Triazole ring compound mesylate crystal form and preparation method and application thereof

Abstract

The invention discloses a triazolo ring compound mesylate crystal form as well as a preparation method and application thereof. Specifically, the invention discloses a mesylate crystal form of a compound shown as a formula (I) and a preparation method and application thereof, the mesylate crystal form is selected from a crystal form A-I, the preparation method of the crystal form and a pharmaceutical composition containing the crystal form. The preparation method disclosed by the invention is simple and easy to implement and suitable for industrial large-scale production, and the prepared mesylate crystal form A-I of the compound shown as the formula (I) has good solubility and stability and is beneficial to preparation and storage of pharmaceutical preparations.

Description

A triazolocyclic compound mesylate crystal form and its preparation method and application Technical Field

[0001] The present invention belongs to the field of biomedicine, and specifically relates to a 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 methanesulfonate, a crystal form of the salt, a preparation method thereof, and applications thereof. Background Art

[0002] The compound of formula (I), Chinese name: 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, English name: 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, has the following structural formula:

[0003] The hepatocyte growth factor (HGF) receptor, also known as C-Met, is a tyrosine kinase receptor. Abnormal C-Met activation is associated with poor prognosis in cancer, often characterized by overexpression of C-Met. C-Met abnormalities are also found in various tumor types, including hepatocellular carcinoma (HCC), non-small cell lung cancer (NSCLC), bladder cancer, liver cancer, kidney cancer, breast cancer, squamous cell carcinoma, brain cancer, gastric cancer, and colon cancer. Abnormal C-Met expression can manifest as elevated expression, gene amplification, gene mutation, or elevated HGF expression. Under these conditions, C-Met can be abnormally activated, leading to carcinogenesis and poor prognosis. Abnormal C-Met activation can trigger tumor growth and the formation of new blood vessels (angiogenesis, which provides nutrients to the tumor), aiding the spread of cancer to other organs (metastasis). Therefore, inhibiting the C-Met signaling pathway is an important strategy for cancer treatment. The compound of formula I is an effective C-Met / HGFR (hepatocyte growth factor receptor) kinase inhibitor. As a tyrosine kinase inhibitor, the compound of formula I can effectively block the HGF / C-Met signaling pathway to achieve the purpose of treating abnormal cell growth (such as cancer) in mammals.

[0004] Jiangsu Hansoh Pharmaceuticals Co., Ltd., in patent CN201580025022.6, discloses a crystalline free base or crystalline acid salt of the compound of formula (I), its preparation method, and its use. It also discloses methods for preparing mesylate crystalline forms I, II, III, IV, and V, as well as pharmaceutical compositions containing the same.

[0005] Summary of the Invention

[0006] The present invention aims to provide a crystalline form of a mesylate salt of a compound of formula (I) suitable for drug development, a preparation method thereof, and an application thereof. By in-depth study of different aggregation states of the mesylate salt, nine polymorphs of the mesylate salt of the compound of formula (I) are obtained.

[0007] The object of the present invention is to provide a compound of formula (I) 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 methanesulfonate.

[0008] In a preferred embodiment of the present invention, the methanesulfonate salt of the compound of formula (I) is in a crystalline or amorphous form.

[0009] In a preferred embodiment of the present invention, the crystal forms include Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H and Form I.

[0010] Wherein, the X-ray powder diffraction pattern of the mesylate salt form A of the compound of formula (I) has a diffraction peak at 2θ of 5.4±0.2°, or a diffraction peak at 6.1±0.2°, or a diffraction peak at 10.6±0.2°, or a diffraction peak at 13.7±0.2°, or a diffraction peak at 18.1±0.2°, or a diffraction peak at 19.6±0.2°, or a diffraction peak at 24.7±0.2°, preferably including any 2 to 5 of the above diffraction peaks, or 3 to 5, or 3 to 6, or 3 to 7, more preferably including any 4, 6 or 7 thereof,

[0011] Preferably, the X-ray powder diffraction pattern of Form A has diffraction peaks at 2θ of 5.4±0.2°, 6.1±0.2°, 10.6±0.2° and 13.7±0.2°, preferably further comprising diffraction peaks at 2θ° of 18.1±0.2°, 19.6±0.2°, and 24.7±0.2°, more preferably further comprising diffraction peaks at 2θ of 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°. Further preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 1, and its nuclear magnetic resonance hydrogen spectrum is shown in Figure 1A.

[0012] In a preferred embodiment of the present invention, hydrogen nuclear magnetic resonance spectroscopy shows that the molar ratio of the free base to the methanesulfonate in Form A is approximately 1:2.

[0013] The X-ray powder diffraction pattern of the mesylate salt form B of the compound of formula (I) has a diffraction peak at 2θ of 5.4±0.2°, or a diffraction peak at 7.8±0.2°, or a diffraction peak at 10.6±0.2°, or a diffraction peak at 13.7±0.2°, or a diffraction peak at 14.4±0.2°, or a diffraction peak at 15.6±0.2°, or a diffraction peak at 19.7±0.2°, preferably including any 2 to 5 of the above diffraction peaks, or 3 to 5, or 3 to 6, or 3 to 7, more preferably including any 4, 6 or 7 thereof.

[0014] Preferably, the X-ray powder diffraction pattern of Form B has diffraction peaks at 2θ of 5.4±0.2°, 7.8±0.2°, 10.6±0.2° and 13.7±0.2°, preferably further comprising characteristic peaks at 2θ° of 14.4±0.2, 15.6±0.2 and 19.7±0.2, more preferably further comprising diffraction peaks at 2θ of 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°; further preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 2.

[0015] The X-ray powder diffraction pattern of the mesylate salt form C of the compound of formula (I) has a diffraction peak at 2θ of 7.8±0.2°, or a diffraction peak at 9.6±0.2°, or a diffraction peak at 11.7±0.2°, or a diffraction peak at 15.6±0.2°, or a diffraction peak at 17.7±0.2°, or a diffraction peak at 23.4±0.2, or a diffraction peak at 26.5±0.2, preferably including any 2 to 5 of the above diffraction peaks, or 3 to 5, or 3 to 6, or 3 to 7, more preferably including any 4, 6 or 7 thereof.

