stated shall be selected according to conventional methods and conditions or product descriptions.

[0212] Equipment information and methods 1. Powder X-ray diffraction (XRPD) The XRPD patterns were collected using a powder X-ray diffractometer manufactured by PANalytacal, and the scan parameters are as shown in Table 16.

[0213] [Table 16]

[0214] 2. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) TGA and DSC curves were collected using a TA 5500 thermogravimetric analyzer and a TA 2500 differential scanning calorimeter, respectively, with the test parameters shown in Table 17.

[0215] [Table 17]

[0216] 3. Dynamic water vapor adsorption (DVS) Dynamic water vapor adsorption (DVS) curves were collected using the DVS IntrInsic of Surface Measurement Systems (SMS). Relative humidity at 25°C was corrected using the deliquescence points of LiCl, Mg(NO3)2, and KCl. The DVS test parameters are shown in Table 18.

[0217] [Table 18]

[0218] 4. Polarizing Microscope (PLM) Polarized light microscope images were taken at room temperature using a Zeiss Axio Scope.A1 microscope.

[0219] 5. Liquid nuclear magnetic resonance ( 1 (H NMR) Liquid nuclear magnetic resonance spectra were collected using a Bruker 400M liquid nuclear magnetic resonance spectrometer, with DMSO-d6 or CD3OD used as the solvent.

[0220] 6. High-performance liquid chromatography and ion chromatography (HPLC / IC) In the tests, purity, dynamic solubility, and stability were measured using an Agilent 1260 high-performance liquid chromatograph, and the molar ratio of ions to form salts was detected by ion chromatography. The analytical conditions are as shown in Tables 19 and 20.

[0221] [Table 19]

[0222] [Table 20]

[0223] Japanese-English Glossary of Solvents Table 21 shows a correspondence between solvent abbreviations and their corresponding Japanese names.

[0224] [Table 21] TIFF2026529489000026.tif24169

[0225] Preparation of the compound represented by formula I The synthesis route is as follows:

[0226] [ka]

[0227] Step 1: Synthesis of 1-bromo-4-(2-bromoethoxy)-2-methylbenzene 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 reacted under reflux at 80°C for 18 hours. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated, and the residue was separated by column chromatography (petroleum ether:ethyl acetate (V / V) = 30:1) to obtain 1-bromo-4-(2-bromoethoxy)-2-methylbenzene (1.3 g, colorless oil, yield: 82.8%).

[0228] Step 2: (3aR,6aS)-5-(2-(4-bromo-3-methylphenoxy)ethyl)hexahydro-1H-fl[3,4-c]pyrrole 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-fl[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 by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to obtain (3aR,6aS)-5-(2-(4-bromo-3-methylphenoxy)ethyl)hexahydro-1H-fl[3,4-c]pyrrole (1.0 g, yellow oily substance, yield: 69.1%).

[0229] LC-MS, M / Z (ESI): 326.0 [M+H] + . Step 3: N-benzyl-2-(5-(2-methyl-4-(2-((3aR,6aS)-tetrahydro-1H-fluoro[3,4-c]pyrrole-5(3H)-yl)ethoxy)phenyl)pyridine-2-yl)acetamide(I)

[0230] [ka]

[0231] (3aR,6aS)-5-(2-(4-bromo-3-methylphenoxy)ethyl)hexahydro-1H-fl[3,4-c]pyrrole (150 mg, 0.460 mmol) was dissolved in dried 1,4-dioxane (5 mL), and N-benzyl-2-(5-(tributylstannyl)pyridine-2-yl)acetamide (355 mg, 0.690 mmol) and bis(triphenylphosphine)palladium(II) dichloride (32.3 mg, 0.046 mmol) were added. After three purgings with argon gas, the mixture was heated to 100°C under argon gas protection and reacted for 4 hours. The reaction solution was cooled to room temperature, diluted with water (50 mL), extracted with dichloromethane (50 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was separated by silica gel plate (ethyl acetate:methanol (V / V) = 20:1, NH3·H2O) to obtain N-benzyl-2-(5-(2-methyl-4-(2-((3aR,6aS)-tetrahydro-1H-fluoro[3,4-c]pyrrole-5(3H)-yl)ethoxy)phenyl)pyridine-2-yl)acetamide (compound represented by formula I) (20 mg, yield: 9.22%), which was an amorphous solid of the compound represented by formula I.

[0232] 1 H NMR (400 MHz, DMSO-d6):δ 8.62 (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).

[0233] LC-MS, M / Z (ESI): 472.2 [M+H] + . Example 1: Free-state A-type crystal Production of free-state type A crystals: Under room temperature conditions, the compound represented by formula I was dissolved in a THF solution with stirring. After dissolution, the solution was filtered and slowly evaporated at room temperature to obtain free type A crystals. The solid was vacuum-dried at room temperature and then characterized by XRPD and TGA / DSC.

[0234] The XRPD and TGA / DSC characterization results for the free-state A-type crystal sample are shown in Figures 1-3, and the XRPD diffraction peak data for the free-state A-type crystal are shown in Table 22. The TGA results show that the sample exhibits a 0.98% weight loss when heated to 150°C. The DSC results show that the sample has one endothermic peak at 96.6°C, with an initial temperature of 94.7°C. The TGA weight loss of the free-state A-type crystal was low, the DSC showed only a single melting signal, and the free-state A-type crystal was in an anhydrous crystalline form. 1 1H NMR was collected using CD3OD as the solvent, and the specific data is shown below.

[0235] 1 H NMR(400 MHz, CD3OD): δ 8.40 (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).

[0236] [Table 22]

[0237] Example 2: Free-state B-type crystal The free-state B-type crystal sample was obtained by dissolving the compound represented by formula I in MeOH, removing the solvent by rotational evaporation under reduced pressure, and then vacuum-drying the resulting gel-like sample at 50°C. The XRPD and TGA / DSC characterization results are shown in Figures 4-6, and the XRPD diffraction peak data for the free-state B-type crystal is shown in Table 23. The TGA results show that the sample exhibits a weight loss of 0.48% when heated to 150°C, and the DSC results show that the sample has two endothermic peaks at 84.5°C and 92.4°C (peak temperature). 1 H The NMR results are shown below, and the NMR data indicates that no MeOH residue was detected in the B-type crystal sample. The TGA weight loss of the free B-type crystal was low, and the free B-type crystal was in anhydrous crystalline form. When the free B-type crystal was heated to 86°C, cooled to room temperature, and then exposed to air, the sample converted to a free A-type crystal.

[0238] 1 H NMR(400 MHz, CD3OD): δ 8.66 (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).

[0239] [Table 23]

[0240] Example 3: Study on the transformation relationship between free crystal forms Furthermore, to study the conversion relationship between free-state type A crystals and free-state type B crystals, suspension competition tests were conducted between free-state type A crystals and free-state type B crystals in CPME and IPAc systems at room temperature and 50°C.

[0241] Specific steps are as follows. 1) Saturated solutions of free Form A crystal samples in different solvent systems at corresponding temperatures were prepared. 2) Equal masses of free Form A crystals and free Form B crystal samples were added to the saturated solution to prepare a suspension. 3) Magnetic stirring was performed at room temperature. 4) After stirring for 2 days, the solid was separated and subjected to XRPD testing. The results are as shown in Table 24, and free Form A crystals were obtained in all tests. Experimental results showed that compared with free Form B crystals, free Form A crystals are a thermodynamically more stable crystalline form under the conditions of room temperature and 50°C.

[0242] [Table 24]

[0243] Example 4 Form A crystals of phosphate 300 mg of the compound represented by 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 Form A crystals of phosphate. The XRPD pattern of the Form A phosphate crystal sample is as shown in Figure 7, and the XRPD data is as shown in Table 25 below. The TGA / DSC results are as shown in Figure 8 and Figure 9. TGA results showed that there was a weight loss of 4.40% when the sample was heated to 150°C; DSC results showed that the sample had two endothermic peaks at 103.6°C and 174.5°C (peak temperatures). 1 The ¹H NMR results are as shown below. The results showed that the molar ratio of IPA to the compound represented by Formula I in the sample was 0.04 (~0.4% by weight). HPLC / IC results showed that the molar ratio of phosphoric acid to the compound represented by Formula I was 1:1.

[0244] The A-type crystals of phosphate were identified via VT-XRPD, and the results (Figure 10) showed that after purging the A-type crystals of phosphate under N2 conditions for 20 minutes, the crystal form did not change; after heating to 150°C under nitrogen gas protection and cooling to 30°C, and then exposure to air, conversion to the free B-type crystal was observed. TGA / DSC and 1 Combining the 1H NMR results, it was found that the A-type crystals of the phosphate were hydrated, and that dehydration under heating conditions converted them to anhydrous B-type crystals of the phosphate. The XRPD pattern of the B-type crystals of the phosphate is shown in Figure 11, and the XRPD data is shown in section 26 below.

