Crystals of compounds as C-MET kinase inhibitors, methods for preparing them, and their use.

Abstract

To provide crystals of compounds for treating diseases mediated by c-Met kinase, having excellent properties in at least one of the following aspects: pharmacokinetics, bioavailability, hygroscopicity, stability, solubility, purity, ease of preparation, etc.SOLUTION: The present invention provides a compound having crystalline form A of formula I. In the X-ray powder diffraction pattern of the crystalline form A with CuKα radiation, diffraction peaks are present at 2θ angles of 13.38, 15.71, 16.47, 20.15, 20.86, and 21.43 degrees.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] Cross-reference to Related Applications This application claims the priority and benefit of Chinese Patent Application No. 201810174767.4, filed with the China National Intellectual Property Administration on March 2, 2018. The disclosure of this application is hereby incorporated by reference in its entirety into this specification.

[0002] This application pertains to the field of pharmaceutical chemistry and relates to crystals of compounds as c-Met kinase inhibitors. In particular, it relates to crystals of N-(4-((7-((1-(cyclopentylamino)cyclopropyl)methoxy)-6-methoxy-quinolin-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, methods for preparing the same, its crystalline compositions, and its pharmaceutical compositions, as well as the use of the crystals for treating diseases related to the inhibition of growth factor receptor (e.g., c-Met) protein tyrosine kinase activity.

Background Art

[0003] The kinase c-Met is a typical member of the subfamily of heterodimeric receptor tyrosine kinases (RTKs) that includes Met, Ron, and Sea. The anti-angiogenic and anti-proliferative activities of c-Met are attractive targets. The endogenous ligand of c-Met is hepatocyte growth factor (HGF), which is also known as scatter factor (SF) because of its ability to interfere with colony formation in vitro. HGF is a derived cytokine known to induce receptor activation via autophosphorylation and to result in an increase in receptor-dependent signaling in normal and neoplastic cells (Sonnenberg et al., J. Cell Biol., 123:223-235, 1993; Matsumato et al., Crit. Rev. Oncog., 3:27-54, 1992; Stoker et al., Nature, 327:239-242, 1987). Anti-HGF antibodies or HGF antagonists also show inhibition of tumor metastasis.

[0004] International Publication No. 2012 / 034055 discloses N-(4-((7-((1-(cyclopentylamino)cyclopropyl)methoxy)-6-methoxy-quinoline-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (hereinafter referred to as the compound of formula I) as a c-Met kinase inhibitor, and a method for preparing the same. [ka] [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] International Publication No. 2012 / 034055 [Overview of the project] [Problems that the invention aims to solve]

[0006] Drugs are generally expected to possess superior properties in terms of pharmacokinetics, bioavailability, hygroscopicity, stability, solubility, purity, and ease of preparation, thereby meeting the needs for drug manufacturing, storage, and formulation. Currently, there is a need to provide compounds of formula I with improved properties. [Means for solving the problem]

[0007] In one embodiment, this application provides crystalline form A of a compound of formula I, [ka] In the X-ray powder diffraction pattern of crystal form A induced by Cu Kα radiation, diffraction peaks are present at 2θ angles of approximately 13.38 degrees, 15.71 degrees, 16.47 degrees, 20.15 degrees, 20.86 degrees, and 21.43 degrees.

[0008] In another embodiment, the present application provides a crystalline form B of the compound of formula I, wherein in the X-ray powder diffraction pattern of crystalline form B irradiated with Cu Kα radiation, diffraction peaks are present at 2θ angles of approximately 7.44 degrees, 8.93 degrees, 10.44 degrees, and 17.84 degrees.

[0009] In another embodiment, the present application provides a crystalline form C of the compound of formula I, wherein in the X-ray powder diffraction pattern of crystalline form C by Cu Kα radiation, the diffraction peaks are present at 2θ angles of approximately 7.38 degrees, 10.33 degrees, and 17.84 degrees.

[0010] In another embodiment, the present application provides a crystalline form D of the compound of formula I, wherein in the X-ray powder diffraction pattern of crystalline form D by Cu Kα radiation, diffraction peaks are present at 2θ angles of approximately 7.44°, 13.38°, 16.43°, 20.14°, 20.88°, and 21.45°.

[0011] In another embodiment, the present application provides a crystalline form E of a compound of formula I, wherein in the X-ray powder diffraction pattern of crystalline form E irradiated with Cu Kα radiation, diffraction peaks are present at 2θ angles of approximately 4.51 degrees, 6.64 degrees, and 10.66 degrees.

[0012] In yet another embodiment, the present application provides a crystalline composition comprising crystals of a compound of formula I, wherein the crystals of the compound of formula I constitute 50% by weight or more, preferably 80% by weight or more, more preferably 90% by weight or more, or most preferably 95% by weight or more of the crystalline composition, and the crystals of the compound of formula I are crystalline form A of the compound of formula I, crystalline form B of the compound of formula I, crystalline form C of the compound of formula I, crystalline form D of the compound of formula I, or crystalline form E of the compound of formula I, or a mixture thereof.

[0013] In yet another embodiment, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of crystals of a compound of formula I or the above-described crystalline composition, wherein the crystals of the compound of formula I are crystalline form A of the compound of formula I, crystalline form B of the compound of formula I, crystalline form C of the compound of formula I, crystalline form D of the compound of formula I, or crystalline form E of the compound of formula I, or a mixture thereof.

