A crystalline form of a pyrimidine derivative and a preparation method thereof

Abstract

Provided are crystalline forms of pyrimidine derivatives and methods for preparing the same. This series of crystalline forms exhibit good drug properties (such as stability, etc.), providing multiple choices of active pharmaceutical ingredients for subsequent drug development.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and particularly relates to crystal forms of a series of pyrimidine derivatives, a preparation method thereof, a raw drug, a pharmaceutical composition and a drug containing the crystal forms. Background Art

[0002] Influenza is a major public health problem. According to the estimation of the WHO, seasonal influenza causes about 3 million to 5 million severe cases and 290,000 to 650,000 respiratory disease-related deaths every year. Influenza has brought a heavy burden of death and hospitalization to the world.

[0003] Influenza virus is a negative-stranded single-stranded RNA virus. Its replication does not involve RNA proofreading enzymes, so the mutation frequency is much higher than that of other viruses, and it is easy to cause changes in surface antigens. Influenza viruses can be divided into three types: A, B, and C according to nucleoprotein (NP) and matrix protein (MP). Among them, influenza A virus has the strongest variability and has caused many pandemics. Influenza is a serious public health security event globally, yet effective therapeutic drugs have been lacking.

[0004] M2 ion channel inhibitors have been widely used in the treatment of influenza, which has induced the emergence of influenza drug-resistant strains. Since the outbreak of H1N1 in 2009, the drug resistance of influenza viruses to such drugs has become non-negligible, and their use is no longer recommended. Currently, the main anti-influenza virus drugs are neuraminidase inhibitors (NAIs), such as oseltamivir (Tamiflu), which have obvious effects on influenza A virus. However, through clinical observation, drug-resistant virus strains have emerged for such neuraminidase inhibitors.

[0005] In the field of anti-influenza virus, there is an urgent clinical need for anti-influenza virus drugs with a new mechanism of action, which can support the single-drug use for the treatment of influenza A, or be used in combination with other anti-influenza virus drugs with existing mechanisms of action on the market for the prevention and treatment of influenza A.

[0006] Patent WO2018041263 discloses a series of pyrimidine derivatives. In vitro activity data show that some compounds exhibit positive effects in the influenza virus replication inhibition test. In further animal tests, some compounds also show significant therapeutic effects on the influenza A virus H1N1 mouse infection model. Among them, the compound WX-216 (Example 4) has relatively prominent comprehensive performance and is considered to have good drug development prospects.

[0007]

[0008] Patent WO2019170067 discloses a series of crystal forms, salt forms and crystal forms of salts of WX-216. This series of salt forms / crystal forms have good stability and application prospects in production / clinical practice, providing various choices of intermediate products and / or active pharmaceutical ingredients for the large-scale production of active pharmaceutical ingredients and the downstream processes of pharmaceutical products (such as formulation processes).

[0009] Patent WO2021012864 discloses the sodium salts of WX-216. The crystal forms of this series of compounds show good drug properties (such as stability, fluidity, compressibility, etc.), providing various choices of active pharmaceutical ingredients for subsequent drug development.

[0010] Salt form screening and crystal form screening are one of the important links in drug development. For a specific compound, the advantages and disadvantages of the physical and chemical properties of its free form, various salt forms and corresponding crystal forms are unknown. Based on further consideration of its drug properties, finding suitable salt forms and their corresponding dominant crystal forms and providing various choices of intermediate products and / or active pharmaceutical ingredients for subsequent drug development are of great significance for drug development. Summary of the Invention

[0011] The object of the present invention is to provide hydrates or solvates of the free base of WX-216, and for the first time disclose a series of crystal forms of hydrates or solvates of the free base of WX-216. The crystal forms of this series of compounds show good drug properties (stability, fluidity, compressibility, solubility, bioavailability, etc.), providing various choices of active pharmaceutical ingredients for subsequent drug development.

[0012]

[0013] Specifically, WX-216 is a pyrimidine derivative containing a carboxyl group. Those skilled in the art can understand that WX-216 can exist in the form of hydrates or solvates. Further experimental studies show that for the hydrate of WX-216, the number of water molecules n can be 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5 and 4, that is, 1 molecule of WX-216 combines with n water molecules in a manner well-known in the art to form a hydrate, which is a well-known situation of a free base compound forming a hydrate in the art.

[0014] The present invention also relates to solvates of WX-216. The "solvent" in the solvates is an organic solvent, and the organic solvents include but are not limited to common organic solvents in the art such as methanol, ethanol, propanol, isopropanol, acetone, butanone, acetonitrile, dichloromethane, chloroform, ethyl acetate, etc.

[0015] For the characterization of compound crystal forms, those skilled in the art can understand that for a specific crystal form of a specific compound, due to the influence of instrument equipment, operation methods, sample purity, human factors, etc. during the characterization process, there will be certain fluctuations in the 2θ angles of each diffraction peak in the X-ray powder diffraction pattern (XRPD) during repeated experiments. The fluctuation range (error range) is usually within ±0.2°; in addition, those skilled in the art can also understand that considering factors such as the 2θ angles and absorption intensities (peak heights) of each diffraction peak in the X-ray powder diffraction pattern, the stability and repeatability of the diffraction peaks will be affected; specifically, the diffraction peaks with stronger absorption intensity, better separation, and smaller 2θ angles have better stability and repeatability and are more suitable for characterizing the specific crystal form; while for diffraction peaks with larger 2θ angles and / or poorer separation and / or relatively weaker intensities, they may show large fluctuations due to the influence of instrument equipment, operation methods, sample purity, human factors, etc., and may not reappear during repeated experiments. Therefore, for those skilled in the art, such absorption peaks are not necessary diffraction peaks for characterizing this crystal form; more specifically, in accordance with the consensus in the art regarding crystal form characterization, the selection of diffraction peaks comprehensively considers factors such as 2θ angles and absorption intensities (peak heights) and is grouped according to stability and repeatability.

[0016] Those skilled in the art can also understand that for the differential scanning calorimetry curve (DSC) and thermogravimetric analysis curve (TGA) of samples, the same batch and / or between-batch samples will also show fluctuations in the test results due to the influence of instrument equipment, detection conditions, testers, etc. Therefore, in accordance with the consensus in the art regarding crystal form characterization, the fluctuation range of the starting points of endothermic and exothermic peaks in the DSC pattern is set to ±3°C, and the fluctuation range of the weight loss values in the TGA pattern is set to ±1%.

[0017] Unless otherwise specified, "room temperature" in the present invention refers to 25 ± 5°C, and "no obvious weight loss" in the thermogravimetric analysis curve (TGA) of the present invention means that the weight loss is ≤1% before the detection end temperature.

