WO2021098850A1 - 一种核蛋白抑制剂的晶型及其应用 - Google Patents

一种核蛋白抑制剂的晶型及其应用 Download PDF

Info

Publication number
WO2021098850A1
WO2021098850A1 PCT/CN2020/130612 CN2020130612W WO2021098850A1 WO 2021098850 A1 WO2021098850 A1 WO 2021098850A1 CN 2020130612 W CN2020130612 W CN 2020130612W WO 2021098850 A1 WO2021098850 A1 WO 2021098850A1
Authority
WO
WIPO (PCT)
Prior art keywords
angles
following
ray powder
crystal form
powder diffraction
Prior art date
Application number
PCT/CN2020/130612
Other languages
English (en)
French (fr)
Inventor
贺海鹰
夏建华
谭海忠
Original Assignee
正大天晴药业集团股份有限公司
南京明德新药研发有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 正大天晴药业集团股份有限公司, 南京明德新药研发有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to CN202080078475.6A priority Critical patent/CN114728973A/zh
Priority to AU2020385518A priority patent/AU2020385518A1/en
Priority to CA3159096A priority patent/CA3159096A1/en
Priority to US17/779,035 priority patent/US20230026869A1/en
Priority to EP20890696.6A priority patent/EP4063366A4/en
Priority to JP2022529375A priority patent/JP2023502675A/ja
Publication of WO2021098850A1 publication Critical patent/WO2021098850A1/zh

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the application relates to a crystal form of a nuclear protein inhibitor and its application in the preparation of a medicine for treating HBV-related diseases.
  • Hepatitis B is an inflammatory reaction caused by the invasion of hepatitis B virus, which easily develops into liver fibrosis and cirrhosis, and is the direct cause of 80% of primary liver cancers worldwide.
  • Hepatitis B is a worldwide medical problem. At present, there is no specific medicine for hepatitis B in the world. Nucleosides and interferons occupy a major position in the global hepatitis B drug market; the first-line drugs for hepatitis B treatment are mainly nucleoside drugs and interferons. However, there are problems such as high cost and easy recurrence, so it is imperative to develop a new type of anti-hepatitis B drug.
  • the present application provides a crystal form of the compound of formula (I), its hydrate, its solvate, or a water-solvent co-complex
  • This application provides crystal form A of the compound of formula (I), and its X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 6.20 ⁇ 0.20°, 8.90 ⁇ 0.20°, 16.30 ⁇ 0.20° and 24.78 ⁇ 0.20 °.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 6.20 ⁇ 0.20°, 8.90 ⁇ 0.20°, 14.22 ⁇ 0.20°, 16.30 ⁇ 0.20°, 22.32 ⁇ 0.20 ° and 24.78 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 6.20 ⁇ 0.20°, 8.90 ⁇ 0.20°, 11.26 ⁇ 0.20°, 14.22 ⁇ 0.20°, 16.30 ⁇ 0.20 °, 17.89 ⁇ 0.20°, 22.32 ⁇ 0.20° and 24.78 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 6.20 ⁇ 0.20°, 8.90 ⁇ 0.20°, 10.09 ⁇ 0.20°, 11.26 ⁇ 0.20°, 14.22 ⁇ 0.20 °, 16.30 ⁇ 0.20°, 17.89 ⁇ 0.20°, 20.35 ⁇ 0.20°, 22.32 ⁇ 0.20°, 24.78 ⁇ 0.20° and 27.78 ⁇ 0.20°.
  • the XRPD pattern of the above-mentioned crystal form A is shown in FIG. 1.
  • the XRPD pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles, as shown in Table 1:
  • Table 1 XRPD pattern data of crystal form A
  • thermogravimetric analysis curve (TGA) of the above-mentioned crystal form A has a weight loss of 2.50% when the temperature is raised to 200.0 ⁇ 3°C.
  • the differential scanning calorimetry (DSC) of the above-mentioned crystal form A has an endothermic peak at 234.8 ⁇ 3°C.
  • this application provides a method for preparing the above-mentioned crystal form A, which includes: 1) adding the compound of formula (I) or its crude product to methyl tert-butyl ether; 2) optionally concentrating; 3) lyophilizing to obtain A crystal form.
  • This application provides the B crystal form of the compound of formula (I), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 9.13 ⁇ 0.20°, 10.53 ⁇ 0.20°, 21.17 ⁇ 0.20° and 22.64 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 9.13 ⁇ 0.20°, 10.53 ⁇ 0.20°, 11.67 ⁇ 0.20°, 20.09 ⁇ 0.20°, 21.17 ⁇ 0.20 ° and 22.64 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 9.13 ⁇ 0.20°, 10.53 ⁇ 0.20°, 11.67 ⁇ 0.20°, 13.52 ⁇ 0.20°, 20.09 ⁇ 0.20 °, 21.17 ⁇ 0.20° and 22.64 ⁇ 0.20°.
  • the XRPD pattern of the above-mentioned crystal form B is shown in FIG. 4.
  • the XRPD pattern of the above-mentioned crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles, as shown in Table 2:
  • thermogravimetric analysis curve of the above-mentioned crystal form B loses weight by 14.37% when the temperature is raised to 160.0 ⁇ 3°C.
  • the TGA pattern of the above-mentioned crystal form B is shown in FIG. 5.
  • the differential scanning calorimetry (DSC) of the above-mentioned crystal form B has an endothermic peak at 149.2 ⁇ 3°C. In some solutions of the present application, the differential scanning calorimetry (DSC) of the above-mentioned crystal form B has an endothermic peak at 236.6 ⁇ 3°C. In some solutions of the present application, the differential scanning calorimetry (DSC) of the above-mentioned crystal form B has an endothermic peak at 149.2 ⁇ 3°C and/or 236.6 ⁇ 3°C.
  • the above-mentioned crystal form B is a DMSO compound crystal form of the compound of formula (I).
  • the ratio of the number of molecules of formula (I) to DMSO in the B crystal form is selected from 1:0.8 to 2.0, preferably 1:1.8.
  • this application provides a method for preparing the above-mentioned crystal form B, which includes: 1) dissolving the compound of formula (I) in DMSO; 2) adding water to precipitate a solid to obtain crystal form B.
  • the crystal form A of the compound of formula (I) is added to DMSO.
  • water is added by a dropwise addition method.
  • This application provides crystal form C of the compound of formula (I), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 8.94 ⁇ 0.20°, 9.83 ⁇ 0.20° and 10.99 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles: 8.94 ⁇ 0.20°, 9.83 ⁇ 0.20°, 10.99 ⁇ 0.20°, 18.62 ⁇ 0.20°, and 19.82 ⁇ 0.20 °.
  • the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles: 8.94 ⁇ 0.20°, 9.83 ⁇ 0.20°, 10.99 ⁇ 0.20°, 13.36 ⁇ 0.20°, 17.21 ⁇ 0.20 °, 18.62 ⁇ 0.20°, 19.82 ⁇ 0.20° and 21.56 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles: 8.94 ⁇ 0.20°, 9.39 ⁇ 0.20°, 9.83 ⁇ 0.20°, 10.48 ⁇ 0.20° ⁇ 0.20°, 10.99 ⁇ 0.20°, 13.36 ⁇ 0.20°, 14.29 ⁇ 0.20°, 17.21 ⁇ 0.20°, 18.14 ⁇ 0.20°, 18.62 ⁇ 0.20°, 19.82 ⁇ 0.20° and 21.56 ⁇ 0.20°.
  • the XRPD pattern of the above-mentioned crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles, as shown in Table 3:
  • thermogravimetric analysis curve of the above-mentioned crystal form C has a weight loss of 18.33% when the temperature is raised to 140.0 ⁇ 3°C.
  • the TGA pattern of the above-mentioned crystal form C is shown in FIG. 8.
  • the differential scanning calorimetry (DSC) of the above-mentioned crystal form C has an endothermic peak at 103.4 ⁇ 3°C. In some solutions of this application, the differential scanning calorimetry (DSC) of the above-mentioned crystal form C has an endothermic peak at 236.7 ⁇ 3°C. In some solutions of the present application, the differential scanning calorimetry (DSC) of the above-mentioned crystal form C has an exothermic peak at 218.4 ⁇ 3°C.
  • the differential scanning calorimetry curve (DSC) of the above crystal form C has an endothermic peak at 103.4 ⁇ 3°C, and/or 236.7 ⁇ 3°C, and/or has an endothermic peak at 218.4 ⁇ 3°C Exothermic peak.
  • the above-mentioned crystal form C is a hydrate crystal form of the compound of formula (I).
  • the ratio of the number of compounds of formula (I) to water molecules in the crystal form C is selected from 1:6 to 8, preferably 1:6.9.
  • this application provides a method for preparing the above-mentioned crystal form C, which includes: 1) dissolving the compound of formula (I) in THF; 2) adding MTBE; 3) separating out a solid to obtain crystal form C.
  • the crystal form A of the compound of formula (I) is added to THF.
  • step 2) adopts a dropwise addition method to add MTBE.
  • This application provides the D crystal form of the compound of formula (I), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 7.52 ⁇ 0.20°, 11.21 ⁇ 0.20°, 12.40 ⁇ 0.20° and 14.41 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form D has characteristic diffraction peaks at the following 2 ⁇ angles: 7.52 ⁇ 0.20°, 8.70 ⁇ 0.20°, 11.21 ⁇ 0.20°, 12.40 ⁇ 0.20°, 14.41 ⁇ 0.20 °, 17.49 ⁇ 0.20° and 22.92 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form D has characteristic diffraction peaks at the following 2 ⁇ angles: 7.52 ⁇ 0.20°, 8.70 ⁇ 0.20°, 11.21 ⁇ 0.20°, 12.40 ⁇ 0.20°, 14.41 ⁇ 0.20 °, 16.06 ⁇ 0.20°, 17.49 ⁇ 0.20°, 20.98 ⁇ 0.20°, 21.98 ⁇ 0.20° and 22.92 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form D has characteristic diffraction peaks at the following 2 ⁇ angles: 7.17 ⁇ 0.20°, 7.52 ⁇ 0.20°, 7.99 ⁇ 0.20°, 8.70 ⁇ 0.20°, 9.99 ⁇ 0.20 °, 10.74 ⁇ 0.20°, 11.21 ⁇ 0.20°, 12.40 ⁇ 0.20°, 14.41 ⁇ 0.20°, 14.88 ⁇ 0.20°, 16.06 ⁇ 0.20°, 17.05 ⁇ 0.20°, 17.49 ⁇ 0.20°, 20.98 ⁇ 0.20°, 21.98 ⁇ 0.20 °, 22.48 ⁇ 0.20°, 22.92 ⁇ 0.20°, 23.50 ⁇ 0.20°, 26.47 ⁇ 0.20°, 27.05 ⁇ 0.20° and 28.04 ⁇ 0.20°.
  • the XRPD pattern of the above-mentioned crystal form D has characteristic diffraction peaks at the following 2 ⁇ angles, as shown in Table 4:
  • this application provides a method for preparing the above-mentioned crystal form D, which includes: 1) dissolving the compound of formula (I) in THF; 2) adding DCM; 3) separating a solid to obtain crystal form D.
  • the crystal form A of the compound of formula (I) is added to THF.
  • step 2) adopts a dropwise addition method to add DCM.
  • This application provides the E crystal form of the compound of formula (I), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 6.72 ⁇ 0.20°, 8.53 ⁇ 0.20°, 17.76 ⁇ 0.20° and 20.38 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form E has characteristic diffraction peaks at the following 2 ⁇ angles: 6.72 ⁇ 0.20°, 8.53 ⁇ 0.20°, 10.50 ⁇ 0.20°, 13.53 ⁇ 0.20°, 17.76 ⁇ 0.20 °, 18.83 ⁇ 0.20° and 20.38 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form E has characteristic diffraction peaks at the following 2 ⁇ angles: 6.72 ⁇ 0.20°, 8.53 ⁇ 0.20°, 10.50 ⁇ 0.20°, 13.53 ⁇ 0.20°, 17.76 ⁇ 0.20 °, 18.83 ⁇ 0.20°, 20.38 ⁇ 0.20°, 21.06 ⁇ 0.20° and 24.00 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form E has characteristic diffraction peaks at the following 2 ⁇ angles: 6.72 ⁇ 0.20°, 8.53 ⁇ 0.20°, 10.50 ⁇ 0.20°, 11.41 ⁇ 0.20°, 13.53 ⁇ 0.20 °, 17.76 ⁇ 0.20°, 18.83 ⁇ 0.20°, 19.99 ⁇ 0.20°, 20.38 ⁇ 0.20°, 21.06 ⁇ 0.20°, 22.23 ⁇ 0.20°, 24.00 ⁇ 0.20°, 24.42 ⁇ 0.20° and 25.90 ⁇ 0.20°.
  • the XRPD pattern of the above-mentioned crystal form E has characteristic diffraction peaks at the following 2 ⁇ angles, as shown in Table 5:
  • thermogravimetric analysis curve of the above crystal form E has a weight loss of 6.61% when the temperature is raised to 170.0 ⁇ 3°C, and/or a weight loss of 3.53% when the temperature is raised from 170 ⁇ 3°C to 210.0 ⁇ 3°C.
  • the TGA pattern of the above-mentioned crystal form E is shown in FIG. 12.
  • the differential scanning calorimetry (DSC) of the above-mentioned crystal form E has an endothermic peak at 236.8 ⁇ 3°C.
  • the aforementioned crystal form E is a 1,4-dioxane and/or water co-solvate crystal form/solvate crystal form of the compound of formula (I).
  • the ratio of the number of compounds of formula (I), 1,4-dioxane and water molecules in the E crystal form is selected from 1:0.5 to 1.0: 0.5 to 1.5; preferably 1:0.5:1.
  • this application provides a method for preparing the above crystal form E, including: 1) dissolving the compound of formula (I) in 1,4-dioxane; 2) adding 1,4-dioxane Acetonitrile; 3) A solid is precipitated to obtain crystal form E.
  • the crystal form A of the compound of formula (I) is added to 1,4-dioxane.
  • acetonitrile is added to 1,4-dioxane by volatizing acetonitrile into 1,4-dioxane.
