Crystalline form of methanesulfonates of triazolocyclic compounds, their manufacturing method and applications

Abstract

This invention discloses crystalline forms of methanesulfonates of triazolocyclic compounds, methods for producing them, and applications. Specifically, it discloses crystalline forms of methanesulfonates of compounds of formula (I), selected from crystalline forms A to I, methods for producing them, and applications, as well as methods for producing the above crystalline forms and pharmaceutical compositions containing them. The production method of this invention is simple and easy to implement, suitable for industrialized mass production, and the crystalline forms A to I of methanesulfonates of compounds of formula (I) produced have good solubility and stability, which is advantageous for the manufacture and storage of pharmaceutical formulations. [Formula 1] TIFF2026510251000006.tif53161

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine. Specifically, it relates to the methanesulfonate of 9-((8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-thio)-4-methyl-2H-[1,4]oxazino[3,2-c]quinolin-3(4H)-one, the crystal form of the salt, its manufacturing method and application.

Background Art

[0002] The compound of formula (I) has the Chinese name JPEG2026510251000002.jpg31165, and the English name is 9-((8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-Thio)-4-methyl-2H-[1,4]oxazino[3,2-c]quinoline-3(4H)-one methanesulfonate, and its structural formula is as shown below.

Chemical

[0003] The hepatocyte growth factor (HFG) receptor, also known as C-Met, is a tyrosine kinase receptor. Abnormal activation of C-Met is associated with a poor prognosis in cancer, and in all cases, there is a problem of C-Met overexpression. Abnormalities of C-Met have been found in various types of tumors, such as liver cancer (HCC), non-small cell carcinoma (NSCLC), bladder cancer, kidney cancer, breast cancer, squamous cell carcinoma, brain cancer, gastric cancer, and colon cancer. Abnormalities of C-Met can manifest as increased expression, gene amplification, gene mutation, or increased HGF expression. In these abnormal conditions, C-Met is in an abnormally activated state, which can lead to malignancy and a poor prognosis. When C-Met is abnormally activated, it causes tumor growth and neovascularization (regeneration of blood vessels that can nourish the tumor), and helps the cancer spread to other organs (metastasis). Therefore, inhibiting the C-Met signaling pathway is one of the important strategies in cancer treatment. The compound of formula I is an effective C-Met / HGFR (hepatocyte growth factor receptor) kinase inhibitor, and as a tyrosine kinase inhibitor, it can effectively block the HGF / C-Met signaling pathway to achieve the goal of treating abnormal cell proliferation in mammals (e.g., cancer).

[0004] Jiangsu Haosen Pharmaceutical Group Co., Ltd. discloses in patent CN201580025022.6 a crystalline free base or crystalline acidic salt thereof of a compound of formula (I), a method for producing the same, and its applications. A method for producing crystalline forms I, II, III, IV, and V of methanesulfonates and pharmaceutical compositions containing the same are disclosed. [Overview of the project]

[0005] This invention aims to provide a crystalline form of methanesulfonate of the compound of formula (I), a method for producing the same, and its applications, suitable for drug development. By diligently studying different aggregation states of methanesulfonate, nine polymorphs of methanesulfonate of the compound of formula (I) were obtained.

[0006] The present invention aims to provide a methanesulfonate of 9-((8-fluoro-6-(1-methyl-1H-pyrazole-4-yl)-[1,2,4]triazolo[4,3-a]pyridine-3-yl)-thio)-4-methyl-2H-[1,4]oxazino[3,2-c]quinoline-3(4H)-one, a compound of formula (I). [ka]

[0007] In a preferred embodiment of the present invention, the methanesulfonate of the compound of formula (I) is crystalline or amorphous.

[0008] In a preferred embodiment of the present invention, the crystal forms include crystal forms A, B, C, D, E, F, G, H, and I.

[0009] The powder X-ray diffraction pattern of crystalline form A of the methanesulfonate of the compound of formula (I) has diffraction peaks at positions where 2θ is 5.4±0.2°, or 6.1±0.2°, or 10.6±0.2°, or 13.7±0.2°, or 18.1±0.2°, or 19.6±0.2°, or 24.7±0.2°, preferably including diffraction peaks at any 2 to 5 positions, 3 to 5 positions, 3 to 6 positions, or 3 to 7 positions among the above diffraction peaks, and more preferably including diffraction peaks at any 4, 6, or 7 positions among the above diffraction peaks. Preferably, the powder X-ray diffraction pattern of crystalline form A has diffraction peaks at positions where 2θ is 5.4±0.2°, 6.1±0.2°, 10.6±0.2° and 13.7±0.2°, preferably further having diffraction peaks at positions where 2θ is 18.1±0.2°, 19.6±0.2° and 24.7±0.2°, more preferably further having diffraction peaks at positions where 2θ is 8.7±0.2°, 11.7±0.2°, 14.8±0.2°, 17.4±0.2°, 21.1±0.2° and 27.1±0.2°, and even more preferably its powder X-ray diffraction pattern is substantially as shown in Figure 1, and its hydrogen nuclear magnetic resonance spectrum is as shown in Figure 1A.

[0010] In a preferred embodiment of the present invention, according to the hydrogen nuclear magnetic resonance spectrum, the molar ratio of free base to methanesulfonate in crystal form A is approximately 1:2.

[0011] The powder X-ray diffraction pattern of crystalline form B of the methanesulfonate of the compound of formula (I) has diffraction peaks at positions where 2θ is 5.4±0.2°, or 7.8±0.2°, or 10.6±0.2°, or 13.7±0.2°, or 14.4±0.2°, or 15.6±0.2°, or 19.7±0.2°, preferably including diffraction peaks at any 2 to 5 positions, 3 to 5 positions, 3 to 6 positions, or 3 to 7 positions among the above diffraction peaks, and more preferably including diffraction peaks at any 4, 6, or 7 positions among the above diffraction peaks. Preferably, the powder X-ray diffraction pattern of crystalline form B has diffraction peaks at positions where 2θ is 5.4±0.2°, 7.8±0.2°, 10.6±0.2° and 13.7±0.2°, preferably further having characteristic peaks at positions where 2θ is 14.4±0.2°, 15.6±0.2° and 19.7±0.2°, more preferably further having diffraction peaks at positions where 2θ is 4.9±0.2°, 8.7±0.2°, 9.7±0.2°, 11.5±0.2°, 17.6±0.2°, 24.4±0.2°, 25.2±0.2° and 27.6±0.2°, and even more preferably its powder X-ray diffraction pattern is substantially as shown in Figure 2.

[0012] The powder X-ray diffraction pattern of crystalline form C of the methanesulfonate of the compound of formula (I) has diffraction peaks at positions where 2θ is 7.8±0.2°, or 9.6±0.2°, or 11.7±0.2°, or 15.6±0.2°, or 17.7±0.2°, or 23.4±0.2°, or 26.5±0.2°, preferably including diffraction peaks at any 2 to 5, 3 to 5, 3 to 6, or 3 to 7 positions among the above diffraction peaks, and more preferably including diffraction peaks at any 4, 6, or 7 positions among the above diffraction peaks. Preferably, the powder X-ray diffraction pattern of crystalline form C has diffraction peaks at positions where 2θ is 7.8±0.2°, 9.6±0.2°, 11.7±0.2° and 15.6±0.2°, preferably further having characteristic peaks at positions where 2θ is 17.7±0.2°, 23.4±0.2° and 26.5±0.2°, more preferably at positions where 2θ is 11.3±0.2°, 12.4±0.2°, 19.1±0.2°, 21.9±0.2°, 24.6±0.2°, 25.1±0.2°, 29.4±0.2°, 31.3±0.2° and 3 The material further has a diffraction peak at a position of 4.2 ± 0.2°, and more preferably its powder X-ray diffraction pattern is substantially as shown in Figure 3, its DSC pattern is substantially as shown in Figure 3A, its TGA pattern is as shown in Figure 3B, and more preferably the DSC pattern of crystal form C has a characteristic peak in the range of 50 to 105°C and a characteristic peak in the range of 157 to 164°C, or the TGA pattern of crystal form C has a weight loss of 10 to 13% at 35 to 165°C.