[0018] The first object of the present invention is to provide a series of crystal forms of the compound of formula (I), and this series of crystal forms exhibit good drug-forming properties.

[0019]

[0020] Wherein, n is selected from any value in the range of 0 to 4.

[0021] Specifically, n is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, and 4.

[0022] Specifically, a preferred embodiment of the present invention relates to crystal form I of the aforementioned compound of formula (I), and its structure is as shown in (1):

[0023]

[0024] Its XRPD pattern has diffraction peaks that stably appear at 2θ of 6.9, 11.0, 11.8, 17.1, 17.9, 18.4, 18.7, 19.8, 22.2, 22.6, 23.8, 26.3, 26.7, 27.7 ± 0.2°.

[0025] Furthermore, for polymorph I of the aforementioned compound of formula (I), its XRPD pattern also has diffraction peaks at 2θ of 8.4, 13.9, 15.0, 20.3, 23.4, 25.3, 25.7, 28.1, 29.4 ± 0.2°.

[0026] Furthermore, in some embodiments of the present invention, for polymorph I of the aforementioned compound of formula (I), the diffraction peaks of its XRPD pattern are shown in the following table:

[0027] Number 2θ (±0.2°) Peak height % Number 2θ (±0.2°) Peak height % 1 6.9 15.2 15 22.2 95.5 2 8.4 6.5 16 22.6 56.7 3 11.0 100.0 17 23.4 6.4 4 11.8 43.4 18 23.8 32.9 5 13.9 7.9 19 25.3 3.6 6 15.0 4.8 20 25.7 3.0 7 16.4 2.6 21 26.3 14.6 8 17.1 10.7 22 26.7 37.7 9 17.9 16.6 23 27.7 20.2 10 18.4 15.0 24 28.1 3.1 11 18.7 30.5 25 29.4 6.7 12 19.8 18.3 26 29.8 2.0 13 20.3 3.7 27 30.7 3.5 14 21.0 2.0

[0028] Furthermore, in some embodiments of the present invention, for polymorph I of the aforementioned compound of formula (I), its XRPD pattern is substantially as Figure 1 shown.

[0029] For polymorph I of the aforementioned compound of formula (I), its differential scanning calorimetry curve (DSC) has the starting points of endothermic peaks at 126.1 ± 3 °C and 195.1 ± 3 °C.

[0030] Furthermore, in some embodiments of the present invention, for polymorph I of the aforementioned compound of formula (I), its DSC pattern is substantially as Figure 2 shown.

[0031] For polymorph I of the aforementioned compound of formula (I), its thermogravimetric analysis curve (TGA) shows a weight loss of 4.14 ± 1% at 160 °C and a weight loss of 0.46 ± 1% at 210 °C.

[0032] Furthermore, in some embodiments of the present invention, for polymorph I of the aforementioned compound of formula (I), its TGA pattern is substantially as Figure 3 shown.

[0033] Specifically, according to a preferred embodiment of the present invention, it relates to polymorph II of the aforementioned compound of formula (I), and its structure is as shown in (2):

[0034]

[0035] Its XRPD pattern has diffraction peaks that stably appear at 2θ of 6.5, 9.2, 12.9, 14.5, 16.5, 19.6, 20.5, 21.7 ± 0.2°.

[0036] Further, for Polymorph II of the compound of formula (I) above, its XRPD pattern further has diffraction peaks at 2θ = 10.2, 16.1, 17.4, 18.5, 23.4, 24.5, 26.2, 26.9, 27.8, 30.0, 31.0 ± 0.2°.

[0037] Further, in some embodiments of the present invention, for Polymorph II of the compound of formula (I) above, the diffraction peaks of its XRPD pattern are as shown in the following table:

[0038]

[0039]

[0040] Further, in some embodiments of the present invention, for Polymorph II of the compound of formula (I) above, its XRPD pattern is substantially as Figure 5 shown.

[0041] For Polymorph II of the compound of formula (I) above, its differential scanning calorimetry curve (DSC) has a starting point of an endothermic peak at 164.0 ± 3 °C.

[0042] Further, in some embodiments of the present invention, for Polymorph II of the compound of formula (I) above, its DSC pattern is substantially as Figure 6 shown.

[0043] For Polymorph II of the compound of formula (I) above, its thermogravimetric analysis curve (TGA) shows a weight loss of 7.41 ± 1% at 150 °C;

[0044] Further, in some embodiments of the present invention, for Polymorph II of the compound of formula (I) above, its TGA pattern is substantially as Figure 7 shown.

[0045] Specifically, according to a preferred embodiment of the present invention, it relates to Polymorph III of the compound of formula (I) above, and its structural formula is as shown in (1) above;

[0046] Its XRPD pattern has diffraction peaks stably appearing at 2θ = 3.7, 6.4, 8.2, 9.5, 9.8, 11.1, 14.8, 18.5, 22.1, 23.6, 25.8 ± 0.2°.

[0047] Further, for Polymorph III of the compound of formula (I) above, its XRPD pattern further has diffraction peaks at 2θ = 4.8, 7.4, 16.5, 29.5 ± 0.2°.

[0048] Furthermore, in some embodiments of the present invention, for polymorph III of the compound of formula (I), the diffraction peaks of its XRPD pattern are shown in the following table:

[0049]

[0050]

[0051] Furthermore, in some embodiments of the present invention, for polymorph III of the compound of formula (I), its XRPD pattern is substantially as Figure 9 shown.

[0052] For polymorph III of the compound of formula (I), its differential scanning calorimetry curve (DSC) has a starting point of an endothermic peak at 177.6 ± 3 °C and a starting point of an endothermic peak at 209.77 ± 3 °C;

[0053] Furthermore, in some embodiments of the present invention, for polymorph III of the compound of formula (I), its DSC pattern is substantially as Figure 10 shown.

[0054] For polymorph III of the compound of formula (I), its thermogravimetric analysis curve (TGA) shows a weight loss of 1.62 ± 1% at 90 °C and a weight loss of 5.50 ± 1% at 200 °C;

[0055] Furthermore, in some embodiments of the present invention, for polymorph III of the compound of formula (I), its TGA pattern is substantially as Figure 11 shown.

[0056] Specifically, according to a preferred embodiment of the present invention, it relates to polymorph IV of the compound of formula (I), and its XRPD pattern has diffraction peaks stably appearing at 2θ = 8.2, 8.7, 10.2, 16.9, 20.4 ± 0.2 °.