[0014] In yet another aspect, the present application provides the use of crystals of the compound of formula I or the crystalline composition thereof or the pharmaceutical composition thereof in the manufacture of a pharmaceutical for treating and / or preventing diseases mediated by c-Met kinase, wherein the crystals of the compound of formula I are crystalline form A of the compound of formula I, crystalline form B of the compound of formula I, crystalline form C of the compound of formula I, crystalline form D of the compound of formula I, or crystalline form E of the compound of formula I, or a mixture thereof.

[0015] In another aspect, the present application provides the use of a crystal of the compound of formula I or the above crystalline composition or the above pharmaceutical composition in the manufacture of a pharmaceutical for treating and / or preventing a disease mediated by c-Met kinase, wherein the crystal of the compound of formula I is crystalline form A of the compound of formula I, crystalline form B of the compound of formula I, crystalline form C of the compound of formula I, crystalline form D of the compound of formula I, or crystalline form E of the compound of formula I, or a mixture thereof.

[0016] In yet another embodiment, the present application provides crystals of the compound of formula I, or the crystalline composition thereof, or the pharmaceutical composition thereof, for the prevention and / or treatment of diseases mediated by c-Met kinase, wherein the crystals of the compound of formula I are crystalline form A of the compound of formula I, crystalline form B of the compound of formula I, crystalline form C of the compound of formula I, crystalline form D of the compound of formula I, or crystalline form E of the compound of formula I, or a mixture thereof. [Brief explanation of the drawing]

[0017] [Figure 1] This figure shows the XRPD pattern of crystalline form A of the compound of formula I prepared in Example 1. [Figure 2] This figure shows the DSC pattern of crystalline form A of the compound of formula I prepared in Example 1. [Figure 3] This figure shows the thermogravimetric analysis (TGA) pattern of crystalline form A of the compound of formula I prepared in Example 1. [Figure 4] This figure shows the XRPD pattern of crystalline form B of the compound of formula I prepared in Example 2. [Figure 5]It is a figure showing the DSC pattern of crystalline form B of the compound of formula I prepared in Example 2. [Figure 6] It is a figure showing the thermogravimetric analysis (TGA) pattern of crystalline form B of the compound of formula I prepared in Example 2. [Figure 7] It is a figure showing the XRPD pattern of crystalline form C of the compound of formula I prepared in Example 3. [Figure 8] It is a figure showing the DSC pattern of crystalline form C of the compound of formula I prepared in Example 3. [Figure 9] It is a figure showing the thermogravimetric analysis (TGA) pattern of crystalline form C of the compound of formula I prepared in Example 3. [Figure 10] It is a figure showing the XRPD pattern of crystalline form D of the compound of formula I prepared in Example 4. [Figure 11] It is a figure showing the DSC pattern of crystalline form D of the compound of formula I prepared in Example 4. [Figure 12] It is a figure showing the thermogravimetric analysis (TGA) pattern of crystalline form D of the compound of formula I prepared in Example 4. [Figure 13] It is a figure showing the XRPD pattern of crystalline form E of the compound of formula I prepared in Example 5. [Figure 14] It is a figure showing the DSC pattern of crystalline form E of the compound of formula I prepared in Example 5. [Figure 15] It is a figure showing the thermogravimetric analysis (TGA) pattern of crystalline form E of the compound of formula I prepared in Example 5.

Mode for Carrying Out the Invention

[0018] This application provides crystals of N-(4-((7-((1-(cyclopentylamino)cyclopropyl)methoxy)-6-methoxy-quinolin-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (hereinafter referred to as crystals of the compound of formula I), which have excellent properties in at least one of pharmacokinetics, bioavailability, hygroscopicity, stability, solubility, purity, ease of preparation, etc.

[0019] According to specific embodiments of this application, the crystals of the compound of formula I provided herein include crystal A of N-(4-((7-((1-(cyclopentylamino)cyclopropyl)methoxy)-6-methoxy-quinoline-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (hereinafter referred to as crystal form A of the compound of formula I), crystal B of N-(4-((7-((1-(cyclopentylamino)cyclopropyl)methoxy)-6-methoxy-quinoline-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (hereinafter referred to as crystal form B of the compound of formula I), and N-(4-((7-((1-(cyclopentylamino)cyclopropyl)methoxy)-6-methoxy-quinoline Examples include crystal form C of N-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (hereinafter referred to as crystal form C of the compound of formula I), crystal form D of N-(4-((7-((1-(cyclopentylamino)cyclopropyl)methoxy)-6-methoxy-quinoline-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (hereinafter referred to as crystal form D of the compound of formula I), and crystal form E of N-(4-((7-((1-(cyclopentylamino)cyclopropyl)methoxy)-6-methoxy-quinoline-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (hereinafter referred to as crystal form E of the compound of formula I).