[0245] 1 H NMR(400 MHz, DMSO-d6): δ 8.67 (1H, t), 8.43 (1H, d), 7.71 (1H, dd), 7.41~7.15 (7H, m), 6.93 (1H, d), 6.87 (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).

[0246] [Table 25]

[0247] [Table 26]

[0248] Fumarate type A crystals A-type crystals of fumarate were obtained by slurring a 6 mL MTBE solution of 300 mg of the compound represented by formula I and 73.5 mg of fumaric acid at room temperature for 2 days. The XRPD of the fumarate-type A crystal sample is shown in Figure 12. The TGA / DSC results are shown in Figures 13 and 14. The TGA results showed a weight loss of 1.17% when the sample was heated to 150°C; the DSC results showed that the sample had one endothermic peak at 130.3°C, with an onset temperature of 128.2°C. 1 The 1H NMR results are as follows. The results show that the molar ratio of fumaric acid to the compound represented by formula I in the sample is 1:1, and the molar ratio of the residual solvent MTBE to the compound represented by formula I is 0.01 (~0.1 wt%).

[0249] We studied the A-type crystals of fumarate using variable humidity XRPD (VH-XRPD), and the results (Figure 15) showed that after placing the A-type fumarate crystals under 85% RH conditions, a shift in the diffraction peak was observed; when the sample was subsequently returned to 30% RH, it was shown that the sample was converted back into the A-type fumarate crystals. Combined with the DVS test results of the A-type fumarate crystals (as shown in Figure 52), the fumarate sample showed a significant weight increase under high humidity conditions (>70% RH), suggesting that fumarate exists in a hydrated state under high humidity conditions, while under low humidity conditions (e.g., 30% RH), the sample was converted back into anhydrous A-type fumarate crystals.

[0250] 1 H NMR(400 MHz, DMSO-d6): δ 8.67 (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).

[0251] [Table 27]

[0252] p-toluenesulfonate type A crystals A 6 mL solution of IPAc containing 300 mg of the compound represented by formula I and 121.5 mg of p-toluenesulfonic acid monohydrate was slurryed at room temperature for 2 days to obtain type A crystals of p-toluenesulfonate. The XRPD of the type A crystalline sample of p-toluenesulfonate is shown in Figure 16. As shown above, the TGA / DSC results are shown in Figures 17 and 18. The TGA results showed that the sample had a weight loss of 0.94% when heated to 150°C; the DSC results showed that the sample had one endothermic peak at 152.1°C, with an onset temperature of 149.9°C. 1 The 1H NMR results are shown below. The results indicate 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%).

[0253] 1 H NMR(400 MHz, DMSO-d6): δ 9.79 (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).

[0254] [Table 28]

[0255] A-type crystals of benzenesulfonates A-type crystals of benzenesulfonate were obtained by slurring a 6 mL IPAc solution of 300 mg of the compound represented by formula I and 100.5 mg of benzenesulfonic acid at room temperature for 2 days. The XRPD pattern of the A-type crystalline sample of benzenesulfonate is shown in Figure 19. The TGA / DSC results are shown in Figures 20 and 21. The TGA boundary showed a 1.28% weight loss when the sample was heated to 140°C, and the DSC results showed that the sample had one endothermic peak at 146.4°C, with an initial temperature of 144.5°C. 1 ¹H NMR was measured using DMSO-d6, and the results are as follows. The results showed that the molar ratio of benzenesulfonic acid to the compound represented by formula I in the sample was 1:1, and the molar ratio of the residual solvent IPAc to the compound represented by formula I was 0.01 (~0.1 wt%).

[0256] 1 H NMR(400 MHz, DMSO-d6): δ 9.79 (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).

[0257] [Table 29]

[0258] Oxalate type B crystals A 12 mL solution of 300 mg of the compound represented by formula I and 79.5 mg of oxalic acid dihydrate was slurryed in acetone / n-heptane (1:1, v / v) at room temperature for 7 days, followed by slurrying at 55°C for 1 day to obtain B-type crystals of oxalate. The XRPD pattern of the B-type oxalate crystal sample is shown in Figure 22. The TGA / DSC results are shown in Figures 23 and 24. The TGA results showed a weight loss of 1.21% when the sample was heated to 150°C; the DSC results showed that the sample had two endothermic peaks at 158.2°C and 218.7°C (peak temperature). 1 The 1H NMR results are shown below, indicating that the molar ratio of the residual solvent acetone to the compound represented by formula I was 0.01 (~0.1 wt%). The HPLC / IC results showed that the molar ratio of oxalic acid to the compound represented by formula I was 1:1.

[0259] 1 H NMR(400 MHz, DMSO-d6): δ 8.68 (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).

[0260] [Table 30]

[0261] Maleate type A crystals A solution of the compound represented by formula I (828906-01-A) and equimolar amounts of maleic acid in acetone / n-heptane (1:1, v / v) was slurryed for 3 days. After separation of the solid sample, it was vacuum-dried to obtain type A crystals of maleate. The XRPD and TGA / DSC results of the type A crystal sample of maleate are shown in Figures 25-27. The TGA results showed that the sample underwent a 2.56% weight loss upon heating to 120°C, and the DSC results showed that the sample had three endothermic peaks at 54.7°C, 125.2°C, and 200.7°C (peak temperature). 1 The 1H NMR results are shown below, and the maleate A-type crystals... The results showed that the molar ratio of maleic acid to the compound represented by formula I was 1.0, and the molar ratio of the residual solvent acetone to the compound represented by formula I was 0.03 (~0.3 wt%), while no residual n-heptane was observed. 1 H NMR(400 MHz, DMSO-d6): δ 8.67 (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).

[0262] [Table 31]

[0263] Malate type A crystals A solution of the compound represented by formula I and equimolar amounts of malic acid in acetone / n-heptane (1:1, v / v) was slurryed for 6 days. After separating the solid sample, it was vacuum-dried to obtain type A crystals of malate. Powder diffraction, TGA, and DSC experiments were performed on the sample. The resulting XRPD is shown in Figure 28, and the TGA / DSC results are shown in Figures 29 and 30. The TGA results showed that the sample underwent a 2.26% weight loss when heated to 150°C. The DSC results showed that the sample had three endothermic peaks at 44.6°C, 96.3°C, and 215.8°C (peak temperature). 1 The 1H NMR results are shown below. In the A-type crystalline sample of malate, 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%).

[0264] 1 H NMR(400 MHz, CD3OD): δ 8.40 (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).

[0265] [Table 32]

[0266] succinate type A crystals Type A succinate crystals were obtained by slurring a compound represented by formula I and equimolar amounts of succinic acid in MTBE solution for 6 days, then separating the solid sample and vacuum drying it. The XRPD and TGA / DSC results for the Type A succinate crystals are shown in Figures 31-33. The TGA results showed that the sample underwent a 4.49% weight loss when heated to 150°C. The DSC results showed that the sample had two endothermic peaks at 57.3°C and 85.4°C (peak temperature). 1 The 1H NMR results are shown below. In the succinate type A crystal, the molar ratio of succinic acid to the compound represented by formula I was 1.2:1, and no residual MTBE solvent was observed.

[0267] 1 H NMR(400 MHz, CD3OD): δ 8.40 (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).

[0268] [Table 33]

[0269] Methanesulfonate type A crystals / type B crystals Type A crystals of methanesulfonate were obtained by slurring the compound represented by formula I and methanesulfonic acid in a 1:1 molar ratio in an acetone / n-heptane (1:1, v / v) solution for 3 days, then separating the gel-like solid sample and vacuum drying; Type B crystals of methanesulfonate were obtained by slurring the compound represented by formula I and methanesulfonic acid in a 1:2 molar ratio in IPAc for 3 days, then separating the solid sample and vacuum drying. The XRPD patterns of Type A and Type B crystals of methanesulfonate are shown in Figures 34 and 35, respectively.

[0270] The TGA / DSC results for the B-type crystals of methanesulfonate are shown in Figures 36 and 37. The TGA results showed that the sample had a weight loss of 0.91% when heated to 80°C and a weight loss of 2.40% when heated from 80°C to 130°C; the DSC results showed that the sample had one endothermic peak at 109.4°C (peak temperature). 1 The 1H NMR results are shown below. In the B-type crystal of the methanesulfonate, the molar ratio of methanesulfonic acid to the compound represented by formula I was 2.1, and the molar ratio of the residual solvent IPAc to the compound represented by formula I was 0.04 (~0.7 wt%).

[0271] Methanesulfonate type B crystals: 1 H NMR(400 MHz, CD3OD): δ 8.80 (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).

[0272] [Table 34]

[0273] [Table 35]

[0274] Oxalate type A crystals The A-type oxalate crystals were obtained by slurring the compound represented by formula I and equimolar amounts of oxalic acid in an IPA / H2O (19:1, v / v) solution for 3 days, then separating the solid sample and vacuum drying. It was obtained by doing so. The XRPD of the A-type oxalate crystal is shown in Figure 38.