  • This application provides the F crystal form of the compound of formula (I), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 4.18 ⁇ 0.20°, 8.35 ⁇ 0.20°, 10.58 ⁇ 0.20° and 16.86 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form F has characteristic diffraction peaks at the following 2 ⁇ angles: 4.18 ⁇ 0.20°, 8.35 ⁇ 0.20°, 10.58 ⁇ 0.20°, 11.87 ⁇ 0.20°, 16.86 ⁇ 0.20 ° and 21.16 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form F has characteristic diffraction peaks at the following 2 ⁇ angles: 4.18 ⁇ 0.20°, 8.35 ⁇ 0.20°, 10.58 ⁇ 0.20°, 11.87 ⁇ 0.20°, 12.32 ⁇ 0.20 °, 16.86 ⁇ 0.20°, 21.16 ⁇ 0.20°, 25.47 ⁇ 0.20° and 29.17 ⁇ 0.20°.
  • the XRPD pattern of the above-mentioned crystal form F has characteristic diffraction peaks at the following 2 ⁇ angles, as shown in Table 6:
  • thermogravimetric analysis curve of the above-mentioned crystal form F has a weight loss of 3.22% when the temperature is raised to 150.0 ⁇ 3°C.
  • the TGA pattern of the above-mentioned crystal form F is shown in FIG. 15.
  • the differential scanning calorimetry (DSC) of the above-mentioned crystal form F has an endothermic peak at 229.9 ⁇ 3°C. In some solutions of the present application, the differential scanning calorimetry (DSC) of the above-mentioned crystal form F has an endothermic peak at 188.6 ⁇ 3°C. In some solutions of the present application, the differential scanning calorimetry (DSC) of the above-mentioned crystal form F has an endothermic peak at 98.9 ⁇ 3°C.
  • the differential scanning calorimetry (DSC) of the above-mentioned crystal form F has an endothermic peak at 229.9 ⁇ 3°C, and/or 188.6 ⁇ 3°C, and/or 98.9 ⁇ 3°C.
  • the above-mentioned crystal form F is a hydrate crystal form of the compound of formula (I).
  • the ratio of the number of compounds of formula (I) to water molecules in crystal form F is selected from 1:0.8 to 1.2; preferably 1:1.
  • this application provides a method for preparing the above-mentioned crystal form F, which includes: 1) dissolving the compound of formula (I) in DMF; 2) mixing the obtained solution with water; 3) precipitating a solid to obtain crystal form F.
  • the preparation method of crystal form F in the preparation method of crystal form F, the crystal form A of the compound of formula (I) is added to DMF.
  • the method of mixing the solution with water in step 2), is selected from dropping the solution into water.
  • This application provides the G crystal form of the compound of formula (I), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 7.03 ⁇ 0.20°, 8.31 ⁇ 0.20°, 19.18 ⁇ 0.20° and 25.99 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form G has characteristic diffraction peaks at the following 2 ⁇ angles: 7.03 ⁇ 0.20°, 8.31 ⁇ 0.20°, 15.86 ⁇ 0.20°, 19.18 ⁇ 0.20°, 21.05 ⁇ 0.20 ° and 25.99 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form G has characteristic diffraction peaks at the following 2 ⁇ angles: 7.03 ⁇ 0.20°, 8.31 ⁇ 0.20°, 11.62 ⁇ 0.20°, 12.91 ⁇ 0.20°, 15.86 ⁇ 0.20 °, 19.18 ⁇ 0.20°, 21.05 ⁇ 0.20°, 24.67 ⁇ 0.20° and 25.99 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form G has characteristic diffraction peaks at the following 2 ⁇ angles: 7.03 ⁇ 0.20°, 8.31 ⁇ 0.20°, 11.62 ⁇ 0.20°, 12.91 ⁇ 0.20°, 15.86 ⁇ 0.20 °, 17.17 ⁇ 0.20°, 18.20 ⁇ 0.20°, 19.18 ⁇ 0.20°, 19.74 ⁇ 0.20°, 21.05 ⁇ 0.20°, 21.30 ⁇ 0.20°, 24.67 ⁇ 0.20° and 25.99 ⁇ 0.20°.
  • the XRPD pattern of the above-mentioned crystal form G is shown in FIG. 17.
  • the XRPD pattern of the above-mentioned crystal form G has characteristic diffraction peaks at the following 2 ⁇ angles, as shown in Table 7:
  • thermogravimetric analysis curve of the above-mentioned crystal form G loses weight by 7.39% when the temperature is raised to 150.0 ⁇ 3°C.
  • the TGA pattern of the above-mentioned crystal form G is shown in FIG. 18.
  • the differential scanning calorimetry (DSC) of the above-mentioned crystal form G has an endothermic peak at 235.7 ⁇ 3°C. In some solutions of the present application, the differential scanning calorimetry (DSC) of the above-mentioned crystal form G has an exothermic peak at 177.8 ⁇ 3°C. In some solutions of the present application, the differential scanning calorimetry (DSC) of the above-mentioned crystal form G has an endothermic peak at 235.7 ⁇ 3°C and/or an exothermic peak at 177.8 ⁇ 3°C.
  • this application provides a method for preparing the above-mentioned crystal form G, which includes: 1) adding a compound of formula (I) to a mixed solvent of CHCl 3 and THF; 2) separating a solid to obtain crystal form G.
  • the A crystal form of the compound of formula (I) is added to the mixed solvent of CHCl 3 and THF.
  • This application provides the H crystal form of the compound of formula (I), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 7.05 ⁇ 0.20°, 9.10 ⁇ 0.20°, 10.78 ⁇ 0.20° and 22.90 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form H has characteristic diffraction peaks at the following 2 ⁇ angles: 7.05 ⁇ 0.20°, 9.10 ⁇ 0.20°, 10.78 ⁇ 0.20°, 21.24 ⁇ 0.20°, 21.74 ⁇ 0.20 ° and 22.90 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form H has characteristic diffraction peaks at the following 2 ⁇ angles: 7.05 ⁇ 0.20°, 9.10 ⁇ 0.20°, 10.78 ⁇ 0.20°, 13.07 ⁇ 0.20°, 19.57 ⁇ 0.20 °, 21.24 ⁇ 0.20°, 21.74 ⁇ 0.20°, 22.24 ⁇ 0.20° and 22.90 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form H has characteristic diffraction peaks at the following 2 ⁇ angles: 7.05 ⁇ 0.20°, 9.10 ⁇ 0.20°, 10.78 ⁇ 0.20°, 11.34 ⁇ 0.20°, 13.07 ⁇ 0.20 °, 14.07 ⁇ 0.20°, 14.99 ⁇ 0.20°, 15.86 ⁇ 0.20°, 16.17 ⁇ 0.20°, 18.60 ⁇ 0.20°, 19.57 ⁇ 0.20°, 21.24 ⁇ 0.20°, 21.46 ⁇ 0.20°, 21.74 ⁇ 0.20°, 22.24 ⁇ 0.20 °, 22.72 ⁇ 0.20° and 22.90 ⁇ 0.20°.
  • the XRPD pattern of the above-mentioned crystal form H is shown in FIG. 20.
  • the XRPD pattern of the above crystal form H has characteristic diffraction peaks at the following 2 ⁇ angles, as shown in Table 8:
  • thermogravimetric analysis curve of the above crystal form H has a weight loss of 11.77% when the temperature is raised to 160.0 ⁇ 3°C.
  • the differential scanning calorimetry (DSC) of the above-mentioned crystal form H has an endothermic peak at 140.4 ⁇ 3°C. In some solutions of the present application, the differential scanning calorimetry (DSC) of the above-mentioned crystal form H has an endothermic peak at 236.9 ⁇ 3°C. In some solutions of the present application, the differential scanning calorimetry (DSC) of the above crystal form H has an endothermic peak at 140.4 ⁇ 3°C and/or 236.9 ⁇ 3°C.
  • the above-mentioned crystal form H is a DMF compound crystal form of the compound of formula (I).
  • the ratio of the number of the compound of formula (I) to DMF molecules in the crystal form H is selected from 1:0.6 to 1.0; preferably 1:0.8.
  • this application provides a method for preparing the above-mentioned crystal form H, which includes: 1) adding a compound of formula (I) into a mixed solvent of EtOH and DMF; 2) separating a solid to obtain crystal form H.
  • the crystal form A of the compound of formula (I) is added to the mixed solvent of EtOH and DMF.
  • This application provides the I crystal form of the compound of formula (I), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 5.56 ⁇ 0.20°, 11.25 ⁇ 0.20° and 14.09 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form I has characteristic diffraction peaks at the following 2 ⁇ angles: 5.56 ⁇ 0.20°, 7.54 ⁇ 0.20°, 11.25 ⁇ 0.20°, 14.09 ⁇ 0.20°, and 19.64 ⁇ 0.20° .
  • the X-ray powder diffraction pattern of the above-mentioned crystal form I has characteristic diffraction peaks at the following 2 ⁇ angles: 5.56 ⁇ 0.20°, 7.54 ⁇ 0.20°, 11.25 ⁇ 0.20°, 14.09 ⁇ 0.20°, 18.07 ⁇ 0.20 °, 19.64 ⁇ 0.20° and 20.33 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form I has characteristic diffraction peaks at the following 2 ⁇ angles: 5.56 ⁇ 0.20°, 7.54 ⁇ 0.20°, 11.25 ⁇ 0.20°, 14.09 ⁇ 0.20°, 18.07 ⁇ 0.20 °, 19.64 ⁇ 0.20°, 20.33 ⁇ 0.20°, 21.65 ⁇ 0.20°, 22.31 ⁇ 0.20°.
  • the XRPD pattern of the above-mentioned crystal form I is shown in FIG. 23.
  • the XRPD pattern of the above-mentioned crystal form I has characteristic diffraction peaks at the following 2 ⁇ angles, as shown in Table 9:
  • thermogravimetric analysis curve of the above-mentioned crystal form I has a weight loss of 3.52% when the temperature is raised to 100.0 ⁇ 3°C.
  • the differential scanning calorimetry (DSC) of the above-mentioned crystal form I has an endothermic peak at 94.7 ⁇ 3°C. In some solutions of the present application, the differential scanning calorimetry (DSC) of the above-mentioned crystal form I has an endothermic peak at 234.4 ⁇ 3°C. In some solutions of the present application, the differential scanning calorimetry (DSC) of the above-mentioned crystal form I has an exothermic peak at 185.2 ⁇ 3°C.
  • the differential scanning calorimetry curve (DSC) of the above-mentioned crystal form I has an endothermic peak at 94.7 ⁇ 3°C, and/or 234.4 ⁇ 3°C, and/or has an endothermic peak at 185.2 ⁇ 3°C Exothermic peak.
  • the above-mentioned crystal form I is a hydrate crystal form of the compound of formula (I).
  • the ratio of the number of compounds of formula (I) to water molecules in the I crystal form is selected from 1:1.0 to 1.2; preferably 1:1.1.
  • the present application provides a method for preparing the above-mentioned crystal form I, which includes: 1) adding a compound of formula (I) to water; 2) suspending and stirring, and isolating and obtaining crystal form I.
  • the crystal form A of the compound of formula (I) is added to water.
  • stirring is required under heating conditions.
  • the heating temperature is selected from 45 to 60°C; or 55°C.
  • This application provides the J crystal form of the compound of formula (I), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 9.28 ⁇ 0.20°, 10.34 ⁇ 0.20°, 22.66 ⁇ 0.20° and 26.12 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form J has characteristic diffraction peaks at the following 2 ⁇ angles: 9.28 ⁇ 0.20°, 10.34 ⁇ 0.20°, 19.45 ⁇ 0.20°, 20.93 ⁇ 0.20°, 22.66 ⁇ 0.20 ° and 26.12 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form J has characteristic diffraction peaks at the following 2 ⁇ angles: 9.28 ⁇ 0.20°, 10.34 ⁇ 0.20°, 12.35 ⁇ 0.20°, 14.95 ⁇ 0.20°, 17.88 ⁇ 0.20 °, 19.45 ⁇ 0.20°, 20.93 ⁇ 0.20°, 22.66 ⁇ 0.20° and 26.12 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form J has characteristic diffraction peaks at the following 2 ⁇ angles: 3.47 ⁇ 0.20°, 9.28 ⁇ 0.20°, 10.34 ⁇ 0.20°, 10.92 ⁇ 0.20°, 12.35 ⁇ 0.20 ° ⁇ 14.95 ⁇ 0.20° ⁇ 17.62 ⁇ 0.20° ⁇ 17.88 ⁇ 0.20° ⁇ 19.09 ⁇ 0.20° ⁇ 19.45 ⁇ 0.20° ⁇ 20.08 ⁇ 0.20° ⁇ 20.93 ⁇ 0.20° ⁇ 22.66 ⁇ 0.20° ⁇ 23.98 ⁇ 0.20° ⁇ 26.12 ⁇ 0.20° and 28.63 ⁇ 0.20°.
  • the XRPD pattern of the above-mentioned crystal form J has characteristic diffraction peaks at the following 2 ⁇ angles, as shown in Table 10:
  • thermogravimetric analysis curve of the above-mentioned crystal form J has a weight loss of 27.46% when the temperature is raised to 140.0 ⁇ 3°C.
  • the TGA pattern of the above-mentioned crystal form J is shown in FIG. 27.
  • the differential scanning calorimetry (DSC) of the above-mentioned crystal form J has an endothermic peak at 86.7 ⁇ 3°C. In some solutions of the present application, the differential scanning calorimetry (DSC) of the above-mentioned crystal form J has an endothermic peak at 229.4 ⁇ 3°C. In some solutions of the present application, the differential scanning calorimetry (DSC) of the above-mentioned crystal form J has an endothermic peak at 150.0 ⁇ 3°C. In some solutions of the present application, the differential scanning calorimetry (DSC) of the above-mentioned crystal form J has an exothermic peak at 148.6 ⁇ 3°C.
  • the differential scanning calorimetry (DSC) of the above-mentioned crystal form J has an endothermic peak at 86.7 ⁇ 3°C, and/or 150.0 ⁇ 3°C, and/or 229.4 ⁇ 3°C, and/ Or it has an exothermic peak at 148.6 ⁇ 3°C.
  • the present application provides a method for preparing the above-mentioned crystal form J, which includes: 1) adding the compound of formula (I) to 2-MeTHF; 2) suspension and stirring, and separating to obtain the crystal form J.
  • the preparation method of the crystal form J in the preparation method of the crystal form J, the crystal form A of the compound of formula (I) is added to 2-MeTHF.
  • the preparation method of the crystal form J requires stirring under heating conditions; in some solutions of the application, the heating temperature is selected from 45-60°C; or 50°C.