[0057] Furthermore, for polymorph IV of the compound of formula (I), its XRPD pattern also has diffraction peaks at 2θ = 5.6, 7.2, 12.2, 14.3, 14.6, 15.5, 15.8, 18.8, 21.0, 21.8, 22.7 ± 0.2 °;

[0058] Furthermore, in some embodiments of the present invention, for polymorph IV of the compound of formula (I), the diffraction peaks of its XRPD pattern are shown in the following table:

[0059] Number 2θ (±0.2°) Peak height % Number 2θ (±0.2°) Peak height % 1 5.6 5.7 10 15.8 5.0 2 7.2 7.8 11 16.9 17.6 3 8.2 100.0 12 18.8 9.8 4 8.7 41.1 13 20.4 15.2 5 10.2 20.7 14 21.0 7.7 6 12.2 7.7 15 21.8 4.1 7 14.3 5.5 16 22.7 3.9 8 14.6 6.1 17 25.0 2.8 9 15.5 5.8 18 26.7 2.2

[0060] Furthermore, in some embodiments of the present invention, for polymorph IV of the compound of formula (I), its XRPD pattern is substantially as Figure 13 shown.

[0061] Polymorph IV of the foregoing compound of formula (I), having an onset of an endothermic peak in a differential scanning calorimetry (DSC) curve at 125.0 ± 3 °C.

[0062] Furthermore, in some embodiments of the present invention, polymorph IV of the foregoing compound of formula (I), the DSC pattern thereof is substantially as Figure 14 shown.

[0063] Polymorph IV of the foregoing compound of formula (I), having a weight loss of 9.72 ± 1% at 170 °C in a thermogravimetric analysis (TGA) curve.

[0064] Furthermore, in some embodiments of the present invention, polymorph IV of the foregoing compound of formula (I), the TGA pattern thereof is substantially as Figure 15 shown.

[0065] Specifically, according to a preferred embodiment of the present invention, it relates to polymorph V of the foregoing compound of formula (I), the structural formula of which is as shown in the foregoing (1);

[0066] Its XRPD pattern has diffraction peaks stably appearing at 2θ of 4.9, 8.7, 10.3, 12.2, 14.7, 15.3, 16.5, 18.8, 19.8, 20.6, 21.9, 23.7, 23.9, 25.6, 28.6, 29.7 ± 0.2 °.

[0067] Furthermore, polymorph V of the foregoing compound of formula (I), its XRPD pattern also has diffraction peaks at 2θ of 17.4, 20.4, 22.7, 24.8, 25.1, 25.9, 26.6, 27.6, 29.3, 30.4 ± 0.2 °.

[0068] Furthermore, in some embodiments of the present invention, for polymorph V of the foregoing compound of formula (I), the diffraction peak conditions of its XRPD pattern are shown in the following table:

[0069] Number 2θ (±0.2°) Peak height % Number 2θ (±0.2°) Peak height % 1 4.9 14.5 14 22.7 9.5 2 8.7 100.0 15 23.7 19.5 3 10.3 57.1 16 23.9 15.7 4 12.2 25.4 17 24.8 8.1 5 14.7 54.6 18 25.1 5.5 6 15.3 53.2 19 25.6 10.2 7 16.5 30.0 20 25.9 4.4 8 17.4 5.5 21 26.6 8.7 9 18.8 63.9 22 27.6 8.6 10 19.8 27.5 23 28.6 12.1 11 20.4 8.7 24 29.3 8.2 12 20.6 30.5 25 29.7 11.3 13 21.9 36.8 26 30.4 8.8

[0070] Furthermore, in some embodiments of the present invention, polymorph V of the foregoing compound of formula (I), the XRPD pattern thereof is substantially as Figure 16 shown.

[0071] Polymorph V of the foregoing compound of formula (I), having an onset of an endothermic peak in a differential scanning calorimetry (DSC) curve at 229.5 ± 3 °C.

[0072] Furthermore, in some embodiments of the present invention, polymorph V of the foregoing compound of formula (I), the DSC pattern thereof is substantially as Figure 17 shown.

[0073] Polymorph V of the compound of formula (I) above, whose thermogravimetric analysis curve (TGA) shows a weight loss of 71.02 ± 1% at 125 °C and a weight loss of 3.07 ± 1% at 200 °C.

[0074] Furthermore, in some embodiments of the present invention, polymorph V of the compound of formula (I) above has a TGA pattern substantially as Figure 18 shown.

[0075] Specifically, according to a preferred embodiment of the present invention, it relates to polymorph VI of the compound of formula (I) above, whose structural formula is as shown in (3):

[0076]

[0077] Its XRPD pattern has diffraction peaks stably appearing at 2θ = 6.4, 7.0, 9.0, 11.4, 12.1, 14.2, 15.6, 16.6, 17.2, 17.6, 18.6, 19.3, 19.6, 20.6, 21.4, 21.9, 23.2, 24.9, 26.4, 29.6 ± 0.2°.

[0078] Furthermore, polymorph VI of the compound of formula (I) above also has diffraction peaks at 2θ = 13.5, 25.4, 27.2, 30.3 ± 0.2°.

[0079] Furthermore, in some embodiments of the present invention, the diffraction peak situation of the XRPD pattern of polymorph VI of the compound of formula (I) above is shown in the following table:

[0080]

[0081]

[0082] Furthermore, in some embodiments of the present invention, the XRPD pattern of polymorph VI of the compound of formula (I) above is substantially as Figure 20 shown.

[0083] Polymorph VI of the compound of formula (I) above has the starting point of an endothermic peak at 78.5 ± 3 °C in its differential scanning calorimetry curve (DSC);

[0084] Furthermore, in some embodiments of the present invention, the DSC pattern of polymorph VI of the compound of formula (I) above is substantially as Figure 21 shown.

[0085] Polymorph VI of the compound of formula (I) above has a weight loss of 14.44 ± 1% at 165 °C in its thermogravimetric analysis curve (TGA);

[0086] Further, in some embodiments of the present invention, the polymorph VI of the compound of formula (I) has a TGA pattern substantially as shown in Figure 22 shown.

[0087] The second object of the present invention is to provide a polymorph VII of a solvate of the compound of formula (II), which polymorph exhibits good drugability.

[0088]

[0089] Specifically, the solvate of the compound of formula (II) is a methyl tert-butyl ether solvate of the compound of formula (II).

[0090] Specifically, for the aforementioned polymorph VII, its XRPD pattern has diffraction peaks stably appearing at 2θ of 7.7, 8.9, 12.4, 14.7, 17.9, 18.4, 19.9, 20.6, 23.1, 23.6, 27.8, 28.7 ± 0.2°.