[0275] The TGA / DSC results for type A oxalate crystals are shown in Figures 39 and 40. The TGA results showed that the sample underwent a 4.10% weight loss when heated to 150°C. The DSC results showed that the sample had three endothermic peaks at 153.6°C, 162.8°C, and 218.8°C (peak temperature). 1 The 1H NMR results are shown below, and in the A-type crystal of the oxalate, the molar ratio of the residual solvent IPA to the compound represented by formula I was 0.03 (~0.3 wt%).

[0276] Oxalate type A crystals: 1 H NMR(400 MHz, 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).

[0277] [Table 36]

[0278] 2-hydroxyethanesulfonate type A crystals Type A crystals of 2-hydroxyethanesulfonate were obtained by slurring the compound represented by formula I and equimolar amounts of 2-hydroxyethanesulfonic acid in an acetone / n-heptane (1:1, v / v) solution for 3 days, then separating the solid sample and vacuum drying it. The XRPD of the Type A crystal sample of 2-hydroxyethanesulfonate is shown in Figure 41, and the TGA / DSC results are shown in Figures 42 and 43. The TGA results showed that the sample had a weight loss of 1.28% when heated to 110°C. The DSC results showed that the sample had a weight loss of 5 The study showed that the molecule has two endothermic peaks at 7.4°C and 118.4°C (peak temperature). 1 The 1H NMR results are shown below. In the type A crystal of 2-hydroxyethanesulfonate, the molar ratio of 2-hydroxyethanesulfonic acid to the compound represented by formula I was 1.2, the molar ratio of the residual solvent acetone to the compound represented by formula I was 0.03 (~0.3 wt%), and the molar ratio of n-heptane to the compound represented by formula I was 0.01 (~0.2 wt%).

[0279] 1 H NMR (400 MHz, DMSO-d6): δ 9.78 (1H, s), 8.67 (1H, t), 8.44 (1H, d), 7.73 (1H, dd), 7.43~7.21 (7H, m), 7.00~6.94 (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).

[0280] [Table 37]

[0281] Example 5: Performance Evaluation Experiment Dynamic solubility experiment The solids were supplied at a concentration of 10 mg / mL (calculated using the compound represented by formula I) and mixed by rotation 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 (using a 0.45 μm PTFE filter head). The HPLC concentration and pH of the filtrate were measured, and the solid samples after centrifugation were detected by XRPD. The results of the solubility tests are summarized in Table 38, and the solubility curves for each system are shown in Figures 44-47. Compared to the free form A crystal, the various salt forms of the samples showed varying degrees of solubility improvement in H2O, SGF, and FaSSIF. Among these, the fumarate A crystal and the oxalate B crystal showed higher solubility in H2O and FaSSIF compared to the other salt forms.

[0282] Production of biological solvents Production of artificial gastric juice (SGF) 100 mg of NaCl and 50 mg of Triton X-100 were weighed into a 50 mL volumetric flask and completely dissolved in purified water. 816 μL of 1 M hydrochloric acid was added, and the pH was adjusted to 1.8 with 1 M hydrochloric acid or 1 M NaOH solution. Purified water was added to bring the volume to a final level.

[0283] Production of Fasting-Simulated Intestinal Fluid (FaSSIF) 340 mg of anhydrous NaH2PO4 and 620 mg of NaCl were weighed into a 100 mL volumetric flask. After completely dissolving them in purified water, 55.44 μL of 50% NaOH solution was added, and the pH was adjusted to 6.5 with 1 M hydrochloric acid or 1 M NaOH solution. Purified water was added to bring the volume to a final level. Next, 110 mg of SIF powder was weighed into a 50 mL volumetric flask, and the above solution was added to completely dissolve it and bring the volume to a final level.

[0284] Production of FeSSIF (Feeding Simulated Intestinal Fluid) 0.82 mL of glacial acetic acid and 1.18 g of NaCl were weighed into a 100 mL volumetric flask, and purified water was added to completely dissolve them. Then, 528 μL of 50% NaOH solution was added, and the pH was adjusted to 5.0 with 1 M hydrochloric acid or 1 M NaOH solution. Purified water was then added to bring the volume to a final level. Next, 560 mg of SIF powder was weighed into a 50 mL volumetric flask, and the above solution was added to completely dissolve it and bring the volume to a final level.

[0285] [Table 38] TIFF2026529489000046.tif231168

[0286] Hygroscopic experiment Dynamic water vapor adsorption (DVS) yields type A phosphate crystals, type A fumarate crystals, and p-True. The hygroscopic properties of type A crystals of benzenesulfonates, type A crystals of benzenesulfonates, type B crystals of oxalates, and free type A crystals were evaluated. Under constant temperature conditions of 25°C, the rate of change in sample mass was collected as humidity changed (0%RH to 95%RH). DVS test results and DVS test The XRPD results of the samples before and after the test are shown in Figures 48 to 59. The results showed that the free-state type A crystals were almost hygroscopic, while the type A crystals of p-toluenesulfonate, type A crystals of benzenesulfonate, and type B crystals of oxalate were slightly hygroscopic. The type A crystals of phosphate were hydrated and rapidly dehydrated below 10% RH. The type A crystals of fumarate showed significant hygroscopicity above 70% RH. None of the above crystal forms showed any change in crystal form after the DVS test, indicating high stability even under high humidity conditions.

[0287] solid state stability A-type crystals of phosphate, fumarate, p-toluenesulfonate, benzenesulfonate, oxalate, and free A-type crystals were opened and left for one week under conditions of 25°C / 60%RH and 40°C / 75%RH, respectively. The physical and chemical stability of the samples was then measured by XRPD and HPLC. Purity data are shown in Table 39, and XRPD results are shown in Figures 60-65. The results showed no significant change in purity after leaving the free A-type crystals and various salt forms open at 25°C / 60%RH and 40°C / 75%RH for one week, and no change in the crystal form of each sample was observed after the stability test, indicating that all of the above crystal forms possess high solid stability.

[0288] [Table 39] TIFF2026529489000048.tif205168

[0289] The control compound (trade name: Tirbanibulin) used in the test examples of this invention is a dual-action inhibitor of Src kinase and tubulin polymerization, and is approved by the FDA and the European Union as a topical treatment for actinic keratosis of the face or scalp. The manufacture of the control compound can be found in patent WO 2008 / 002676 A2, and the structure of the control compound is as follows.

[0290] [ka]

[0291] Test Example 1: Inhibition of tubulin monomer polymerization The tubulin monomer polymerization inhibition test of the compound was performed using the Tubulin Polymerization Assay Kit (cytoskeleton, Cat. # BK011P).

[0292] Before testing, the 96-well plate (Corning Costar, Cat. # 3686) included in the kit was first placed on a microplate reader (MD, SpectraMax M5), heated to 37°C, maintained for 10 minutes, removed the 96-well plate, added 5 μL of 12.5 μM compound solution or blank solution, returned the 96-well plate to the microplate reader and incubated at 37°C for 1 minute to raise the compound solution temperature to 37°C, removed the 96-well plate, quickly added 50 μL of reaction mixture prepared according to the supplier's instructions to each well, completing sample addition within 1 minute to avoid foam formation, then immediately returned the 96-well plate to the microplate reader, shook for 5 seconds, and performed continuous detection at 37°C for 30-60 minutes using kinetic mode under conditions of excitation light 360 nm and emission light 420 nm, detecting once every 30 seconds. A polymerization curve of tubulin monomer was obtained with detection time on the X axis and fluorescence signal value on the Y axis. As shown in Figure 66 and Table 40, a larger Vmax value in the polymerization curve and a higher maximum fluorescence signal value indicate lower inhibition efficiency of the compound.

[0293] [Table 40]

[0294] The test results for the compound's inhibition of tubulin polymerization are shown in Figure 66 and Table 40. The results show that the Vmax value and maximum fluorescence signal value of the polymerization curve corresponding to the compound represented by Formula I of the present invention were significantly smaller, indicating that it can significantly inhibit the polymerization of tubulin monomer and exhibited superior inhibitory activity compared to the control compound.

[0295] Test Example 2: Cell proliferation inhibition test of a compound The inhibitory effects of small molecule compounds on cell proliferation were detected using proliferation tests of human cutaneous squamous cell carcinoma cells A-431 (ATCC, CRL-1555) and cells derived from actinic keratosis patients HT 297.T (ATCC, CRL-7782).

[0296] A-431 cells and HT297.T cells were cultured in DMEM medium containing 10% fetal bovine serum and incubated at 37°C in a 5% CO2 incubator. 9 cells in the logarithmic growth phase were cultured. Cells were seeded at 1000 cells / well in a 6-well cell culture plate with 100 μL of solution per well, and incubated overnight at 37°C in a 5% CO2 incubator. The following day, 100 μL of a gradient-diluted 2-fold test compound solution was added to each well. DMSO was set as the positive control, and 10 μM staurosporine (Aladdin, S102392) was set as the negative control. The culture plates with the added compounds were incubated for a further 4 days at 37°C in a 5% CO2 incubator. After incubation was complete, fluorescence signal values ​​were measured using an Envision 2104 Multilabel Reader according to the supplier's instructions, using a Steady-Glo® luciferase assay system (Promega, G9243). After calculating the inhibition rate using the following formula, a curve was plotted with the logarithm of the inhibitor concentration on the X-axis and the inhibition rate on the Y-axis, and IC was calculated using Graphpad 8.0. 50 The result was calculated.