[0016] Preferably, the X-ray powder diffraction pattern of Form C has diffraction peaks at 2θ of 7.8±0.2°, 9.6±0.2°, 11.7±0.2° and 15.6±0.2°, preferably further comprises characteristic peaks at 2θ of 17.7±0.2, 23.4±0.2 and 26.5±0.2, more preferably further comprises characteristic peaks at 2θ of 11.3±0.2°, 12.4±0.2°, 19.1±0.2°, 21.9±0.2°, 24.6±0.2°, 25.1±0.2°. 3A, and its TGA spectrum is shown in FIG3B; Still further preferably, the DSC spectrum of the crystalline 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 graph of the crystalline form C has a weight loss of 10 to 13% at 35 to 165°C.

[0017] The X-ray powder diffraction pattern of the mesylate salt form D of the compound of formula (I) has a diffraction peak at 2θ of 5.2±0.2°, or a diffraction peak at 11.5±0.2°, or a diffraction peak at 13.5±0.2°, or a diffraction peak at 17.1±0.2°, or a diffraction peak at 19.8±0.2, or a diffraction peak at 22.8±0.2, or a diffraction peak at 23.3±0.2, or a diffraction peak at 24.2±0.2, preferably including any 2 to 5 of the above diffraction peaks, or 3 to 5, or 3 to 6, or 3 to 8, more preferably including any 4, 6 or 8 thereof,

[0018] Preferably, the X-ray powder diffraction pattern of Form D has diffraction peaks at 2θ of 5.2±0.2°, 11.5±0.2°, 13.5±0.2° and 17.1±0.2°, preferably further comprises characteristic peaks at 2θ of 19.8±0.2, 22.8±0.2, 23.3±0.2 and 24.2±0.2, more preferably further comprises characteristic peaks at 2θ of 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 4A , and its TGA spectrum is shown in FIG4B . Preferably, the DSC spectrum of Form D has a characteristic peak in the range of 71 to 100° C., a characteristic peak in the range of 133 to 155° C., and a characteristic peak in the range of 160 to 170° C., or the TGA spectrum of Form D has a weight loss of 8 to 10% at 32 to 105° C.

[0019] In a preferred embodiment of the present invention, Form D is a methanesulfonate hydrate, and the detected water content is 10.8%.

[0020] In a preferred embodiment of the present invention, the molar ratio of water to mesylate in Form D is approximately 3:1.

[0021] The X-ray powder diffraction pattern of the mesylate salt form E of the compound of formula (I) has a diffraction peak at 6.4±0.2°, or a diffraction peak at 7.8±0.2°, or a diffraction peak at 9.7±0.2°, or a diffraction peak at 10.7±0.2°; or a diffraction peak at 12.9±0.2°, or a diffraction peak at 15.4±0.2°, or a diffraction peak at 16.8±0.2°, or a diffraction peak at 19.5±0.2°, preferably including any 2 to 5 of the above diffraction peaks, or 3 to 5, or 3 to 6, or 3 to 8, more preferably including any 4, 6 or 8 thereof.

[0022] Preferably, the X-ray powder diffraction pattern of Form E has diffraction peaks at 2θ of 6.4±0.2°, 7.8±0.2°, 9.7±0.2° and 10.7±0.2°, preferably further comprising characteristic peaks at 2θ of 12.9±0.2, 15.4±0.2, 16.8±0.2 and 19.5±0.2, more preferably further comprising diffraction peaks at 2θ of 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°. Further preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 5.

[0023] The X-ray powder diffraction pattern of the mesylate salt form F of the compound of formula (I) has a diffraction peak at 2θ of 5.4±0.2°, or a diffraction peak at 6.5±0.2°, or a diffraction peak at 8.1±0.2°, or a diffraction peak at 9.7±0.2°, or a diffraction peak at 13.3±0.2°, or a diffraction peak at 15.5±0.2°, or a diffraction peak at 16.9±0.2°, or a diffraction peak at 21.6±0.2°, preferably including any 2 to 5 of the above diffraction peaks, or 3 to 5, or 3 to 6, or 3 to 8, more preferably including any 4, 6 or 8 thereof.

[0024] Preferably, the X-ray powder diffraction pattern of Form F has diffraction peaks at 2θ of 5.4±0.2°, 6.5±0.2°, 8.1±0.2° and 9.7±0.2°, preferably further comprising characteristic peaks at 2θ of 13.3±0.2°, 15.5±0.2°, 16.9±0.2° and 21.6±0.2°, more preferably further comprising diffraction peaks at 2θ of 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°. Further preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 6.

[0025] The X-ray powder diffraction pattern of the mesylate salt form G of the compound of formula (I) has a diffraction peak at 8.5±0.2°, or a diffraction peak at 9.0±0.2°, or a diffraction peak at 9.8±0.2°, or a diffraction peak at 16.9±0.2°, or a diffraction peak at 19.7±0.2°, or a diffraction peak at 22.7±0.2°; or a diffraction peak at 25.5±0.2°, or a diffraction peak at 26.2±0.2°, or a diffraction peak at 31.8±0.2°, or a diffraction peak at 32.5±0.2°, preferably including any 2 to 5 of the above diffraction peaks, or 3 to 5, or 3 to 6, or 3 to 8, more preferably including any 4, 6 or 8 thereof.