[0013] The powder X-ray diffraction pattern of crystalline form D of the methanesulfonate of the compound of formula (I) has diffraction peaks at positions where 2θ is 5.2±0.2°, or at positions where 2θ is 11.5±0.2°, or at positions where 2θ is 13.5±0.2°, or at positions where 2θ is 17.1±0.2°, or at positions where 2θ is 19.8±0.2°, or at positions where 2θ is 22.8±0.2°, or at positions where 2θ is 23.3±0.2°, or at positions where 2θ is 24.2±0.2°, preferably including diffraction peaks at any 2 to 5 positions, 3 to 5 positions, 3 to 6 positions, or 3 to 8 positions among the above diffraction peaks, and more preferably including diffraction peaks at any 4, 6, or 8 positions among the above diffraction peaks. Preferably, the powder X-ray diffraction pattern of crystalline form D has diffraction peaks at positions where 2θ is 5.2±0.2°, 11.5±0.2°, 13.5±0.2° and 17.1±0.2°, preferably further having characteristic peaks at positions where 2θ is 19.8±0.2°, 22.8±0.2°, 23.3±0.2° and 24.2±0.2°, more preferably at positions where 2θ is 8.2±0.2°, 8.6±0.2°, 10.5±0.2°, 14.6±0.2°, 16.4±0.2°, 20.8±0.2°, 21.7±0.2°, 25.7±0.2° and 29.4±0.2°. The powder X-ray diffraction pattern is substantially as shown in Figure 4, the DSC pattern is substantially as shown in Figure 4A, and the TGA pattern is as shown in Figure 4B. Preferably, the DSC pattern of crystal form D has characteristic peaks in the range of 71-100°C, 133-155°C, and 160-170°C, or the TGA pattern of crystal form D has an 8-10% weight loss at 32-105°C.

[0014] In a preferred embodiment of the present invention, crystalline form D is a methanesulfonate hydrate with a measured water content of 10.8%.

[0015] In a preferred embodiment of the present invention, the molar ratio of water to methanesulfonate in crystalline form D is about 3:1.

[0016] The powder X-ray diffraction pattern of crystalline form E of the methanesulfonate of the compound of formula (I) has diffraction peaks at positions where 2θ is 6.4±0.2°, or 7.8±0.2°, or 9.7±0.2°, or 10.7±0.2°, or 12.9±0.2°, or 15.4±0.2°, or 16.8±0.2°, or 19.5±0.2°, preferably including diffraction peaks at any 2 to 5 positions, 3 to 5 positions, 3 to 6 positions, or 3 to 8 positions among the above diffraction peaks, and more preferably including diffraction peaks at any 4, 6, or 8 positions among the above diffraction peaks. Preferably, the powder X-ray diffraction pattern of crystalline form E has diffraction peaks at positions where 2θ is 6.4±0.2°, 7.8±0.2°, 9.7±0.2°, and 10.7±0.2°, preferably further having characteristic peaks at positions where 2θ is 12.9±0.2, 15.4±0.2, 16.8±0.2, and 19.5±0.2, more preferably further having diffraction peaks at positions where 2θ is 11.1±0.2°, 14.1±0.2°, 18.1±0.2°, 21.6±0.2°, 23.5±0.2°, 25.4±0.2°, and 25.9±0.2°, and even more preferably its powder X-ray diffraction pattern is substantially as shown in Figure 5. The powder X-ray diffraction pattern of crystalline form F of the methanesulfonate of the compound of formula (I) has diffraction peaks at positions where 2θ is 5.4±0.2°, or 6.5±0.2°, or 8.1±0.2°, or 9.7±0.2°, or 13.3±0.2°, or 15.5±0.2°, or 16.9±0.2°, or 21.6±0.2°, preferably including diffraction peaks at any 2 to 5, 3 to 5, 3 to 6, or 3 to 8 positions among the above diffraction peaks, and more preferably including diffraction peaks at any 4, 6, or 8 positions among the above diffraction peaks. Preferably, the powder X-ray diffraction pattern of crystalline form F has diffraction peaks at positions where 2θ is 5.4±0.2°, 6.5±0.2°, 8.1±0.2°, and 9.7±0.2°, preferably further having characteristic peaks at positions where 2θ is 13.3±0.2°, 15.5±0.2°, 16.9±0.2°, and 21.6±0.2°, more preferably further having diffraction peaks at positions where 2θ is 10.8±0.2°, 13.0±0.2°, 18.2±0.2°, 18.9±0.2°, 19.6±0.2°, 22.3±0.2°, 23.7±0.2°, and 24.4±0.2°, and even more preferably its powder X-ray diffraction pattern is substantially as shown in Figure 6. The powder X-ray diffraction pattern of crystalline form G of the methanesulfonate of the compound of formula (I) has diffraction peaks at positions where 2θ is 8.5±0.2°, or 9.0±0.2°, or 9.8±0.2°, or 16.9±0.2°, or 19.7±0.2°, or 22.7±0.2°, or 25.5±0.2°, or 26.2±0.2°, or 31.8±0.2°, or 32.5±0.2°, preferably including diffraction peaks at any 2 to 5, 3 to 5, 3 to 6, or 3 to 8 positions among the above diffraction peaks, and more preferably including diffraction peaks at any 4, 6, or 8 positions among the above diffraction peaks.

[0017] Preferably, the powder X-ray diffraction pattern of crystalline form G has diffraction peaks at positions where 2θ is 9.8±0.2°, 16.9±0.2°, and preferably further has characteristic peaks at positions where 2θ is 8.5±0.2° and 9.0±0.2°, preferably further has characteristic peaks at positions where 2θ is 19.7±0.2°, 22.7±0.2°, 25.5±0.2° and 26.2±0.2°, and more preferably at 2θ is 9.4±0.2°. The material further has diffraction peaks at 12.4±0.2°, 13.0±0.2°, 24.8±0.2°, 27.4±0.2°, 28.1±0.2°, 31.8±0.2° and 32.5±0.2°, and more preferably the powder X-ray diffraction pattern of the crystal form G is substantially as shown in Figure 7, its hydrogen nuclear magnetic resonance spectrum is as shown in Figure 7A, and its free base hydrogen nuclear magnetic resonance spectrum is as shown in Figure 7B.

[0018] In a preferred embodiment of the present invention, crystalline form G is a methanesulfonate hydrate with a water content of 5.0 to 8.0%.

[0019] In a preferred embodiment of the present invention, crystalline form G is a methanesulfonate hydrate and has a measured water content of 6.0%.

[0020] In a preferred embodiment of the present invention, the molar ratio of water to methanesulfonate in crystalline form G is about 2:1.

[0021] In a preferred embodiment of the present invention, the molar ratio of free base to methanesulfonate in crystalline form G is about 1:1.