[0020] In one embodiment, the disclosure provides a crystalline form A of a compound of formula I, wherein in its X-ray powder diffraction (XRPD) pattern induced by CuKα radiation, diffraction peaks are present at 2θ angles of 13.38°, 15.71°, 16.47°, 20.15°, 20.86°, and 21.43°, preferably at approximately 9.25°, 10.45°, 13.38°, 14.03°, 15.71°, and 16.47°. Diffraction peaks are present at 17.20°, 17.85°, 18.16°, 18.48°, 19.80°, 20.15°, 20.86°, 21.43°, 22.53°, 23.43°, and 24.87°, and more preferably, diffraction peaks are present at approximately 9.25°, 10.45°, 12.48°, 13.38°, 14.03°, 15.71°, 16.47°, 17.20°, 17.85°, 18.16°, and 18. Diffraction peaks are present at 48°, 18.85°, 19.80°, 20.15°, 20.86°, 21.43°, 21.79°, 22.53°, 23.43°, 24.87°, 25.47°, and 29.07°, most preferably at approximately 9.25°, 9.64°, 10.45°, 11.27°, 12.48°, 13.38°, 14.03°, 15.71°, 16.47°, 17.20°, and 1 It exists at 7.85 degrees, 18.16 degrees, 18.48 degrees, 18.85 degrees, 19.80 degrees, 20.15 degrees, 20.86 degrees, 21.43 degrees, 21.79 degrees, 22.53 degrees, 23.43 degrees, 24.25 degrees, 24.87 degrees, 25.47 degrees, 26.54 degrees, 26.76 degrees, 27.78 degrees, 29.07 degrees, 30.51 degrees, 31.99 degrees, 33.01 degrees, 34.65 degrees, 35.10 degrees, and 36.00 degrees.

[0021] Furthermore, in the powder X-ray diffraction pattern of crystalline form A of compound I using CuKα radiation in this application, the peak positions and relative intensities of the diffraction peaks are shown in Table 1 below.

[0022] [Table 1]

[0023] In a particular embodiment, the XRPD pattern of crystalline form A of the compound of formula I in this application is shown in Figure 1.

[0024] Although not limited to these, differential scanning calorimetry (DSC) of crystalline form A of compound I in this application shows an endothermic peak at approximately 177.50°C. Specifically, the differential scanning calorimetry (DSC) pattern of crystalline form A of compound I is shown in Figure 2.

[0025] While not limited to these, the thermogravimetric analysis (TGA) patterns of crystalline form A of the compounds of formula I in this application are shown in Figure 3.

[0026] In another aspect, the present application provides a crystalline form B of a compound of formula I in an X-ray powder diffraction pattern induced by CuKα radiation, wherein diffraction peaks are present at 2θ angles of approximately 7.44°, 8.93°, 10.44°, and 17.84°, preferably with diffraction peaks at approximately 7.44°, 8.93°, 10.26°, 10.44°, 10.70°, 11.17°, 12.65°, 12.96°, 14.35°, 15.49°, 16.34°, 17.84°, 18.28°, 18.73°, 20.96°, 21.88°, 22.42°, 23.03°, 24.17°, 25.27°, and 2θ angles. Diffraction peaks exist at a 2θ angle of 6.16 degrees, and most preferably, at 2θ angles of approximately 7.44 degrees, 8.93 degrees, 9.48 degrees, 10.26 degrees, 10.44 degrees, 10.70 degrees, 11.17 degrees, 11.85 degrees, 12.65 degrees, 12.96 degrees, 13.57 degrees, 14.35 degrees, 15.49 degrees, 15.75 degrees, 16.34 degrees, 17.84 degrees, 18.28 degrees, 18.73 degrees, 19.43 degrees, 20.02 degrees, 20.65 degrees, 20.96 degrees, 21.88 degrees, 22.42 degrees, 23.03 degrees, 24.17 degrees, 25.27 degrees, 25.99 degrees, 26.16 degrees, and 29.24 degrees.

[0027] Furthermore, in the powder X-ray diffraction pattern of crystalline form B of compound I using CuKα radiation in this application, the peak positions and relative intensities of the diffraction peaks are shown in Table 2 below.

[0028] [Table 2]

[0029] In a particular embodiment, the XRPD pattern of crystalline form B of the compound of formula I in this application is shown in Figure 4.

[0030] Although not limited to these, differential scanning calorimetry (DSC) of crystalline form A of compound I in this application shows endothermic peaks at approximately 125.70°C and 174.07°C. Specifically, the differential scanning calorimetry (DSC) pattern of crystalline form B of compound I is shown in Figure 5.

[0031] While not limited to these, the thermogravimetric analysis (TGA) patterns of crystalline form B of the compound of formula I in this application are shown in Figure 6.

[0032] In another aspect, the present application provides a crystalline form C of a compound of formula I in an X-ray powder diffraction pattern induced by CuKα radiation, wherein diffraction peaks are present at 2θ angles of 7.38 degrees, 10.33 degrees, and 17.84 degrees, preferably at 2θ angles of 7.38 degrees, 8.80 degrees, 10.33 degrees, 11.15 degrees, 15.30 degrees, 17.84 degrees, 18.18 degrees, 19.76 degrees, 21.03 degrees, and 21.86 degrees, and also Most preferably, diffraction peaks exist at 2θ angles of 7.38°, 8.80°, 10.33°, 11.15°, 11.71°, 12.33°, 12.58°, 12.88°, 13.50°, 14.28°, 15.30°, 16.04°, 16.33°, 16.55°, 17.84°, 18.18°, 18.43°, 19.76°, 21.03°, 21.86°, 22.83°, 25.34°, and 25.86°.

[0033] Furthermore, in the powder X-ray diffraction pattern of crystalline form C of compound I using CuKα radiation in this application, the peak positions and relative intensities of the diffraction peaks are shown in Table 3 below.