[0091] Further, for the aforementioned polymorph VII, its XRPD pattern also has diffraction peaks at 2θ of 5.9, 15.4, 16.1, 17.5, 19.0, 21.7, 24.5, 28.1, 30.8 ± 0.2°.

[0092] Further, in some embodiments of the present invention, the diffraction peak conditions of the XRPD pattern of the aforementioned polymorph VII are as shown in the following table:

[0093] Number 2θ (±0.2°) Peak height % Number 2θ (±0.2°) Peak height % 1 5.9 6.2 13 20.6 28.1 2 7.7 37.7 14 21.7 8.7 3 8.9 100.0 15 23.1 28.8 4 12.4 81.0 16 23.6 11.9 5 14.7 45.3 17 24.5 7.8 6 15.4 7.4 18 25.3 6.0 7 16.1 4.6 19 25.8 1.8 8 17.5 9.7 20 27.8 10.7 9 17.9 25.7 21 28.1 9.2 10 18.4 22.3 22 28.7 11.5 11 19.0 6.6 23 30.8 7.8 12 19.9 15.1

[0094] Further, in some embodiments of the present invention, the XRPD pattern of the aforementioned polymorph VII is substantially as shown in Figure 23 shown.

[0095] For the aforementioned polymorph VII, its differential scanning calorimetry curve (DSC) has a starting point of an endothermic peak at 161.8 ± 3 °C.

[0096] Further, in some embodiments of the present invention, the DSC pattern of the aforementioned polymorph VII is substantially as shown in Figure 24 shown.

[0097] For the aforementioned polymorph VII, its thermogravimetric analysis curve (TGA) shows a weight loss of 16.56 ± 1% at 185 °C.

[0098] Further, in some embodiments of the present invention, the TGA pattern of the aforementioned polymorph VII is substantially as shown in Figure 25 shown.

[0099] The third object of the present invention is to provide a polymorph VIII of a solvate of the compound of formula (II) and a method for preparing the same.

[0100] Specifically, the solvate of the compound of formula (II) is the N-methylpyrrolidone solvate of the compound of formula (II).

[0101] Specifically, for the aforementioned crystalline form VIII, its XRPD pattern has diffraction peaks stably appearing at 2θ of 7.8, 8.4, 16.2 ± 0.2°.

[0102] Furthermore, for the aforementioned crystalline form VIII, its XRPD pattern also has diffraction peaks at 2θ of 9.9, 13.7, 15.0, 16.9, 18.2, 21.8 ± 0.2°.

[0103] Furthermore, in some embodiments of the present invention, for the aforementioned crystalline form VIII, the diffraction peaks of its XRPD pattern are shown in the following table:

[0104]

[0105]

[0106] Furthermore, in some embodiments of the present invention, for the aforementioned crystalline form VIII, its XRPD pattern is substantially as Figure 27 shown.

[0107] For the aforementioned crystalline form VIII, its differential scanning calorimetry curve (DSC) has the starting point of an endothermic peak at 116.5 ± 3 °C and the starting point of an endothermic peak at 171.6 ± 3 °C.

[0108] Furthermore, in some embodiments of the present invention, for the aforementioned crystalline form VIII, its DSC pattern is substantially as Figure 28 shown.

[0109] For the aforementioned crystalline form VIII, its thermogravimetric analysis curve (TGA) shows a weight loss of 13.50 ± 1% at 165 °C.

[0110] Furthermore, in some embodiments of the present invention, for the aforementioned crystalline form VIII, its TGA pattern is substantially as Figure 29 shown.

[0111] The fourth object of the present invention is to provide a metastable crystalline form of the compound of formula (II) and a preparation method thereof.

[0112] Specifically, for the metastable crystalline form IX of the aforementioned compound of formula (II), its XRPD pattern has diffraction peaks stably appearing at 2θ of 9.0, 10.5, 16.5, 19.6, 21.1, 22.8, 24.2 ± 0.2°.

[0113] Further, the crystalline form IX of the compound of formula (II) has diffraction peaks in its XRPD pattern at 2θ of 11.8, 17.5, 26.4, 27.5 ± 0.2°.

[0114] Further, in some embodiments of the present invention, for the crystalline form IX of the compound of formula (II), the diffraction peaks of its XRPD pattern are shown in the following table:

[0115] Number 2θ (±0.2°) Peak height % Number 2θ (±0.2°) Peak height % 1 9.0 15.1 7 21.1 25.7 2 10.5 19.4 8 22.8 37.3 3 11.8 8.5 9 24.2 36.7 4 16.5 33.8 10 26.4 14.2 5 17.5 27.8 11 27.5 15.2 6 19.6 100.0

[0116] Further, in some embodiments of the present invention, for the crystalline form IX of the compound of formula (II), its XRPD pattern is substantially as Figure 30 shown.

[0117] The fifth object of the present invention is to provide a bulk drug substance, which contains at least one of crystalline forms I to IX of the compound WX-216 of the present invention or other hydrates and solvates of the compound WX-216.

[0118] Based on the beneficial effects of the crystalline forms I to IX of the compound WX-216 of the present invention and other hydrates and solvates of the compound WX-216, the bulk drug substance containing the crystalline forms also exhibits beneficial effects (such as stability, water solubility, etc.) substantially consistent with the crystalline forms. Specifically, the bulk drug substance may be the compound WX-216, or the compound WX-216 and / or a hydrate of the compound WX-216; more specifically, the mass percentage of the crystalline form I of the compound WX-216 and / or the crystalline form II of the compound WX-216 and / or the crystalline form III of the compound WX-216 and / or the crystalline form IV of the compound WX-216 and / or the crystalline form V of the compound WX-216 and / or the crystalline form VI of the compound WX-216 and / or the crystalline form VII of the compound WX-216 and / or the crystalline form VIII of the compound WX-216 and / or the crystalline form IX of the compound WX-216 in the bulk drug substance is any value from 0.01 to 99.99%. Further, the mass percentage of the crystalline form I of the compound WX-216 and / or the crystalline form II of the compound WX-216 and / or the crystalline form III of the compound WX-216 and / or the crystalline form IV of the compound WX-216 and / or the crystalline form V of the compound WX-216 and / or the crystalline form VI of the compound WX-216 and / or the crystalline form VII of the compound WX-216 and / or the crystalline form VIII of the compound WX-216 and / or the crystalline form IX of the compound WX-216 in the bulk drug substance is any value from 1.00 to 99.00%.