  • This application provides the K crystal form of the compound of formula (I), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 7.49 ⁇ 0.20°, 8.46 ⁇ 0.20°, 15.99 ⁇ 0.20° and 17.02 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form K has characteristic diffraction peaks at the following 2 ⁇ angles: 7.49 ⁇ 0.20°, 8.46 ⁇ 0.20°, 13.18 ⁇ 0.20°, 14.43 ⁇ 0.20°, 15.99 ⁇ 0.20 ° and 17.02 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form K has characteristic diffraction peaks at the following 2 ⁇ angles: 7.49 ⁇ 0.20°, 8.46 ⁇ 0.20°, 9.91 ⁇ 0.20°, 13.18 ⁇ 0.20°, 14.43 ⁇ 0.20 °, 15.99 ⁇ 0.20°, 17.02 ⁇ 0.20°, 20.97 ⁇ 0.20° and 24.20 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form K has characteristic diffraction peaks at the following 2 ⁇ angles: 7.49 ⁇ 0.20°, 8.46 ⁇ 0.20°, 9.12 ⁇ 0.20°, 9.91 ⁇ 0.20°, 10.67 ⁇ 0.20 °, 13.18 ⁇ 0.20°, 14.43 ⁇ 0.20°, 15.99 ⁇ 0.20°, 17.02 ⁇ 0.20°, 18.34 ⁇ 0.20°, 19.95 ⁇ 0.20°, 20.29 ⁇ 0.20°, 20.97 ⁇ 0.20°, 21.66 ⁇ 0.20°, 23.03 ⁇ 0.20 °, 24.20 ⁇ 0.20°, 24.94 ⁇ 0.20° and 25.69 ⁇ 0.20°.
  • the XRPD pattern of the above-mentioned crystal form K is shown in FIG. 29.
  • the XRPD pattern of the above-mentioned crystal form K has characteristic diffraction peaks at the following 2 ⁇ angles, as shown in Table 11:
  • thermogravimetric analysis curve of the above-mentioned crystal form K has a weight loss of 1.35% when the temperature is raised to 150.0 ⁇ 3°C.
  • the TGA spectrum of the above-mentioned crystal form K is shown in FIG. 30.
  • the differential scanning calorimetry (DSC) of the above-mentioned crystal form K has an endothermic peak at 231.2 ⁇ 3°C. In some solutions of the present application, the differential scanning calorimetry (DSC) of the above-mentioned crystal form K has an exothermic peak at 164.1 ⁇ 3°C. In some solutions of the present application, the differential scanning calorimetry (DSC) of the above-mentioned crystal form K has an endothermic peak at 160.6 ⁇ 3°C.
  • the differential scanning calorimetry (DSC) of the above-mentioned crystal form K has an endothermic peak at 231.2 ⁇ 3°C, and/or 160.6 ⁇ 3°C, and/or has an endothermic peak at 164.1 ⁇ 3°C Exothermic peak.
  • the present application provides a method for preparing the above crystal form K, which includes: 1) dissolving the compound of formula (I) in a mixed solvent of DCM and MeOH; 2) precipitate a solid, and isolate the crystal form K.
  • the crystal form A of the compound of formula (I) is added to the mixed solvent of DCM and MeOH.
  • the preparation method of the K crystal form needs to be dissolved under heating conditions.
  • the heating temperature is selected from 45 to 60°C; or 50°C.
  • a cooling method is used to precipitate solids.
  • This application provides the L crystal form of the compound of formula (I), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 8.53 ⁇ 0.20°, 11.09 ⁇ 0.20°, 22.34 ⁇ 0.20° and 23.12 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form L has characteristic diffraction peaks at the following 2 ⁇ angles: 8.53 ⁇ 0.20°, 11.09 ⁇ 0.20°, 15.00 ⁇ 0.20°, 20.76 ⁇ 0.20°, 22.34 ⁇ 0.20 ° and 23.12 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form L has characteristic diffraction peaks at the following 2 ⁇ angles: 7.03 ⁇ 0.20°, 8.53 ⁇ 0.20°, 11.09 ⁇ 0.20°, 14.14 ⁇ 0.20°, 15.00 ⁇ 0.20 °, 20.76 ⁇ 0.20°, 22.34 ⁇ 0.20°, 23.12 ⁇ 0.20° and 26.85 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form L has characteristic diffraction peaks at the following 2 ⁇ angles: 7.03 ⁇ 0.20°, 8.53 ⁇ 0.20°, 10.50 ⁇ 0.20°, 11.09 ⁇ 0.20°, 14.14 ⁇ 0.20 °, 15.00 ⁇ 0.20°, 20.76 ⁇ 0.20°, 22.34 ⁇ 0.20°, 23.12 ⁇ 0.20° and 26.85 ⁇ 0.20°.
  • the XRPD pattern of the above-mentioned crystal form L is shown in FIG. 32.
  • the XRPD pattern of the above-mentioned crystal form L has characteristic diffraction peaks at the following 2 ⁇ angles, as shown in Table 12:
  • thermogravimetric analysis curve of the above crystal form L has a weight loss of 10.37% when the temperature is raised to 160.0 ⁇ 3°C.
  • the differential scanning calorimetry (DSC) of the above-mentioned crystal form L has an endothermic peak at 150.1 ⁇ 3°C. In some solutions of the present application, the differential scanning calorimetry (DSC) of the above-mentioned crystal form L has an endothermic peak at 210.7 ⁇ 3°C. In some solutions of the present application, the differential scanning calorimetry (DSC) of the above-mentioned crystal form L has an endothermic peak at 150.1 ⁇ 3°C and/or 210.7 ⁇ 3°C.
  • the above-mentioned crystal form L is the NMP compound crystal form of the compound of formula (I).
  • the ratio of the number of the compound of formula (I) to the NMP molecule in the L crystal form is selected from 1:0.5 to 1.0; preferably 1:0.8.
  • this application provides a method for preparing the above-mentioned crystal form L, which includes: 1) dissolving the compound of formula (I) in NMP; 2) adding EtOAc to the NMP solution; 3) separating solids to obtain crystal form L.
  • the crystal form A of the compound of formula (I) is added to NMP.
  • EtOAc is added to NMP by volatilizing EtOAc into NMP.
  • This application provides the M crystal form of the compound of formula (I), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 9.32 ⁇ 0.20°, 10.43 ⁇ 0.20°, 12.46 ⁇ 0.20° and 19.62 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form M has characteristic diffraction peaks at the following 2 ⁇ angles: 9.32 ⁇ 0.20°, 10.43 ⁇ 0.20°, 10.81 ⁇ 0.20°, 12.46 ⁇ 0.20°, 19.62 ⁇ 0.20 ° and 21.03 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form M has characteristic diffraction peaks at the following 2 ⁇ angles: 9.32 ⁇ 0.20°, 10.43 ⁇ 0.20°, 10.81 ⁇ 0.20°, 12.46 ⁇ 0.20°, 17.55 ⁇ 0.20 °, 17.99 ⁇ 0.20°, 19.62 ⁇ 0.20°, 21.03 ⁇ 0.20° and 22.90 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form M has characteristic diffraction peaks at the following 2 ⁇ angles: 9.32 ⁇ 0.20°, 10.43 ⁇ 0.20°, 10.81 ⁇ 0.20°, 12.46 ⁇ 0.20°, 13.00 ⁇ 0.20 °, 15.06 ⁇ 0.20°, 17.55 ⁇ 0.20°, 17.99 ⁇ 0.20°, 19.62 ⁇ 0.20°, 21.03 ⁇ 0.20° and 22.90 ⁇ 0.20°.
  • the XRPD pattern of the above-mentioned crystal form M is shown in FIG. 35.
  • the XRPD pattern of the above-mentioned crystal form M has characteristic diffraction peaks at the following 2 ⁇ angles, as shown in Table 13:
  • thermogravimetric analysis curve of the above-mentioned crystal form M loses weight by 10.98% when the temperature is raised to 130.0 ⁇ 3°C.
  • the TGA spectrum of the above-mentioned crystal form M is shown in FIG. 36.
  • the differential scanning calorimetry (DSC) of the above-mentioned crystal form M has an endothermic peak at 109.7 ⁇ 3°C. In some aspects of the application, the differential scanning calorimetry (DSC) of the above-mentioned crystal form M has an endothermic peak at 235.9 ⁇ 3°C. In some solutions of the present application, the differential scanning calorimetry (DSC) of the above-mentioned crystal form M has an endothermic peak at 109.7 ⁇ 3°C and/or 235.9 ⁇ 3°C.
  • the above-mentioned crystal form M is a THF compound crystal form of the compound of formula (I).
  • the ratio of the number of compounds of formula (I) to TMF molecules in the M crystal form is selected from 1:0.6 to 1.0; preferably 1:0.8.
  • this application provides a method for preparing the above-mentioned crystal form M, which includes: 1) dissolving the compound of formula (I) in THF; 2) precipitating a solid, and isolating the crystal form M.
  • the crystal form A of the compound of formula (I) is added to THF.
  • This application provides the N crystal form of the compound of formula (I), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 8.47° ⁇ 0.20°, 12.62 ⁇ 0.20°, 15.70 ⁇ 0.20° and 18.41 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form N has characteristic diffraction peaks at the following 2 ⁇ angles: 8.47 ⁇ 0.20°, 11.23 ⁇ 0.20°, 12.62 ⁇ 0.20°, 15.70 ⁇ 0.20°, 18.41 ⁇ 0.20 ° and 21.49 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form N has characteristic diffraction peaks at the following 2 ⁇ angles: 7.04 ⁇ 0.20°, 8.47 ⁇ 0.20°, 10.01 ⁇ 0.20°, 11.23 ⁇ 0.20°, 12.62 ⁇ 0.20 °, 15.70 ⁇ 0.20°, 18.41 ⁇ 0.20°, 21.49 ⁇ 0.20° and 22.53 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form N has characteristic diffraction peaks at the following 2 ⁇ angles: 7.04 ⁇ 0.20°, 8.47 ⁇ 0.20°, 10.01 ⁇ 0.20°, 11.23 ⁇ 0.20°, 12.62 ⁇ 0.20 °, 15.70 ⁇ 0.20°, 17.32 ⁇ 0.20°, 18.41 ⁇ 0.20°, 20.31 ⁇ 0.20°, 21.49 ⁇ 0.20°, 22.53 ⁇ 0.20° and 26.34 ⁇ 0.20°.
  • the XRPD pattern of the above-mentioned N crystal form is shown in FIG. 38.
  • the XRPD pattern of the above-mentioned crystal form N has characteristic diffraction peaks at the following 2 ⁇ angles, as shown in Table 14:
  • thermogravimetric analysis curve of the above-mentioned crystal form N has a weight loss of 1.99% when the temperature is raised to 200.0 ⁇ 3°C.
  • the differential scanning calorimetry (DSC) of the above-mentioned N crystal form has an endothermic peak at 236.3 ⁇ 3°C.
  • the present application provides a method for preparing the above-mentioned crystal form N, which includes: 1) dissolving the compound of formula (I) in EtOH; 2) separating solids to obtain crystal form N.
  • the preparation method of the N crystal form in the preparation method of the N crystal form, the A crystal form of the compound of formula (I) is added to EtOH.
  • This application provides the O crystal form of the compound of formula (I), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 7.50 ⁇ 0.20°, 10.65 ⁇ 0.20° and 11.10 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form O has characteristic diffraction peaks at the following 2 ⁇ angles: 7.18 ⁇ 0.20°, 7.50 ⁇ 0.20°, 10.65 ⁇ 0.20°, 11.10 ⁇ 0.20°, 14.04 ⁇ 0.20 ° and 21.48 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form O has characteristic diffraction peaks at the following 2 ⁇ angles: 7.18 ⁇ 0.20°, 7.50 ⁇ 0.20°, 10.65 ⁇ 0.20°, 11.10 ⁇ 0.20°, 14.04 ⁇ 0.20 °, 21.48 ⁇ 0.20°, 22.79 ⁇ 0.20° and 27.02 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form O has characteristic diffraction peaks at the following 2 ⁇ angles: 7.18 ⁇ 0.20°, 7.50 ⁇ 0.20°, 10.65 ⁇ 0.20°, 11.10 ⁇ 0.20°, 14.04 ⁇ 0.20 °, 15.67 ⁇ 0.20°, 19.16 ⁇ 0.20°, 21.48 ⁇ 0.20°, 22.79 ⁇ 0.20°, 23.39 ⁇ 0.20°, 26.28 ⁇ 0.20° and 27.02 ⁇ 0.20°.
  • the XRPD pattern of the above-mentioned crystal form O is shown in FIG. 41.
  • the XRPD pattern of the above crystal form O has characteristic diffraction peaks at the following 2 ⁇ angles, as shown in Table 15:
  • thermogravimetric analysis curve of the above crystal form O loses weight by 2.23% when the temperature is raised to 140.0 ⁇ 3°C.
  • the TGA pattern of the above crystal form O is shown in FIG. 42.
  • the differential scanning calorimetry (DSC) of the above crystal form O has an endothermic peak at 123.3 ⁇ 3°C. In some solutions of the present application, the differential scanning calorimetry (DSC) of the above crystal form O has an exothermic peak at 128.5 ⁇ 3°C. In some solutions of the present application, the differential scanning calorimetry (DSC) of the above-mentioned crystal form O has an endothermic peak at 231.1 ⁇ 3°C. In some solutions of the present application, the differential scanning calorimetry (DSC) of the above crystal form O has an endothermic peak at 237.1 ⁇ 3°C.
  • the differential scanning calorimetry (DSC) of the above crystal form O has an endothermic peak at 123.3 ⁇ 3°C, and/or 231.1 ⁇ 3°C, and/or 237.1 ⁇ 3°C, and/ Or there is an exothermic peak at 128.5 ⁇ 3°C.
  • the above-mentioned crystal form O is a hydrate crystal form of the compound of formula (I).
  • the ratio of the number of compounds of formula (I) to water molecules in the O crystal form is selected from 1:0.6 to 1.0; preferably 1:0.7.
  • this application provides a method for preparing the above-mentioned crystal form O, which includes: drying the above-mentioned crystal form D under vacuum and room temperature conditions to obtain crystal form O.