[0022] The crystalline form G of the methanesulfonate hydrate of the compound of formula (I) produced by the present invention has a simple production method, high purity of the crystalline form, stable chemical state, and can not only improve the physicochemical properties of the crystalline free base of the compound of formula (I), but also be stable under high humidity conditions and difficult to undergo crystal transition and dissociation, and is very suitable for pharmaceutical development.

[0023] The powder X-ray diffraction pattern of crystalline form H of the methanesulfonate of the compound of formula (I) has a diffraction peak at a position where 2θ is 7.5±0.2°, or has a diffraction peak at a position where 2θ is 8.1±0.2°, or has a diffraction peak at a position where 2θ is 15.1±0.2°, or has a diffraction peak at a position where 2θ is 17.1±0.2°, or has a diffraction peak at a position where 2θ is 19.5±0.2°, or has a diffraction peak at a position where 2θ is 22.7±0.2°, or has a diffraction peak at a position where 2θ is 23.3±0.2°, or has a diffraction peak at a position where 2θ is 30.5±0.2°. Preferably, it includes diffraction peaks at any 2 to 5 positions or 3 to 5 positions or 3 to 6 positions or 3 to 8 positions of the above diffraction peaks, and more preferably, it includes diffraction peaks at any 4 positions, 6 positions or 8 positions of the above diffraction peaks.

[0024] Preferably, the powder X-ray diffraction pattern of crystalline form H has diffraction peaks at positions where 2θ is 7.5 ± 0.2°, 8.1 ± 0.2°, 15.1 ± 0.2° and 17.1 ± 0.2°, preferably further has characteristic peaks at positions where 2θ is 19.5 ± 0.2°, 22.7 ± 0.2°, 23.3 ± 0.2° and 30.5 ± 0.2°, more preferably further has diffraction peaks at positions where 2θ is 11.5 ± 0.2°, 16.4 ± 0.2°, 19.1 ± 0.2°, 21.9 ± 0.2°, 24.0 ± 0.2°, 25.6 ± 0.2° and 29.5 ± 0.2°, and still more preferably, the powder X-ray diffraction pattern of the crystalline form H is substantially as shown in FIG. 8.

[0025] The powder X-ray diffraction pattern of crystalline form I of the methanesulfonate of the compound of formula (I) has a diffraction peak at a position where 2θ is 6.4 ± 0.2°, or has a diffraction peak at a position where 2θ is 8.4 ± 0.2°, or has a diffraction peak at a position where 2θ is 9.7 ± 0.2°, or has a diffraction peak at a position where 2θ is 15.5 ± 0.2°, or has a diffraction peak at a position where 2θ is 16.8 ± 0.2°, or has a diffraction peak at a position where 2θ is 17.1 ± 0.2°, or has a diffraction peak at a position where 2θ is 19.5 ± 0.2°, or has a diffraction peak at a position where 2θ is 23.6 ± 0.2°, preferably includes diffraction peaks at any 2 to 5 positions or 3 to 5 positions or 3 to 6 positions or 3 to 8 positions of the above diffraction peaks, and more preferably includes diffraction peaks at any 4 positions, 6 positions or 8 positions of the above diffraction peaks.

[0026] Preferably, the powder X-ray diffraction pattern of crystalline form I has diffraction peaks at positions where 2θ is 6.4 ± 0.2°, 8.4 ± 0.2°, 9.7 ± 0.2° and 15.5 ± 0.2°, preferably further has characteristic peaks at positions where 2θ is 16.8 ± 0.2°, 17.1 ± 0.2°, 19.5 ± 0.2° and 23.6 ± 0.2°, more preferably further has diffraction peaks at positions where 2θ is 10.7 ± 0.2°, 13.0 ± 0.2°, 21.7 ± 0.2°, 25.4 ± 0.2°, 25.9 ± 0.2° and 27.2 ± 0.2°, and still more preferably, the powder X-ray diffraction pattern of the crystalline form I is substantially as shown in FIG. 9.

[0027] In a preferred embodiment of the present invention, a method for producing crystalline form A of the methanesulfonate of compound (I) is: Step 1) involves dispersing the free base of the compound of formula (I) in acetonitrile solvent under constant temperature conditions to form a suspension, Step 2) involves adding methanesulfonic acid, Step 3) involves stirring continuously, filtering, and drying to obtain crystalline form A of the methanesulfonate of the compound of formula (I).

[0028] Here, The temperature conditions described in step 1) are 1 to 60°C, preferably 5 to 30°C, and the solid-liquid ratio of free base to acetonitrile is preferably 0.2 to 2 g:30 mL, preferably 1 to 1.5 g:30 mL. The amount of methanesulfonic acid used in step 2) is preferably 1 to 6 times the molar amount of free base, and preferably 2 to 4 times. The stirring time in step 3) is 3 to 30 hours, preferably 5 to 24 hours.

[0029] In a preferred embodiment of the present invention, a method for producing crystalline form B of the methanesulfonate of compound (I) is: Step 1) involves dispersing the compound of formula (I) in a dichloromethane solvent under constant temperature conditions to form a suspension, Step 2) involves adding methanesulfonic acid, Step 3) involves stirring continuously, filtering, and drying to obtain crystalline form B of the methanesulfonate of the compound of formula (I).

[0030] Here, The temperature conditions described in Step 1) are 1 to 60°C, preferably 5 to 30°C, and the solid-liquid ratio of free base to dichloromethane is preferably 0.2 to 2 g:30 mL, preferably 1 to 1.5 g:30 mL. The amount of methanesulfonic acid used in step 2) is preferably 1 to 3 times the molar amount of free base, and preferably 1 to 2 times. The stirring time in step 3) is 3 to 30 hours, preferably 5 to 24 hours.

[0031] In a preferred embodiment of the present invention, a method for producing crystalline form C of the methanesulfonate of compound (I) is: Step 1) involves dissolving the compound of formula (I) in acetic acid solvent under constant temperature conditions to form a suspension, Step 2) involves adding the poor solvent, 2-butanone. Step 3) involves stirring continuously, filtering, and drying to obtain the crystalline form C of the methanesulfonate of the compound of formula (I).

[0032] Here, The temperature conditions described in step 1) are 30 to 80°C, preferably 40 to 60°C, and the solid-liquid ratio of the compound of formula (I) to acetic acid is preferably 0.2 to 2 g:30 mL, preferably 1 to 1.5 g:30 mL. The amount of 2-butanone used as described in step 2) is preferably 30 to 100 mL, preferably 50 to 80 mL.

[0033] The stirring time in step 3) is 1 to 7 days, preferably 2 to 5 days.

[0034] In a preferred embodiment of the present invention, a method for producing crystalline form D of the methanesulfonate of the compound of formula (I) is: Step 1) involves dispersing the free base of the compound of formula (I) in an organic solvent under constant temperature conditions to form a suspension, Step 2) involves adding methanesulfonic acid, The process includes step 3) continuing to stir to precipitate the solid, filtering and drying to obtain crystalline form D of the methanesulfonate of the compound of formula (I).

[0035] Here, The organic solvent described in step 1) is one or more selected from acetonitrile, ethyl acetate, n-propyl acetate, and isopropyl acetate, preferably acetonitrile and ethyl acetate; the temperature is 30 to 90°C, preferably 40 to 60°C; and the solid-liquid ratio of the free base to acetonitrile is preferably 0.2 to 2 g:30 mL, preferably 1 to 1.5 g:30 mL. The amount of methanesulfonic acid used in step 2) is preferably 1 to 3 times the molar amount of free base, and preferably 1 to 2 times. The stirring time in step 3) is 3 to 30 hours, preferably 5 to 24 hours.