[0119] The sixth object of the present invention is to provide a pharmaceutical composition, which comprises a pharmaceutically acceptable excipient and the aforementioned active pharmaceutical ingredient. Specifically, the pharmaceutically acceptable excipient includes but is not limited to at least one of fillers, binders, disintegrants, and lubricants. Specifically, based on the beneficial effects of the aforementioned crystal forms I to IX of the compound WX-216, other hydrates, and solvates of the compound WX-216 of the present invention, the beneficial effects are ultimately reflected in the pharmaceutical composition; more specifically, the mass percentage of the aforementioned active pharmaceutical ingredient contained in the pharmaceutical composition is any value from 1.00% to 99.00%, further, the mass percentage of the aforementioned active pharmaceutical ingredient contained in the pharmaceutical composition is any value from 5.00% to 95.00%, and still further, the mass percentage of the aforementioned active pharmaceutical ingredient contained in the pharmaceutical composition is any value from 10.00% to 90.00%.

[0120] The seventh object of the present invention is to provide a drug, which comprises at least one of the aforementioned crystal forms I to IX of the compound WX-216, other hydrates, and solvates of the compound WX-216, the aforementioned active pharmaceutical ingredient, or the aforementioned pharmaceutical composition.

[0121] The eighth object of the present invention is to provide the use of the aforementioned crystal forms I to IX of the compound WX-216, other hydrates, and solvates of the compound WX-216, the aforementioned active pharmaceutical ingredient, or the aforementioned pharmaceutical composition in the preparation of drugs for treating influenza.

[0122] In summary, the crystal forms I to IX of the compound WX-216 and other hydrates and solvates of the compound WX-216 of the present invention have certain prospects for drug development. Therefore, if it is proven by detection means that the crystal forms I to IX of the compound WX-216 or other hydrates and solvates of the compound WX-216 are present in the aforementioned active pharmaceutical ingredient and / or pharmaceutical composition, it should be regarded as using the crystal forms I to IX of the compound WX-216 or other hydrates and solvates of the compound WX-216 provided by the present invention. In addition to the aforementioned X-ray powder diffraction, the detection means may further include differential scanning calorimetry (DSC), infrared spectroscopy (IR), Raman spectroscopy (Raman), solid-state nuclear magnetic resonance (SSNMR) and other methods, as well as all other detection methods that can prove alone or comprehensively the use of the crystal forms I to IX of the compound WX-216 or other hydrates and solvates of the compound WX-216 of the present invention, and the commonly used methods by those skilled in the art can be used to remove the influence brought by pharmaceutical excipients, etc., such as the subtraction spectrum method, etc.

[0123] The present invention has the following advantages and beneficial effects compared with the prior art:

[0124] 1. For the first time, a crystalline form I of a compound of formula (I) and its preparation method are disclosed. It is a hydrate of WX-216. This crystalline form has the characteristics of high stability and has considerable prospects for drug development.

[0125] 2. For the first time, a crystalline form II of a compound of formula (I) and its preparation method are disclosed. It is a hydrate of WX-216. This crystalline form has the characteristics of high stability and has considerable prospects for drug development.

[0126] 3. For the first time, a crystalline form III of a compound of formula (I) and its preparation method are disclosed. It is a hydrate of WX-216. This crystalline form has the characteristics of high stability, especially in a non-aqueous system, and has considerable prospects for drug development.

[0127] 4. For the first time, a crystalline form IV of a compound of formula (I) and its preparation method are disclosed. It is a hydrate of WX-216, providing various choices of intermediate products and / or active pharmaceutical ingredients for the large-scale production of active pharmaceutical ingredients and the downstream processes of pharmaceutical products (such as formulation processes).

[0128] 5. For the first time, a crystalline form V of a compound of formula (I) and its preparation method are disclosed. It is a hydrate of WX-216, providing various choices of intermediate products and / or active pharmaceutical ingredients for the large-scale production of active pharmaceutical ingredients and the downstream processes of pharmaceutical products (such as formulation processes).

[0129] 6. For the first time, a crystalline form VI of a compound of formula (I) and its preparation method are disclosed. It is a hydrate of WX-216, providing various choices of intermediate products and / or active pharmaceutical ingredients for the large-scale production of active pharmaceutical ingredients and the downstream processes of pharmaceutical products (such as formulation processes).

[0130] 7. For the first time, a crystalline form VII of a methyl tert-butyl ether solvate of a compound of formula (II) and its preparation method are disclosed. This crystalline form has the characteristics of high stability and has considerable prospects for drug development.

[0131] 8. For the first time, a crystalline form VIII of an N-methylpyrrolidone solvate of a compound of formula (II) and its preparation method are disclosed, providing various choices of intermediate products and / or active pharmaceutical ingredients for the large-scale production of active pharmaceutical ingredients and the downstream processes of pharmaceutical products (such as formulation processes).

[0132] 9. For the first time, a crystalline form IX of a compound of formula (II) and its preparation method are disclosed. It is a metastable state of WX-216, providing various choices of intermediate products and / or active pharmaceutical ingredients for the large-scale production of active pharmaceutical ingredients and the downstream processes of pharmaceutical products (such as formulation processes).

[0133] 10. Provided is a bulk drug substance which contains at least one of polymorphic forms I to IX of the compound WX-216 of the present invention or other hydrates or solvates of the compound WX-216, and the bulk drug substance exhibits beneficial effects substantially consistent with those of polymorphic forms I to IX of the compound WX-216 of the present invention or other hydrates or solvates of the compound WX-216;

[0134] 11. Provided is a pharmaceutical composition which includes a pharmaceutically acceptable excipient and the bulk drug substance of the present invention, and it has beneficial effects substantially consistent with those of polymorphic forms I to IX of the compound WX-216 of the present invention or the compound WX-216 or its hydrates or solvates. BRIEF DESCRIPTION OF THE DRAWINGS

[0135] Figure 1 : XRPD spectrum of polymorphic form I of the compound of formula (I);

[0136] Figure 2 : DSC spectrum of polymorphic form I of the compound of formula (I);

[0137] Figure 3 : TGA spectrum of polymorphic form I of the compound of formula (I);

[0138] Figure 4 : Comparative XRPD diagram of polymorphic form I of the compound of formula (I);

[0139] Figure 5 : XRPD spectrum of polymorphic form II of the compound of formula (I);

[0140] Figure 6 : DSC spectrum of polymorphic form II of the compound of formula (I);

[0141] Figure 7 : TGA spectrum of polymorphic form II of the compound of formula (I);

[0142] Figure 8 : Comparative XRPD diagram of polymorphic form II of the compound of formula (I);

[0143] Figure 9 : XRPD spectrum of polymorphic form III of the compound of formula (I);