  • This application provides the P crystal form of the compound of formula (I), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 7.08 ⁇ 0.20° and 21.48 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form P has characteristic diffraction peaks at the following 2 ⁇ angles: 7.08 ⁇ 0.20°, 21.25 ⁇ 0.20°, and 21.48 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form P has characteristic diffraction peaks at the following 2 ⁇ angles: 7.08 ⁇ 0.20°, 20.39 ⁇ 0.20°, 21.25 ⁇ 0.20°, 21.48 ⁇ 0.20°, 26.74 ⁇ 0.20 ° and 27.46 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form P has characteristic diffraction peaks at the following 2 ⁇ angles: 7.08 ⁇ 0.20°, 20.39 ⁇ 0.20°, 21.48 ⁇ 0.20°, 26.74 ⁇ 0.20°, and 27.46 ⁇ 0.20 °.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form P has characteristic diffraction peaks at the following 2 ⁇ angles: 7.08 ⁇ 0.20°, 12.92 ⁇ 0.20°, 18.61 ⁇ 0.20°, 20.39 ⁇ 0.20°, 21.48 ⁇ 0.20 °, 22.71 ⁇ 0.20°, 26.74 ⁇ 0.20°, 27.46 ⁇ 0.20° and 27.83 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form P has characteristic diffraction peaks at the following 2 ⁇ angles: 7.08 ⁇ 0.20°, 12.92 ⁇ 0.20°, 18.61 ⁇ 0.20°, 20.39 ⁇ 0.20°, 21.25 ⁇ 0.20 °, 21.48 ⁇ 0.20°, 22.71 ⁇ 0.20°, 25.01 ⁇ 0.20°, 26.74 ⁇ 0.20°, 27.46 ⁇ 0.20° and 27.83 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the P crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.08 ⁇ 0.20°, 15.36 ⁇ 0.20°, 21.25 ⁇ 0.20°, 21.48 ⁇ 0.20°, and 22.71 ⁇ 0.20 °.
  • the P crystal X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 7.08 ⁇ 0.20°, 12.92 ⁇ 0.20°, 15.36 ⁇ 0.20°, 21.25 ⁇ 0.20°, 21.48 ⁇ 0.20 °, 22.71 ⁇ 0.20° and 27.46 ⁇ 0.20°.
  • the crystal form P X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 7.08 ⁇ 0.20°, 12.92 ⁇ 0.20°, 15.36 ⁇ 0.20°, 20.39 ⁇ 0.20°, 21.25 ⁇ 0.20 °, 21.48 ⁇ 0.20°, 22.71 ⁇ 0.20°, 26.74 ⁇ 0.20° and 27.46 ⁇ 0.20°.
  • the crystal form P X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 7.08 ⁇ 0.20°, 12.92 ⁇ 0.20°, 15.36 ⁇ 0.20°, 18.61 ⁇ 0.20°, 20.39 ⁇ 0.20 °, 21.25 ⁇ 0.20°, 21.48 ⁇ 0.20°, 22.71 ⁇ 0.20°, 26.74 ⁇ 0.20°, 27.46 ⁇ 0.20° and 27.83 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystal form P has characteristic diffraction peaks at the following 2 ⁇ angles: 7.08 ⁇ 0.20°, 11.61 ⁇ 0.20°, 12.92 ⁇ 0.20°, 15.36 ⁇ 0.20°, 15.89 ⁇ 0.20 °, 18.61 ⁇ 0.20°, 20.39 ⁇ 0.20°, 21.25 ⁇ 0.20°, 21.48 ⁇ 0.20°, 22.71 ⁇ 0.20°, 26.74 ⁇ 0.20°, 27.46 ⁇ 0.20° and 27.83 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystal form P has characteristic diffraction peaks at the following 2 ⁇ angles: 7.08 ⁇ 0.20°, 11.61 ⁇ 0.20°, 12.92 ⁇ 0.20°, 15.36 ⁇ 0.20°, 15.89 ⁇ 0.20 °, 18.61 ⁇ 0.20°, 19.89 ⁇ 0.20°, 20.39 ⁇ 0.20°, 21.25 ⁇ 0.20°, 21.48 ⁇ 0.20°, 22.71 ⁇ 0.20°, 26.05 ⁇ 0.20°, 26.74 ⁇ 0.20°, 27.46 ⁇ 0.20° and 27.83 ⁇ 0.20 °
  • the XRPD pattern of the above-mentioned crystal form P is shown in FIG. 44A or FIG. 44B.
  • the XRPD pattern of the above-mentioned crystal form P has characteristic diffraction peaks at the following 2 ⁇ angles, as shown in Table 16A:
  • Table 16A XRPD pattern data of P crystal form
  • the XRPD pattern of the above-mentioned crystal form P has characteristic diffraction peaks at the following 2 ⁇ angles, as shown in Table 16B:
  • Table 16B XRPD pattern data of P crystal form
  • thermogravimetric analysis curve of the above-mentioned crystal form P loses weight by 2.76% when the temperature is raised to 150.0 ⁇ 3°C.
  • the TGA pattern of the above-mentioned P crystal form is shown in FIG. 45.
  • the differential scanning calorimetry (DSC) of the above-mentioned crystal form P has an endothermic peak at 236.1 ⁇ 3°C.
  • the X-ray powder diffraction pattern of the crystal form P has characteristic diffraction peaks at the following 2 ⁇ angles: 7.12 ⁇ 0.20° and 21.46 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form P has characteristic diffraction peaks at the following 2 ⁇ angles: 7.12 ⁇ 0.20°, 21.28 ⁇ 0.20° and 21.46 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form P has characteristic diffraction peaks at the following 2 ⁇ angles: 7.12 ⁇ 0.20°, 20.38 ⁇ 0.20°, 21.28 ⁇ 0.20°, 21.46 ⁇ 0.20°, 26.72 ⁇ 0.20 ° and 27.48 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form P has characteristic diffraction peaks at the following 2 ⁇ angles: 7.12 ⁇ 0.20°, 20.38 ⁇ 0.20°, 21.46 ⁇ 0.20°, 26.72 ⁇ 0.20°, and 27.48 ⁇ 0.20 °.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form P has characteristic diffraction peaks at the following 2 ⁇ angles: 7.12 ⁇ 0.20°, 12.96 ⁇ 0.20°, 18.66 ⁇ 0.20°, 20.38 ⁇ 0.20°, 21.46 ⁇ 0.20 °, 22.74 ⁇ 0.20°, 26.72 ⁇ 0.20°, 27.48 ⁇ 0.20° and 27.82 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form P has characteristic diffraction peaks at the following 2 ⁇ angles: 7.12 ⁇ 0.20°, 12.96 ⁇ 0.20°, 18.66 ⁇ 0.20°, 20.38 ⁇ 0.20°, 21.28 ⁇ 0.20 °, 21.46 ⁇ 0.20°, 22.74 ⁇ 0.20°, 24.84 ⁇ 0.20°, 26.72 ⁇ 0.20°, 27.48 ⁇ 0.20° and 27.82 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the P crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.12 ⁇ 0.20°, 15.40 ⁇ 0.20°, 21.28 ⁇ 0.20°, 21.46 ⁇ 0.20°, and 22.74 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form P has characteristic diffraction peaks at the following 2 ⁇ angles: 7.12 ⁇ 0.20°, 12.96 ⁇ 0.20°, 15.40 ⁇ 0.20°, 21.28 ⁇ 0.20°, 21.46 ⁇ 0.20 °, 22.74 ⁇ 0.20° and 27.48 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form P has characteristic diffraction peaks at the following 2 ⁇ angles: 7.12 ⁇ 0.20°, 12.96 ⁇ 0.20°, 15.40 ⁇ 0.20°, 20.38 ⁇ 0.20°, 21.28 ⁇ 0.20 °, 21.46 ⁇ 0.20°, 22.74 ⁇ 0.20°, 26.72 ⁇ 0.20° and 27.48 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form P has characteristic diffraction peaks at the following 2 ⁇ angles: 7.12 ⁇ 0.20°, 12.96 ⁇ 0.20°, 15.40 ⁇ 0.20°, 18.66 ⁇ 0.20°, 20.38 ⁇ 0.20 °, 21.28 ⁇ 0.20°, 21.46 ⁇ 0.20°, 22.74 ⁇ 0.20°, 26.72 ⁇ 0.20°, 27.48 ⁇ 0.20° and 27.82 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form P has characteristic diffraction peaks at the following 2 ⁇ angles: 7.12 ⁇ 0.20°, 8.74 ⁇ 0.20°, 12.96 ⁇ 0.20°, 15.40 ⁇ 0.20°, 15.92 ⁇ 0.20°, 18.66 ⁇ 0.20°, 20.38 ⁇ 0.20°, 21.28 ⁇ 0.20°, 21.46 ⁇ 0.20°, 22.74 ⁇ 0.20°, 26.72 ⁇ 0.20° and 27.48 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form P has characteristic diffraction peaks at the following 2 ⁇ angles: 7.12 ⁇ 0.20°, 8.74 ⁇ 0.20°, 11.66 ⁇ 0.20°, 12.96 ⁇ 0.20°, 15.40 ⁇ 0.20 °, 15.92 ⁇ 0.20°, 16.22 ⁇ 0.20°, 18.66 ⁇ 0.20°, 20.38 ⁇ 0.20°, 21.28 ⁇ 0.20°, 21.46 ⁇ 0.20°, 22.74 ⁇ 0.20°, 26.72 ⁇ 0.20°, 27.48 ⁇ 0.20° and 27.82 ⁇ 0.20 °.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form P has characteristic diffraction peaks at the following 2 ⁇ angles: 7.12 ⁇ 0.20°, 8.74 ⁇ 0.20°, 9.29 ⁇ 0.20°, 11.66 ⁇ 0.20°, 12.96 ⁇ 0.20 °, 15.40 ⁇ 0.20°, 15.92 ⁇ 0.20°, 16.22 ⁇ 0.20°, 17.54 ⁇ 0.20°, 18.66 ⁇ 0.20°, 20.38 ⁇ 0.20°, 21.28 ⁇ 0.20°, 21.46 ⁇ 0.20°, 22.74 ⁇ 0.20°, 26.72 ⁇ 0.20 °, 27.48 ⁇ 0.20° and 27.82 ⁇ 0.20°.
  • the XRPD pattern of the above-mentioned crystal form P is shown in FIG. 59.
  • the XRPD pattern of the above-mentioned crystal form P has characteristic diffraction peaks at the following 2 ⁇ angles, as shown in Table 16C:
  • This application provides the P crystal form of the compound of formula (I), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 7.12 ⁇ 0.20° and 21.46 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form P has characteristic diffraction peaks at the following 2 ⁇ angles: 7.12 ⁇ 0.20°, 21.28 ⁇ 0.20° and 21.46 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form P has characteristic diffraction peaks at the following 2 ⁇ angles: 7.12 ⁇ 0.20°, 20.38 ⁇ 0.20°, 21.28 ⁇ 0.20°, 21.46 ⁇ 0.20°, 26.72 ⁇ 0.20 ° and 27.48 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form P has characteristic diffraction peaks at the following 2 ⁇ angles: 7.12 ⁇ 0.20°, 20.38 ⁇ 0.20°, 21.46 ⁇ 0.20°, 26.72 ⁇ 0.20°, and 27.48 ⁇ 0.20 °.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form P has characteristic diffraction peaks at the following 2 ⁇ angles: 7.12 ⁇ 0.20°, 12.96 ⁇ 0.20°, 18.66 ⁇ 0.20°, 20.38 ⁇ 0.20°, 21.46 ⁇ 0.20 °, 22.74 ⁇ 0.20°, 26.72 ⁇ 0.20°, 27.48 ⁇ 0.20° and 27.82 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form P has characteristic diffraction peaks at the following 2 ⁇ angles: 7.12 ⁇ 0.20°, 12.96 ⁇ 0.20°, 18.66 ⁇ 0.20°, 20.38 ⁇ 0.20°, 21.28 ⁇ 0.20 °, 21.46 ⁇ 0.20°, 22.74 ⁇ 0.20°, 24.84 ⁇ 0.20°, 26.72 ⁇ 0.20°, 27.48 ⁇ 0.20° and 27.82 ⁇ 0.20°.
  • This application provides the P crystal form of the compound of formula (I), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 7.12 ⁇ 0.20°, 15.40 ⁇ 0.20°, 21.28 ⁇ 0.20°, 21.46 ⁇ 0.20° and 22.74 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form P has characteristic diffraction peaks at the following 2 ⁇ angles: 7.12 ⁇ 0.20°, 12.96 ⁇ 0.20°, 15.40 ⁇ 0.20°, 21.28 ⁇ 0.20°, 21.46 ⁇ 0.20 °, 22.74 ⁇ 0.20° and 27.48 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form P has characteristic diffraction peaks at the following 2 ⁇ angles: 7.12 ⁇ 0.20°, 12.96 ⁇ 0.20°, 15.40 ⁇ 0.20°, 20.38 ⁇ 0.20°, 21.28 ⁇ 0.20 °, 21.46 ⁇ 0.20°, 22.74 ⁇ 0.20°, 26.72 ⁇ 0.20° and 27.48 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form P has characteristic diffraction peaks at the following 2 ⁇ angles: 7.12 ⁇ 0.20°, 12.96 ⁇ 0.20°, 15.40 ⁇ 0.20°, 18.66 ⁇ 0.20°, 20.38 ⁇ 0.20 °, 21.28 ⁇ 0.20°, 21.46 ⁇ 0.20°, 22.74 ⁇ 0.20°, 26.72 ⁇ 0.20°, 27.48 ⁇ 0.20° and 27.82 ⁇ 0.20°.
  • This application provides the P crystal form of the compound of formula (I), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 7.12 ⁇ 0.20°, 8.74 ⁇ 0.20°, 12.96 ⁇ 0.20°, 15.40 ⁇ 0.20°, 15.92 ⁇ 0.20°, 18.66 ⁇ 0.20°, 20.38 ⁇ 0.20°, 21.28 ⁇ 0.20°, 21.46 ⁇ 0.20°, 22.74 ⁇ 0.20°, 26.72 ⁇ 0.20° and 27.48 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form P has characteristic diffraction peaks at the following 2 ⁇ angles: 7.12 ⁇ 0.20°, 8.74 ⁇ 0.20°, 11.66 ⁇ 0.20°, 12.96 ⁇ 0.20°, 15.40 ⁇ 0.20 °, 15.92 ⁇ 0.20°, 16.22 ⁇ 0.20°, 18.66 ⁇ 0.20°, 20.38 ⁇ 0.20°, 21.28 ⁇ 0.20°, 21.46 ⁇ 0.20°, 22.74 ⁇ 0.20°, 26.72 ⁇ 0.20°, 27.48 ⁇ 0.20° and 27.82 ⁇ 0.20 °.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form P has characteristic diffraction peaks at the following 2 ⁇ angles: 7.12 ⁇ 0.20°, 8.74 ⁇ 0.20°, 9.29 ⁇ 0.20°, 11.66 ⁇ 0.20°, 12.96 ⁇ 0.20 °, 15.40 ⁇ 0.20°, 15.92 ⁇ 0.20°, 16.22 ⁇ 0.20°, 17.54 ⁇ 0.20°, 18.66 ⁇ 0.20°, 20.38 ⁇ 0.20°, 21.28 ⁇ 0.20°, 21.46 ⁇ 0.20°, 22.74 ⁇ 0.20°, 26.72 ⁇ 0.20 °, 27.48 ⁇ 0.20° and 27.82 ⁇ 0.20°.