[0026] Preferably, the X-ray powder diffraction pattern of Form G has diffraction peaks at 9.8±0.2°, 16.9±0.2°, and 2θ, preferably further comprising characteristic peaks at 8.5±0.2° and 9.0±0.2°, preferably further comprising characteristic peaks at 19.7±0.2°, 22.7±0.2°, 25.5±0.2°, and 26.2±0.2°, more preferably further comprising characteristic peaks at 2θ. There are diffraction peaks at 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°. Further preferably, the X-ray powder diffraction pattern of its crystalline form G is substantially as shown in Figure 7, its nuclear magnetic resonance hydrogen spectrum is shown in Figure 7A, and its free base nuclear magnetic resonance hydrogen spectrum is shown in Figure 7B.

[0027] In a preferred embodiment of the present invention, the crystal form G is a methanesulfonate hydrate with a water content of 5.0-8.0%.

[0028] In a preferred embodiment of the present invention, the crystal form G is a methanesulfonate hydrate, and the detected water content is 6.0%.

[0029] In a preferred embodiment of the present invention, the molar ratio of water to mesylate in Form G is approximately 2:1.

[0030] In a preferred embodiment of the present invention, the molar ratio of the free base to the mesylate salt in Form G is approximately 1:1.

[0031] The mesylate hydrate crystal form G of the compound of formula (I) prepared by the present invention has a simple preparation method, high crystal purity, and a stable chemical state. It can not only improve the physical and chemical properties of the crystalline free base of the compound of formula (I), but also is stable under high humidity conditions and is not easy to crystallize or dissociate, making it very suitable for pharmaceutical development.

[0032] The X-ray powder diffraction pattern of the mesylate salt form H of the compound of formula (I) has a diffraction peak at 7.5±0.2°, or a diffraction peak at 8.1±0.2°, or a diffraction peak at 15.1±0.2°, or a diffraction peak at 17.1±0.2°; or a diffraction peak at 19.5±0.2°, or a diffraction peak at 22.7±0.2°, or a diffraction peak at 23.3±0.2°, or a diffraction peak at 30.5±0.2°, preferably including any 2 to 5 of the above diffraction peaks, or 3 to 5, or 3 to 6, or 3 to 8, more preferably including any 4, 6 or 8 of them.

[0033] Preferably, the X-ray powder diffraction pattern of Form H has diffraction peaks at 2θ of 7.5±0.2°, 8.1±0.2°, 15.1±0.2° and 17.1±0.2°, preferably further comprising characteristic peaks at 2θ of 19.5±0.2°, 22.7±0.2°, 23.3±0.2° and 30.5±0.2°, more preferably further comprising diffraction peaks at 2θ of 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°. Further preferably, the X-ray powder diffraction pattern of Form H is substantially as shown in Figure 8.

[0034] The X-ray powder diffraction pattern of the mesylate salt form I of the compound of formula (I) has a diffraction peak at 6.4±0.2°, or a diffraction peak at 8.4±0.2°, or a diffraction peak at 9.7±0.2°, or a diffraction peak at 15.5±0.2°; or a diffraction peak at 16.8±0.2°, or a diffraction peak at 17.1±0.2°, or a diffraction peak at 19.5±0.2°, or a diffraction peak at 23.6±0.2°, preferably including any 2 to 5 of the above-mentioned diffraction peaks, or 3 to 5, or 3 to 6, or 3 to 8, more preferably including any 4, 6 or 8 thereof.

[0035] Preferably, the X-ray powder diffraction pattern of Form I has diffraction peaks at 2θ of 6.4±0.2°, 8.4±0.2°, 9.7±0.2° and 15.5±0.2°, preferably further comprising characteristic peaks at 2θ of 16.8±0.2°, 17.1±0.2°, 19.5±0.2° and 23.6±0.2°, more preferably further comprising diffraction peaks at 2θ of 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°. Further preferably, the X-ray powder diffraction pattern of Form I is substantially as shown in Figure 9.

[0036] In a preferred embodiment of the present invention, the method for preparing the mesylate crystalline form A of the compound of formula (I) comprises the following steps:

[0037] 1) dispersing the free base of the compound of formula (I) in acetonitrile solvent under certain temperature conditions to form a suspension;

[0038] 2) adding methanesulfonic acid;

[0039] 3) Continue stirring, filtering, and drying to obtain Form A of the mesylate salt of the compound of formula (I).

[0040] in:

[0041] The temperature condition of step 1) is 1-60° C., preferably 5-30° C., and the material-liquid ratio of free base to acetonitrile is preferably 0.2-2 g:30 mL, preferably 1-1.5 g:30 mL;

[0042] In step 2), the amount of methanesulfonic acid is preferably 1 to 6 times, preferably 2 to 4 times, the molar amount of the free base;

[0043] The stirring time in step 3) is 3 to 30 hours, preferably 5 to 24 hours.

[0044] In a preferred embodiment of the present invention, the method for preparing the mesylate crystal form B of the compound of formula (I) comprises the following steps:

[0045] 1) dispersing the compound of formula (I) in dichloromethane solvent under certain temperature conditions to form a suspension;

[0046] 2) adding methanesulfonic acid;

[0047] 3) Continue stirring, filtering, and drying to obtain the mesylate crystal form B of the compound of formula (I).

[0048] in:

[0049] The temperature condition of step 1) is 1-60°C, preferably 5-30°C, and the material-liquid ratio of free base to dichloromethane is preferably 0.2-2g:30mL, preferably 1-1.5g:30mL;

[0050] In step 2), the amount of methanesulfonic acid is preferably 1 to 3 times the molar amount of the free base, preferably 1 to 2 times;

[0051] The stirring time in step 3) is 3 to 30 hours, preferably 5 to 24 hours.

[0052] In a preferred embodiment of the present invention, the method for preparing the mesylate crystal form C of the compound of formula (I) comprises the following steps:

[0053] 1) dissolving the compound of formula (I) in acetic acid solvent under certain temperature conditions to form a suspension;

[0054] 2) adding anti-solvent 2-butanone solvent;

[0055] 3) Continue stirring, filtering, and drying to obtain Form C of the methanesulfonate salt of the compound of formula (I).