[0144] Figure 10 : DSC spectrum of polymorphic form III of the compound of formula (I);

[0145] Figure 11 : TGA spectrum of polymorphic form III of the compound of formula (I);

[0146] Figure 12 : Comparative XRPD diagram of polymorphic form III of the compound of formula (I);

[0147] Figure 13 : XRPD spectrum of polymorph IV of the compound of formula (I);

[0148] Figure 14 : DSC spectrum of polymorph IV of the compound of formula (I);

[0149] Figure 15 : TGA spectrum of polymorph IV of the compound of formula (I);

[0150] Figure 16 : XRPD spectrum of polymorph V of the compound of formula (I);

[0151] Figure 17 : DSC spectrum of polymorph V of the compound of formula (I);

[0152] Figure 18 : TGA spectrum of polymorph V of the compound of formula (I);

[0153] Figure 19 : Comparative XRPD diagram of polymorph V of the compound of formula (I);

[0154] Figure 20 : XRPD spectrum of polymorph VI of the compound of formula (I);

[0155] Figure 21 : DSC spectrum of polymorph VI of the compound of formula (I);

[0156] Figure 22 : TGA spectrum of polymorph VI of the compound of formula (I);

[0157] Figure 23 : XRPD spectrum of polymorph VII of the compound of formula (II);

[0158] Figure 24 : DSC spectrum of polymorph VII of the compound of formula (II);

[0159] Figure 25 : TGA spectrum of polymorph VII of the compound of formula (II);

[0160] Figure 26 : Comparative XRPD diagram of polymorph VII of the compound of formula (II);

[0161] Figure 27 : XRPD spectrum of polymorph VIII of the compound of formula (II);

[0162] Figure 28 : DSC spectrum of polymorph VIII of the compound of formula (II);

[0163] Figure 29 : TGA spectrum of polymorph VIII of the compound of formula (II);

[0164] Figure 30 : XRPD pattern of crystalline form IX of the compound of formula (II). Detailed implementation manners

[0165] The present invention will be further described in detail below in conjunction with examples and the accompanying drawings, but the implementation manners of the invention are not limited thereto.

[0166] Detection conditions

[0167] X-ray powder diffraction

[0168] X-ray powder diffractometer: Bruker D8 Advance;

[0169] 2θ scanning angle: from 3° to 45°;

[0170] Scanning step size: 0.02°;

[0171] Exposure time: 0.2 s;

[0172] Tube voltage and current: 40 kV, 40 mA.

[0173] Differential scanning calorimetry

[0174] Differential scanning calorimeter: TA Discovery 2500 (TA, US);

[0175] Heating rate: 10 °C / min;

[0176] Detection method: After the sample is accurately weighed, it is placed in a DSC Tzero sample pan and heated to 350 °C, and the nitrogen purge rate in the furnace is 50 mL / min.

[0177] Thermogravimetric analysis

[0178] Thermogravimetric analyzer: TA Discovery 55 (TA, US);

[0179] Detection method: The sample is placed in an open aluminum sample pan that has been balanced and automatically weighed in the heating furnace. The sample is heated to 400 °C at a rate of 10 °C / min, the nitrogen purge rate at the sample is 60 mL / min, and the nitrogen purge rate at the balance is 40 mL / min.

[0180] Preparation method of compound WX-216 in Example 1

[0181] WX-216 was prepared by referring to the method disclosed in Example 4 of Patent WO2018041263A1.

[0182] Preparation method of crystalline form I of the compound of formula (I) in Example 2

[0183] Weigh 202.3 mg of WX-216 prepared by the method of Example 1, add it to 2.5 mL of n-heptane to prepare a suspension, place the obtained suspension under stirring at room temperature (~25 °C) for 70 h, centrifuge the suspension, and dry it under vacuum at room temperature to obtain a white solid, which is Crystal Form I. The XRPD pattern of the obtained Crystal Form I is as Figure 1 shown, and the DSC pattern is as Figure 2 shown, and the TGA pattern is as Figure 3 shown.

[0184] Preparation method of Crystal Form I of the compound of formula (I) in Example 3

[0185] Weigh 201.2 mg of WX-216 prepared by the method of Example 1, add it to 2.5 mL of ethyl acetoacetate to prepare a suspension, place the obtained suspension under stirring at room temperature (~25 °C) for 70 h, centrifuge the suspension, and dry it under vacuum at room temperature to obtain a white solid, which is Crystal Form I.

[0186] The comparison of the XRPD patterns of the obtained Crystal Form I is as Figure 4 shown.

[0187] Preparation method of Crystal Form II of the compound of formula (I) in Example 4

[0188] Weigh 202.1 mg of Crystal Form I prepared by the method of Example 2, add it to 1.0 mL of 1,4-dioxane to prepare a suspension, place the obtained suspension under stirring at room temperature (~25 °C) for 70 h, centrifuge the suspension, and dry it under vacuum at room temperature to obtain a white solid, which is Crystal Form II. The XRPD pattern of the obtained Crystal Form II is as Figure 5 shown, and the DSC pattern is as Figure 6 shown, and the TGA pattern is as Figure 7 shown.

[0189] Preparation method of Crystal Form II of the compound of formula (I) in Example 5

[0190] Weigh 101.0 mg of Crystal Form I prepared by the method of Example 2, add 10.0 mL of toluene and heat to 90 °C. It cannot be completely dissolved. Cool to 60 °C and carry out suspension milling for 19 h. Centrifuge the suspension and dry it under vacuum at room temperature to obtain a white solid, which is Crystal Form II.

[0191] The comparison of the XRPD patterns of the obtained Crystal Form II is as Figure 8 shown.

[0192] Preparation method of Crystal Form III of the compound of formula (I) in Example 6

[0193] Weigh 203.1 mg of Form I prepared by the method of Example 2, add it to 2.5 mL of isopropanol to prepare a suspension, place the obtained suspension under stirring at room temperature (~25 °C) for 70 h, centrifuge the suspension, and dry it under vacuum at room temperature to obtain a white solid, which is Form III. The XRPD pattern of the obtained Form III is as shown in Figure 9 shown, and the DSC pattern is as shown in Figure 10 shown, and the TGA pattern is as shown in Figure 11 shown.

[0194] Preparation method of Form III of the compound of formula (I) in Example 7

[0195] Weigh 102.5 mg of Form I prepared by the method of Example 2, add it to 1.0 mL of n-propanol, heat it to 60 °C until completely dissolved, let the clear solution stand at 5 °C for 12 h, centrifuge the suspension, and dry it under vacuum at room temperature to obtain a white solid, which is Form III.