  • the XRPD pattern of the above-mentioned crystal form P is shown in FIG. 59.
  • the XRPD pattern of the above-mentioned crystal form P has characteristic diffraction peaks at the following 2 ⁇ angles, as shown in Table 16D:
  • Table 16D XRPD pattern data of P crystal form
  • the present application provides a method for preparing the above crystal form P, which includes: 1) dissolving the compound of formula (I) in a mixed solvent of MTBE and MeOH; 2) after the solid is precipitated, the crystal form P is isolated.
  • the crystal form A of the compound of formula (I) is added to the mixed solvent of MTBE and MeOH.
  • the volume ratio of MTBE to MeOH is 3:2.
  • the mass-volume ratio of the compound of formula (I) to MTBE and MeOH is selected from 1mg:0.01 ⁇ 0.4mL:0.005-0.3mL; or, is selected from 1mg:0.02 ⁇ 0.1mL: 0.01 ⁇ 0.1mL; or, selected from 1mg:0.04mL:0.027mL.
  • the present application provides a method for preparing the above-mentioned crystal form P, which includes: 1) dissolving the compound of formula (I) in methanol or acetone; 2) after the solid is precipitated, the crystal form P is isolated.
  • This application provides the Q crystal form of the compound of formula (I), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 7.03 ⁇ 0.20°, 8.22 ⁇ 0.20° and 14.10 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form Q has characteristic diffraction peaks at the following 2 ⁇ angles: 7.03 ⁇ 0.20°, 8.22 ⁇ 0.20°, 10.34 ⁇ 0.20°, 14.10 ⁇ 0.20°, 14.66 ⁇ 0.20 ° and 21.61 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form Q has characteristic diffraction peaks at the following 2 ⁇ angles: 7.03 ⁇ 0.20°, 8.22 ⁇ 0.20°, 8.53 ⁇ 0.20°, 10.34 ⁇ 0.20°, 14.10 ⁇ 0.20 °, 14.66 ⁇ 0.20°, 16.47 ⁇ 0.20°, 17.07 ⁇ 0.20°, and 21.61 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form Q has characteristic diffraction peaks at the following 2 ⁇ angles: 7.03 ⁇ 0.20°, 8.22 ⁇ 0.20°, 8.53 ⁇ 0.20°, 8.95 ⁇ 0.20°, 10.34 ⁇ 0.20 °, 14.10 ⁇ 0.20°, 14.66 ⁇ 0.20°, 15.90 ⁇ 0.20°, 16.47 ⁇ 0.20°, 17.07 ⁇ 0.20°, 19.45 ⁇ 0.20°, 21.61 ⁇ 0.20°, 22.89 ⁇ 0.20° and 23.36 ⁇ 0.20°.
  • the XRPD pattern of the above-mentioned crystal form Q is shown in FIG. 47.
  • the XRPD pattern of the above-mentioned crystal form Q has characteristic diffraction peaks at the following 2 ⁇ angles, as shown in Table 17:
  • thermogravimetric analysis curve of the above-mentioned crystal form Q loses weight by 9.29% when the temperature is raised to 140.0 ⁇ 3°C.
  • the TGA spectrum of the above-mentioned crystal form Q is shown in FIG. 48.
  • the differential scanning calorimetry (DSC) of the above-mentioned crystal form Q has an endothermic peak at 162.9 ⁇ 3°C. In some solutions of the present application, the differential scanning calorimetry (DSC) of the above-mentioned crystal form Q has an endothermic peak at 235.6 ⁇ 3°C. In some solutions of the present application, the differential scanning calorimetry (DSC) of the above-mentioned crystal form Q has an exothermic peak at 168.5 ⁇ 3°C.
  • the differential scanning calorimetry curve (DSC) of the above-mentioned crystal form Q has an endothermic peak at 162.9 ⁇ 3°C, and/or 235.6 ⁇ 3°C, and/or has an endothermic peak at 168.5 ⁇ 3°C Exothermic peak.
  • the above-mentioned crystal form Q is a hydrate crystal form of the compound of formula (I).
  • the ratio of the number of the compound of formula (I) to water molecules in the Q crystal form is selected from 1:2.5 to 3.5; preferably 1:3.1.
  • this application provides a method for preparing the above-mentioned crystal form Q, which includes: 1) dissolving the compound of formula (I) in MeOH, adding ACN dropwise, and 2) separating the solid form to obtain the crystal form Q.
  • the crystal form A of the compound of formula (I) is added to MeOH.
  • This application provides the R crystal form of the compound of formula (I), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 6.60 ⁇ 0.20°, 8.55 ⁇ 0.20° and 15.21 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form R has characteristic diffraction peaks at the following 2 ⁇ angles: 6.60 ⁇ 0.20°, 8.55 ⁇ 0.20°, 11.67 ⁇ 0.20°, 15.21 ⁇ 0.20°, 17.60 ⁇ 0.20 °, and 24.56 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form R has characteristic diffraction peaks at the following 2 ⁇ angles: 6.60 ⁇ 0.20°, 8.55 ⁇ 0.20°, 11.67 ⁇ 0.20°, 15.21 ⁇ 0.20°, 17.12 ⁇ 0.20 °, 17.60 ⁇ 0.20°, 23.25 ⁇ 0.20°, 24.56 ⁇ 0.20° and 27.31 ⁇ 0.20°.
  • the XRPD pattern of the above-mentioned crystal form R is shown in FIG. 50.
  • the XRPD pattern of the above-mentioned crystal form R has characteristic diffraction peaks at the following 2 ⁇ angles, as shown in Table 18:
  • the present application provides a method for preparing the above-mentioned crystal form R, which includes: heating the above-mentioned crystal form O to 120-180° C. and cooling to room temperature to obtain the crystal form R.
  • the O crystal form is heated to 150°C.
  • This application provides the S crystal form of the compound of formula (I), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 6.15 ⁇ 0.20°, 8.43 ⁇ 0.20°, 21.57 ⁇ 0.20° and 23.90 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form S has characteristic diffraction peaks at the following 2 ⁇ angles: 6.15 ⁇ 0.20°, 8.43 ⁇ 0.20°, 14.94 ⁇ 0.20°, 16.29 ⁇ 0.20°, 16.84 ⁇ 0.20 °, 21.57 ⁇ 0.20° and 23.90 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form S has characteristic diffraction peaks at the following 2 ⁇ angles: 6.15 ⁇ 0.20°, 6.57 ⁇ 0.20°, 8.43 ⁇ 0.20°, 11.27 ⁇ 0.20°, 14.94 ⁇ 0.20 °, 16.29 ⁇ 0.20°, 16.84 ⁇ 0.20°, 17.71 ⁇ 0.20°, 21.57 ⁇ 0.20° and 23.90 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form S has characteristic diffraction peaks at the following 2 ⁇ angles: 6.15 ⁇ 0.20°, 6.57 ⁇ 0.20°, 8.43 ⁇ 0.20°, 8.83 ⁇ 0.20°, 11.27 ⁇ 0.20 °, 13.97 ⁇ 0.20°, 14.23 ⁇ 0.20°, 14.94 ⁇ 0.20°, 16.29 ⁇ 0.20°, 16.84 ⁇ 0.20°, 17.20 ⁇ 0.20°, 17.71 ⁇ 0.20°, 18.48 ⁇ 0.20°, 19.19 ⁇ 0.20°, 20.36 ⁇ 0.20 °, 20.74 ⁇ 0.20°, 21.57 ⁇ 0.20°, 22.61 ⁇ 0.20°, 23.02 ⁇ 0.20°, 23.90 ⁇ 0.20°, 26.16 ⁇ 0.20°, 26.67 ⁇ 0.20° and 27.74 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form S has characteristic diffraction peaks at the following 2 ⁇ angles: 6.15 ⁇ 0.20°, 6.57 ⁇ 0.20°, 8.43 ⁇ 0.20°, 8.83 ⁇ 0.20°, 9.90 ⁇ 0.20 °, 11.27 ⁇ 0.20°, 11.54 ⁇ 0.20°, 13.13 ⁇ 0.20°, 13.97 ⁇ 0.20°, 14.23 ⁇ 0.20°, 14.94 ⁇ 0.20°, 16.29 ⁇ 0.20°, 16.84 ⁇ 0.20°, 17.20 ⁇ 0.20°, 17.71 ⁇ 0.20 °, 18.48 ⁇ 0.20°, 19.19 ⁇ 0.20°, 20.36 ⁇ 0.20°, 20.74 ⁇ 0.20°, 21.57 ⁇ 0.20°, 22.20 ⁇ 0.20°, 22.61 ⁇ 0.20°, 23.02 ⁇ 0.20°, 23.90 ⁇ 0.20°, 24.92 ⁇ 0.20 °, 25.58 ⁇ 0.20°, 26.16 ⁇ 0.20°, 26.67 ⁇ 0.20°, 27.74 ⁇ 0.20
  • the XRPD pattern of the above-mentioned crystal form S has characteristic diffraction peaks at the following 2 ⁇ angles, as shown in Table 19:
  • the present application provides a method for preparing the above crystal form S, including: heating the above crystal form E to 180-240° C. to obtain the crystal form S.
  • heating is performed to 210°C.
  • This application provides the T crystal form of the compound of formula (I), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 7.23 ⁇ 0.20°, 8.45 ⁇ 0.20°, 16.18 ⁇ 0.20° and 26.35 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form T has characteristic diffraction peaks at the following 2 ⁇ angles: 7.23 ⁇ 0.20°, 8.45 ⁇ 0.20°, 12.85 ⁇ 0.20°, 16.18 ⁇ 0.20°, 19.41 ⁇ 0.20 ° and 26.35 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form T has characteristic diffraction peaks at the following 2 ⁇ angles: 7.23 ⁇ 0.20°, 8.45 ⁇ 0.20°, 12.85 ⁇ 0.20°, 16.18 ⁇ 0.20°, 18.46 ⁇ 0.20 °, 19.41 ⁇ 0.20°, 19.97 ⁇ 0.20°, 21.46 ⁇ 0.20° and 26.35 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form T has characteristic diffraction peaks at the following 2 ⁇ angles: 7.23 ⁇ 0.20°, 8.45 ⁇ 0.20°, 9.72 ⁇ 0.20°, 12.85 ⁇ 0.20°, 14.41 ⁇ 0.20 °, 16.18 ⁇ 0.20°, 18.46 ⁇ 0.20°, 19.41 ⁇ 0.20°, 19.97 ⁇ 0.20°, 21.46 ⁇ 0.20°, 24.95 ⁇ 0.20° and 26.35 ⁇ 0.20°.
  • the XRPD pattern of the above-mentioned crystal form T is shown in FIG. 52.
  • the XRPD pattern of the above-mentioned crystal form T has characteristic diffraction peaks at the following 2 ⁇ angles, as shown in Table 20:
  • thermogravimetric analysis curve of the above-mentioned crystal form T loses weight up to 0.47% when the temperature is raised to 150.0 ⁇ 3°C.
  • the TGA spectrum of the above-mentioned crystal form T is shown in FIG. 53.
  • the differential scanning calorimetry (DSC) of the above-mentioned crystal form T has an endothermic peak at 235.3 ⁇ 3°C. In some solutions of the present application, the differential scanning calorimetry (DSC) of the above-mentioned crystal form T has an exothermic peak at 178.1 ⁇ 3°C. In some solutions of the present application, the differential scanning calorimetry (DSC) of the above-mentioned crystal form T has an endothermic peak at 235.3 ⁇ 3°C and/or an exothermic peak at 178.1 ⁇ 3°C.
  • the present application provides a method for preparing the above-mentioned crystal form T, which includes: heating the above-mentioned crystal form G to 120-180° C. and cooling to room temperature to obtain the crystal form T.
  • the G crystal form is heated to 150°C.
  • This application provides the U crystal form of the compound of formula (I), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 3.50 ⁇ 0.20°, 6.97 ⁇ 0.20°, 9.51 ⁇ 0.20° and 19.13 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above U crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 3.50 ⁇ 0.20°, 6.97 ⁇ 0.20°, 9.51 ⁇ 0.20°, 11.55 ⁇ 0.20°, 17.53 ⁇ 0.20 °, 19.13 ⁇ 0.20° and 19.62 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above U crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 3.50 ⁇ 0.20°, 6.97 ⁇ 0.20°, 9.51 ⁇ 0.20°, 10.29 ⁇ 0.20°, 11.55 ⁇ 0.20 °, 14.00 ⁇ 0.20°, 17.53 ⁇ 0.20°, 19.13 ⁇ 0.20°, 19.62 ⁇ 0.20° and 21.09 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above U crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 3.50 ⁇ 0.20°, 6.97 ⁇ 0.20°, 9.51 ⁇ 0.20°, 9.98 ⁇ 0.20°, 10.29 ⁇ 0.20 °, 11.55 ⁇ 0.20°, 14.00 ⁇ 0.20°, 17.53 ⁇ 0.20°, 19.13 ⁇ 0.20°, 19.62 ⁇ 0.20°, 20.71 ⁇ 0.20°, 21.09 ⁇ 0.20°, 21.41 ⁇ 0.20°, 22.32 ⁇ 0.20°, 24.35 ⁇ 0.20 °, 26.98 ⁇ 0.20°, 35.53 ⁇ 0.20°.
  • the XRPD pattern of the above-mentioned U crystal form has characteristic diffraction peaks at the following 2 ⁇ angles, as shown in Table 21:
  • Table 21 XRPD pattern data of U crystal form
  • the present application provides a method for preparing the U crystal form, which includes: 1) dissolving the compound of formula (I) in DMAc; 2) adding toluene to the DMAc solution; 3) after the solid is precipitated, the U crystal is isolated. type.
  • the preparation method of the U crystal form in the preparation method of the U crystal form, the A crystal form of the compound of formula (I) is dissolved in DMAc.
  • adding toluene to the DMAc solution adopts a method of volatilizing toluene to the DMAc solution.