[0036] In a preferred embodiment of the present invention, a method for producing crystalline form E of the methanesulfonate of compound (I) is: Step 1) involves dispersing the free base of the compound of formula (I) in ethyl acetate solvent under constant temperature conditions to form a suspension, Step 2) involves adding methanesulfonic acid, The process includes step 3) continuing to stir to precipitate the solid, filtering and drying to obtain crystalline form E of the methanesulfonate of the compound of formula (I).

[0037] Here, The temperature conditions described in Step 1) are -30 to 10°C, preferably -10 to 0°C, and the solid-liquid ratio of the compound of formula I to ethyl acetate is preferably 0.2 to 2 g:30 mL, preferably 1 to 1.5 g:30 mL. The amount of methanesulfonic acid used in step 2) is preferably 1 to 3 times the molar amount of free base, and preferably 1 to 2 times. The stirring time in step 3) is 3 to 30 hours, preferably 5 to 24 hours.

[0038] In a preferred embodiment of the present invention, a method for producing the crystalline form F of the methanesulfonate of the compound of formula (I) is: Step 1) involves dispersing the free base of the compound of formula (I) in an n-propyl alcohol solvent under constant temperature conditions to form a suspension, Step 2) involves adding methanesulfonic acid, The process includes step 3) continuing to stir to precipitate the solid, filtering and drying to obtain the crystalline form F of the methanesulfonate of the compound of formula (I).

[0039] Here, The temperature conditions described in step 1) are -30 to 10°C, preferably -10 to 0°C, and the solid-liquid ratio of the compound of formula (I) to n-propyl alcohol is preferably 0.2 to 2 g:30 mL, preferably 1 to 1.5 g:30 mL. The amount of methanesulfonic acid used in step 2) is preferably 1 to 3 times the molar amount of free base, and preferably 1 to 2 times. The stirring time in step 3) is 3 to 30 hours, preferably 5 to 24 hours.

[0040] In a preferred embodiment of the present invention, a method for producing the crystalline form G of the methanesulfonate of the compound of formula (I) is: Step 1) involves dispersing or dissolving the compound of formula (I) in a mixed solvent of an organic solvent and water to form a suspension, Step 2) involves continuing to stir the suspension or adding a certain proportion of seed crystals to induce crystallization, Step 3) involves stirring continuously, filtering, and drying to obtain the target product, Here, the organic solvent is one or more selected from methanol, ethanol, n-propyl alcohol, n-butanol, isopropanol, ethyl acetate, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, isopropyl ether, dichloromethane, 1,4-dioxane, tetrahydrofuran, acetonitrile, acetone, 2-butanone, and water, and preferably one or more of 1,4-dioxane, acetonitrile, acetone, 2-butanone, or water.

[0041] Here, The temperature conditions in step 1) are 10 to 80°C, preferably 20 to 50°C, and the ratio of organic solvent to water is 1 to 6:1, preferably 3 to 6:1. In step 2), the compound of formula (I) can be stirred in a mixed solvent of organic solvent and water for 3 to 5 weeks to obtain seed crystals of crystalline form G, and the proportion of seed crystals added is 1% to 5%, preferably 1% to 3%. The stirring time in step 3) is 1 to 7 days, preferably 2 to 5 days.

[0042] In a preferred embodiment of the present invention, a method for producing the crystalline form H of the methanesulfonate of the compound of formula (I) is: Step 1) involves dispersing the free base of the compound of formula (I) in acetonitrile solvent under constant temperature conditions to form a suspension, Step 2) involves adding methanesulfonic acid, Step 3) involves stirring continuously, filtering, and drying to obtain crystalline form H of the methanesulfonate of the compound of formula (I).

[0043] Here, The temperature conditions described in step 1) are 1 to 60°C, preferably 5 to 30°C, and the solid-liquid ratio of free base to acetonitrile is preferably 0.2 to 2 g:30 mL, preferably 1 to 1.5 g:30 mL. The amount of methanesulfonic acid used in step 2) is preferably 1 to 3 times the molar amount of free base, and preferably 1 to 2 times. The stirring time in step 3) is 1 to 7 days, preferably 2 to 5 days.

[0044] In a preferred embodiment of the present invention, a method for producing crystalline form I of the methanesulfonate of the compound of formula (I) is: Step 1) involves allowing the crystalline form H of the methanesulfonate of the compound of formula (I) to stand under constant temperature conditions and under air humidity conditions, Step 2) involves allowing the compound of formula (I) to stand for a certain period of time to obtain crystalline form I of the methanesulfonate, Here, The temperature conditions described in step 1) are 1 to 60°C, preferably 5 to 30°C. The duration of step 3) is 1 to 30 hours, preferably 3 to 10 hours.

[0045] Furthermore, those skilled in the art will understand that modifications or equivalent substitutions can be made to the technical means of the invention, and for example, the use of some of the organic solvents listed in the aforementioned part of the present invention also falls within the spirit and scope of the technical means of the present invention and should all be included in the scope of the invention.

[0046] Another aspect of the present invention provides a pharmaceutical composition containing a therapeutically effective amount of a crystalline free base or crystalline acidic salt of the compound of formula (I) described above, or a pharmaceutically acceptable carrier or excipient.

[0047] Another aspect of the present invention provides the use of the aforementioned crystalline acidic salt of the compound of formula (I), the aforementioned crystalline polymorph of the acidic salt, and the aforementioned pharmaceutical composition in the manufacture of a drug for treating a disease related to a protein kinase, wherein the protein kinase is selected from c-Met and VEGFR receptor tyrosine kinase.

[0048] Another aspect of the present invention provides the use of the aforementioned crystalline acidic salt of the compound of formula (I), the crystalline polymorph of the aforementioned acidic salt, and the aforementioned pharmaceutical composition in the production of a protein kinase inhibitor, wherein the protein kinase is selected from c-Met and VEGFR receptor tyrosine kinase.

[0049] Another aspect of the present invention provides a method for modulating the catalytic activity of a protein kinase, comprising the step of contacting the protein kinase with the aforementioned crystalline acidic salt of the compound of formula (I), a crystalline polymorph of the aforementioned acidic salt, or the aforementioned pharmaceutical composition, wherein the protein kinase is selected from c-met and VEGFR receptor tyrosine kinase.

[0050] The crystalline acidic salts of the compound of formula (I) described above, crystalline polymorphs of the acidic salts described above, and the pharmaceutical compositions described above may further be used in the manufacture of drugs for treating cancer (solid tumors), including lymphoid hematopoietic malignancies, myeloid hematopoietic malignancies, mesenchymal tumors, tumors of the central and peripheral nervous systems, or other tumors, and for treating cancer metastasis. The cancers described above include, but are not limited to, the following: The cancers are selected from bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, gastric cancer, lung cancer (non-small cell lung cancer), or skin cancer; the lymphoid hematopoietic malignancies are selected from leukemia, acute lymphoblastic leukemia, or chronic lymphoblastic leukemia; the myeloid hematopoietic malignancies are selected from acute or chronic myeloid leukemia, myelodysplastic syndrome, or promyelocytic leukemia; the mesenchymal tumors are selected from fibrosarcoma, rhabdomyosarcoma, soft tissue sarcoma, or osteosarcoma; the central and peripheral nervous system tumors are selected from astrocytoma, neuroblastoma, glioma, or peripheral neuroma; and the other tumors are selected from malignant melanoma, seminomas, teratoma, follicular thyroid carcinoma, or Kaposi's sarcoma.