[0034] [Table 3]

[0035] In a particular embodiment, the XRPD pattern of crystalline form C of the compound of formula I in this application is shown in Figure 7.

[0036] In some embodiments of this application, in crystalline form C of the compound of formula I, the compound of formula I exists in the form of a dioxane solvate of the compound of formula I. Specifically, in the dioxane solvate of the compound of formula I, the molar ratio of the compound of formula I to dioxane is 1 to 10:1, preferably 2 to 8:1, more preferably 2 to 3:1, and most preferably about 2.33:1.

[0037] Although not limited to these, differential scanning calorimetry (DSC) of crystalline form C of compound I in this application shows an endothermic peak at approximately 174.16°C. Specifically, the differential scanning calorimetry (DSC) pattern of crystalline form C of compound I is shown in Figure 8.

[0038] While not limited to these, the thermogravimetric analysis (TGA) patterns of crystalline form C of the compounds of formula I in this application are shown in Figure 9.

[0039] In yet another aspect, the present application provides a crystalline form D of a compound of formula I in an X-ray powder diffraction pattern induced by CuKα radiation, wherein diffraction peaks are present at 2θ angles of 7.44°, 13.38°, 16.43°, 20.14°, 20.88°, and 21.45°, preferably at 7.07°, 7.44°, 8.92°, 9.23°, 10.46°, 13.38°, 14.06°, 15.76°, 16.43°, 17.21°, 17.84°, 18.17°, 18.47°, 19.82°, 20.14°, 20.88°, 21.45°, 21.82°, 22.49°, 23.44°, 24.87°, 25.44°, and Diffraction peaks are present at 29.09 degrees, most preferably at 7.07 degrees, 7.44 degrees, 8.05 degrees, 8.92 degrees, 9.23 degrees, 9.64 degrees, 10.46 degrees, 11.24 degrees, 12.63 degrees, 13.38 degrees, 14.06 degrees, 15.76 degrees, 16.43 degrees, 17.21 degrees, 17.84 degrees, 18.17 degrees, and 18.47 degrees. It exists at 2θ angles of 1 degree, 18.77 degrees, 19.82 degrees, 20.14 degrees, 20.88 degrees, 21.45 degrees, 21.82 degrees, 22.49 degrees, 23.44 degrees, 24.26 degrees, 24.87 degrees, 25.44 degrees, 26.06 degrees, 26.48 degrees, 26.80 degrees, 29.09 degrees, 33.00 degrees, 34.64 degrees, and 36.02 degrees.

[0040] Furthermore, in the powder X-ray diffraction pattern of crystalline form D of compound I using CuKα radiation in this application, the peak positions and relative intensities of the diffraction peaks are shown in Table 4 below.

[0041] [Table 4]

[0042] In a particular embodiment, the XRPD pattern of crystalline form D of the compound of formula I in this application is shown in Figure 10.

[0043] Although not limited to these, differential scanning calorimetry (DSC) of crystalline form D of compound I in this application shows an endothermic peak at approximately 176.14°C. Specifically, the differential scanning calorimetry (DSC) pattern of crystalline form D of compound I is shown in Figure 11.

[0044] While not limited to these, the thermogravimetric analysis (TGA) patterns of crystalline form D of the compounds of formula I in this application are shown in Figure 12.

[0045] In yet another embodiment, the present application provides a crystalline form D of a compound of formula I in an X-ray powder diffraction pattern induced by CuKα radiation, wherein diffraction peaks are present at 2θ angles of 4.51°, 6.64°, and 10.66°, preferably at 2θ angles of 4.51°, 6.64°, 9.03°, 9.64°, 10.66°, 16.69°, and 17.12°, and more preferably at 4.51°, 6.64°, 9.03°, 9.64°, 10.66°, 13.26°, and 13.59°. , 15.20°, 15.85°, 16.69°, 17.12°, 19.33°, 20.49°, 22.12°, and 22.50° are present, and most preferably, diffraction peaks are present at 2θ angles of 4.51°, 6.64°, 9.03°, 9.64°, 10.66°, 13.26°, 13.59°, 14.40°, 15.20°, 15.85°, 16.69°, 17.12°, 17.36°, 18.10°, 19.33°, 20.49°, 21.38°, 22.12°, and 22.50°.

[0046] Furthermore, in the powder X-ray diffraction pattern of crystalline form E of compound I using CuKα radiation in this application, the peak positions and relative intensities of the diffraction peaks are shown in Table 5 below.

[0047] [Table 5]

[0048] In a particular embodiment, the XRPD pattern of crystalline form E of the compound of formula I in this application is shown in Figure 13.

[0049] Although not limited to these, differential scanning calorimetry (DSC) of crystalline form E of compound I in this application shows an endothermic peak at approximately 136.34°C. Specifically, the differential scanning calorimetry (DSC) pattern of crystalline form E of compound I is shown in Figure 14.

[0050] While not limited to these, the thermogravimetric analysis (TGA) patterns of crystalline form E of the compounds of formula I in this application are shown in Figure 15.