[0196] The comparison of the XRPD patterns of the obtained Form III is as shown in Figure 12 shown.

[0197] Preparation method of Form IV of the compound of formula (I) in Example 8

[0198] Weigh 202.9 mg of Form I prepared by the method of Example 2, add it to 2.5 mL of acetylacetone to prepare a suspension, place the obtained suspension under stirring at room temperature (~25 °C) for 70 h, centrifuge the suspension, and dry it under vacuum at room temperature to obtain a white solid, which is Form IV. The XRPD pattern of the obtained Form IV is as shown in Figure 13 shown, and the DSC pattern is as shown in Figure 14 shown, and the TGA pattern is as shown in Figure 15 shown.

[0199] Preparation method of Form V of the compound of formula (I) in Example 9

[0200] Weigh 202.6 mg of Form I prepared by the method of Example 2, suspend it in 2 mL of water, add 6 mL of NMP dropwise at 60 °C until the solid is completely dissolved, then cool it to room temperature and stir until a solid precipitates, centrifuge and dry it under vacuum at room temperature to obtain a white solid, which is Form V. The XRPD pattern of the obtained Form V is as shown in Figure 16 shown, and the DSC pattern is as shown in Figure 17 shown, and the TGA pattern is as shown in Figure 18 shown.

[0201] Preparation method of Form V of the compound of formula (I) in Example 10

[0202] Weigh 103.1 mg of Crystal Form I prepared by the method of Example 2, add 0.5 mL of NMP, heat to 60 °C and dissolve completely. Place the clear solution at 5 °C and let it stand for 20 h. Centrifuge the suspension and dry it under vacuum at room temperature to obtain a white solid, which is Crystal Form V.

[0203] The comparison of the XRPD spectra of the obtained Crystal Form V is as Figure 19 shown.

[0204] Preparation method of Crystal Form VI of the compound of Formula (I) in Example 11

[0205] Weigh 1.0 g of Crystal Form I prepared by the method of Example 2, prepare a saturated solution (tetrahydrofuran / water), and add 2.2 mL of the saturated solution dropwise to 1.5 mL of water under stirring at room temperature (~25 °C) until a solid precipitates. After centrifugation, dry it under vacuum at room temperature to obtain an off-white solid, which is Crystal Form VI. The XRPD spectrum of the obtained Crystal Form VI is as Figure 20 shown, and the DSC spectrum is as Figure 21 shown, and the TGA spectrum is as Figure 22 shown.

[0206] Preparation method of Crystal Form VII of the methyl tert-butyl ether solvate of the compound of Formula (II) in Example 12

[0207] Weigh 202.0 mg of Crystal Form I prepared by the method of Example 2, add it to 2.5 mL of methyl tert-butyl ether to prepare a suspension. Place the obtained suspension under stirring at room temperature (~25 °C) for 70 h. Centrifuge the suspension and dry it under vacuum at room temperature to obtain an off-white solid, which is Crystal Form VII. The XRPD spectrum of the obtained Crystal Form VII is as Figure 23 shown, and the DSC spectrum is as Figure 24 shown, and the TGA spectrum is as Figure 25 shown.

[0208] Preparation method of Crystal Form VII of the methyl tert-butyl ether solvate of the compound of Formula (II) in Example 13

[0209] Weigh 102.1 mg of Crystal Form I prepared by the method of Example 2, suspend it in 2 mL of ethanol, add 0.2 mL of methyl tert-butyl ether dropwise at 60 °C until the solid dissolves completely, then cool to room temperature and stir until a solid precipitates. After centrifugation, dry it under vacuum at room temperature to obtain an off-white solid, which is Crystal Form VII.

[0210] The comparison of the XRPD spectra of the obtained Crystal Form VII is as Figure 26 shown.

[0211] Preparation method of Crystal Form VIII of the N-methylpyrrolidone solvate of the compound of Formula (II) in Example 14

[0212] Weigh 202.6 mg of Crystal Form I prepared by the method of Example 2, suspend it in 2 mL of acetonitrile, add 6 mL of NMP dropwise at 60 °C until the solid is completely dissolved, then cool to room temperature and stir until a solid precipitates. After centrifugal separation, dry it under vacuum at room temperature to obtain an off-white solid, which is Crystal Form VIII. The XRPD pattern of the obtained Crystal Form VIII is as shown in Figure 27 shown, and the DSC pattern is as shown in Figure 28 shown, and the TGA pattern is as shown in Figure 29 shown.

[0213] Preparation method of Crystal Form IX of the compound of formula (II) in Example 15

[0214] Weigh 1.0 g of Crystal Form I prepared by the method of Example 2, dissolve it in tetrahydrofuran to prepare a saturated solution, and add 0.6 mL of the saturated solution dropwise to 1.5 mL of cyclohexane under stirring at room temperature (~25 °C) until a solid precipitates. After centrifugal separation, dry it under vacuum at room temperature to obtain an off-white solid, which is Crystal Form IX. The XRPD pattern of the obtained Crystal Form IX is as shown in Figure 30 shown.

[0215] Example 16 Stability study

[0216] Weigh a certain amount of the sample to be tested and place it in a petri dish. Place it under high temperature (60 °C), high humidity (25 °C, 92.5% RH), light (25 °C, 4500 Lux), and accelerated conditions (40 °C, 75% RH) respectively, and take samples for XRPD characterization after 14 days.

[0217] Perform stability studies on Crystal Form I, Crystal Form II, Crystal Form III, and Crystal Form IV under high temperature (60 °C), high humidity (25 °C, 92.5% RH), light (25 °C, 4500 Lux), and accelerated conditions (40 °C, 75% RH) respectively. The results are shown in Table 1:

[0218] Table 1 Results of stability study (crystal form)

[0219]

[0220]

[0221] Table 2 Results of stability study

[0222]

[0223]

[0224] *N.D. means not detected

[0225] The results showed that no crystal transformation occurred for crystal forms I, II, III, and VII under the conditions of the stability study; the test results of related substances showed that crystal forms II and III were unstable under light conditions, and the increase in impurities was obvious. The stability study results showed that crystal forms I, II, and III were relatively stable in terms of crystal form and related substances.

[0226] Example 17 Competitive Suspension Experiment

[0227] Weigh a certain amount of crystal form I, crystal form II, crystal form III, and crystal form VII respectively and add them to absolute ethanol. Prepare saturated solutions at room temperature (~25 °C), 40 °C, and 60 °C respectively, stir at different temperatures, and timely take solid samples for characterization.