[0051] Preferably, it can be used in the manufacture of drugs for treating liver cancer, lung cancer, breast cancer, squamous cell carcinoma, or gastric cancer.

[0052] More preferably, it may be used in the manufacture of drugs for treating non-small cell lung cancer.

[0053] "Pharmaceutical composition" means a mixture of one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs with other chemical components, and other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism and to facilitate the absorption of the active ingredient, thereby exerting biological activity.

[0054] Different phrases such as "X is selected from A, B, or C," "X is selected from A, B, and C," "X is A, B, or C," and "X is A, B, and C" all have the same meaning, that is, X can be one or more of A, B, or C.

[0055] The crystalline form of the methanesulfonate of the compound of formula (I) described in the present invention has good solubility and stability, can improve its bioavailability, is advantageous for drug processing and use in pharmaceutical compositions, and the manufacturing method of the present invention is simple, easy to implement, and suitable for industrial production. [Brief explanation of the drawing]

[0056] [Figure 1] This is the X-ray diffraction pattern of crystalline form A of the methanesulfonate of the compound of formula (I). [Figure 1A] This is the hydrogen nuclear magnetic resonance spectrum of crystalline form A of the methanesulfonate of the compound of formula (I). [Figure 2] This is the X-ray diffraction pattern of crystalline form B of the methanesulfonate of the compound of formula (I). [Figure 3] This is the X-ray diffraction pattern of crystalline form C of the methanesulfonate of the compound of formula (I). [Figure 3A] This is the DSC pattern of crystalline form C of the methanesulfonate of the compound of formula (I). [Figure 3B] This is the TGA pattern of crystalline form C of the methanesulfonate of the compound of formula (I). [Figure 4] This is the X-ray diffraction pattern of crystalline form D of the methanesulfonate of the compound of formula (I). [Figure 4A] This is the DSC pattern of crystalline form D of the methanesulfonate of the compound of formula (I). [Figure 4B] This is the TGA pattern of crystalline form D of the methanesulfonate of the compound of formula (I). [Figure 5] This is the X-ray diffraction pattern of crystalline form E of the methanesulfonate of the compound of formula (I). [Figure 6] This is the X-ray diffraction pattern of the crystalline form F of the methanesulfonate of the compound of formula (I). [Figure 7] This is the X-ray diffraction pattern of crystalline form G of the methanesulfonate of the compound of formula (I). [Figure 7A]This is the hydrogen nuclear magnetic resonance spectrum of the methanesulfonate of the compound of formula (I) in crystalline form G. [Figure 7B] This is the hydrogen nuclear magnetic resonance spectrum of the free base of the compound of formula (I). [Figure 8] This is the X-ray diffraction pattern of the crystalline form H of the methanesulfonate of the compound of formula (I). [Figure 9] This is the X-ray diffraction pattern of crystalline form I of the methanesulfonate of the compound of formula (I). [Modes for carrying out the invention]

[0057] Specific embodiments of the present invention will be described in more detail below with reference to the drawings and examples. The following examples are for illustrative purposes only and do not limit the scope of the present invention.

[0058] Example 1: Production of Crystal Form A Under room temperature conditions of 25°C, a sample of 1 g of the free base of the compound of formula (I) was dispersed in 30 mL of acetonitrile solvent to obtain a suspension. 3.2 eq of methanesulfonic acid was slowly added dropwise to the alkaline solution, the mixture was stirred for 24 hours, filtered, and then air-dried at 50°C for 24 hours to obtain crystalline form A of the methanesulfonate salt of the compound of formula I.

[0059] Example 2: Production of Crystal Form A Under room temperature conditions of 25°C, a sample of 1 g of the free base of the compound of formula (I) was dispersed in 30 mL of a mixed solvent of acetonitrile and water to obtain a suspension. 3.2 eq of methanesulfonic acid was slowly added dropwise to the alkaline solution, stirred for 24 hours, filtered, and then air-dried at 50°C for 24 hours to obtain crystalline form A of the methanesulfonate of the compound of formula (I).

[0060] Example 3: Production of Crystal Form B Under room temperature conditions of 25°C, a sample of 1 g of the free base of the compound of formula (I) was dispersed in 30 mL of dichloromethane solvent to obtain a suspension. 1.2 eq of methanesulfonic acid was slowly added dropwise to the alkaline solution, stirred for 24 hours, filtered, and then air-dried at 50°C for 24 hours to obtain crystalline form B of the methanesulfonate of the compound of formula (I).

[0061] Example 4: Production of Crystal Form B Under conditions of 10°C, a sample of 1 g of the free base of the compound of formula (I) was dispersed in 30 mL of dichloromethane solvent to obtain a suspension. 1.2 eq of methanesulfonic acid was slowly added dropwise to the alkaline solution, stirred for 24 hours, filtered, and then air-dried at 50°C for 24 hours to obtain crystalline form B of the methanesulfonate of the compound of formula (I).

[0062] Example 5: Production of crystalline form C Under room temperature conditions of 25°C, a 1 g sample of methanesulfonate of compound (I) was dissolved in 20 mL of acetic acid to obtain a solution. 40 mL of the poor solvent n-heptane was added to precipitate a solid, which was stirred for 2 days, filtered, and then air-dried at 50°C for 24 hours to obtain crystalline form C of methanesulfonate of compound (I).

[0063] Example 6: Production of crystalline form C Under conditions of 50°C, a 1 g sample of methanesulfonate of the compound of formula (I) was dissolved in 20 mL of acetic acid solvent to obtain a solution. 40 mL of the poor solvent 2-butanone was added to precipitate a solid, which was stirred for 2 days, filtered, and then air-dried at 50°C for 24 hours to obtain crystalline form C of methanesulfonate of the compound of formula (I).

[0064] Example 7: Production of crystal form D Under conditions of 50°C, a sample of 1 g of the free base of the compound of formula (I) was dispersed in 30 mL of acetonitrile solvent to obtain a suspension. 1.2 eq of methanesulfonic acid was slowly added dropwise to the alkaline solution, stirred for 24 hours, filtered, and then air-dried at 50°C for 24 hours to obtain crystalline form D of the methanesulfonate of the compound of formula (I).

[0065] Example 8: Production of crystal form D Under conditions of 50°C, a sample of 1 g of the free base of the compound of formula (I) was dispersed in 30 mL of ethyl acetate solvent to obtain a suspension. 1.2 eq of methanesulfonic acid was slowly added dropwise to the alkaline solution, stirred for 24 hours, filtered, and then air-dried at 50°C for 24 hours to obtain crystalline form D of the methanesulfonate of the compound of formula (I).

[0066] Example 9: Production of crystal form E Under conditions of -10°C, a sample of 1 g of the free base of the compound of formula (I) was dispersed in 30 mL of ethyl acetate solvent to obtain a suspension. 1.2 eq of methanesulfonic acid was slowly added dropwise to the alkaline solution, the mixture was stirred for 24 hours, filtered, and then air-dried at 50°C for 12 hours to obtain crystalline form E of the methanesulfonate of the compound of formula (I).

[0067] Example 10: Production of crystal form E Under conditions of -10°C, a sample of 1 g of the free base of the compound of formula (I) was dispersed in 30 mL of isopropyl acetate solvent to obtain a suspension. 1.2 eq of methanesulfonic acid was slowly added dropwise to the alkaline solution, stirred for 24 hours, filtered, and then air-dried at 50°C for 24 hours to obtain crystalline form E of the methanesulfonate of the compound of formula (I).