[0051] In this application, the instrument model for X-ray powder diffraction spectroscopy is a Bruker D2 X-ray diffractometer. Conditions and method: 30kV 10mA, slit: 0.6 / 3 / Ni / 8, 2θ: 4-40, time [seconds]: 0.1, step: 0.02

[0052] In this application, the instrument model for DSC spectroscopy is the METTLER TOLEDO DSC1. Conditions and method: The temperature is increased by 10°C / min in the range of 30 to 300°C.

[0053] In this application, the instrument model for TGA spectroscopic analysis is a PerKinElmerPyris 1 thermogravimetric analyzer. Conditions and method: The temperature is increased by 20°C / min in the range of 25 to 700°C.

[0054] For any given crystal form, the relative intensity of the diffraction peaks can change due to preferential orientation caused by factors such as crystal form, which are well known in the field of crystallography. While the peak intensity changes due to the influence of preferential orientation, the position of the diffraction peaks in the crystal cannot change. Furthermore, for any given crystal form, as is well known in the field of crystallography, there can be slight errors in the peak position. For example, temperature changes during sample analysis, sample movement, and instrument calibration can cause the peak position to shift, sometimes resulting in a measurement error of approximately ±0.2 degrees in the 2θ value. Therefore, it is well known to those skilled in the art that this error should be taken into account when determining each crystal structure.

[0055] DSC measures the transition temperature of a crystal when it absorbs or releases heat due to a change in crystal structure or crystal melting. For the same crystalline form of the same compound, the thermal transition temperature and melting point error in sequential analysis is usually within about 5°C, and typically within about 3°C. When it is said that a compound has a given DSC peak or melting point, this means the DSC peak or melting point ± 5°C. DSC is an auxiliary method for identifying various crystalline forms. Different crystalline forms can be identified by their different transition temperature characteristics. It should be noted that in the case of mixtures, the DSC peak or melting point can vary over a wider range. Furthermore, due to the decomposition that accompanies the melting of the substance, the melting temperature is related to the rate at which the temperature rises.

[0056] In another aspect, the present application provides a method for preparing crystalline form A of a compound of formula I, the method is (1) A step of mixing the compound of formula I with solvent A to obtain a solution of the compound of formula I, (2) The step of precipitating a solid, Solvent A in step (1) is selected from toluene, butanone, acetonitrile, and a mixed solvent of acetonitrile and water or ethyl acetate, and is preferably toluene.

[0057] In some embodiments of this application, solvent A is selected from a mixed solvent of acetonitrile and water, and the volume fraction of acetonitrile in the mixed solvent is 65% to 95%.

[0058] In some embodiments of this application, the volume of solvent A is 1 to 50 mL, preferably 2 to 15 mL, based on 1 g of compound I.

[0059] In some embodiments of this application, the volume of solvent A is 5 mL based on 1 g of compound I.

[0060] In some embodiments of this application, step (1) is carried out at a temperature in the range from 0°C to the boiling point of the solvent system after mixing, and preferably at the boiling point temperature of the solvent system after mixing.

[0061] In some embodiments of this application, the solid is precipitated in step (2) under conditions of standing, shaking, or stirring, preferably in step (2) under stirring. Step (2) may be carried out at room temperature.

[0062] In some embodiments of this application, the method for preparing crystalline form A further includes a step of separating the solid precipitated in step (2), for example, by filtration. In some embodiments of this application, the method further includes a step of drying the separated solid, the drying temperature may be 60°C.

[0063] In another aspect, the present application provides a method for preparing crystalline form B of a compound of formula I, the method being (1) A step of mixing the compound of formula I with solvent B to obtain a solution of the compound of formula I, (2) The step of precipitating a solid, Solvent B in step (1) is selected from methanol, ethanol, acetone, a mixed solvent of methanol and water, a mixed solvent of ethanol and water, a mixed solvent of acetone and water, or a mixed solvent of ethanol and butanone, preferably ethanol; the volume fraction of methanol in the mixed solvent of methanol and water is 95%; the volume fraction of ethanol in the mixed solvent of ethanol and water is 65% to 95%; the volume fraction of acetone in the mixed solvent of acetone and water is 65% to 95%; and the volume fraction of butanone in the mixed solvent of ethanol and butanone is 30% or less.

[0064] In some embodiments of this application, the volume of solvent B is 1 to 50 mL, preferably 5 to 20 mL, based on 1 g of compound I.

[0065] In some specific embodiments of this application, the volume of solvent B is 8.75 mL based on 1 g of compound I.

[0066] In some embodiments of this application, step (1) is carried out at a temperature in the range from 0°C to the boiling point of the solvent system after mixing, and preferably at the boiling point temperature of the solvent system after mixing.

[0067] In some embodiments of this application, the solid is precipitated in step (2) under conditions of standing, shaking, or stirring, preferably in step (2) under stirring. Step (2) may be carried out at room temperature.

[0068] In some embodiments of this application, the method for preparing crystalline form B further includes a step of separating the solid precipitated in step (2), for example, by filtration. In some embodiments of this application, the method further includes a step of drying the separated solid, the drying temperature may be 60°C, and the drying may be carried out under reduced pressure.

[0069] In yet another aspect, the present application provides a method for preparing crystalline form C of a compound of formula I, the method is (1) A step of mixing the compound of formula I with solvent C to obtain a solution of the compound of formula I, (2) The step of precipitating a solid, The solvent C in step (1) is dioxane.

[0070] In some embodiments of this application, the volume of solvent C is 1 to 100 mL, preferably 5 to 20 mL, based on 1 g of compound I.