[0056] in:

[0057] The temperature condition of step 1) is 30-80° C., preferably 40-60° C., and the material-liquid ratio of the compound of formula (I) to acetic acid is preferably 0.2-2 g:30 mL, preferably 1-1.5 g:30 mL;

[0058] Step 2) The amount of 2-butanone is preferably 30 to 100 mL, preferably 50 to 80 mL

[0059] The stirring time in step 3) is 1 to 7 days, preferably 2 to 5 days.

[0060] In a preferred embodiment of the present invention, the preparation method of the mesylate salt of the compound of formula (I) in Form D comprises the following steps:

[0061] 1) dispersing the free base of the compound of formula (I) in an organic solvent under certain temperature conditions to form a suspension;

[0062] 2) adding methanesulfonic acid;

[0063] 3) Continue stirring to precipitate solid, filter and dry to obtain the mesylate crystal form D of the compound of formula (I).

[0064] in:

[0065] The organic solvent in step 1) is selected from one or more of acetonitrile, ethyl acetate, n-propyl acetate, and isopropyl acetate, preferably acetonitrile and ethyl acetate, and the temperature is 30-90° C., preferably 40-60° C. The material-liquid ratio of free base to acetonitrile is preferably 0.2-2 g:30 mL, preferably 1-1.5 g:30 mL;

[0066] In step 2), the amount of methanesulfonic acid is preferably 1 to 3 times the molar amount of the free base, preferably 1 to 2 times;

[0067] The stirring time in step 3) is 3 to 30 hours, preferably 5 to 24 hours.

[0068] In a preferred embodiment of the present invention, the method for preparing the mesylate crystalline form E of the compound of formula (I) comprises the following steps:

[0069] 1) dispersing the free base of the compound of formula (I) in ethyl acetate solvent under certain temperature conditions to form a suspension;

[0070] 2) adding methanesulfonic acid;

[0071] 3) Continue stirring to precipitate a solid, filter and dry to obtain Form E of the methanesulfonate salt of the compound of formula (I).

[0072] in:

[0073] The temperature condition of step 1) is -30 to 10°C, preferably -10 to 0°C, and the material-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;

[0074] In step 2), the amount of methanesulfonic acid is preferably 1 to 3 times the molar amount of the free base, preferably 1 to 2 times;

[0075] The stirring time in step 3) is 3 to 30 hours, preferably 5 to 24 hours.

[0076] In a preferred embodiment of the present invention, the method for preparing the mesylate salt form F of the compound of formula (I) comprises the following steps:

[0077] 1) dispersing the free base of the compound of formula (I) in n-propanol solvent under certain temperature conditions to form a suspension;

[0078] 2) adding methanesulfonic acid;

[0079] 3) Continue stirring to precipitate a solid, filter and dry to obtain the mesylate salt form F of the compound of formula (I).

[0080] in:

[0081] The temperature condition of step 1) is -30 to 10°C, preferably -10 to 0°C, and the material-liquid ratio of the compound of formula (I) to n-propanol is preferably 0.2 to 2 g:30 mL, preferably 1 to 1.5 g:30 mL;

[0082] In step 2), the amount of methanesulfonic acid is preferably 1 to 3 times the molar amount of the free base, preferably 1 to 2 times;

[0083] The stirring time in step 3) is 3 to 30 hours, preferably 5 to 24 hours.

[0084] In a preferred embodiment of the present invention, the method for preparing the mesylate salt form G of the compound of formula (I) comprises the following steps:

[0085] 1) dispersing or dissolving the compound of formula (I) in a mixed solvent of an organic solvent and water to form a suspension;

[0086] 2) Continue stirring the suspension, or add a certain proportion of seed crystals to induce crystallization;

[0087] 3) Continue stirring, filtering and drying to obtain the target product;

[0088] The organic solvent is selected from one or more of methanol, ethanol, n-propanol, n-butanol, isopropanol, ethyl acetate, ethylene glycol methyl ether, ethylene glycol ethyl ether, isopropyl ether, dichloromethane, 1,4-dioxane, tetrahydrofuran, acetonitrile, acetone, 2-butanone and water; preferably one or more of 1,4-dioxane, acetonitrile, acetone, 2-butanone or water.

[0089] in:

[0090] The temperature condition of step 1) is 10-80°C, preferably 20-50°C; the ratio of organic solvent to water is 1-6:1, preferably 3-6:1;

[0091] In step 2), the compound of formula (I) is slurried in a mixed solvent of an organic solvent and water for 3 to 5 weeks to obtain Form G seed crystals, wherein the added ratio of the seed crystals is 1% to 5%, preferably 1% to 3%;

[0092] The stirring time in step 3) is 1 to 7 days, preferably 2 to 5 days.

[0093] In a preferred embodiment of the present invention, the method for preparing the mesylate salt form H of the compound of formula (I) comprises the following steps:

[0094] 1) dispersing the free base of the compound of formula (I) in acetonitrile solvent under certain temperature conditions to form a suspension;

[0095] 2) adding methanesulfonic acid;

[0096] 3) Continue stirring, filtering, and drying to obtain the mesylate salt form H of the compound of formula (I).

[0097] in:

[0098] The temperature condition of step 1) is 1-60° C., preferably 5-30° C., and the material-liquid ratio of free base to acetonitrile is preferably 0.2-2 g:30 mL, preferably 1-1.5 g:30 mL;

[0099] In step 2), the amount of methanesulfonic acid is preferably 1 to 3 times the molar amount of the free base, preferably 1 to 2 times;

[0100] The stirring time in step 3) is 1 to 7 days, preferably 2 to 5 days.

[0101] In a preferred embodiment of the present invention, the method for preparing the mesylate salt crystalline form I of the compound of formula (I) comprises the following steps:

[0102] 1) placing the mesylate salt form H of the compound of formula (I) under certain temperature conditions and humidity conditions;

[0103] 2) after standing for a period of time, obtaining the mesylate salt crystalline form I of the compound of formula (I);

[0104] in:

[0105] The temperature condition of step 1) is 1-60°C, preferably 5-30°C;

[0106] The time in step 3) is 1 to 30 hours, preferably 3 to 10 hours.