[0068] Example 11: Production of crystal form F Under conditions of -10°C, a sample of 1 g of the free base of the compound of formula (I) was dispersed in 30 mL of n-butanol solvent to obtain a suspension. 1.2 eq of methanesulfonic acid was slowly added dropwise to the alkaline solution, the mixture was stirred for 24 hours, filtered, and then air-dried at 50°C for 24 hours to obtain crystalline form F of the methanesulfonate of the compound of formula (I).

[0069] Example 12: Production of crystal form F Under conditions of -10°C, a sample of 1 g of the free base of the compound of formula (I) was dispersed in 30 mL of n-propyl alcohol solvent to obtain a suspension. 1.2 eq of methanesulfonic acid was slowly added dropwise to the alkaline solution, the mixture was stirred for 24 hours, filtered, and then air-dried at 50°C for 24 hours to obtain crystalline form F of the methanesulfonate of the compound of formula (I).

[0070] Example 20: Production of crystal form G Under room temperature conditions of 25°C, a 1 g sample of methanesulfonate of the compound of formula (I) was dispersed in 30 mL of a mixed solvent of acetonitrile and water (3:1) to obtain a suspension. A 1% seed crystal of crystalline form G was added to induce crystallization, the mixture was stirred for 1 day, filtered, and then air-dried at 50°C for 24 hours to obtain crystalline form G of methanesulfonate of the compound of formula (I).

[0071] Example 21: Production of crystal form G Under room temperature conditions of 25°C, a 1 g sample of methanesulfonate of the compound of formula (I) was dispersed in 30 mL of a mixed solvent of acetone and water (3:1) to obtain a suspension. A 1% seed crystal of crystalline form G was added to induce crystallization, the mixture was stirred for 3 days, filtered, and then air-dried at 50°C for 24 hours to obtain crystalline form G of methanesulfonate of the compound of formula (I).

[0072] Example 22: Production of crystalline form G Under conditions of 50°C, a 1 g sample of methanesulfonate of the compound of formula (I) was dispersed in 30 mL of a mixed solvent of 2-butanone and water (3:1) to obtain a suspension. A 2% seed crystal of crystalline form G was added to induce crystallization, the mixture was stirred for 1 day, filtered, and then air-dried at 50°C for 24 hours to obtain crystalline form G of methanesulfonate of the compound of formula (I).

[0073] Example 23: Production of crystal form G Under conditions of 50°C, a 1 g sample of methanesulfonate of the compound of formula (I) was dispersed in 30 mL of a mixed solvent of acetone and water (3:1) to obtain a suspension. The suspension was stirred for 3 days, filtered, and then air-dried at 50°C for 24 hours to obtain crystalline form G of methanesulfonate of the compound of formula (I).

[0074] Example 24, Production of Crystal Form G Under room temperature conditions of 25°C, a 1 g sample of methanesulfonate of compound (I) was dispersed in 30 mL of a mixed solvent of acetone and water (2:1) to obtain a suspension. The suspension was stirred for 3 days, filtered, and then air-dried at 50°C for 24 hours to obtain crystalline form G of methanesulfonate of compound (I).

[0075] Example 25: Production of crystalline form H Under room temperature conditions of 25°C, a sample of 1 g of the free base of the compound of formula (I) was dispersed in 30 mL of acetonitrile solvent to obtain a suspension. 3.2 eq of methanesulfonic acid was slowly added dropwise to the alkaline solution, stirred for 2 days, filtered, and then air-dried at 50°C for 24 hours to obtain the crystalline form H of the methanesulfonate of the compound of formula (I).

[0076] Example 26: Production of crystalline form H Under room temperature conditions of 25°C, a sample of 1 g of the free base of the compound of formula (I) was dispersed in 30 mL of a mixed solvent of acetonitrile and water to obtain a suspension. 3.2 eq of methanesulfonic acid was slowly added dropwise to the alkaline solution, stirred for 5 days, filtered, and then air-dried at 50°C for 24 hours to obtain the crystalline form H of the methanesulfonate of the compound of formula (I).

[0077] Example 27: Production of Crystal Form I Under room temperature conditions of 25°C, a 1 g sample of methanesulfonate of the compound of formula (I), crystalline form H, was spread flat on a watch glass and allowed to stand for 3 hours to obtain crystalline form I of the methanesulfonate of the compound of formula (I).

[0078] Example 28: Production of Crystal Form I Under room temperature conditions of 25°C, a 1 g sample of crystalline form H of the methanesulfonate of compound (I) was spread flat on a watch glass and left to stand for 10 hours under high humidity conditions of 92.5% to obtain crystalline form I of the methanesulfonate of compound (I).

[0079] Experimental Example 1: Stability of Crystal Form G A sample of crystalline form G of the methanesulfonate of compound (I) was subjected to light irradiation (5000 lux), high temperature (60°C), and high humidity (RH92.5%). The stability of this sample over one month was examined, and the results showed that crystalline form G was very stable under high temperature, light irradiation, and high humidity conditions, and virtually no chemical decomposition occurred under these three conditions. The stability data is shown in the table below.

[0080] [Table 1]

[0081] Experimental Example 2: Stability of crystal form G under high humidity conditions The crystalline form G of the methanesulfonate of the compound of formula (I) was left to stand under high humidity conditions of 92.5% RH, and its long-term stability was investigated for 3 months. The results showed that crystalline form G was very stable under high humidity conditions, and no crystallization or dissociation phenomena occurred.

[0082] Finally, it should be noted that the above embodiments are merely for illustrating the technical means of the present invention and do not limit the invention. While the invention has been described in detail with reference to preferred embodiments, those skilled in the art will understand that modifications or equivalent substitutions can be made to the technical means of the invention without departing from the spirit and scope of the invention, and that such modifications should fall within the scope of the claims of the present invention.

Claims

1. Crystalline form G of methanesulfonate of 9-((8-fluoro-6-(1-methyl-1H-pyrazole-4-yl)-[1,2,4]triazolo[4,3-a]pyridine-3-yl)-thio)-4methyl-2H-[1,4]oxazino[3,2-c]quinoline-3(4H)-one, The powder X-ray diffraction pattern of crystal form G has diffraction peaks at positions where 2θ is 8.5±0.2°, or 9.0±0.2°, or 9.4±0.2°, or 9.8±0.2°, or 16.9±0.2°, or 19.7±0.2°, or 22.7±0.2°, or 25.5±0.2°. A crystalline form G of methanesulfonate characterized by having a diffraction peak at a position of 26.2 ± 0.2°, or a diffraction peak at a position of 31.8 ± 0.2°, or a diffraction peak at a position of 32.5 ± 0.2°, preferably including diffraction peaks at any 2 to 5 positions, 3 to 5 positions, 3 to 6 positions, or 3 to 8 positions among the above diffraction peaks, and more preferably including diffraction peaks at any 4 positions, 6 positions, or 8 positions among the above diffraction peaks.

2. The powder X-ray diffraction pattern of crystalline form G has diffraction peaks at positions where 2θ is 9.8±0.2° and 16.9±0.2°, preferably further having characteristic peaks at positions where 2θ is 8.5±0.2° and 9.0±0.2°, preferably further having characteristic peaks at positions where 2θ is 19.7±0.2°, 22.7±0.2°, 25.5±0.2° and 26.2±0.2°, more preferably, The crystalline form G of the methanesulfonate according to claim 1, further having diffraction peaks at positions where 2θ is 9.4±0.2°, 12.4±0.2°, 13.0±0.2°, 24.8±0.2°, 27.4±0.2°, 28.1±0.2°, 31.8±0.2° and 32.5±0.2°, and more preferably, the powder X-ray diffraction pattern of the crystalline form G is substantially as shown in Figure 7.