[0071] In some specific embodiments of this application, the volume of solvent C is 75 mL based on 1 g of compound I.

[0072] In some embodiments of this application, step (1) is carried out at a temperature in the range from 0°C to the boiling point of the solvent system after mixing, and preferably at the boiling point temperature of the solvent system after mixing.

[0073] In some embodiments of this application, the solid is precipitated in step (2) under conditions of standing, shaking, or stirring, preferably in step (2) under stirring. Step (2) may be carried out at room temperature.

[0074] In some embodiments of this application, the method for preparing crystalline form C further includes a step of separating the solid precipitated in step (2), for example, by filtration. In some embodiments of this application, the method further includes a step of drying the separated solid, the drying temperature may be 60°C.

[0075] In yet another aspect, the present application provides a method for preparing crystalline form D of a compound of formula I, the method being (1) A step of mixing the compound of formula I with solvent D to obtain a solution of the compound of formula I, (2) The step of precipitating a solid, In step (1), solvent D is a mixed solvent of ethanol and water, and the volume fraction of ethanol in the mixed solvent of ethanol and water is 55%.

[0076] In some embodiments of this application, the volume of solvent D is 1 to 50 mL, preferably 5 to 20 mL, based on 1 g of compound I.

[0077] In some specific embodiments of this application, the volume of solvent D is 10 mL based on 1 g of compound I.

[0078] In some embodiments of this application, step (1) is carried out at a temperature in the range from 0°C to the boiling point of the solvent system after mixing, and preferably at the boiling point temperature of the solvent system after mixing.

[0079] In some embodiments of this application, the solid is precipitated in step (2) under conditions of standing, shaking, or stirring, preferably in step (2) under stirring. Step (2) may be carried out at room temperature.

[0080] In some embodiments of this application, the method for preparing crystalline form D further includes a step of separating the solid precipitated in step (2), for example, by filtration. In some embodiments of this application, the method further includes a step of drying the separated solid, the drying temperature may be 45°C, and the drying may be carried out under reduced pressure.

[0081] In yet another aspect, the present application provides a method for preparing crystalline form E of a compound of formula I, the method is (1) A step of mixing the compound of formula I with solvent E to obtain a solution of the compound of formula I, (2) The step of precipitating a solid, In step (1), solvent E is a mixed solvent of methanol and water, and the volume fraction of methanol in the mixed solvent of methanol and water is 75-85%.

[0082] In some embodiments of this application, the volume of solvent E is 1 to 50 mL, preferably 5 to 20 mL, based on 1 g of compound I.

[0083] In some specific embodiments of this application, the volume of solvent E is 10 mL based on 1 g of compound I.

[0084] In some embodiments of this application, step (1) is carried out at a temperature in the range from 0°C to the boiling point of the solvent system after mixing, and preferably at the boiling point temperature of the solvent system after mixing.

[0085] In some embodiments of this application, the solid is precipitated in step (2) under conditions of standing, shaking, or stirring, preferably in step (2) under stirring. Step (2) may be carried out at room temperature.

[0086] In some embodiments of this application, the method for preparing crystalline form E further includes the step of separating the solid precipitated in step (2), for example, by filtration. In some embodiments of this application, the method further includes the step of drying the separated solid.

[0087] In yet another embodiment, the present application provides a crystalline composition comprising crystals of a compound of formula I, wherein the crystals of the compound of formula I constitute 50% by weight or more, preferably 80% by weight or more, more preferably 90% by weight or more, or most preferably 95% by weight or more of the crystalline composition, and the crystals of the compound of formula I are crystalline form A of the compound of formula I, crystalline form B of the compound of formula I, crystalline form C of the compound of formula I, crystalline form D of the compound of formula I, or crystalline form E of the compound of formula I, or a mixture thereof.

[0088] In yet another embodiment, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I described herein, or the above-described crystalline composition, wherein the crystalline compound of formula I is crystalline form A, crystalline form B, crystalline form C, crystalline form D, or crystalline form E of the compound of formula I, or a mixture thereof. The pharmaceutical composition of the present application may or may not contain pharmaceutically acceptable excipients. Furthermore, the pharmaceutical composition of the present application may further contain one or more other therapeutic agents.

[0089] "Pharmacologically acceptable excipients" refer to, but are not limited to, any acceptable fluid facilitators, sweeteners, diluents, preservatives, dyes / colorants, flavorings, surfactants, lubricants, dispersants, disintegrants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that are authorized by the State Food and Drug Administration for use in humans or animals (e.g., livestock). Non-exclusive examples of such excipients include calcium carbonate, calcium phosphate, various sugars and various types of starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol.

[0090] The pharmaceutical compositions of this application can be incorporated into solid, semi-solid, liquid, or gaseous formulations such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols.

[0091] Typical routes for administering the pharmaceutical composition of this application include, but are not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, parenteral, sublingual, vaginal, nasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration. The preferred route of administration is oral administration.

[0092] In yet another aspect, the present application provides the use of crystals of the compound of formula I or the crystalline composition thereof or the pharmaceutical composition thereof in the manufacture of a pharmaceutical for treating and / or preventing diseases mediated by c-Met kinase, wherein the crystals of the compound of formula I are crystalline form A of the compound of formula I, crystalline form B of the compound of formula I, crystalline form C of the compound of formula I, crystalline form D of the compound of formula I, or crystalline form E of the compound of formula I, or a mixture thereof.