  • This application provides the V crystal form of the compound of formula (I), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 7.17 ⁇ 0.20°, 9.44 ⁇ 0.20°, 19.06 ⁇ 0.20° and 19.56 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form V has characteristic diffraction peaks at the following 2 ⁇ angles: 7.17 ⁇ 0.20°, 9.44 ⁇ 0.20°, 10.22 ⁇ 0.20°, 11.48 ⁇ 0.20°, 19.06 ⁇ 0.20 °, 19.56 ⁇ 0.20° and 21.35 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form V has characteristic diffraction peaks at the following 2 ⁇ angles: 6.90 ⁇ 0.20°, 7.17 ⁇ 0.20°, 8.99 ⁇ 0.20°, 9.44 ⁇ 0.20°, 9.91 ⁇ 0.20 °, 10.22 ⁇ 0.20°, 11.48 ⁇ 0.20°, 19.06 ⁇ 0.20°, 19.56 ⁇ 0.20° and 21.35 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form V has characteristic diffraction peaks at the following 2 ⁇ angles: 6.90 ⁇ 0.20°, 7.17 ⁇ 0.20°, 8.99 ⁇ 0.20°, 9.44 ⁇ 0.20°, 9.91 ⁇ 0.20 °, 10.22 ⁇ 0.20°, 11.48 ⁇ 0.20°, 14.50 ⁇ 0.20°, 17.46 ⁇ 0.20°, 19.06 ⁇ 0.20°, 19.56 ⁇ 0.20°, 21.01 ⁇ 0.20°, 21.35 ⁇ 0.20°, 21.85 ⁇ 0.20°, 22.25 ⁇ 0.20 ° and 24.27 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form V has characteristic diffraction peaks at the following 2 ⁇ angles: 6.90 ⁇ 0.20°, 7.17 ⁇ 0.20°, 8.99 ⁇ 0.20°, 9.44 ⁇ 0.20°, 9.91 ⁇ 0.20 °, 10.22 ⁇ 0.20°, 10.41 ⁇ 0.20°, 10.57 ⁇ 0.20°, 11.48 ⁇ 0.20°, 13.93 ⁇ 0.20°, 14.50 ⁇ 0.20°, 17.46 ⁇ 0.20°, 19.06 ⁇ 0.20°, 19.56 ⁇ 0.20°, 20.64 ⁇ 0.20 °, 21.01 ⁇ 0.20°, 21.35 ⁇ 0.20°, 21.85 ⁇ 0.20°, 22.25 ⁇ 0.20°, 24.27 ⁇ 0.20°, 26.88 ⁇ 0.20° and 29.30 ⁇ 0.20°.
  • the XRPD pattern of the above-mentioned crystal form V is shown in FIG. 56.
  • the XRPD pattern of the above-mentioned crystal form V has characteristic diffraction peaks at the following 2 ⁇ angles, as shown in Table 22:
  • thermogravimetric analysis curve of the above-mentioned crystal form V has a weight loss of 14.05% when the temperature is raised to 110.0 ⁇ 3°C. In some solutions of the present application, the thermogravimetric analysis curve of the above-mentioned crystal form V has a weight loss of 16.46% when the temperature is raised from 110.0 ⁇ 3°C to 160.0 ⁇ 3°C. In some solutions of the present application, the thermogravimetric analysis curve of the above-mentioned crystal form V has a weight loss of 14.05% when heated to 110.0 ⁇ 3°C, and/or a weight loss of 16.46% when heated from 110.0 ⁇ 3°C to 160.0 ⁇ 3°C.
  • the TGA spectrum of the above-mentioned crystal form V is shown in FIG. 57.
  • the differential scanning calorimetry (DSC) of the above-mentioned crystal form V has an endothermic peak at 231.1 ⁇ 3°C. In some solutions of the present application, the differential scanning calorimetry (DSC) of the above-mentioned crystal form V has an endothermic peak at 153.9 ⁇ 3°C. In some solutions of the present application, the differential scanning calorimetry (DSC) of the above-mentioned crystal form V has an endothermic peak at 231.1 ⁇ 3°C and/or 153.9 ⁇ 3°C.
  • the present application provides a method for preparing the above-mentioned crystal form V, which includes: drying the above-mentioned crystal form U at 50° C. under vacuum conditions to obtain crystal form V.
  • the present application provides a crystalline composition comprising the above-mentioned crystalline form, wherein the crystalline form accounts for more than 50% of the weight of the crystalline composition, preferably more than 80%, more preferably more than 90%, It is preferably more than 95%.
  • the present application provides a pharmaceutical composition, which contains a therapeutically effective amount of the crystal form described in the present application, or a crystal form composition thereof.
  • the pharmaceutical composition of the present application may or may not contain pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the present application may further include one or more other therapeutic agents.
  • the application also provides the application of the above-mentioned crystal form, crystal form composition, or pharmaceutical composition thereof in the preparation of drugs for inhibiting nucleoprotein.
  • the present application also provides a method for inhibiting nucleoprotein, which includes administering a therapeutically effective amount of the above-mentioned crystal form, crystal form composition, or pharmaceutical composition thereof to a mammal in need of such treatment or prevention, preferably a human.
  • the application also provides the above-mentioned crystal form, crystal form composition, or pharmaceutical composition thereof for use as a nuclear protein inhibitor.
  • the application also provides the application of the above-mentioned crystal form, crystal form composition, or pharmaceutical composition thereof in inhibiting nucleoprotein.
  • the above application or method is characterized in that the nucleoprotein inhibitor drug is a drug for treating or preventing HBV infection-related diseases.
  • the application also provides the application of the above-mentioned crystal form, crystal form composition, or pharmaceutical composition thereof in the preparation of medicines for treating or preventing HBV infection-related diseases.
  • the application also provides the application of the above-mentioned crystal form, crystal form composition, or pharmaceutical composition thereof in the treatment or prevention of HBV infection-related diseases.
  • This application also provides the above-mentioned crystal form, crystal form composition, or pharmaceutical composition thereof for treating or preventing HBV infection-related diseases.
  • the application also provides the application of the above-mentioned crystal form, crystal form composition, or pharmaceutical composition thereof in the treatment or prevention of HBV infection-related diseases.
  • the compound of formula (I) of the present application has good drug efficacy for in vivo administration, and its various crystal forms are stable, are less affected by light, heat and humidity, have good solubility, and have broad prospects for preparation of medicines.
  • the crystalline form of the present application has good pharmacokinetic properties and is suitable for use as drugs. The pharmacokinetic properties can be measured in pre-clinical animal experiments such as SD rats and beagle dogs, or in Measured in clinical human trials.
  • the crystal form of the present application contributes to the solid form of the compound.
  • the position of the peak or the relative intensity of the peak may be different due to factors such as the measuring instrument and the measuring method/condition.
  • the measurement error of the 2 ⁇ value may be ⁇ 0.2°. Therefore, when determining each crystal type, this error should be taken into account, and the error also belongs to the scope of this application.
  • the crystal grains in the sample are significantly inclined to a certain crystallographic direction, which is called preferred orientation.
  • preferred orientation For substances with strong cleavage, the phenomenon of preferred orientation can be easily found visually.
  • preferential orientation tends to occur when making test samples.
  • the discovery of the flaky crystal face tends to coincide with the axis of the sample tube.
  • the normal line of the lamellae crystal surface tends to be perpendicular to the base surface of the sample holder.
  • the preferred orientation will affect the detection results of the powder diffraction method to determine the crystal structure.
  • the XRPD detection results of different batches of crystal forms are different, but this does not hinder those skilled in the art from making judgments about whether they are the same crystal form.
  • the position of the endothermic peak of DSC may be different due to factors such as measuring instrument, measuring method/condition and so on.
  • there may be an error in the position of the endothermic peak which can be ⁇ 5°C or ⁇ 3°C. Therefore, when determining each crystal type, this error should be taken into account, and the error also belongs to the scope of this application.
  • solvate refers to a substance formed by combining the compound of formula (I) in this application with a pharmaceutically acceptable solvent, and this application does not include water.
  • Pharmaceutically acceptable solvents include ethanol, acetic acid and the like. Solvates include stoichiometric solvates and non-stoichiometric solvates.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues, but not Many toxicity, irritation, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable excipients” refer to inert substances that are administered together with the active ingredients to facilitate the administration of the active ingredients, including but not limited to those acceptable for use in humans or animals (such as those approved by the State Food and Drug Administration).
  • Livestock any glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, Isotonic agent, solvent or emulsifier.
  • auxiliary materials include calcium carbonate, calcium phosphate, various sugars and various starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
  • pharmaceutical composition refers to a mixture of one or more of the compounds of the application or their salts and pharmaceutically acceptable excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound of the present application to the organism.
  • the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, and powders. , Granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Typical routes for administering the crystal form described in the present application or its pharmaceutical composition include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, Intravenous administration.
  • the pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing method, dissolution method, granulation method, sugar-coated pill method, grinding method, emulsification method, freeze-drying method, etc.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These auxiliary materials enable the compound of the present application to be formulated into tablets, pills, lozenges, sugar-coated agents, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.
  • the therapeutic dose of the compound of the present application may be determined based on, for example, the following: the specific purpose of the treatment, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician.
  • the ratio or concentration of the compound of the present application in the pharmaceutical composition may not be fixed, depending on various factors, including dosage, chemical properties (for example, hydrophobicity), and route of administration.
  • treatment means administering the compound or formulation described in this application to improve or eliminate a disease or one or more symptoms related to the disease, and includes:
  • prevention means administering the compound or preparation described in this application to prevent a disease or one or more symptoms related to the disease, and includes: preventing the occurrence of a disease or disease state in a mammal, especially when Such mammals are susceptible to the disease state, but have not been diagnosed as having the disease state.
  • the term "therapeutically effective amount” refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect.
  • the determination of the effective amount varies from person to person, and depends on the age and general conditions of the recipient, as well as the specific active substance. The appropriate effective amount in a case can be determined by those skilled in the art according to routine experiments.
  • the therapeutically effective amount of the crystal form described in the present application is from about 0.0001 to 20 mg/Kg body weight/day, for example, from 0.001 to 10 mg/Kg body weight/day.
  • the dosage frequency of the crystal form described in the present application is determined by the needs of the individual patient, for example, once or twice a day, or more times a day.
  • the administration may be intermittent, for example, where the patient receives the daily dose of the crystal form during a period of several days, and then the patient does not receive the daily dose of the crystal form during a period of several days or more.
  • the intermediate compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and those of those skilled in the art.
  • Well-known equivalent alternatives, and preferred implementations include but are not limited to the examples of the present application.
  • DCM dichloromethane
  • DMF N,N-dimethylformamide
  • DMSO dimethyl sulfoxide
  • EtOH stands for ethanol
  • MeOH stands for methanol
  • TFA trifluoroacetic acid
  • ATP stands for Adenosine triphosphate
  • HEPES 4-hydroxyethylpiperazine ethanesulfonic acid
  • EGTA stands for ethylene glycol bis(2-aminoethyl ether) tetraacetic acid
  • MgCl 2 stands for magnesium dichloride
  • NMP stands for N-methylpyrrolidone
  • THF stands for tetrahydrofuran
  • 2-MeTHF stands for 2-methyltetrahydrofuran
  • MTBE stands for methyl tert-butyl ether
  • DMAc stands for dimethylacetamide
  • ACN stands for acetonitrile.
  • Test method Approximately 10 mg of sample is used for XRPD detection.
  • Light tube voltage 45kV
  • light tube current 40mA
  • the first solar slit 0.04rad
  • the second solar slit 0.04rad
  • Step width angle 0.0263deg(X'Pert 3 )/0.0167deg(Empyrean)
  • Step length 46.665 seconds (X'Pert 3 )/17.780 seconds (Empyrean)
  • Test method Take a sample ( ⁇ 1-5mg) and place it in a DSC aluminum pan for testing. Under the condition of 50mL/min N 2 and at a heating rate of 10°C/min, heat the sample from 25°C (room temperature) to before the sample is decomposed .
  • TGA Thermal Gravimetric Analyzer
  • Test method Take a sample ( ⁇ 1-5mg) and place it in a TGA aluminum pan for testing. Under the condition of 10mL/min N 2 and at a heating rate of 10°C/min, heat the sample from room temperature to 350°C.
  • Figure 1 XRPD pattern of crystal form A.
  • Figure 4 XRPD pattern of Form B.
  • Figure 14 XRPD pattern of Form F.
  • Figure 17 XRPD pattern of Form G.
  • FIG. 18 TGA pattern of crystal form G.
  • Figure 32 XRPD pattern of crystal form L.
  • Figure 38 XRPD pattern of N crystal form.
  • Figure 41 XRPD pattern of crystal form O.
  • Figure 42 TGA pattern of O crystal form.
  • Figure 44A XRPD pattern 1 of crystal form P.
  • Figure 44B XRPD pattern 2 of the P crystal form.
  • FIG. 45 TGA pattern 1 of the P crystal form.
  • Figure 46 DSC profile 1 of the P crystal form.
  • Figure 47 XRPD pattern of crystal form Q.
  • Figure 50 XRPD pattern of Form R.
  • Figure 51 XRPD pattern of S crystal form.
  • Figure 55 XRPD pattern of U crystal form.
  • Figure 59 XRPD pattern 3 of crystal form P.
  • Figure 60 DSC profile 2 of the P crystal form.
  • Fig. 61 XRPD pattern of crystal form P calculated from single crystal data.
  • Figure 62 Polarized light microscope (PLM) picture of P crystal form.
  • Figure 63 Figure 44B (upper figure), Figure 59 (middle figure), and Figure 61 (lower figure) superimposed.
  • compound 13-4 (1.3g, 3.97mmol, 1eq) was dissolved in ethyl acetate (30mL) and hydrochloric acid/ethyl acetate (4M, 10mL, 10.08eq) was added, and the reaction was stirred at 30°C 16 hours. The reaction solution was directly concentrated to obtain compound 13-5.
  • reaction solution was poured into water (50mL), then the aqueous phase was extracted with dichloromethane (20mL*3), the organic phase was washed with 0.5M dilute hydrochloric acid (20mL*3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure Compound 13-6 was obtained.
  • Compound 13-6 was separated by SFC (chromatographic column: DAICELCHIRALCELOJ (250mm*30mm, 10 ⁇ m); mobile phase [Neu-ETOH]; B%: 30%-30%, 9min). Obtain compound 1-1 (SFC retention time 1.7min), SFC analysis conditions (chromatographic column: Daicel OJ-3 chiral column, specification 0.46cm id x 5cm; mobile phase: [A: carbon dioxide, B: chromatographic ethanol ( 0.05% isopropylamine)]; B%: 5%-40%; flow rate: 4 ml/min; 4 minutes; system back pressure: 100 bar).