3. Crystalline forms A to F, H and I of methanesulfonate of 9-((8-fluoro-6-(1-methyl-1H-pyrazole-4-yl)-[1,2,4]triazolo[4,3-a]pyridine-3-yl)-thio)-4methyl-2H-[1,4]oxazino[3,2-c]quinoline-3(4H)-one, The powder X-ray diffraction pattern of crystal form A has diffraction peaks at positions where 2θ is 5.4±0.2°, or 6.1±0.2°, or 10.6±0.2°, or 13.7±0.2°, or 18.1±0.2°, or 19.6±0.2°, or 24.7±0.2°, preferably including diffraction peaks at any 2 to 5, 3 to 5, 3 to 6, or 3 to 7 positions among the above diffraction peaks, and more preferably including diffraction peaks at any 4, 6, or 7 positions among the above diffraction peaks. The powder X-ray diffraction pattern of crystal form B has diffraction peaks at positions where 2θ is 5.4±0.2°, or 7.8±0.2°, or 10.6±0.2°, or 13.7±0.2°, or 14.4±0.2°, or 15.6±0.2°, or 19.7±0.2°, preferably including diffraction peaks at any 2 to 5, 3 to 5, 3 to 6, or 3 to 7 positions among the above diffraction peaks, and more preferably including diffraction peaks at any 4, 6, or 7 positions among the above diffraction peaks. The powder X-ray diffraction pattern of crystalline form C has diffraction peaks at positions where 2θ is 7.8±0.2°, or 9.6±0.2°, or 11.7±0.2°, or 15.6±0.2°, or 17.7±0.2°, or 23.4±0.2°, or 26.5±0.2°, preferably including diffraction peaks at any 2 to 5, 3 to 5, 3 to 6, or 3 to 7 positions among the above diffraction peaks, and more preferably including diffraction peaks at any 4, 6, or 7 positions among the above diffraction peaks. The powder X-ray diffraction pattern of crystal form D has diffraction peaks at positions where 2θ is 5.2±0.2°, or at positions where 2θ is 11.5±0.2°, or at positions where 2θ is 13.5±0.2°, or at positions where 2θ is 17.1±0.2°, or at positions where 2θ is 19.8±0.2°, or at positions where 2θ is 22.8±0.2°, or at positions where 2θ is 23.3±0.2°, or at positions where 2θ is 24.2±0.2°, preferably including diffraction peaks at any 2 to 5 positions, 3 to 5 positions, 3 to 6 positions, or 3 to 8 positions among the above diffraction peaks, and more preferably including diffraction peaks at any 4, 6, or 8 positions among the above diffraction peaks. The powder X-ray diffraction pattern of crystal form E has diffraction peaks at positions where 2θ is 6.4±0.2°, or 7.8±0.2°, or 9.7±0.2°, or 10.7±0.2°, or 12.9±0.2°, or 15.4±0.2°, or 16.8±0.2°, or 19.5±0.2°, preferably including diffraction peaks at any 2 to 5, 3 to 5, 3 to 6, or 3 to 8 positions among the above diffraction peaks, and more preferably including diffraction peaks at any 4, 6, or 8 positions among the above diffraction peaks. The powder X-ray diffraction pattern of crystalline form F has diffraction peaks at positions where 2θ is 5.4±0.2°, or 6.5±0.2°, or 8.1±0.2°, or 9.7±0.2°, or 13.3±0.2°, or 15.5±0.2°, or 16.9±0.2°, or 21.6±0.2°, preferably including diffraction peaks at any 2 to 5, 3 to 5, 3 to 6, or 3 to 8 positions among the above diffraction peaks, and more preferably including diffraction peaks at any 4, 6, or 8 positions among the above diffraction peaks. The powder X-ray diffraction pattern of crystalline form H has diffraction peaks at positions where 2θ is 7.5±0.2°, or 8.1±0.2°, or 15.1±0.2°, or 17.1±0.2°, or 19.5±0.2°, or 22.7±0.2°, or 23.3±0.2°, or 30.5±0.2°, preferably including diffraction peaks at any 2 to 5, 3 to 5, 3 to 6, or 3 to 8 positions among the above diffraction peaks, and more preferably including diffraction peaks at any 4, 6, or 8 positions among the above diffraction peaks. The powder X-ray diffraction pattern of crystal form I has a diffraction peak at a position where 2θ is 6.4±0.2°, or at a position where 2θ is 8.4±0.2°, or at a position where 2θ is 9.7±0.2°, or at a position where 2θ is 15.5±0.2°, or at a position where 2θ is 16.8±0.2°, or at a position where 2θ is 17.1±0.2°, or at a position where 2θ is 19.5±0.2°, or at a position where 2θ is 23.6±0.2°, preferably including diffraction peaks at any 2 to 5 positions, 3 to 5 positions, 3 to 6 positions, or 3 to 8 positions among the above diffraction peaks, and more preferably including diffraction peaks at any 4 positions, 6 positions, or 8 positions among the above diffraction peaks, characterized in that the crystal forms A to F, H and I of methanesulfonate.