[0093] In yet another embodiment, the present application provides the use of crystals of the compound of formula I or the above crystalline composition or the above pharmaceutical composition for treating and / or preventing diseases mediated by c-Met kinase, wherein the crystals of the compound of formula I are crystalline form A of the compound of formula I, crystalline form B of the compound of formula I, crystalline form C of the compound of formula I, crystalline form D of the compound of formula I, or crystalline form E of the compound of formula I, or a mixture thereof.

[0094] In yet another embodiment, the present application provides a method for treating a disease mediated by c-Met kinase, the method comprising administering to a mammal, preferably a human, a therapeutically effective amount of crystals of the compound of formula I, or the crystalline composition thereof, or the pharmaceutical composition thereof, wherein the crystals of the compound of formula I are crystalline form A of the compound of formula I, crystalline form B of the compound of formula I, crystalline form C of the compound of formula I, crystalline form D of the compound of formula I, or crystalline form E of the compound of formula I, or a mixture thereof.

[0095] In the case of drugs or pharmacological agents, the term "therapeutic effective dose" refers to a sufficient amount of the drug or pharmaceutical that is non-toxic and capable of achieving the desired effect. Determining the effective dose varies from person to person, depending on the recipient's age and general health, as well as the specific active substance. An appropriate effective dose in a case can be determined by those skilled in the art based on routine experiments.

[0096] In yet another embodiment, the present application provides crystals of the compound of formula I, or the crystalline composition thereof, or the pharmaceutical composition thereof, for preventing or treating diseases mediated by c-Met kinase, wherein the crystals of the compound of formula I are crystalline form A of the compound of formula I, crystalline form B of the compound of formula I, crystalline form C of the compound of formula I, crystalline form D of the compound of formula I, or crystalline form E of the compound of formula I, or a mixture thereof.

[0097] In some embodiments of this application, the disease mediated by c-Met kinase is a cancer such as lung cancer.

[0098] The technical solutions of this application are described in detail below in conjunction with the drawings and examples, but the scope of protection of this application is not limited to these, but includes them. Compounds of formula I are prepared by referring to the method disclosed in International Publication No. 2012034055. [Examples]

[0099] Preparation of crystalline form A of compound I 20 g of compound I was dissolved in toluene (100 mL), refluxed, dissolved and clarified, filtered, and the filtrate was stirred at room temperature to crystallize. The filtrate was filtered again and air-dried at 60°C under atmospheric pressure to obtain crystal form A. The X-ray powder diffraction pattern using CuKα radiation is shown in Figure 1, the differential scanning calorimetry (DSC) pattern is shown in Figure 2, and the thermogravimetric analysis (TGA) pattern is shown in Figure 3. [Examples]

[0100] Preparation of crystalline form B of compound I 20 g of compound I was dissolved in ethanol (175 mL), refluxed, dissolved and clarified, filtered, and the filtrate was stirred at room temperature to crystallize. The filtrate was filtered again and dried under reduced pressure at 60°C to obtain crystal form B. The X-ray powder diffraction pattern using CuKα radiation is shown in Figure 4, the differential scanning calorimetry (DSC) pattern is shown in Figure 5, and the thermogravimetric analysis (TGA) pattern is shown in Figure 6. [Examples]

[0101] Preparation of crystalline form C of compound I 20 g of compound I was dissolved in dioxane (150 mL), refluxed, dissolved and clarified, filtered, and the filtrate was stirred at room temperature to crystallize. The filtrate was filtered and air-dried at 60°C under atmospheric pressure to obtain crystalline form C. The X-ray powder diffraction pattern using CuKα radiation is shown in Figure 7, the differential scanning calorimetry (DSC) pattern is shown in Figure 8, and the thermogravimetric analysis (TGA) pattern is shown in Figure 9. [Examples]

[0102] Preparation of crystalline form D of compound I 20 g of compound I was dissolved in 200 mL of a 55% ethanol aqueous solution, refluxed until dissolved and clarified, filtered, and the filtrate was stirred at room temperature to crystallize. The filtrate was filtered, dried under reduced pressure at 45°C to obtain crystal form D. The X-ray powder diffraction pattern using CuKα radiation is shown in Figure 10, the differential scanning calorimetry (DSC) pattern is shown in Figure 11, and the thermogravimetric analysis (TGA) pattern is shown in Figure 12. [Examples]

[0103] Preparation of crystalline form E of compound I 20 g of compound I was dissolved in 200 mL of 85% methanol aqueous solution, refluxed, dissolved, clarified, filtered, and the filtrate was stirred at room temperature to crystallize. The filtrate was filtered again and allowed to stand at room temperature for 10 days to obtain crystal form E. The X-ray powder diffraction pattern using CuKα radiation is shown in Figure 13, the differential scanning calorimetry (DSC) pattern is shown in Figure 14, and the thermogravimetric analysis (TGA) pattern is shown in Figure 15. [Examples]

[0104] Moisture absorption test Crystal forms A, B, D, and E of the compound of formula I were selected, and each was tested according to the "Guidelines for Drug Moisture Test" in Chapter 9103 of the Chinese Pharmacopoeia 2015, 4th edition, and the weight increase of the sample due to hygroscopicity was calculated. The results are shown in Figure 6.