  • SFC chromatographic column: DAICELCHIRALCELOJ (250mm*30mm, 10 ⁇ m); mobile phase [Neu-ETOH]; B%: 30%-30%, 9min).
  • Obtain compound 1-1 SFC retention time 1.7min
  • SFC analysis conditions chromatographic column: Daicel OJ-3 chiral column, specification 0.46cm id x 5c
  • compound 1-1 (550.00mg, 1.14mmol, 1eq) was dissolved in tetrahydrofuran (10mL), water (10mL) and methanol (10mL) and added lithium hydroxide monohydrate (239.91mg, 5.72mmol, 5eq) ), the reaction was stirred at 30°C for 16 hours. LCMS showed that the reaction was complete.
  • Preparation method of crystal form A Dissolve 7.5 g of compound 1-5 in dichloromethane (80 mL), then add trifluoroacetic acid (40 mL), and stir the reaction at 15° C. for 1 hour. HPLC showed that the reaction was complete, and the reaction solution was directly concentrated under reduced pressure. The crude product was slurried and purified by methyl tert-butyl ether (100 mL), filtered and concentrated, and lyophilized to obtain a white solid product. The XRPD was separated and tested, and it was crystal form A.
  • Preparation method of crystal form B dissolve about 15 mg of crystal form A sample in 0.04 ml DMSO, add water dropwise until the solid precipitates, suspend and stir overnight, separate and test XRPD, that is, crystal form B.
  • Preparation method of crystal form C dissolve about 15 mg of crystal form A sample in 0.18 ml of THF, add MTBE dropwise until the solid precipitates, suspend and stir overnight, separate and test XRPD, that is crystal form C.
  • Preparation method of crystal form D dissolve about 15 mg of crystal form A sample in 0.13 ml of THF, add DCM dropwise until a solid precipitates, suspend and stir overnight, separate and test XRPD, which is crystal form D.
  • Preparation method of crystal form E Dissolve about 15 mg of crystal form A sample in 0.6 ml 1,4-Dioxane (1,4-dioxane), place the above solution in a 3 ml glass bottle, and then The 3 ml glass bottle of the above solution is placed in a 20 ml glass bottle containing 3 ml of ACN (acetonitrile), and the ACN (acetonitrile) is slowly volatilized into the 1,4-Dioxane (1,4-dioxane) solution. To produce a solid in a 1,4-Dioxane (1,4-dioxane) solution, and after the solid is obtained, the solid is separated and tested for XRPD, which is the crystal form E.
  • Preparation method of crystal form F dissolve about 15 mg of crystal form A sample in 0.3 ml of DMF to obtain a clear solution, add the clear solution dropwise to 3 ml of H 2 O, suspend at room temperature and stir overnight, separate the solid to test XRPD, which is Form F.
  • Preparation method of crystal form G disperse about 15 mg of crystal form A sample in 0.1 ml of CHCl 3 /THF (9:1, v/v), suspend and stir at room temperature for about 2 weeks, separate and test XRPD, which is crystal form G.
  • Preparation method of crystal form H Disperse about 15 mg of crystal form A sample in 0.1 ml of EtOH/DMF (19:1, v/v), suspend and stir at room temperature for about 2 weeks, separate and test XRPD, which is crystal form H.
  • Preparation method of crystal form I Disperse about 15 mg of crystal form A sample in 0.1 ml of water, suspend and stir at 50°C for about 2 weeks, and separate and test XRPD, which is crystal form I.
  • Preparation method of crystal form J disperse about 15 mg of crystal form A sample in 0.1 ml 2-MeTHF, suspend and stir at 50°C for about 2 weeks, and separate and test XRPD, which is crystal form J.
  • Preparation method of crystal form K Dissolve about 15 mg of crystal form A sample in 0.2 ml DCM/MeOH (4:1, v/v) at 50°C, and directly lower the temperature to 5°C, separate and test XRPD, which is crystal form K .
  • Preparation method of crystal form L dissolve about 15 mg of crystal form A sample in 0.1 ml of NMP (N-methylpyrrolidone), put the above solution in a 3 ml glass bottle, and then put the 3 ml glass bottle containing the above solution Placed in a 20 ml glass bottle containing 3 ml of EtOAc (ethyl acetate), let EtOAc (ethyl acetate) slowly evaporate into the NMP (N-methylpyrrolidone) solution, so that the NMP (N-methylpyrrolidone) A solid is generated in the solution. After the solid is obtained, the solid is separated and tested for XRPD, which is the crystal form L.
  • NMP N-methylpyrrolidone
  • Preparation method of crystal form M dissolve about 15 mg of crystal form A sample in 0.4 ml of THF, slowly volatilize at room temperature to obtain a solid, separate and test XRPD, that is, crystal form M.
  • Preparation method of crystal form N dissolve about 15 mg of crystal form A sample in 1.5 ml of EtOH at 50°C, directly cool to 5°C, and separate and test XRPD, which is crystal form N.
  • Preparation method of crystal form O dry crystal form D in vacuum at room temperature for about 1 hour, test XRPD, it is crystal form O.
  • Preparation method of crystal form P 1 dissolve about 15 mg of crystal form A sample in 1.0 ml MTBE/MeOH (3:2, v/v), slowly volatilize at room temperature to obtain a solid, separate and test XRPD, that is, crystal form P.
  • the XRPD test results of the obtained crystal form P are shown in Fig. 44A and Fig. 44B, and the TGA and DSC test results are shown in Fig. 45 and Fig. 46, respectively.
  • Preparation method of crystal form Q dissolve about 15 mg of crystal form A sample in 1.5 ml of MeOH, add about 3 ml of ACN dropwise to obtain a clear solution, turn to -20°C for suspension and stirring, separate the solid to test XRPD, it is crystal form Q .
  • Preparation method of crystal form R heat crystal form O to 150°C and then to room temperature, test XRPD, it is crystal form R.
  • Preparation method of crystal form S heating crystal form E to 210°C and testing XRPD in situ, it is crystal form S.
  • Preparation method of crystal form T heating crystal form G to 150° C. and then to room temperature, it is crystal form T.
  • the preparation method of crystal form V the crystal form U is vacuum dried at 50° C. for 2 to 3 hours, and the XRPD is tested, and the crystal form is V crystal form.
  • the compound of formula (I) is dissolved in methanol and obtained after 10 days of incubation at room temperature by solvent volatilization method.
  • Real-time quantitative qPCR test (real time-qPCR) was used to detect the HBV DNA content in HepG2.2.15 cells, and the compound's EC 50 value was used as an indicator to evaluate the compound's inhibitory effect on HBV.
  • HepG2.2.15 cell culture medium (DMEM/F12, Invitrogen-11330057; 10% serum, Invitrogen-10099141; 100units/ml penicillin and 10 ⁇ g/ml streptomycin, Invitrogen-15140122; 1% non-essential amino acids, Invitrogen-11140076; 2mM L-glutamine, Invitrogen-25030081; 300 ⁇ g/ml geneticin, Invitrogen-10131027)
  • HepG2.2.15 cells 4 ⁇ 10 4 cells/well were transferred to a 96-well plate and cultured overnight at 37° C., 5% CO 2.
  • Upstream primer sequence GTGTCTGCGGCGTTTTATCA
  • the PCR reaction conditions are: heating at 95°C for 10 minutes; then denaturation at 95°C for 15 seconds, and extension at 60°C for 1 minute, a total of 40 cycles.
  • %Inh. [1-(number of DNA copies in the sample – 1 ⁇ M number of DNA copies in GLS4)/(number of DNA copies in the DMSO control – 1 ⁇ M number of DNA copies in GLS4)] ⁇ 100.
  • An automatic patch clamp method is used to detect the effect of the compound of the application to be tested on the hERG potassium ion channel.
  • the cells stably expressing the hERG potassium channel used in the experiment were derived from CHO-hERE of Aviva Biosciences, and the CHO-hERG was cultured in an environment of 5% CO 2 and 37°C.
  • CHO hERG culture medium is shown in Table 28.
  • Reagent supplier Volume (mL) F12 medium Invitrogen 500 Fetal Bovine Serum Invitrogen 50 G418/genetic toxin Invitrogen 1 Hygromycin B Invitrogen 1
  • the CHO-hERG cells to be used in the experiment should be cultured for at least two days, and the cell density should reach 75% or more. Before the experiment, the cells were digested with TrypLE, and then resuspended in extracellular fluid to collect the cells.
  • Extracellular fluid needs to be prepared once a month.
  • the intracellular fluid must be aliquoted and frozen at -20°C. See Table 29 for the composition of the intracellular and extracellular fluid.
  • Extracellular fluid Extracellular fluid (mM) Intracellular fluid (mM) NaCl 145 - KCl 4 120 KOH - 31.25 CaCl 2 2 5.374 MgCl 2 1 1.75 Glucose 10 - Na 2 ATP - 4 HEPES 10 10 EGTA - 10 pH Sodium hydroxide adjusts the pH to 7.4 Potassium hydroxide adjusts the pH to 7.4 Osmotic pressure 295mOsm 285mOsm .
  • test compound and the positive control amitriptyline are dissolved in DMSO into a stock solution of a certain concentration, and then diluted according to different gradients, and finally added to the extracellular fluid in a certain proportion to be diluted to the test concentration. Check with the naked eye for precipitation before starting the experiment. Finally, the concentration of DMSO in the test solution and the positive control amitriptyline should not exceed 0.3%.
  • the hERG QPatch HTX experiment was performed at room temperature.
  • the whole cell protocol, voltage stimulation protocol and compound detection protocol were established on the software of QPatch Assay Software 5.2 (Sophion Bioscience).
  • I (C) I b +(I fr -I b )*c n /(IC 50 n +c n )
  • C is the test concentration of the compound
  • n is the slope
  • I is the current
  • the curve fitting and the calculation of the inhibition rate are all analyzed by the Qpatch analysis software. If the inhibition rate at the lowest concentration exceeds the half inhibition or the inhibition rate at the highest concentration does not reach the half inhibition, the corresponding IC 50 of the compound is lower than the lowest concentration or IC 50 value Greater than the highest concentration.
  • Test sample hERG IC50( ⁇ M) Compound of formula (I) >40 .
  • the test compound (10mM) is gradient, and the working solution (100 ⁇ final concentration) is prepared.
  • the concentration of the working solution are: 5, 1.5, 0.5, 0.15, 0.05, 0.015, 0.005 mM, and the P450 coworker is prepared at the same time
  • Enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4
  • each positive inhibitor and the working solution of the specific substrate mixture thaw the human liver microsomes frozen at -80°C on ice, and wait until the human liver microsomes are all Dissolve and dilute with PB (phosphate buffer) to prepare a working solution of a certain concentration (0.253mg/ml); and add 20 ⁇ l of the substrate mixture to the reaction plate (add 20 ⁇ l PB to the Blank well) and 158 ⁇ l of human liver particles
  • test compound control sample is 1:1DMSO:MeOH
  • positive control sample is 1:9DMSO:MeOH
  • control sample is 1:1DMSO:MeOH
  • test compound control sample is 1:1DMSO:MeOH
  • positive control sample is 1:9DMSO:MeOH
  • control sample is 1:1DMSO:MeOH
  • 20 ⁇ l of coenzyme factor (NADPH) solution to the reaction plate and incubate in a 37°C water bath for 10 minutes
  • 400 ⁇ L of cold acetonitrile solution internal standard: 200ng/mL Tolbutamide and Labetalol
  • RLU Sample is the signal value of the sample well
  • AverageRLU Cellcontrol is the average signal of the cell control well
  • AverageRLU Mediumcontrol is the average signal of the medium control well.
  • test compound (10mM) is diluted in two steps, the intermediate concentration is 100% methanol diluted to 100 ⁇ M, the working solution concentration is potassium phosphate buffer diluted to 10 ⁇ M; prepare 8 96-well incubation plates, named as T0, T5, T10, T20, T30, T60, Blank and NCF60; the reaction time points corresponding to the first 6 incubation plates are 0, 5, 10, 20, 30, and 60 minutes, respectively.
  • the blank plate does not add test compound or For the control compound, use potassium phosphate buffer in the NCF60 plate instead of the NADPH regeneration system solution to incubate for 60 minutes; add 10 ⁇ L of the test compound working solution and 80 ⁇ L of microsomes to the T0, T5, T10, T20, T30, T60 and NCF60 plates, respectively Working solution (liver microsomal protein concentration is 0.625mg/mL), add only the microsomal working solution to the Blank plate, and then place the above incubation plate in a 37°C water bath for pre-incubation for about 10 minutes; after the pre-incubation, remove In addition to the NCF60 plate and T0 plate, add 10 ⁇ L of NADPH regeneration system working solution to each sample well to start the reaction, and add 10 ⁇ L of potassium phosphate buffer to each well of the NCF60 plate; therefore, in the sample of the test compound or the control compound, The final concentration of the compound, testosterone, diclofenac and propafenone in the reaction was
  • test compound (10mM) is diluted in two steps, the intermediate concentration is 100% methanol diluted to 100 ⁇ M, the working solution concentration is potassium phosphate buffer diluted to 10 ⁇ M; prepare 8 96-well incubation plates, named as T0, T5, T10, T20, T30, T60, Blank and NCF60; the reaction time points corresponding to the first 6 incubation plates are 0, 5, 10, 20, 30 and 60 minutes, respectively.
  • test compound was mixed with 10% dimethyl sulfoxide/60% polyethylene glycol 400/30% aqueous solution, vortexed and sonicated to prepare a 0.2 mg/mL clear solution, which was filtered through a microporous membrane for use.
  • Balb/c female mice aged 7 to 10 weeks were selected, and the candidate compound solution was administered intravenously at a dose of 1 mg/kg.
  • test compound was mixed with a 10% polyethylene glycol stearate aqueous solution, vortexed and sonicated to prepare a 0.3 mg/mL clear solution for later use.
  • Balb/c female mice aged 7 to 10 weeks were selected, and the candidate compound solution was orally administered at a dose of 3 mg/kg.
  • the compound of formula (I) is mixed with 10% polyethylene glycol-15 hydroxystearate aqueous solution, vortexed and sonicated to prepare a 0.3 mg/mL clear solution for later use.
  • Balb/c female mice aged 7 to 10 weeks were selected, and the candidate compound solution was orally administered at a dose of 3 mg/kg.
  • the solvent is 10% polyethylene glycol-15 hydroxystearate; a certain amount of tested compound of formula (I) is dissolved in 10% polyethylene glycol-15 hydroxystearate aqueous solution, and vortex Spin and sonicate to prepare a uniform suspension and store it at 4°C for later use.