[0297] Inhibition rate % = (Signal in positive control group - Signal in test well) / (Signal in positive control group - Signal in negative control group) × 100

[0298] [Table 41]

[0299] The test results for the compounds against cell proliferation inhibition are shown in Table 41. The results indicate that the compound represented by formula I of the present invention can significantly inhibit cell proliferation. In particular, the inhibitory effect on HT297.T cells derived from actinic keratosis patients was significantly superior to that of the control compound, indicating that the compound represented by formula I of the present invention has a superior therapeutic effect against actinic keratosis.

[0300] Test Example 3: Thermodynamic Solubility Test A pH 7.4 phosphate buffer (PBS), a pH 6.5 FeSSIF solution, and a pH 1.6 FaSSGF solution were prepared. The compound was accurately weighed, and the prepared pH 7.4 phosphate buffer, pH 6.5 FeSSIF solution, and pH 1.6 FaSSGF solution were added to prepare a 4 mg / mL solution. The solution was shaken at 1000 rpm for 1 hour and then incubated overnight at room temperature. The cultured solution was centrifuged at 12000 rpm for 10 minutes to remove undissolved granules, and the supernatant was transferred to a new centrifuge tube. After appropriately diluting the supernatant, an acetonitrile solution containing an internal standard was added, and quantification was performed using a standard curve prepared with the same matrix.

[0301] [Table 42]

[0302] The results of the thermodynamic solubility test are shown in Table 42. The results indicate that, compared to the control compound, the compound represented by formula I of the present invention has greater thermodynamic solubility under neutral conditions and exhibits good pharmacokinetic properties.

[0303] Test Example 4: Pharmacokinetic Study In the mouse pharmacokinetic study, three male ICR mice weighing 20-25 g were used. After fasting overnight, they were administered intra-tail vein injection (1 mg / kg or 5 mg / kg), and blood was collected before administration and at 15, 30 minutes, and 1, 2, 4, 8, and 24 hours after administration. Three more mice were selected and administered orally (5 mg / kg), and blood was collected before administration and at 15, 30 minutes, and 1, 2, 4, 8, and 24 hours after administration. Blood samples were centrifuged at 6800 g at 2-8°C for 6 minutes to collect plasma, which was then stored at -80°C. Plasma was collected at each time point, mixed with acetonitrile solution containing 3-5 times the volume of the internal standard, vortexed for 1 minute, then centrifuged at 13000 rpm at 4°C for 10 minutes, the supernatant was collected, 3 times the volume of water was added and mixed, and an appropriate amount of the mixed solution was taken and analyzed by LC-MS / MS. The main pharmacokinetic parameters were analyzed using a non-compartment model in WinNonlin 7.0 software.

[0304] [Table 43]

[0305] [Table 44]

[0306] The results of pharmacokinetic studies in mice are shown in Tables 43 and 44. The results indicate that, compared to the control compound, the compound represented by Formula I of the present invention is metabolized more rapidly in mice, has a lower potential for systemic toxicity, and is more readily available as a drug.

[0307] Test Example 5: Human Liver Microsome Stability Test Human liver microsome stability testing was performed by culturing the compound and human liver microsomes together in vitro. First, the test compound was prepared in a 10 mM stock solution with DMSO solvent, and then diluted to 0.5 mM with acetonitrile. Human liver microsomes (Corning) were diluted in microsome / buffer with PBS, and a working solution was prepared by diluting the 0.5 mM compound using this solution. The concentration of the compound in the working solution was 1.5 μM, and the concentration of human liver microsomes was 0.75 mg / mL. A deep-well plate was prepared, 30 μL of the working solution was added to each well, and then 15 μL of preheated 6 mM NADPH solution was added to initiate the reaction. The mixture was then incubated at 37°C. At 0, 5, 15, 30, and 45 minutes of incubation, the reaction was stopped by adding 135 μL of acetonitrile to the corresponding well. Finally, after stopping the reaction with acetonitrile at 45 minutes, the deep-well plate was vortexed, shaken for 10 minutes (600 rpm), and then centrifuged for 15 minutes. After centrifugation, the supernatant was collected, purified water was added in a 1:1 ratio, and LC-MS / MS detection was 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 ratio of the compound's peak area at 5, 15, 30, and 45 minutes was compared with the peak area ratio at 0 minutes to calculate the remaining percentage of the compound at each time point, and the results were analyzed using GraphPad 5 software. 1 / 2 The result was calculated.

[0308] [Table 45]

[0309] 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, and the potential systemic toxicity is... It showed low levels of toxicity and good drug-forming properties.

[0310] Test Example 6: Inhibition of the Src signaling pathway by a compound The inhibitory effect of compounds on the SRC signaling pathway was evaluated by detecting p-SRC inhibition of the compounds against A-431 skin cancer cells (ATCC, CRL-1555) using the Western blot method.

[0311] A-431 cells were cultured in DMEM medium containing 10% fetal bovine serum and grown in a 37°C, 5% CO2 incubator. 500,000 cells / well were seeded into 12-well cell culture plates and cultured overnight in a 37°C, 5% CO2 incubator. The following day, the culture medium was changed, different concentrations of the compound were added, and DMSO was used as a control. The culture plates with the added compounds were further cultured in a 5% CO2 incubator at 37°C for 24 hours. The cells were washed once with PBS, lysed in RIPA lysis solution (R0010, Solarbio) at low temperature for 30 minutes, and the protein lysis solution was collected in a centrifuge tube and centrifuged at 14,000 g for 10 minutes at 4°C. The supernatant was transferred to a new tube. Protein concentration was detected and calculated using a BCA protein concentration test kit (P0009, Beyotime Biotechnology). The proteins in each sample were uniformly quantified using 5× protein loading buffer, boiled at 100°C for 5 minutes, and then p-SRC levels were detected by Western blotting. The p-SRC antibody (Ab185617) was purchased from Abcam, and the GAPDH antibody (60004-1-Ig) was purchased from Proteintech.

[0312] The test results are shown in Figure 67. The results indicate that the compound represented by Formula I of the present invention significantly inhibits SRC phosphorylation at 80 nM, exhibits superior p-SRC inhibitory activity compared to the control compound, and can block the SRC downstream signaling pathway.

[0313] While embodiments of the invention are illustrated and described above, it should be understood that these embodiments are illustrative and should not be construed as limiting the present disclosure. Those skilled in the art can modify, alter, substitute, and transform the above embodiments within the scope of the present invention.

Claims

1. The crystalline form or salt form of the compound represented by formula I, 【Chemistry 1】 However, the crystalline form of the compound represented by formula I is a free-state A-type crystal or a free-state B-type crystal. Using the Cu-Kα rays from the free-state A-type crystal, the powder X-ray diffraction pattern represented by a 2θ angle was analyzed. The line has diffraction peaks at the positions of 14.49±0.2°, 17.02±0.2°, 18.42±0.2°, and 20.53±0.2°; Using the Cu-Kα rays from the free-state B-type crystal, the powder X-ray diffraction pattern represented by a 2θ angle was analyzed. The line has diffraction peaks at the following positions: 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 represented by formula I is a phosphate, fumarate, p-toluenesulfonate, benzenesulfonate, oxalate, maleate, malate, succinate, methanesulfonate, or 2-hydroxyethanesulfonate, which is the crystalline form or salt form of the compound represented by formula I.