[0105] [Table 6] [Examples]

[0106] Determination of intrinsic dissolution rate Crystal forms A, B, D, and E of the compound of formula I were each approximately 80 mg in size and were directly compressed into tablets under high pressure (tablet core diameter 4 mm, pressure 150 kg, maintenance time 2 minutes, repeated 3 times). 700 mL of 0.01 mol / L hydrochloric acid solution was used as the medium, and the intrinsic dissolution rate of the active pharmaceutical ingredient was measured. The results are shown in Figure 7.

[0107] [Table 7] [Examples]

[0108] Pharmacokinetic studies in rats 1.1 Test Objectives SD rats were force-fed with crystalline forms A, B, D, and E of the compound of formula I, and the relative bioavailability of the compound of formula I in vivo was evaluated.

[0109] 1.2 Test Materials SD rats: Purchased from Shanghai Cipur Bikai Laboratory Animal Co., Ltd. Test sample: Crystal forms A, B, D, and E of compound I, separately filled into No. 9 forced oral administration capsules.

[0110] 1.3 Test Method a) Group administration SD rats (body weight 180-200g) were randomly divided into four groups (4 rats / group) after 3-5 days of acclimatization. Crystal forms A, B, D, and E of the compound of formula I were administered intragastricly at a dose of 20 mg / kg. The rats were fasted for 12 hours before administration and fed 4 hours after administration. Drinking water was available before, during, and after the experiment.

[0111] b) Sampling After administration, the collection points were 0.167 hours (10 minutes), 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, and 24 hours. Approximately 0.3 mL of blood was collected from the orbital venous plexus and placed in a centrifuge tube containing EDTA-K2. It was stored at 4°C. The sample was centrifuged at 4°C, 4000 rpm for 10 minutes within 1 hour, stored at -20°C, and then tested.

[0112] A 50 μL sample of the test plasma was pipetteed, 300 μL of acetonitrile solution containing an internal standard was added, the mixture was shaken for 5 minutes, and the mixture was centrifuged at 13,000 rpm for 10 minutes. A 30 μL supernatant was taken, 150 μL of 50% acetonitrile aqueous solution was added, and 1 μL was pipetteed in for LC / MS / MS analysis and measurement.

[0113] a) Detection method Liquid chromatography-tandem mass spectrometry (LC-MS / MS) using diazepam as an internal standard (IS) was employed. The analyte and internal standard were extracted from plasma using protein precipitation, and the compound and internal standard were separated using a reversed-phase chromatography column. The analyte was quantified by electrospray ionization (ESI) mode on a tandem quadrupole mass spectrometer.

[0114] [Table 8]

[0115] [Table 9]

[0116] [Table 10]

[0117] 1.4 Test Results [Table 11]

Claims

1. A crystal of compound B of formula I, 【Chemistry 1】 In the X-ray powder diffraction pattern of crystal B induced by CuKα radiation, diffraction peaks are present at 2θ angles of 7.44 degrees, 8.93 degrees, 10.44 degrees, and 17.84 degrees, for crystal B of compound I.

2. A crystal of compound B of formula I, 【Chemistry 2】 Crystal B of the compound of formula I according to claim 1, wherein, in the X-ray powder diffraction pattern of crystal B induced by CuKα radiation, diffraction peaks exist at 2θ angles of 7.44 degrees, 8.93 degrees, 10.26 degrees, 10.44 degrees, 10.70 degrees, 11.17 degrees, 12.65 degrees, 12.96 degrees, 14.35 degrees, 15.49 degrees, 16.34 degrees, 17.84 degrees, 18.28 degrees, 18.73 degrees, 20.96 degrees, 21.88 degrees, 22.42 degrees, 23.03 degrees, 24.17 degrees, 25.27 degrees, and 26.16 degrees.

3. A crystal of compound B of formula I, 【Transformation 3】 Crystal B of the compound of formula I according to claim 1, wherein, in the X-ray powder diffraction pattern of crystal B induced by CuKα radiation, diffraction peaks exist at 2θ angles of 7.44 degrees, 8.93 degrees, 9.48 degrees, 10.26 degrees, 10.44 degrees, 10.70 degrees, 11.17 degrees, 11.85 degrees, 12.65 degrees, 12.96 degrees, 13.57 degrees, 14.35 degrees, 15.49 degrees, 15.75 degrees, 16.34 degrees, 17.84 degrees, 18.28 degrees, 18.73 degrees, 19.43 degrees, 20.02 degrees, 20.65 degrees, 20.96 degrees, 21.88 degrees, 22.42 degrees, 23.03 degrees, 24.17 degrees, 25.27 degrees, 25.99 degrees, 26.16 degrees, and 29.24 degrees.

4. A pharmaceutical composition containing a therapeutically effective amount of compound B of formula I, 【Chemistry 4】 A pharmaceutical composition wherein the crystal B of the compound of formula I is the crystal B of the compound of formula I described in any one of claims 1 to 3.

5. Use of crystal B of the compound of formula I according to any one of claims 1 to 3 in the manufacture of a pharmaceutical product for treating a disease mediated by c-Met kinase.

6. The use according to claim 5, wherein the disease mediated by c-Met kinase is cancer.

7. The use according to claim 5, wherein the disease mediated by c-Met kinase is lung cancer.

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