[0228] Table 3 Results of Competitive Suspension Experiment

[0229]

[0230]

[0231] The results showed that within the range of room temperature (~25 °C) to 60 °C, crystal form III was generated after the experiment for both crystal form I and crystal form II, and crystal form I was generated from crystal form VII at 60 °C. It can be seen that crystal form III has better stability than other crystal forms in the anhydrous system.

[0232] The functions of crystal form I and crystal form II also lie in that they can be used as intermediate crystal forms to further prepare some other stable crystal forms described in the present invention;

[0233] In addition, the inventors also found during the experiment and further research:

[0234] Crystal form IV can be obtained by adding acetylacetone to crystal form I and stirring for a long time and then crystallizing. Those skilled in the art can understand that crystal form IV has high stability;

[0235] Crystal form V can be obtained by suspending crystal form I in water, then adding NMP and heating to 60 °C to completely dissolve it, and leaving the clarified solution to stand at 5 °C for 20 h to crystallize. Those skilled in the art can understand that crystal form V has high stability;

[0236] Crystal form VI can be obtained by preparing a saturated solution (tetrahydrofuran / water) of crystal form I and dropping the saturated solution into water under stirring at room temperature and then crystallizing. Those skilled in the art can understand that crystal form VI has high stability;

[0237] Crystal form VII can be obtained by preparing a suspension in crystal form I with methyl tert-butyl ether, placing the obtained suspension at room temperature, stirring the suspension for 70 h, and crystallizing. Those skilled in the art can understand that crystal form VII has high stability;

[0238] Polymorph VIII can be obtained by suspending Polymorph I in acetonitrile, dropwise adding NMP at 60 °C, and cooling to room temperature followed by stirring for crystallization. Those skilled in the art can understand that Polymorph VIII has high stability;

[0239] Polymorph IX is an intermediate metastable polymorph. During the experiment, it was found that Polymorph IX can only exist in the wet state. Transcrystallization will occur if the suction filtration time is too long or during drying, and it will turn into Polymorph I, indicating that Polymorph I has high stability.

[0240] In summary, the polymorphs of the compound WX-216 described in the present invention have at least one of the effects such as stability, providing various choices of intermediate products and / or active pharmaceutical ingredients for the large-scale production of active pharmaceutical ingredients and the downstream processes of pharmaceutical products (such as formulation processes).

[0241] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement methods and are all included in the protection scope of the present invention.

Claims

1. Crystal form I of a compound, the structural formula of which is shown in (1): It is characterized in that the XRPD pattern of crystal form I of the said compound has diffraction peaks at 2θ of 6.9, 11.0, 11.8, 17.1, 17.9, 18.4, 18.7, 19.8, 22.2, 22.6, 23.8, 26.3, 26.7, 27.7 ± 0.2°.

2. Crystal form I of the compound according to claim 1, It is characterized in that the XRPD pattern of crystal form I of the said compound also has diffraction peaks at 2θ of 8.4, 13.9, 15.0, 20.3, 23.4, 25.3, 25.7, 28.1, 29.4 ± 0.2°.

3. Crystal form I of the compound according to claim 1, It is characterized in that the diffraction peak conditions of the XRPD pattern of crystal form I of the said compound are shown in the following table: 。 4. Crystal form I of the compound according to claim 1, It is characterized in that for crystal form I of the said compound, its XRPD pattern is basically as shown in Figure 1.

5. Crystal form I of the compound according to claim 1, It is characterized in that the DSC pattern of crystal form I of the said compound has the starting point of an endothermic peak at 126.1 ± 3 °C and the starting point of an endothermic peak at 195.1 ± 3 °C.

6. Crystal form I of the compound according to claim 5, It is characterized in that for crystal form I of the said compound, its DSC pattern is basically as shown in Figure 2.

7. Crystal form I of the compound according to claim 1, It is characterized in that the TGA pattern of crystal form I of the said compound has a weight loss of 4.14 ± 1% at 160 °C and a weight loss of 0.46 ± 1% at 210 °C.

8. Crystal form I of the compound according to claim 7, It is characterized in that for crystal form I of the said compound, its TGA pattern is basically as shown in Figure 3.

9. Crystal form VII of a solvate of a compound of formula (II), the solvate of the compound of formula (II) is a methyl tert-butyl ether solvate of the compound of formula (II); It is characterized in that the XRPD pattern of crystal form VII has diffraction peaks at 2θ of 7.7, 8.9, 12.4, 14.7, 17.9, 18.4, 19.9, 20.6, 23.1, 23.6, 27.8, 28.7 ± 0.2°.

10. Crystal form VII according to claim 9, It is characterized in that the XRPD pattern of crystal form VII also has diffraction peaks at 2θ of 5.9, 15.4, 16.1, 17.5, 19.0, 21.7, 24.5, 28.1, 30.8 ± 0.2°.

11. Crystal form VII according to claim 9, It is characterized in that the diffraction peak conditions of the XRPD pattern of crystal form VII are shown in the following table:

12. Crystal form VII according to claim 9, It is characterized in that for crystal form VII, its XRPD pattern is basically as shown in Figure 23.

13. Crystal form VII according to claim 9, It is characterized in that The DSC pattern of crystalline form VII of the solvate of the compound of formula (II) has an onset of an endothermic peak at 161.8 ± 3 °C.

14. The crystalline form VII according to claim 13, wherein, the DSC pattern of crystalline form VII of the solvate of the compound of formula (II) is substantially as shown in Figure 24.

15. The crystalline form VII according to claim 13, wherein, the TGA pattern of the crystalline form VII shows a weight loss of 16.56 ± 1% at 185 °C.

16. The crystalline form VII according to claim 15, wherein, the TGA pattern of the crystalline form VII is substantially as shown in Figure 25.

17. An active pharmaceutical ingredient, wherein, the active pharmaceutical ingredient comprises at least one of the crystalline forms according to any one of claims 1-16.

18. A pharmaceutical composition, wherein the pharmaceutical composition comprises a pharmaceutically acceptable excipient and the active pharmaceutical ingredient according to claim 17.

19. The pharmaceutical composition according to claim 18, wherein, the pharmaceutically acceptable excipient comprises at least one of a filler, a binder, a disintegrant, and a lubricant.

20. A medicament, wherein, the medicament comprises at least one of the crystalline forms according to any one of claims 1-16, or the active pharmaceutical ingredient according to claim 17, or the pharmaceutical composition according to any one of claims 18-19.

21. Use of the crystalline form according to any one of claims 1-16, or the active pharmaceutical ingredient according to claim 17, or the pharmaceutical composition according to any one of claims 18-19 in the preparation of a medicament for treating influenza.

Images