2. The compound phosphate represented by formula I is either a type A crystal of the compound phosphate represented by formula I or a type B crystal of the phosphate, Using the Cu-Kα rays from the A-type crystal of the aforementioned phosphate, a powder X-ray diffraction pattern represented by a 2θ angle was obtained. The diffraction peaks are located at 6.74±0.2°, 13.47±0.2°, 15.69±0.2°, 18.09±0.2°, and 20.26±0.2°; Using the Cu-Kα rays from the B-type crystal of the aforementioned phosphate, the powder X-ray diffraction pattern represented by a 2θ angle was obtained. The diffraction peaks are located 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°; Alternatively, the fumarate of the compound represented by formula I is a type A crystal of the fumarate of the compound represented by formula I; Using the Cu-Kα rays from the fumarate type A crystal, powder X-ray diffraction patterns expressed at a 2θ angle are measured. The turn has diffraction peaks at the positions of 13.51±0.2°, 15.41±0.2°, 17.57±0.2°, 19.48±0.2°, and 20.11±0.2°; Alternatively, the compound p-toluenesulfonate represented by formula I is a type A crystal of the compound p-toluenesulfonate represented by formula I; Using the Cu-Kα rays of the p-toluenesalt type A crystal, powder X-rays expressed at a 2θ angle are used. The diffraction pattern has diffraction peaks at the following positions: 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°; Alternatively, the benzenesulfonate of the compound represented by formula I is a type A crystal of the benzenesulfonate of the compound represented by formula I; Using the Cu-Kα line of the A-type crystal of the aforementioned benzenesulfonate, the powder is represented by a 2θ angle. The X-ray diffraction pattern has diffraction peaks at the following positions: 4.29±0.2°, 8.49±0.2°, 10.02±0.2°, 13.81±0.2°, and 15.26±0.2°; Alternatively, the oxalate of the compound represented by formula I is a type B crystal of the oxalate of the compound represented by formula I, or a type A crystal of the oxalate; Using the Cu-Kα rays of the B-type crystal of the oxalate mentioned above, powder X-ray diffraction patterns expressed at a 2θ angle were measured. The turn has diffraction peaks at the following positions: 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°; Using the Cu-Kα rays of the A-type crystal of the aforementioned oxalate, powder X-ray diffraction patterns expressed at a 2θ angle were measured. The turn has diffraction peaks at the following positions: 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°; Alternatively, the maleate of the compound represented by formula I is a type A crystal of the maleate of the compound represented by formula I; Using the Cu-Kα rays from the maleate type A crystal, powder X-ray diffraction is performed at a 2θ angle. The pattern has diffraction peaks at the following positions: 13.54±0.2°, 16.92±0.2°, 17.64±0.2°, 19.61±0.2°, and 23.77±0.2°; Alternatively, the malate salt of the compound represented by formula I is a type A crystal of the malate salt of the compound represented by formula I; Using the Cu-Kα rays of the aforementioned malate type A crystal, powder X-ray diffraction patterns expressed at a 2θ angle are measured. The turn has diffraction peaks at the following positions: 8.95±0.2°, 9.89±0.2°, 13.21±0.2°, 16.53±0.2°, and 18.93±0.2°; Alternatively, the succinate salt of the compound represented by formula I is a type A crystal of the succinate salt of the compound represented by formula I; Using the Cu-Kα rays of the succinate type A crystal, powder X-ray diffraction patterns expressed at a 2θ angle are measured. The turn has diffraction peaks at the following positions: 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°; Alternatively, the methanesulfonate of the compound represented by formula I is either a type A crystal of the methanesulfonate of the compound represented by formula I or a type B crystal of the methanesulfonate; Using the Cu-Kα line of the A-type crystal of the aforementioned methanesulfonate, the powder X is represented by a 2θ angle. The linear diffraction pattern has diffraction peaks at the following positions: 5.03±0.2°, 17.03±0.2°, 18.11±0.2°, 20.60±0.2°, and 23.40±0.2°; Using the Cu-Kα line of the B-type crystal of the aforementioned methanesulfonate, the powder X is represented by a 2θ angle. The linear diffraction pattern has diffraction peaks at the following positions: 18.89±0.2°, 20.43±0.2°, 21.07±0.2°, 23.44±0.2°, and 24.46±0.2°; Alternatively, the 2-hydroxyethanesulfonate of the compound represented by formula I is a type A crystal of the 2-hydroxyethanesulfonate of the compound represented by formula I; Using the Cu-Kα line of the A-type crystal of the aforementioned 2-hydroxyethanesulfonate, at a 2θ angle... The crystalline or salt form of the compound represented by formula I according to claim 1 is characterized in that the powder X-ray diffraction pattern shown has diffraction peaks at the positions of 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. Using the Cu-Kα rays from the free-state A-type crystal, the powder X-ray diffraction pattern represented by a 2θ angle was analyzed. The line must meet one of the following conditions: (1) Conditions in which diffraction peaks are present 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°; (2) Conditions in which diffraction peaks are present at the following positions: 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）７．２５±０．２°、９．２０±０．２°、１２．３９±０．２°、１３．７７ Conditions for having diffraction peaks at the following positions: ±0.2°, 14.49±0.2°, 17.02±0.2°, 17.78±0.2°, 18.42±0.2°, and 20.53±0.2°; (4) Conditions in which diffraction peaks are present at the following positions: 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) Conditions for having diffraction peaks at the following positions: 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 position and relative intensity of the diffraction peaks contained therein are as shown in the table below; Table 1 Alternatively, using the Cu-Kα rays from the free-state B-type crystal, powder X-rays expressed at a 2θ angle are used. The diffraction pattern satisfies one of the following conditions: (1) Conditions in which diffraction peaks are present 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°; (2) Conditions in which diffraction peaks are present at the following positions: 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) Conditions for having diffraction peaks at the following positions: 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 position and relative intensity of the diffraction peaks included therein are as shown in the table below; Table 2 Alternatively, using the Cu-Kα rays of the A-type crystal of the phosphate, powder X-rays expressed at a 2θ angle are used. The diffraction pattern satisfies one of the following conditions: (1) Conditions in which diffraction peaks are present 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°; (2) Conditions in which diffraction peaks are present at the following positions: 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) Conditions in which diffraction peaks are present at the following positions: 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 position and relative intensity of the diffraction peaks included therein are as shown in the table below; Table 3 Alternatively, using the Cu-Kα rays of the B-type crystal of the phosphate, powder X-rays expressed at a 2θ angle are used. The diffraction pattern satisfies one of the following conditions: (1) Conditions in which diffraction peaks are present 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°; (2) Conditions in which diffraction peaks are present at the following positions: 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) Conditions in which diffraction peaks are present at the following positions: 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 position and relative intensity of the diffraction peaks included therein are as shown in the table below; Table 4 Alternatively, using the Cu-Kα line of the fumarate type A crystal, the powder X represented by a 2θ angle is obtained. The linear diffraction pattern satisfies one of the following conditions: (1) Conditions in which diffraction peaks are present 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°; (2) Conditions in which diffraction peaks are present at the following positions: 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°; (3) Conditions in which diffraction peaks are present at the following positions: 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 position and relative intensity of the diffraction peaks included therein are as shown in the table below; Table 5 Alternatively, using the Cu-Kα line of the p-toluenesulfonate type A crystal, at a 2θ angle The resulting powder X-ray diffraction pattern must satisfy one of the following conditions: (1) Conditions in which diffraction peaks are present 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°; (2) Conditions in which diffraction peaks are present at the following positions: 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) Conditions in which diffraction peaks are present at the following positions: 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 position and relative intensity of the diffraction peaks included therein are as shown in the table below; Table 6 Alternatively, the Cu-Kα line of the A-type crystal of the benzenesulfonate is used and expressed in terms of a 2θ angle. The resulting powder X-ray diffraction pattern must satisfy one of the following conditions: (1) Conditions in which diffraction peaks are present 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°; (2) Conditions in which diffraction peaks are present at the following positions: 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) Conditions for having diffraction peaks at the following positions: 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 position and relative intensity of the diffraction peaks included therein are as shown in the table below; Table 7 Alternatively, using the Cu-Kα line of the B-type crystal of the oxalate, the powder X represented by a 2θ angle is obtained. The linear diffraction pattern satisfies one of the following conditions: (1) Conditions in which diffraction peaks are present 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°; (2) Conditions in which diffraction peaks are present at the following positions: 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) Conditions in which diffraction peaks are present at the following positions: 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 positions and relative intensities of the diffraction peaks contained therein are as shown in the table below. conditions; Table 8 Alternatively, using the Cu-Kα line of the A-type crystal of the oxalate, the powder X represented by a 2θ angle is obtained. The linear diffraction pattern satisfies one of the following conditions: (1) Conditions in which diffraction peaks are present 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°; (2) Conditions in which diffraction peaks are present at the following positions: 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) Conditions in which diffraction peaks are present at the following positions: 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°; (4) The position and relative intensity of the diffraction peaks included therein are as shown in the table below; Table 9 Alternatively, the Cu-Kα line of the maleate type A crystal can be used to represent the powder at a 2θ angle. The X-ray diffraction pattern satisfies one of the following conditions: (1) Conditions in which diffraction peaks are present 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°; (2) Conditions in which diffraction peaks are present at the following positions: 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) Conditions in which diffraction peaks are present at the following positions: 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 position and relative intensity of the diffraction peaks included therein are as shown in the table below; Table 10 Alternatively, using the Cu-Kα line of the A-type crystal of the malate salt, the powder X represented by a 2θ angle is obtained. The linear diffraction pattern satisfies one of the following conditions: (1) Conditions in which diffraction peaks are present at the following positions: 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) Using Cu-Kα rays, the powder X-ray diffraction pattern expressed at a 2θ angle is 6.63 ± Conditions for having diffraction peaks at the following positions: 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 position and relative intensity of the diffraction peaks included therein are as shown in the table below; Table 11 Alternatively, using the Cu-Kα line of the succinate type A crystal, the powder X represented by a 2θ angle is obtained. The linear diffraction pattern satisfies one of the following conditions: (1) Conditions in which diffraction peaks are present 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°; (2) Conditions in which diffraction peaks are present at the following positions: 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) Conditions in which diffraction peaks are present at the following positions: 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 position and relative intensity of the diffraction peaks included therein are as shown in the table below; Table 12 Alternatively, using the Cu-Kα line of the A-type crystal of the methanesulfonate, expressed in terms of a 2θ angle, The position and relative intensity of the diffraction peaks included in the powder X-ray diffraction pattern are as shown in the table below; Table 13 Alternatively, using the Cu-Kα line of the B-type crystal of the methanesulfonate, expressed in terms of a 2θ angle, The powder X-ray diffraction pattern must satisfy one of the following conditions: (1) Conditions in which diffraction peaks are present 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°; (2) Conditions in which diffraction peaks are present at the following positions: 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) Conditions for having diffraction peaks at the following positions: 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 position and relative intensity of the diffraction peaks included therein are as shown in the table below; Table 14 Alternatively, using the Cu-Kα rays of the A-type crystal of the 2-hydroxyethanesulfonate, the powder X-ray diffraction pattern represented by a 2θ angle satisfies one of the following conditions. A characteristic feature is the crystalline form or salt form of the compound represented by formula I as described in claim 2; (1) Conditions in which diffraction peaks are present 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°; (2) Conditions in which diffraction peaks are present at the following positions: 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) Conditions in which diffraction peaks are present at the following positions: 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 position and relative intensity of the diffraction peaks contained therein are as shown in the table below. Table 15