4. The powder X-ray diffraction pattern of crystal form A has diffraction peaks at positions where 2θ is 5.4±0.2°, 6.1±0.2°, 10.6±0.2°, and 13.7±0.2°, preferably further having diffraction peaks at positions where 2θ is 18.1±0.2°, 19.6±0.2°, and 24.7±0.2°, more preferably further having diffraction peaks at positions where 2θ is 8.7±0.2°, 11.7±0.2°, 14.8±0.2°, 17.4±0.2°, 21.1±0.2°, and 27.1±0.2°, and even more preferably the powder X-ray diffraction pattern of crystal form A is substantially as shown in Figure 1. The powder X-ray diffraction pattern of crystal form B has diffraction peaks at positions where 2θ is 5.4±0.2°, 7.8±0.2°, 10.6±0.2°, and 13.7±0.2°, preferably further having characteristic peaks at positions where 2θ is 14.4±0.2°, 15.6±0.2°, and 19.7±0.2°, more preferably further having diffraction peaks at positions where 2θ is 4.9±0.2°, 8.7±0.2°, 9.7±0.2°, 11.5±0.2°, 17.6±0.2°, 24.4±0.2°, 25.2±0.2°, and 27.6±0.2°, and even more preferably the powder X-ray diffraction pattern of crystal form B is substantially as shown in Figure 2. The powder X-ray diffraction pattern of crystalline form C has diffraction peaks at positions where 2θ is 7.8±0.2°, 9.6±0.2°, 11.7±0.2°, and 15.6±0.2°, preferably further having characteristic peaks at positions where 2θ is 17.7±0.2°, 23.4±0.2°, and 26.5±0.2°, more preferably further having diffraction peaks at positions where 2θ is 11.3±0.2°, 12.4±0.2°, 19.1±0.2°, 21.9±0.2°, 24.6±0.2°, 25.1±0.2°, 29.4±0.2°, 31.3±0.2°, and 34.2±0.2°, and even more preferably the powder X-ray diffraction pattern of crystalline form C is substantially as shown in Figure 3. The powder X-ray diffraction pattern of crystalline form D has diffraction peaks at positions where 2θ is 5.2±0.2°, 11.5±0.2°, 13.5±0.2°, and 17.1±0.2°, preferably further having characteristic peaks at positions where 2θ is 19.8±0.2°, 22.8±0.2°, 23.3±0.2°, and 24.2±0.2°, more preferably further having diffraction peaks at positions where 2θ is 8.2±0.2°, 8.6±0.2°, 10.5±0.2°, 14.6±0.2°, 16.4±0.2°, 20.8±0.2°, 21.7±0.2°, 25.7±0.2°, 29.4±0.2°, and 30.6±0.2°, and even more preferably the powder X-ray diffraction pattern of crystalline form D is substantially as shown in Figure 4. The powder X-ray diffraction pattern of crystal form E has diffraction peaks at positions where 2θ is 6.4±0.2°, 7.8±0.2°, 9.7±0.2°, and 10.7±0.2°, preferably further having characteristic peaks at positions where 2θ is 12.9±0.2°, 15.4±0.2°, 16.8±0.2°, and 19.5±0.2°, more preferably further having diffraction peaks at positions where 2θ is 11.1±0.2°, 14.1±0.2°, 18.1±0.2°, 21.6±0.2°, 23.5±0.2°, 25.4±0.2°, and 25.9±0.2°, and even more preferably the powder X-ray diffraction pattern of crystal form E is substantially as shown in Figure 5. The powder X-ray diffraction pattern of crystalline form F has diffraction peaks at positions where 2θ is 5.4±0.2°, 6.5±0.2°, 8.1±0.2°, and 9.7±0.2°, preferably further having characteristic peaks at positions where 2θ is 13.3±0.2°, 15.5±0.2°, 16.9±0.2°, and 21.6±0.2°, more preferably further having diffraction peaks at positions where 2θ is 10.8±0.2°, 13.0±0.2°, 18.2±0.2°, 18.9±0.2°, 19.6±0.2°, 22.3±0.2°, 23.7±0.2°, and 24.4±0.2°, and even more preferably the powder X-ray diffraction pattern of crystalline form F is substantially as shown in Figure 6. The powder X-ray diffraction pattern of crystalline form H has diffraction peaks at positions where 2θ is 7.5±0.2°, 8.1±0.2°, 15.1±0.2°, and 17.1±0.2°, preferably further having characteristic peaks at positions where 2θ is 19.5±0.2°, 22.7±0.2°, 23.3±0.2°, and 30.5±0.2°, more preferably further having diffraction peaks at positions where 2θ is 11.5±0.2°, 16.4±0.2°, 19.1±0.2°, 21.9±0.2°, 24.0±0.2°, 25.6±0.2°, and 29.5±0.2°, and even more preferably the powder X-ray diffraction pattern of crystalline form H is substantially as shown in Figure 8. The powder X-ray diffraction pattern of crystal form I has diffraction peaks at positions where 2θ is 6.4±0.2°, 8.4±0.2°, 9.7±0.2° and 15.5±0.2°, preferably further having characteristic peaks at positions where 2θ is 16.8±0.2°, 17.1±0.2°, 19.5±0.2° and 23.6±0.2°, more preferably further having diffraction peaks at positions where 2θ is 10.7±0.2°, 13.0±0.2°, 21.7±0.2°, 25.4±0.2°, 25.9±0.2° and 27.2±0.2°, and even more preferably the powder X-ray diffraction pattern of crystal form I is substantially as shown in Figure 9, characterized in that the crystal forms A to F, H and I of the methanesulfonate according to claim 3.

5. A method for producing the crystalline form G of the methanesulfonate of 9-((8-fluoro-6-(1-methyl-1H-pyrazole-4-yl)-[1,2,4]triazolo[4,3-a]pyridine-3-yl)-thio)-4-methyl-2H-[1,4]oxazino[3,2-c]quinoline-3(4H)-one according to claim 1 or 2, Step 1) involves dispersing or dissolving the methanesulfonate of the compound of formula (I) in a mixed solvent consisting of an organic solvent and water to form a suspension, Step 2) involves continuing to stir the above suspension or adding a certain proportion of seed crystals to induce crystallization, A method for producing crystalline form G of methanesulfonate, comprising step 3) continuously stirring, filtering, and drying to obtain the target product.

6. The method for producing crystalline form G of methanesulfonate according to claim 5, wherein the organic solvent in step 1) is one or more selected from methanol, ethanol, n-propyl alcohol, n-butanol, isopropanol, ethyl acetate, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, isopropyl ether, dichloromethane, 1,4-dioxane, tetrahydrofuran, acetonitrile, acetone, 2-butanone, or water, and preferably one or more of 1,4-dioxane, acetonitrile, acetone, 2-butanone, or water.

7. The method for producing crystalline form G of methanesulfonate according to claim 5, characterized in that the temperature conditions in step 1) are -30 to 80°C, preferably 0 to 50°C, the ratio of organic solvent to water is 1 to 6:1, preferably 3 to 6:1, the proportion of seed crystals added in step 2) is 1% to 5%, preferably 1% to 3%, and the stirring time in step 3) is 1 to 7 days, preferably 2 to 5 days.

8. A pharmaceutical composition comprising a therapeutically effective amount of a crystalline acidic salt or crystalline polymorph thereof of 9-((8-fluoro-6-(1-methyl-1H-pyrazole-4-yl)-[1,2,4]triazolo[4,3-a]pyridine-3-yl)-thio)-4-methyl-2H-[1,4]oxazino[3,2-c]quinoline-3(4H)-one as described in claims 1 to 4, and one or more pharmaceutically acceptable carriers or excipients.

9. Use of the crystalline acidic salt or crystalline polymorph of 9-((8-fluoro-6-(1-methyl-1H-pyrazole-4-yl)-[1,2,4]triazolo[4,3-a]pyridine-3-yl)-thio)-4-methyl-2H-[1,4]oxazino[3,2-c]quinoline-3(4H)-one according to claims 1 to 4, in the manufacture of a drug for treating a disease related to protein kinase, wherein the protein kinase is selected from c-Met and VEGFR receptor tyrosine kinase.

10. Use in the manufacture of drugs for treating cancer and cancer metastasis, including cancer, lymphoid hematopoietic malignancies, myeloid hematopoietic malignancies, mesenchymal tumors, central nervous system and peripheral nervous system tumors or other tumors, of the crystalline acidic salt or crystalline polymorph thereof of 9-((8-fluoro-6-(1-methyl-1H-pyrazole-4-yl)-[1,2,4]triazolo[4,3-a]pyridine-3-yl)-thio)-4-methyl-2H-[1,4]oxazino[3,2-c]quinoline-3(4H)-one according to claims 1 to 4 and the crystalline polymorph thereof of the pharmaceutical composition according to claim 8, Preferably, the cancer is selected from bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, gastric cancer, or skin cancer; the lymphoid hematopoietic malignancy is selected from leukemia, acute lymphoblastic leukemia, or chronic lymphoblastic leukemia; the myeloid hematopoietic malignancy is selected from acute or chronic myeloid leukemia, myelodysplastic syndrome, or promyelocytic leukemia; the mesenchymal tumor is selected from fibrosarcoma, rhabdomyosarcoma, soft tissue sarcoma, or osteosarcoma; the central and peripheral nervous system tumors are selected from astrocytoma, neuroblastoma, glioma, or peripheral neuroma; and the other tumors are selected from malignant melanoma, seminomas, teratoma, follicular thyroid carcinoma, or Kaposi's sarcoma, and more preferably non-small cell lung cancer.

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