[0107] It should be noted that those skilled in the art should understand that the technical solution of the invention may be modified or replaced by equivalents. For example, the use of some of the organic solvents listed in the preceding part of the present invention also encompasses the spirit and scope of the technical solution of the present invention, and should all be included in the content of the present invention.

[0108] Another aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective dose of the crystalline free base or the crystalline acid salt of the compound of formula (I), or a pharmaceutically acceptable carrier or excipient.

[0109] Another aspect of the present invention provides the use of the aforementioned crystalline acid salt, the aforementioned acid salt polymorph, and the aforementioned pharmaceutical composition of the compound of formula (I) in the preparation of a drug for treating diseases related to protein kinases, wherein the protein kinase is selected from c-Met and VEGFR receptor tyrosine kinase.

[0110] Another aspect of the present invention provides the use of the aforementioned crystalline acid salt, the aforementioned acid salt polymorph, and the aforementioned pharmaceutical composition of the compound of formula (I) for preparing protein kinase inhibitors, wherein the protein kinase is selected from c-Met and VEGFR receptor tyrosine kinase.

[0111] Another aspect of the present invention provides a method for regulating the catalytic activity of a protein kinase, which comprises contacting the protein kinase with the aforementioned crystalline acid salt, the aforementioned acid salt polymorph, and the aforementioned pharmaceutical composition of the aforementioned compound of formula (I), wherein the protein kinase is selected from c-met and VEGFR receptor tyrosine kinase.

[0112] The aforementioned crystalline acid salt, the aforementioned acid salt polymorph, and the aforementioned pharmaceutical composition of the aforementioned compound of formula (I) of the present invention can also be used to prepare drugs for treating cancer and metastasis, including cancer (solid tumors), lymphatic system hematopoietic tumors, bone marrow system hematopoietic tumors, tumors of mesenchymal origin, tumors of the central and peripheral nervous systems, or other tumors. Including but not limited to: the cancer is 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 lymphatic system hematopoietic tumor is selected from leukemia, acute lymphocytic leukemia or chronic lymphocytic leukemia; the bone marrow system hematopoietic tumor is selected from acute or chronic myeloid leukemia, myelodysplastic syndrome or promyelocytic leukemia; the mesenchymal origin tumor is selected from fibrosarcoma, rhabdomyosarcoma, soft tissue sarcoma or osteosarcoma; the tumor of the central and peripheral nervous system is selected from astrocytoma, neuroblastoma, glioma or nerve terminal tumor; the other tumors are selected from malignant melanoma, seminoma, teratoma, thyroid follicular carcinoma or Kaposi sarcoma.

[0113] Preferably, the invention is used in the preparation of a drug for treating liver cancer, lung cancer, breast cancer, epidermal squamous cell carcinoma or gastric cancer.

[0114] More preferably, the compound is used in the preparation of a drug for treating non-small cell lung cancer.

[0115] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together 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 an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0116] Different expressions 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 express the same meaning, which means that X can be any one or more of A, B, and C.

[0117] The methanesulfonate crystalline form of the compound of formula (I) of the present invention has good solubility and stability, which can improve its bioavailability, facilitate its pharmaceutical processing and use in pharmaceutical compositions, and the preparation method of the present invention is simple and easy to perform, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0118] FIG1 is an X-ray diffraction pattern of the mesylate salt form A of the compound of formula (I).

[0119] FIG1A is a hydrogen nuclear magnetic resonance spectrum of the mesylate salt form A of the compound of formula (I).

[0120] FIG2 is an X-ray diffraction pattern of Form B of the mesylate salt of the compound of formula (I).

[0121] FIG3 is an X-ray diffraction pattern of Form C of the methanesulfonate salt of the compound of formula (I).

[0122] FIG3A is a DSC spectrum of Form C of the mesylate salt of the compound of formula (I).

[0123] FIG3B is a TGA spectrum of Form C of the methanesulfonate salt of the compound of formula (I).

[0124] FIG4 is an X-ray diffraction pattern of Form D of the mesylate salt of the compound of formula (I).

[0125] FIG4A is a DSC spectrum of Form D of the mesylate salt of the compound of formula (I).

[0126] FIG4B is a TGA spectrum of Form D of the mesylate salt of the compound of formula (I).

[0127] FIG5 is an X-ray diffraction pattern of Form E of the methanesulfonate salt of the compound of formula (I).

[0128] FIG6 is an X-ray diffraction pattern of Form F of the methanesulfonate salt of the compound of formula (I).

[0129] FIG7 is an X-ray diffraction pattern of the mesylate salt form G of the compound of formula (I).

[0130] FIG7A is a hydrogen nuclear magnetic resonance spectrum of the mesylate salt form G of the compound of formula (I).

[0131] FIG7B is a hydrogen nuclear magnetic resonance spectrum of the free base of the compound of formula (I).

[0132] FIG8 is an X-ray diffraction pattern of Form H of the mesylate salt of the compound of formula (I).

[0133] FIG9 is an X-ray diffraction pattern of Form I of the methanesulfonate salt of the compound of formula (I). DETAILED DESCRIPTION

[0134] The following embodiments of the present invention are described in further detail with reference to the accompanying drawings and examples. The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention.

[0135] Example 1: Preparation of Form A

[0136] At room temperature (25°C), 1 g of the free base sample 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 24 h, filtered, and dried at 50°C for 24 h to obtain the mesylate salt form A of the compound of formula I.

[0137] Example 2: Preparation of Form A

[0138] At room temperature (25°C), 1 g of the free base sample 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 h, filtered, and dried at 50°C for 24 h to obtain Form A of the methanesulfonate salt of the compound of formula (I).