4. The free-state A-type crystal of the compound represented by formula I satisfies one or more of the following conditions: (1) The condition that it is in anhydrous crystalline form; (2) Using Cu-Kα rays, the powder X-ray diffraction pattern represented by a 2θ angle is shown in Figure 1. The condition for being in that way; (3) The condition in which the differential scanning calorimetry curve has the starting point of one endothermic peak at 94.7 ± 3°C; (4) The condition in which the differential scanning calorimetry curve has one endothermic peak at 96.6 ± 3°C; (5) Conditions under which the thermogravimetric analysis curve shows a weight loss of approximately 0.98% at 150°C; (6) Conditions under which the differential scanning calorimetry curve is as shown in Figure 3; (7) The condition under which the thermogravimetric analysis curve is as shown in Figure 2; Alternatively, the free-state type B crystal satisfies one or more of the following conditions: (1) The condition that it is in anhydrous crystalline form; (2) Using Cu-Kα rays, the powder X-ray diffraction pattern represented by a 2θ angle is shown in Figure 4. The condition for being in that way; (3) The condition in which the differential scanning calorimetry curve has the starting point of one endothermic peak at 77.2 ± 3°C; (4) The condition in which the differential scanning calorimetry curve has one endothermic peak at 84.5 ± 3°C; (5) Conditions under which the differential scanning calorimetry curve has one endothermic peak at 92.4 ± 3°C; (6) Conditions under which the thermogravimetric analysis curve shows a weight loss of approximately 0.48% at 150°C; (7) Conditions under which the differential scanning calorimetry curve is as shown in Figure 6; (8) The condition under which the thermogravimetric analysis curve is as shown in Figure 5; Alternatively, the type A crystal of the phosphate satisfies one or more of the following conditions: (1) Using Cu-Kα rays, the powder X-ray diffraction pattern represented by a 2θ angle is shown in Figure 7. The condition for being in that way; (2) The differential scanning calorimetry curve shows the starting point of one endothermic peak at 172.8 ± 3°C. Conditions that must be met; (3) The condition in which the differential scanning calorimetry curve has one endothermic peak at 174.5 ± 3°C; (4) Conditions under which the thermogravimetric analysis curve shows a weight loss of approximately 4.40% at 150°C; (5) Conditions under which the differential scanning calorimetry curve is as shown in Figure 9; (6) The condition under which the thermogravimetric analysis curve is as shown in Figure 8; (7) In the A-type crystal of the phosphate, the molar ratio of the compound represented by formula I to phosphoric acid is 1:1; Alternatively, the B-type crystal of the phosphate satisfies one or more of the following conditions: (1) The condition that it is in anhydrous crystalline form; (2) Using Cu-Kα rays, the powder X-ray diffraction pattern represented by a 2θ angle is shown in Figure 11. The condition for being in that way; (3) In the B-type crystal of the phosphate, the condition is that the molar ratio of the compound represented by formula I to phosphoric acid is 1:1; Alternatively, the type A crystal of the fumarate satisfies one or more of the following conditions: (1) The condition that it is in anhydrous crystalline form; (2) Using Cu-Kα rays, the powder X-ray diffraction pattern represented by a 2θ angle is shown in Figure 12. The condition for being in that way; (3) The condition in which the differential scanning calorimetry curve has the starting point of one endothermic peak at 128.2 ± 3°C; (4) The condition in which the differential scanning calorimetry curve has one endothermic peak at 130.3 ± 3°C; (5) Conditions under which the thermogravimetric analysis curve shows a weight loss of approximately 1.17% at 150°C; (6) Conditions under which the differential scanning calorimetry curve is as shown in Figure 14; (7) The condition under which the thermogravimetric analysis curve is as shown in Figure 13; (8) In the type A crystal of the fumarate, the condition is that the molar ratio of the compound represented by formula I to fumaric acid is 1:1; Alternatively, the type A crystal of the p-toluenesulfonate satisfies one or more of the following conditions: (1) Using Cu-Kα rays, the powder X-ray diffraction pattern represented by a 2θ angle is shown in Figure 16. The condition for being in that way; (2) The condition in which the differential scanning calorimetry curve has the starting point of one endothermic peak at 149.9 ± 3°C; (3) The condition under which the differential scanning calorimetry curve has one endothermic peak at 152.1 ± 3°C; (4) Conditions under which the thermogravimetric analysis curve shows a weight loss of approximately 0.94% at 150°C; (5) Conditions under which the differential scanning calorimetry curve is as shown in Figure 18; (6) The condition under which the thermogravimetric analysis curve is as shown in Figure 17; (7) In the type A crystal of the p-toluenesulfonate, the condition is that the molar ratio of the compound represented by formula I to p-toluenesulfonic acid is 1:1; Alternatively, the A-type crystals of the benzenesulfonate satisfy one or more of the following conditions: (1) Using Cu-Kα rays, the powder X-ray diffraction pattern represented by a 2θ angle is shown in Figure 19. The condition for being in that way; (2) The condition in which the differential scanning calorimetry curve has the starting point of one endothermic peak at 144.5 ± 3°C; (3) The condition in which the differential scanning calorimetry curve has one endothermic peak at 146.4 ± 3°C; (4) Conditions under which the thermogravimetric analysis curve shows a weight loss of approximately 1.28% at 140°C; (5) Conditions under which the differential scanning calorimetry curve is as shown in Figure 21; (6) The condition under which the thermogravimetric analysis curve is as shown in Figure 20; (7) In the A-type crystal of the benzenesulfonate, the molar ratio of the compound represented by formula I to benzenesulfonic acid is 1:1; Alternatively, the B-type crystal of the oxalate satisfies one or more of the following conditions: (1) Using Cu-Kα rays, the powder X-ray diffraction pattern represented by a 2θ angle is shown in Figure 22. The condition for being in that way; (2) The condition in which the differential scanning calorimetry curve has the starting point of one endothermic peak at 155.5 ± 3°C; (3) The condition in which the differential scanning calorimetry curve has one endothermic peak at 158.2 ± 3°C; (4) The condition in which the differential scanning calorimetry curve has one endothermic peak at 218.7 ± 3°C; (5) Conditions under which the thermogravimetric analysis curve shows a weight loss of approximately 1.21% at 150°C; (6) Conditions under which the differential scanning calorimetry curve is as shown in Figure 24; (7) The condition under which the thermogravimetric analysis curve is as shown in Figure 23; (8) In the B-type crystal of the oxalate, the condition is that the molar ratio of the compound represented by formula I to oxalic acid is 1:1; Alternatively, the type A crystal of the oxalate satisfies one or more of the following conditions: (1) Using Cu-Kα rays, the powder X-ray diffraction pattern represented by a 2θ angle is shown in Figure 38. The condition for being in that way; (2) The condition in which the differential scanning calorimetry curve has the starting point of one endothermic peak at 151.3 ± 3°C; (3) The condition in which the differential scanning calorimetry curve has one endothermic peak at 153.6 ± 3°C; (4) The condition in which the differential scanning calorimetry curve has one endothermic peak at 162.8 ± 3°C; (5) Conditions under which the differential scanning calorimetry curve has one endothermic peak at 218.8 ± 3°C; (6) Conditions under which the thermogravimetric analysis curve shows a weight loss of approximately 4.10% at 150°C; (7) Conditions under which the differential scanning calorimetry curve is as shown in Figure 40; (8) The condition under which the thermogravimetric analysis curve is as shown in Figure 39; Alternatively, the type A crystal of the maleate satisfies one or more of the following conditions: (1) Using Cu-Kα rays, the powder X-ray diffraction pattern represented by a 2θ angle is shown in Figure 25. The condition for being in that way; (2) The condition in which the differential scanning calorimetry curve has the starting point of one endothermic peak at 123.4 ± 3°C; (3) The condition in which the differential scanning calorimetry curve has one endothermic peak at 125.2 ± 3°C; (4) Conditions under which the thermogravimetric analysis curve shows a weight loss of approximately 2.56% at 120°C; (5) Conditions under which the differential scanning calorimetry curve is as shown in Figure 27; (6) The condition under which the thermogravimetric analysis curve is as shown in Figure 26; (7) In the type A crystal of the maleate, the molar ratio of the compound represented by formula I to maleic acid is 1:1; Alternatively, the type A crystal of the malate satisfies one or more of the following conditions: (1) Using Cu-Kα rays, the powder X-ray diffraction pattern represented by a 2θ angle is shown in Figure 28. The condition for being in that way; (2) The condition in which the differential scanning calorimetry curve has the starting point of one endothermic peak at 86.3 ± 3°C; (3) The condition in which the differential scanning calorimetry curve has one endothermic peak at 96.3 ± 3°C; (4) Conditions under which the thermogravimetric analysis curve shows a weight loss of approximately 2.26% at 150°C; (5) Conditions under which the differential scanning calorimetry curve is as shown in Figure 30; (6) The condition under which the thermogravimetric analysis curve is as shown in Figure 29; (7) In the type A crystal of the malate salt, the condition is that the molar ratio of the compound represented by formula I to malic acid is 1:1; Alternatively, the succinate type A crystal satisfies one or more of the following conditions: (1) In the succinate type A crystal, the molar ratio of the compound represented by formula I to succinic acid is 1:1.2, 1:1.1, or 1:1; (2) Using Cu-Kα rays, the powder X-ray diffraction pattern represented by a 2θ angle is shown in Figure 31. The condition for being in that way; (3) The condition in which the differential scanning calorimetry curve has the starting point of one endothermic peak at 75.9 ± 3°C; (4) The condition in which the differential scanning calorimetry curve has one endothermic peak at 85.4 ± 3°C; (5) Conditions under which the thermogravimetric analysis curve shows a weight loss of approximately 4.49% at 150°C; (6) Conditions under which the differential scanning calorimetry curve is as shown in Figure 33; (7) The condition that the thermogravimetric analysis curve is as shown in Figure 32; (8) In the succinate type A crystal, the molar ratio of the compound represented by formula I to succinic acid is 1:1; Alternatively, using the Cu-Kα line of the A-type crystal of the methanesulfonate, expressed in terms of a 2θ angle, The conditions under which the powder X-ray diffraction pattern is as shown in Figure 34; Alternatively, the B-type crystal of the methanesulfonate satisfies one or more of the following conditions: (1) In the type B crystal of the methanesulfonate, the molar ratio of the compound represented by formula I to methanesulfonic acid is 1:2.1 or 1:2; (2) Using Cu-Kα rays, the powder X-ray diffraction pattern represented by a 2θ angle is shown in Figure 35. The condition for being in that way; (3) The condition in which the differential scanning calorimetry curve has the starting point of one endothermic peak at 97.3 ± 3°C; (4) The condition in which the differential scanning calorimetry curve has one endothermic peak at 109.4 ± 3°C; (5) Conditions under which the thermogravimetric analysis curve shows a weight loss of approximately 0.91% at 80°C and a weight loss of approximately 2.40% between 80°C and 130°C; (6) Conditions under which the differential scanning calorimetry curve is as shown in Figure 37; (7) The condition under which the thermogravimetric analysis curve is as shown in Figure 36; (8) In the type B crystal of the methanesulfonate, the molar ratio of the compound represented by formula I to methanesulfonic acid is 1:2; Alternatively, the A-type crystal of the 2-hydroxyethanesulfonate satisfies one or more of the following conditions, characterized in that it is a crystalline form or salt form of the compound represented by formula I according to claim 3, (1) Using Cu-Kα rays, the powder X-ray diffraction pattern represented by a 2θ angle is shown in Figure 41. The condition for being in that way; (2) The condition in which the differential scanning calorimetry curve has the starting point of one endothermic peak at 109.5 ± 3°C; (3) The condition in which the differential scanning calorimetry curve has one endothermic peak at 118.4 ± 3°C; (4) Conditions under which the thermogravimetric analysis curve shows a weight loss of approximately 1.28% at 110°C; (5) Conditions under which the differential scanning calorimetry curve is as shown in Figure 43; (6) The condition under which the thermogravimetric analysis curve is as shown in Figure 42; (7) In the A-type crystal of the 2-hydroxyethanesulfonate, represented by formula I The condition is that the molar ratio of the compound to 2-hydroxyethanesulfonic acid is 1:

1.

5. A method for producing a crystalline form or salt form of a compound represented by formula I, wherein the crystalline form of the compound represented by formula I is a free-state A-type crystal or a free-state B-type crystal as described in any one of claims 1 to 4; 【Chemistry 2】 The salt form of the compound represented by formula I is a type A crystal of phosphate, a type B crystal of phosphate, a type A crystal of fumarate, a type A crystal of p-toluenesulfonate, a type A crystal of benzenesulfonate, a type B crystal of oxalate, a type A crystal of oxalate, a type A crystal of maleate, a type A crystal of malate, a type A crystal of succinate, a type A crystal of methanesulfonate, a type B crystal of methanesulfonate, or a type A crystal of 2-hydroxyethanesulfonate, as described in any one of claims 2 to 4; Here, The method for producing the free-state type A crystals includes the steps of dissolving a compound represented by formula I in a solvent and volatilizing it at room temperature to obtain free-state type A crystals; the solvent is an organic solvent or a mixed solvent, and the organic solvent is preferably CHCl3. ３ The solvents are 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 MeOH and H ２ A mixed solvent of O, acetonitrile and H ２ It is a mixed solvent of O; The method for producing the free-state type B crystals includes the steps of concentrating a solution of the compound represented by formula I under reduced pressure and drying it at 40 to 60°C to obtain free-state type B crystals, wherein the solution is an alcohol-based solution or a halogenated hydrocarbon solution; The method for producing the A-type crystals of the phosphate comprises the steps of mixing a compound represented by formula I, phosphoric acid, and a solvent, and forming a slurry at room temperature to obtain A-type crystals of the phosphate of the compound represented by formula I, wherein the solvent is an ester-based solvent, an ether-based solvent, a mixed solvent of an alcohol-based solvent and water, or a mixed solvent of a ketone-based solvent and a saturated alkane-based solvent; The method for producing the B-type crystals of the phosphate includes the step of heating the A-type crystals of the phosphate to 150 ± 10°C to obtain the B-type crystals of the phosphate; The method for producing the A-type crystals of the fumarate comprises the steps of mixing a compound represented by formula I, fumaric acid, and a solvent, and forming a slurry at room temperature to obtain the A-type crystals of the fumarate; the solvent is an ester-based solvent, an ether-based solvent, a mixed solvent of an alcohol-based solvent and water, or a mixed solvent of a ketone-based solvent and a saturated alkane-based solvent; The method for producing the A-type crystals of p-toluenesulfonate comprises the steps of mixing a compound represented by formula I, p-toluenesulfonic acid, and a solvent, and forming a slurry at room temperature to obtain the A-type crystals of p-toluenesulfonate; the solvent is an ester-based solvent or an ether-based solvent; The method for producing the A-type crystals of the benzenesulfonate comprises the steps of mixing a compound represented by formula I, benzenesulfonic acid, and a solvent, and forming a slurry at room temperature to obtain the A-type crystals of the benzenesulfonate; the solvent is a mixed solvent of an ester-based solvent, an alcohol-based solvent, and water; The method for producing the B-type crystals of the oxalate mentioned above involves mixing the compound represented by formula I, oxalic acid, and a solvent. The process includes the steps of combining the materials and forming a slurry at room temperature to obtain type B crystals of oxalate; the solvent is a mixed solvent of an ester solvent, an ether solvent, a ketone solvent, and a saturated alkane solvent; The method for producing the A-type crystals of the oxalate includes the steps of mixing a compound represented by formula I, oxalic acid, and a solvent, forming a slurry at room temperature to obtain the A-type crystals of the oxalate; the solvent is a mixed solvent of an alcohol-based solvent and water; The method for producing the maleate type A crystals includes the steps of mixing a compound represented by formula I, maleic acid, and a solvent, and forming a slurry at room temperature to obtain maleate type A crystals; the solvent is a mixed solvent of an ester solvent, an ether solvent, a ketone solvent, and a saturated alkane solvent; The method for producing the A-type crystals of the malate salt comprises the steps of mixing a compound represented by formula I, malic acid, and a solvent, and forming a slurry at room temperature to obtain A-type crystals of the malate salt; the solvent is a mixed solvent of a ketone solvent and a saturated alkane solvent; The method for producing the succinate type A crystals includes the steps of mixing a compound represented by formula I, succinic acid, and a solvent, and forming a slurry at room temperature to obtain succinate type A crystals; the solvent is an ether-based solvent; The method for producing the A-type crystals of the methanesulfonate comprises the steps of mixing a compound represented by formula I, methanesulfonic acid, and a solvent, and forming a slurry at room temperature to obtain the A-type crystals of the methanesulfonate; the solvent is a mixed solvent of a ketone solvent and a saturated alkane solvent; The method for producing the B-type crystals of the methanesulfonate comprises the steps of mixing a compound represented by formula I, methanesulfonic acid, and a solvent, and forming a slurry at room temperature to obtain B-type crystals of the methanesulfonate; the solvent is a mixed solvent of an ester solvent, an ether solvent, a ketone solvent, and a saturated alkane solvent; The method for producing type A crystals of 2-hydroxyethanesulfonate comprises the steps of mixing a compound represented by formula I, 2-hydroxyethanesulfonic acid, and a solvent, and forming a slurry at room temperature to obtain type A crystals of 2-hydroxyethanesulfonate; the solvent is characterized in that it is a mixed solvent of an ester solvent, a ketone solvent, and a saturated alkane solvent.

6. In the method for producing the free-state type B crystals, the compound represented by formula I is dissolved in MeOH or dichloromethane, then rotated and evaporated under reduced pressure, and the resulting gel-like sample is transferred to a temperature of 50°C and dried under vacuum to obtain the crystals. Alternatively, in the method for producing type A crystals of the phosphate, the method for producing type A crystals of the phosphate satisfies one or more of the following conditions: (1) The molar ratio of phosphoric acid to the compound represented by formula I is (1.0 to 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 to 0.21 mol / L, preferably 0.16 mol / L; (3) In the mixed solvent of the alcohol-based solvent and water, the volume ratio of the alcohol-based solvent to the water is (14 to 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 to 2):1; (5) The solvent is IPA / H ２ The conditions are that the solvent is a mixed solvent of O (19:1, v / v), a mixed solvent of acetone / n-heptane (1:1, v / v), isopropyl acetate, or methyl tert-butyl ether; Alternatively, in the method for producing type B crystals of the phosphate, the method for producing type B crystals of the phosphate satisfies one or two of the following conditions: (1) Conditions for heating the A-type crystal of the phosphate under the protection of nitrogen gas; (2) The heating temperature is 145 to 155°C, preferably 150°C; Alternatively, in the method for producing type A crystals of the fumarate, the method for producing type A crystals of the fumarate satisfies one or more of the following conditions: (1) The molar ratio of fumaric acid to the compound represented by formula I is (1.0 to 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 to 0.16 mol / L, preferably 0.11 mol / L; (3) In the mixed solvent of the alcohol-based solvent and water, the volume ratio of the alcohol-based solvent to the water is (14 to 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 to 2):1; (5) The solvent is IPA / H ２ The conditions are that the solvent is a mixed solvent of O (19:1, v / v), a mixed solvent of acetone / n-heptane (1:1, v / v), isopropyl acetate, or methyl tert-butyl ether; Alternatively, in the method for producing type A crystals of p-toluenesulfonate, the method for producing type A crystals of p-toluenesulfonate satisfies one or more of the following conditions: (1) The molar ratio of p-toluenesulfonic acid to the compound represented by formula I is (1.0 to 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 to 0.16 mol / L, preferably 0.11 mol / L; (3) The solvent is isopropyl acetate or methyl tert-butyl ether; Alternatively, in the method for producing type A crystals of the benzenesulfonate, the method for producing type A crystals of the benzenesulfonate satisfies one or more of the following conditions: (1) The molar ratio of the benzenesulfonic acid to the compound represented by formula I is (1.0 to 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 to 0.16 mol / L, preferably 0.11 mol / L; (3) In the mixed solvent of the alcohol-based solvent and water, the volume ratio of the alcohol-based solvent to the water is (14 to 24):1, preferably 19:1; (4) The solvent is IPA / H ２ Conditions that the solvent is a mixed solvent of O(19:1, v / v) or isopropyl acetate; Alternatively, in the method for producing type B crystals of the oxalate, the method for producing type B crystals of the oxalate satisfies one or more of the following conditions: (1) The molar ratio of oxalic acid to the compound represented by formula I is (1.0 to 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 to 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 to 2):1; (4) The solvent is a mixed solvent of acetone / n-heptane (1:1, v / v), isopropyl acetate, or methyl tert-butyl ether; Alternatively, in the method for producing type A crystals of the oxalate, the method for producing type A crystals of the oxalate satisfies one or more of the following conditions: (1) The molar ratio of oxalic acid to the compound represented by formula I is (1.0 to 1.5):1, preferably 1.0:1; (2) In the method for producing type A crystals of the oxalate, the mixed solvent of the alcohol-based solvent and water has a volume ratio of (14 to 24):1, preferably 19:1; (3) In the method for producing type A crystals of the oxalate, the solvent is IPA / H ２ Conditions for a mixed solvent of O (19:1, v / v); Alternatively, in the method for producing type A crystals of the maleate, the method for producing type A crystals of the maleate satisfies one or more of the following conditions: (1) The molar ratio of maleic acid to the compound represented by formula I is (1.0 to 1.5):

1. Preferably, the ratio is 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 to 2):1; (3) The solvent is a mixed solvent of acetone / n-heptane (1:1, v / v), isopropyl acetate, or methyl tert-butyl ether; Alternatively, in the method for producing type A crystals of the malate salt, the method for producing type A crystals of the malate salt satisfies one or more of the following conditions: (1) The molar ratio of malic acid to the compound represented by formula I is (1.0 to 1.5):1, preferably 1.0:1; (2) In the method for producing type A crystals of the malate salt, the mixed solvent of the ketone solvent and the saturated alkane solvent is (0.5 to 2):1, preferably 1:1; (3) The condition that the solvent is a mixed solvent of acetone / n-heptane (1:1, v / v); Alternatively, in the method for producing type A crystals of succinate, the method for producing type A crystals of succinate satisfies one or more of the following conditions: (1) The molar ratio of succinic acid to the compound represented by formula I is (1.0 to 1.5):1, preferably 1.0:1; (2) The condition that the solvent is methyl tert-butyl ether; Alternatively, in the method for producing type A crystals of the methanesulfonate, the method for producing type A crystals of the methanesulfonate satisfies one or more of the following conditions: (1) The molar ratio of the methanesulfonic acid to the compound represented by formula I is (1.0 to 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 to 2):1, preferably 1:1; (3) The condition that the solvent is a mixed solvent of acetone / n-heptane (1:1, v / v); Alternatively, in the method for producing type B crystals of the methanesulfonate, the method for producing type B crystals of the methanesulfonate satisfies one or more of the following conditions: (1) The molar ratio of the methanesulfonic acid to the compound represented by formula I is (1.5 to 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 to 2):1; (3) The solvent is a mixed solvent of acetone / n-heptane (1:1, v / v), isopropyl acetate, or methyl tert-butyl ether; Alternatively, the method for producing type A crystals of the 2-hydroxyethanesulfonate according to claim 5 is characterized in that it satisfies one or more of the following conditions, (1) The molar ratio of 2-hydroxyethanesulfonic acid to the compound represented by formula I is (1.5 to 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 to 2):1; (3) The solvent is a mixed solvent of acetone / n-heptane (1:1, v / v) or isopropyl acetate.

7. A pharmaceutical composition comprising a crystalline form or salt form of a compound represented by formula I as described in any one of claims 1 to 6, and at least one pharmaceutical excipient.

8. The use of substance M, wherein substance M is a crystalline form, salt form, or pharmaceutical composition according to any one of claims 1 to 6, The aforementioned use is, 1) Inhibition of tubulin polymerization and / or Src kinase; 2) Prevention and / or treatment of diseases related to tubulin polymerization and / or Src kinase; 3) Production of tubulin polymerization and / or Src kinase inhibitors; 4) Uses characterized by comprising the manufacture of pharmaceuticals or formulations for preventing and / or treating diseases related to tubulin polymerization and / or Src kinase.

9. A use of substance M in the manufacture of a pharmaceutical product for treating tumors and / or skin diseases, wherein substance M is a crystalline form, salt form, or pharmaceutical composition according to any one of claims 1 to 6, of a compound represented by formula I.

10. The tumors include solid tumors, sarcomas, and hematological cancers, and preferably include 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 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 lymphoma, non-Hodgkin lymphoma, acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, myeloma, and / or myelodysplastic syndromes. The use according to claim 9, characterized in that the skin disease includes actinic keratosis, psoriasis, atopic dermatitis, psoriasis, vitiligo, roseola, and / or systemic lupus erythematosus.

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