[0139] Example 3: Preparation of Form B

[0140] At room temperature (25°C), 1 g of the free base sample 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 h, filtered, and dried at 50°C for 24 h to obtain the mesylate salt of the compound of formula (I) in Form B.

[0141] Example 4: Preparation of Form B

[0142] At 10°C, 1 g of the free base sample 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 h, filtered, and dried at 50°C for 24 h to obtain Form B of the methanesulfonate salt of the compound of formula (I).

[0143] Example 5: Preparation of Form C

[0144] At room temperature (25°C), 1 g of a methanesulfonate sample of the compound of formula (I) was dissolved in 20 mL of acetic acid to obtain a solution. 40 mL of an anti-solvent, n-heptane, was added to precipitate a solid. The solid was stirred for 2 days, filtered, and dried at 50°C for 24 h to obtain a methanesulfonate crystalline form C of the compound of formula (I).

[0145] Example 6: Preparation of Form C

[0146] At 50° C., 1 g of a methanesulfonate sample of the compound of formula (I) was dissolved in 20 mL of acetic acid solvent to obtain a solution. 40 mL of an anti-solvent 2-butanone solvent was added to precipitate a solid. The solid was stirred for 2 days, filtered, and dried at 50° C. for 24 h to obtain a methanesulfonate crystalline form C of the compound of formula (I).

[0147] Example 7: Preparation of Form D

[0148] At 50°C, 1 g of the free base sample 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 h, filtered, and dried at 50°C for 24 h to obtain the mesylate salt form D of the compound of formula (I).

[0149] Example 8: Preparation of Form D

[0150] At 50°C, 1 g of the free base sample 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 h, filtered, and dried at 50°C for 24 h to obtain the mesylate salt form D of the compound of formula (I).

[0151] Example 9: Preparation of Form E

[0152] At -10°C, 1 g of the free base sample 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 h, filtered, and dried at 50°C for 12 h to obtain the mesylate salt form E of the compound of formula (I).

[0153] Example 10: Preparation of Form E

[0154] At -10°C, 1 g of the free base sample 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 h, filtered, and dried at 50°C for 24 h to obtain Form E of the methanesulfonate salt of the compound of formula (I).

[0155] Example 11: Preparation of Form F

[0156] At -10°C, 1 g of the free base sample 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, stirred for 24 h, filtered, and dried at 50°C for 24 h to obtain Form F of the methanesulfonate salt of the compound of formula (I).

[0157] Example 12: Preparation of Form F

[0158] At -10°C, 1 g of the free base sample of the compound of formula (I) was dispersed in 30 mL of n-propanol solvent to obtain a suspension. 1.2 eq of methanesulfonic acid was slowly added dropwise to the alkaline solution, stirred for 24 h, filtered, and dried at 50°C for 24 h to obtain Form F of the methanesulfonate salt of the compound of formula (I).

[0159] Example 20: Preparation of Form G

[0160] At room temperature (25°C), 1 g of a methanesulfonate sample 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. 1% of Form G seed crystals was added to induce crystallization. The suspension was beaten for 1 day, filtered, and dried at 50°C for 24 h to obtain Form G of the methanesulfonate of the compound of formula (I).

[0161] Example 21: Preparation of Form G

[0162] At room temperature (25°C), 1 g of a methanesulfonate sample 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. 1% of Form G seed crystals was added to induce crystallization. The suspension was beaten for 3 days, filtered, and dried at 50°C for 24 h to obtain Form G methanesulfonate of the compound of formula (I).

[0163] Example 22: Preparation of Form G

[0164] At 50°C, 1 g of a methanesulfonate sample 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, 2% of Form G seed crystals were added to induce crystallization, and the suspension was beaten for 1 day. After filtration, the suspension was dried at 50°C for 24 h to obtain Form G methanesulfonate of the compound of formula (I).

[0165] Example 23: Preparation of Form G

[0166] At 50°C, 1 g of a methanesulfonate sample 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, which was beaten for 3 days. After filtration, the suspension was dried at 50°C for 24 hours to obtain Form G of the methanesulfonate of the compound of formula (I).

[0167] Example 24: Preparation of Form G

[0168] At room temperature (25°C), 1 g of a methanesulfonate sample of the compound of formula (I) was dispersed in 30 mL of a mixed solvent of acetone and water (2:1) to obtain a suspension. The suspension was beaten for 3 days, filtered, and dried under forced air at 50°C for 24 h to obtain Form G of the methanesulfonate of the compound of formula (I).

[0169] Example 25: Preparation of Form H

[0170] At room temperature (25°C), 1 g of the free base sample 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 dried at 50°C for 24 h to obtain the mesylate salt of the compound of formula (I) in Form H.

[0171] Example 26: Preparation of Form H

[0172] At room temperature (25°C), 1 g of the free base sample 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 dried at 50°C for 24 h to obtain the mesylate salt of the compound of formula (I) in Form H.

[0173] Example 27: Preparation of Form I

[0174] At room temperature (25° C.), 1 g of the mesylate crystal form H sample of the compound of formula (I) was spread on a watch glass and allowed to stand for 3 h to obtain the mesylate crystal form I of the compound of formula (I).

[0175] Example 28: Preparation of Form I

[0176] At room temperature (25° C.), 1 g of the mesylate crystal form H sample of the compound of formula (I) was spread on a watch glass and placed under high humidity conditions of 92.5% for 10 h to obtain the mesylate crystal form I of the compound of formula (I).

[0177] Experimental Example 1: Stability of Form G

[0178] A sample of the mesylate salt of the compound of formula (I), Form G, was subjected to a one-month stability study under conditions of light (5000 lux), high temperature (60°C), and high humidity (RH) (92.5%). The results demonstrated that Form G was highly stable under these conditions, exhibiting virtually no chemical degradation. The stability data is shown in the table below:

[0179] Experimental Example 2: Stability of Form G under high humidity conditions

[0180] The mesylate salt form G of the compound of formula (I) was placed under high humidity RH92.5% for a 3-month long-term stability study. The results showed that the form G was very stable under high humidity conditions and no crystal transformation or dissociation occurred.

[0181] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the invention may be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present invention, which should all be covered by the scope of the claims of the present invention.

Claims

1. 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 methanesulfonate crystal form G, characterized in that: The X-ray powder diffraction pattern of Form G has a diffraction peak at 2θ of 8.5±0.2°, or a diffraction peak at 9.0±0.2°, or a diffraction peak at 9.4±0.2°, or a diffraction peak at 9.8±0.2°, or a diffraction peak at 16.9±0.2°, or a diffraction peak at 19.7±0.2°, or a diffraction peak at 22.7±0.2°; or a diffraction peak at 25.5±0.2°, or a diffraction peak at 26.2±0.2°, or a diffraction peak at 31.8±0.2°, or a diffraction peak at 32.5±0.2°, preferably including any 2 to 5 of the above diffraction peaks, or 3 to 5, or 3 to 6, or 3 to 8, more preferably including any 4, 6 or 8 thereof.

2. The mesylate salt form G according to claim 1, characterized in that: The X-ray powder diffraction pattern of Form G has diffraction peaks at 2θ of 9.8±0.2° and 16.9±0.2°, preferably also includes characteristic peaks at 2θ of 8.5±0.2° and 9.0±0.2°, preferably also includes characteristic peaks at 2θ of 19.7±0.2°, 22.7±0.2°, 25.5±0.2° and 26.2±0.2°, more preferably also includes diffraction peaks at 2θ of 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 further preferably, the X-ray powder diffraction pattern of Form G is substantially as shown in Figure 7.

3. 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 methanesulfonate forms AF, H and I, characterized in that: The X-ray powder diffraction pattern of Form A has a diffraction peak at 2θ of 5.4±0.2°, or at 6.1±0.2°, or at 10.6±0.2°, or at 13.7±0.2°, or at 18.1±0.2°, or at 19.6±0.2°, or at 24.7±0.2°, preferably including any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 7 of the above diffraction peaks, more preferably including any 4, 6 or 7 thereof; The X-ray powder diffraction pattern of Form B has a diffraction peak at 2θ of 5.4±0.2°, or at 7.8±0.2°, or at 10.6±0.2°, or at 13.7±0.2°, or at 14.4±0.2°, or at 15.6±0.2°, or at 19.7±0.2°, preferably including any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 7 of the above diffraction peaks, more preferably including any 4, 6 or 7 thereof; The X-ray powder diffraction pattern of Form C has a diffraction peak at 2θ of 7.8±0.2°, or at 9.6±0.2°, or at 11.7±0.2°, or at 15.6±0.2°, or at 17.7±0.2°, or at 23.4±0.2, or at 26.5±0.2, preferably including any 2 to 5 of the above diffraction peaks, or 3 to 5. or 3 to 6, or 3 to 7, more preferably any 4, 6 or 7 thereof; The X-ray powder diffraction pattern of Form D has a diffraction peak at 2θ of 5.2±0.2°, or at 11.5±0.2°, or at 13.5±0.2°, or at 17.1±0.2°, or at 19.8±0.2, or at 22.8±0.2, or at 23.3±0.2, or at 24.2±0.2, preferably including any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 8 of the above diffraction peaks, more preferably including any 4, 6 or 8 thereof; The X-ray powder diffraction pattern of Form E has a diffraction peak at 2θ of 6.4±0.2°, or at 7.8±0.2°, or at 9.7±0.2°, or at 10.7±0.2°; or at 12.9±0.2°, or at 15.4±0.2°, or at 16.8±0.2°, or at 19.5±0.2°, preferably including any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 8 of the above diffraction peaks, more preferably including any 4, 6 or 8 thereof; The X-ray powder diffraction pattern of Form F has a diffraction peak at 2θ of 5.4±0.2°, or at 6.5±0.2°, or at 8.1±0.2°, or at 9.7±0.2°, or at 13.3±0.2°, or at 15.5±0.2°, or at 16.9±0.2°, or at 21.6±0.2°, preferably including any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 8 of the above diffraction peaks, more preferably including any 4, 6 or 8 thereof; The X-ray powder diffraction pattern of Form H has a diffraction peak at 2θ of 7.5±0.2°, or at 8.1±0.2°, or at 15.1±0.2°, or at 17.1±0.2°; or at 19.5±0.2°, or at 22.7±0.2°, or at 23.3±0.2°, or at 30.5±0.2°, preferably including any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 8 of the above diffraction peaks, more preferably including any 4, 6 or 8 thereof; The X-ray powder diffraction pattern of Form I has a diffraction peak at 2θ of 6.4±0.2°, or at 8.4±0.2°, or at 9.7±0.2°, or at 15.5±0.2°; or at 16.8±0.2°, or at 17.1±0.2°, or at 19.5±0.2°, or at 23.6±0.2°, preferably including any 2 to 5 of the above diffraction peaks, or 3 to 5, or 3 to 6, or 3 to 8, more preferably including any 4, 6 or 8 of them.

4. The mesylate salt forms AF, H and I according to claim 3, characterized in that: The X-ray powder diffraction spectrum of Form A has diffraction peaks at 2θ of 5.4±0.2°, 6.1±0.2°, 10.6±0.2° and 13.7±0.2°, preferably also includes diffraction peaks at 2θ of 18.1±0.2°, 19.6±0.2°, and 24.7±0.2°, more preferably also includes diffraction peaks at 2θ of 8.7±0.2°, 11.7±0.2°, 14.8±0.2°, 1 There are diffraction peaks at 7.4±0.2°, 21.1±0.2° and 27.1±0.2°; further preferably, the X-ray powder diffraction pattern of Form A is substantially as shown in Figure 1; The X-ray powder diffraction pattern of Form B has diffraction peaks at 2θ of 5.4±0.2°, 7.8±0.2°, 10.6±0.2° and 13.7±0.2°, preferably further comprising characteristic peaks at 2θ° of 14.4±0.2, 15.6±0.2 and 19.7±0.2, more preferably further comprising diffraction peaks at 2θ of 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 further preferably, the X-ray powder diffraction pattern of Form B is substantially as shown in Figure 2; The X-ray powder diffraction pattern of Form C has diffraction peaks at 2θ of 7.8±0.2°, 9.6±0.2°, 11.7±0.2° and 15.6±0.2°, preferably further comprising characteristic peaks at 2θ° of 17.7±0.2, 23.4±0.2 and 26.5±0.2, more preferably further comprising diffraction peaks at 2θ of 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 further preferably, the X-ray powder diffraction pattern of Form C is substantially as shown in Figure 3; The X-ray powder diffraction pattern of Form D has diffraction peaks at 2θ of 5.2±0.2°, 11.5±0.2°, 13.5±0.2° and 17.1±0.2°, preferably further comprising characteristic peaks at 2θ° of 19.8±0.2, 22.8±0.2, 23.3±0.2 and 24.2±0.2, more preferably further comprising diffraction peaks at 2θ of 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°. Further preferably, the X-ray powder diffraction pattern of Form D is substantially as shown in Figure 4; The X-ray powder diffraction pattern of Form E has diffraction peaks at 2θ of 6.4±0.2°, 7.8±0.2°, 9.7±0.2° and 10.7±0.2°, preferably further comprising characteristic peaks at 2θ of 12.9±0.2, 15.4±0.2, 16.8±0.2 and 19.5±0.2, more preferably further comprising diffraction peaks at 2θ of 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 further preferably, the X-ray powder diffraction pattern of Form E is substantially as shown in Figure 5; The X-ray powder diffraction pattern of Form F has diffraction peaks at 2θ of 5.4±0.2°, 6.5±0.2°, 8.1±0.2° and 9.7±0.2°, preferably further comprising characteristic peaks at 2θ of 13.3±0.2°, 15.5±0.2°, 16.9±0.2° and 21.6±0.2°, more preferably further comprising diffraction peaks at 2θ of 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 further preferably, the X-ray powder diffraction pattern of Form F is substantially as shown in Figure 6; The X-ray powder diffraction pattern of Form H has diffraction peaks at 2θ of 7.5±0.2°, 8.1±0.2°, 15.1±0.2° and 17.1±0.2°, preferably further comprising characteristic peaks at 2θ of 19.5±0.2°, 22.7±0.2°, 23.3±0.2° and 30.5±0.2°, more preferably further comprising diffraction peaks at 2θ of 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 further preferably, the X-ray powder diffraction pattern of Form H is substantially as shown in Figure 8; The X-ray powder diffraction pattern of Form I has diffraction peaks at 2θ of 6.4±0.2°, 8.4±0.2°, 9.7±0.2° and 15.5±0.2°, preferably also includes characteristic peaks at 2θ of 16.8±0.2°, 17.1±0.2°, 19.5±0.2° and 23.6±0.2°, more preferably also includes characteristic peaks at 2θ of 10.7±0.2°, 13.0±0.2°, There are diffraction peaks at 21.7±0.2°, 25.4±0.2°, 25.9±0.2° and 27.2±0.2°. Further preferably, the X-ray powder diffraction pattern of its crystalline form I is substantially as shown in Figure 9.

5. A method for preparing the crystalline form G 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 methanesulfonate according to claims 1 to 2, characterized in that: The steps include: 1) 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; 2) continuing to stir the suspension, or adding a certain proportion of seed crystals to induce crystallization; 3) Continue stirring, filtering and drying to obtain the target product.

6. The method for preparing the mesylate salt form G according to claim 5, wherein the organic solvent in step 1) is selected from one or more of methanol, ethanol, n-propanol, n-butanol, isopropanol, ethyl acetate, ethylene glycol methyl ether, ethylene glycol ethyl ether, isopropyl ether, dichloromethane, 1,4-dioxane, tetrahydrofuran, acetonitrile, acetone, 2-butanone or water; preferably one or more of 1,4-dioxane, acetonitrile, acetone, 2-butanone or water.

7. The method for preparing the mesylate salt form G according to claim 5, characterized in that: The temperature condition of step 1) is -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 ratio of seed crystals added in step 2) is 1% to 5%, preferably 1% to 3%; 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 the crystalline acid salt 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 or its polymorphic form as described in claims 1-4, and one or more pharmaceutically acceptable carriers or excipients.

9. Use of the crystalline acid salt 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 or its polymorphs as claimed in claims 1 to 4 and the pharmaceutical composition as claimed in claim 8 in the preparation of a medicament for treating a disease associated with protein kinase, wherein the protein kinase is preferably selected from c-Met and VEGFR receptor tyrosine kinase.

10. Use of the crystalline acid salt 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 or its polymorphic forms as claimed in claims 1 to 4 and the pharmaceutical composition as claimed in claim 8 in the preparation of drugs for treating cancer and metastasis, including cancer, hematopoietic tumors of the lymphatic system, hematopoietic tumors of the bone marrow system, tumors of mesenchymal origin, tumors of the central and peripheral nervous systems or other tumors; Preferably, the cancer is selected from bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, stomach cancer or Skin cancer; the lymphatic system hematopoietic tumor is selected from leukemia, acute lymphocytic leukemia or chronic lymphocytic leukemia; the bone marrow system hematopoietic tumor is selected from acute or chronic myeloid leukemia, myelodysplastic syndrome or promyelocytic leukemia; the mesenchymal-derived tumor is selected from fibrosarcoma, rhabdomyosarcoma, soft tissue sarcoma or osteosarcoma; the tumor of the central and peripheral nervous system is selected from astrocytoma, neuroblastoma, glioma or nerve terminal tumor; the other tumor is selected from malignant melanoma, seminoma, teratoma, thyroid follicular carcinoma or Kaposi sarcoma; non-small cell lung cancer is further preferred.

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