  • Mouse tail vein high pressure injection of HBV plasmid DNA solution set the day of plasmid injection as day 0, day 1 after injection as day 1, and so on. On day 0, all animals were injected with a physiological saline solution containing 10 ⁇ g of plasmid DNA through the tail vein at a volume of 8% of their body weight, and the injection was completed within 5 seconds.
  • mice All animals were given intragastric administration twice a day (8/16 hours interval) on day 1-6, and once on day 7, and all animals were euthanized in the afternoon on day 7. The body weight of the mice was monitored every day, and the body weight of the mice remained stable throughout the experiment.
  • Sample collection All animals were collected from the submandibular vein four hours after the first dose in the morning on the first, third and fifth days. All blood samples were collected in K 2 -EDTA anticoagulation tube, 4°C, 7000g Centrifuge for 10 minutes to prepare approximately 40 ⁇ L of plasma. On the 7th day, all animals were euthanized by CO 2 four hours after the administration in the morning, blood was collected from the heart, and the plasma preparation method was the same as above. Collect two liver tissues, 70-100 mg each, and snap frozen in liquid nitrogen. After all the samples were collected, they were stored in a refrigerator at -80°C for detection of HBV DNA content.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Biotechnology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Analysing Materials By The Use Of Radiation (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

涉及式(I)化合物、其水合物、其溶剂合物、或者水与溶剂共合物的晶型，以及其在制备治疗与HBV相关疾病的药物中的应用。

Description

一种核蛋白抑制剂的晶型及其应用
相关申请的交叉引用
本申请主张如下优先权：中国专利申请：201911171978.3，申请日：2019年11月22日，其全文均以引用的方式并入本文中。
技术领域
本申请涉及一种核蛋白抑制剂的晶型，以及其在制备治疗与HBV相关疾病的药物中的应用。
背景技术
乙型肝炎是由乙肝病毒入侵引起的炎症反应，其易发展成肝纤维化、肝硬化，是全球80％原发性肝癌的直接病因。
乙肝是世界性医学难题，目前全世界范围内还没有治疗乙肝的特效药，全球乙肝药物市场中核苷类和干扰素类占据主要地位；乙肝治疗的一线用药主要是核苷类药物，干扰素。但存在费用昂贵、易复发等问题，因此开发出一种新型的抗乙肝药物势在必行。
发明内容
一方面，本申请提供式(I)化合物、其水合物、其溶剂合物、或者水与溶剂共合物的晶型
Figure PCTCN2020130612-appb-000001
本申请提供式(I)化合物的A晶型，其X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：6.20±0.20°、8.90±0.20°、16.30±0.20°和24.78±0.20°。本申请的一些方案中，上述A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.20±0.20°、8.90±0.20°、14.22±0.20°、16.30±0.20°、22.32±0.20°和24.78±0.20°。本申请的一些方案中，上述A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.20±0.20°、8.90±0.20°、11.26±0.20°、14.22±0.20°、16.30±0.20°、17.89±0.20°、22.32±0.20°和24.78±0.20°。本申请的一些方案中，上述A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.20±0.20°、8.90±0.20°、10.09±0.20°、11.26±0.20°、14.22±0.20°、16.30±0.20°、17.89±0.20°、20.35±0.20°、22.32±0.20°、24.78±0.20°和27.78±0.20°。
本申请的一些方案中，上述A晶型的XRPD图谱如图1所示。
本申请的一些方案中，上述A晶型的XRPD图谱在下列2θ角处具有特征衍射峰，如表1所示：
表1：A晶型的XRPD图谱数据
编号 2θ(±0.20°) 相对强度(％) 编号 2θ(±0.20°) 相对强度(％)
1 6.20 100.00 8 17.89 10.83
2 8.90 21.04 9 20.35 8.23
3 10.09 8.08 10 22.32 32.65
4 11.26 17.34 11 24.78 37.82
5 11.63 8.91 12 27.78 7.17
6 14.22 18.82 13 28.58 6.05
7 16.30 22.65      
。
本申请的一些方案中，上述A晶型的热重分析曲线(TGA)在升温至200.0±3℃时失重达2.50％。
本申请的一些方案中，上述A晶型的TGA图谱如图2所示。
本申请的一些方案中，上述A晶型的差示扫描量热曲线(DSC)在234.8±3℃处具有吸热峰。
本申请的一些方案中，上述A晶型的DSC图谱如图3所示。
另一方面，本申请提供上述A晶型的制备方法，包括：1)将式(I)化合物或其粗品加入到甲基叔丁基醚中；2)任选地浓缩；3)冻干得到A晶型。
本申请提供式(I)化合物的B晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.13±0.20°、10.53±0.20°、21.17±0.20°和22.64±0.20°。本申请的一些方案中，上述B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.13±0.20°、10.53±0.20°、11.67±0.20°、20.09±0.20°、21.17±0.20°和22.64±0.20°。本申请的一些方案中，上述B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.13±0.20°、10.53±0.20°、11.67±0.20°、13.52±0.20°、20.09±0.20°、21.17±0.20°和22.64±0.20°。
本申请的一些方案中，上述B晶型的XRPD图谱如图4所示。
本申请的一些方案中，上述B晶型的XRPD图谱在下列2θ角处具有特征衍射峰，如表2所示：
表2：B晶型的XRPD图谱数据
编号 2θ(±0.20°) 相对强度(％)
1 9.13 100.00
2 10.53 48.53
3 11.67 26.24
4 13.52 11.69
5 20.09 20.70
6 21.17 43.87
7 22.64 83.94
。
本申请的一些方案中，上述B晶型的热重分析曲线在升温至160.0±3℃时失重达14.37％。
本申请的一些方案中，上述B晶型的TGA图谱如图5所示。
本申请的一些方案中，上述B晶型的差示扫描量热曲线(DSC)在149.2±3℃处具有吸热峰。本申请的一些方案中，上述B晶型的差示扫描量热曲线(DSC)在236.6±3℃处具有吸热峰。本申请的 一些方案中，上述B晶型的差示扫描量热曲线(DSC)在149.2±3℃和/或236.6±3℃处具有吸热峰。
本申请的一些方案中，上述B晶型的DSC图谱如图6所示。
本申请的一些方案中，上述B晶型是式(I)化合物的DMSO合物晶型。本申请的一些方案中，B晶型中式(I)化合物与DMSO分子个数比例选自1:0.8～2.0，优选1:1.8。
另一方面，本申请提供上述B晶型的制备方法，包括：1)将式(I)化合物溶于DMSO中；2)加入水，析出固体，得到B晶型。本申请的一些方案中，B晶型的制备方法中，以式(I)化合物的A晶型加入到DMSO中。本申请的一些方案中，上述B晶型的制备方法中，步骤2)中采用滴加方法加入水。
本申请提供式(I)化合物的C晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.94±0.20°、9.83±0.20°和10.99±0.20°。本申请的一些方案中，上述C晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.94±0.20°、9.83±0.20°、10.99±0.20°、18.62±0.20°和19.82±0.20°。本申请的一些方案中，上述C晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.94±0.20°、9.83±0.20°、10.99±0.20°、13.36±0.20°、17.21±0.20°、18.62±0.20°、19.82±0.20°和21.56±0.20°。本申请的一些方案中，上述C晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.94±0.20°、9.39±0.20°、9.83±0.20°、10.48±0.20°±0.20°、10.99±0.20°、13.36±0.20°、14.29±0.20°、17.21±0.20°、18.14±0.20°、18.62±0.20°、19.82±0.20°和21.56±0.20°。
本申请的一些方案中，上述C晶型的XRPD图谱如图7所示。
本申请的一些方案中，上述C晶型的XRPD图谱在下列2θ角处具有特征衍射峰，如表3所示：
表3：C晶型的XRPD图谱数据
Figure PCTCN2020130612-appb-000002
本申请的一些方案中，上述C晶型的热重分析曲线在升温至140.0±3℃时失重达18.33％。
本申请的一些方案中，上述C晶型的TGA图谱如图8所示。
本申请的一些方案中，上述C晶型的差示扫描量热曲线(DSC)在103.4±3℃处具有吸热峰。本申请的一些方案中，上述C晶型的差示扫描量热曲线(DSC)在236.7±3℃处具有吸热峰。本申请的一些方案中，上述C晶型的差示扫描量热曲线(DSC)在218.4±3℃处具有放热峰。本申请的一些方案中，上述C晶型的差示扫描量热曲线(DSC)在103.4±3℃、和/或236.7±3℃处具有吸热峰、和/或 在218.4±3℃处具有放热峰。
本申请的一些方案中，上述C晶型的DSC图谱如图9所示。
本申请的一些方案中，上述C晶型是式(I)化合物的水合物晶型。本申请的一些方案中，C晶型中式(I)化合物与水分子个数比例选自1:6～8，优选1:6.9。
另一方面，本申请提供上述C晶型的制备方法，包括：1)将式(I)化合物溶于THF中；2)加入MTBE；3)析出固体，得到C晶型。本申请的一些方案中，C晶型的制备方法中，以式(I)化合物的A晶型加入到THF中。本申请的一些方案中，C晶型的制备方法中，步骤2)中采用滴加方法加入MTBE。
本申请提供式(I)化合物的D晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.52±0.20°、11.21±0.20°、12.40±0.20°和14.41±0.20°。本申请的一些方案中，上述D晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.52±0.20°、8.70±0.20°、11.21±0.20°、12.40±0.20°、14.41±0.20°、17.49±0.20°和22.92±0.20°。本申请的一些方案中，上述D晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.52±0.20°、8.70±0.20°、11.21±0.20°、12.40±0.20°、14.41±0.20°、16.06±0.20°、17.49±0.20°、20.98±0.20°、21.98±0.20°和22.92±0.20°。本申请的一些方案中，上述D晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.17±0.20°、7.52±0.20°、7.99±0.20°、8.70±0.20°、9.99±0.20°、10.74±0.20°、11.21±0.20°、12.40±0.20°、14.41±0.20°、14.88±0.20°、16.06±0.20°、17.05±0.20°、17.49±0.20°、20.98±0.20°、21.98±0.20°、22.48±0.20°、22.92±0.20°、23.50±0.20°、26.47±0.20°、27.05±0.20°和28.04±0.20°。
本申请的一些方案中，上述D晶型的XRPD图谱如图10所示。
本申请的一些方案中，上述D晶型的XRPD图谱在下列2θ角处具有特征衍射峰，如表4所示：
表4：D晶型的XRPD图谱数据
Figure PCTCN2020130612-appb-000003
Figure PCTCN2020130612-appb-000004
另一方面，本申请提供上述D晶型的制备方法，包括：1)将式(I)化合物溶于THF中；2)加入DCM；3)析出固体，得到D晶型。本申请的一些方案中，D晶型的制备方法中，以式(I)化合物的A晶型加入到THF中。本申请的一些方案中，D晶型的制备方法中，步骤2)中采用滴加方法加入DCM。
本申请提供式(I)化合物的E晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.72±0.20°、8.53±0.20°、17.76±0.20°和20.38±0.20°。本申请的一些方案中，上述E晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.72±0.20°、8.53±0.20°、10.50±0.20°、13.53±0.20°、17.76±0.20°、18.83±0.20°和20.38±0.20°。本申请的一些方案中，上述E晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.72±0.20°、8.53±0.20°、10.50±0.20°、13.53±0.20°、17.76±0.20°、18.83±0.20°、20.38±0.20°、21.06±0.20°和24.00±0.20°。本申请的一些方案中，上述E晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.72±0.20°、8.53±0.20°、10.50±0.20°、11.41±0.20°、13.53±0.20°、17.76±0.20°、18.83±0.20°、19.99±0.20°、20.38±0.20°、21.06±0.20°、22.23±0.20°、24.00±0.20°、24.42±0.20°和25.90±0.20°。
本申请的一些方案中，上述E晶型的XRPD图谱如图11所示。
本申请的一些方案中，上述E晶型的XRPD图谱在下列2θ角处具有特征衍射峰，如表5所示：
表5：E晶型的XRPD图谱数据
Figure PCTCN2020130612-appb-000005
本申请的一些方案中，上述E晶型的热重分析曲线在升温至170.0±3℃时失重达6.61％、和/或在由170±3℃升温至210.0±3℃时失重达3.53％。
本申请的一些方案中，上述E晶型的TGA图谱如图12所示。
本申请的一些方案中，上述E晶型的差示扫描量热曲线(DSC)在236.8±3℃处具有吸热峰。
本申请的一些方案中，上述E晶型的DSC图谱如图13所示。
本申请的一些方案中，上述E晶型是式(I)化合物的1，4-二氧六环和/或水的共溶剂合物晶型/溶剂合物晶型。本申请的一些方案中，E晶型中式(I)化合物、1，4-二氧六环与水分子个数比例选自1：0.5～1.0：0.5～1.5；优选1：0.5：1。
另一方面，本申请提供了上述E晶型的制备方法，包括：1)将式(I)化合物溶于1，4-二氧六环中；2)往1，4-二氧六环加入乙腈；3)析出固体，得到E晶型。本申请的一些方案中，E晶型的制备方法中，以式(I)化合物的A晶型加入到1，4-二氧六环中。本申请的一些方案中，E晶型的制备方法中，步骤2)中，采用挥发乙腈入1，4-二氧六环的方法往1，4-二氧六环加入乙腈。
本申请提供式(I)化合物的F晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.18±0.20°、8.35±0.20°、10.58±0.20°和16.86±0.20°。本申请的一些方案中，上述F晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.18±0.20°、8.35±0.20°、10.58±0.20°、11.87±0.20°、16.86±0.20°和21.16±0.20°。本申请的一些方案中，上述F晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.18±0.20°、8.35±0.20°、10.58±0.20°、11.87±0.20°、12.32±0.20°、16.86±0.20°、21.16±0.20°、25.47±0.20°和29.17±0.20°。
本申请的一些方案中，上述F晶型的XRPD图谱如图14所示。
本申请的一些方案中，上述F晶型的XRPD图谱在下列2θ角处具有特征衍射峰，如表6所示：
表6：F晶型的XRPD图谱数据
Figure PCTCN2020130612-appb-000006
本申请的一些方案中，上述F晶型的热重分析曲线在升温至150.0±3℃时失重达3.22％。
本申请的一些方案中，上述F晶型的TGA图谱如图15所示。
本申请的一些方案中，上述F晶型的差示扫描量热曲线(DSC)在229.9±3℃处具有吸热峰。本申请的一些方案中，上述F晶型的差示扫描量热曲线(DSC)在188.6±3℃处具有吸热峰。本申请的一些方案中，上述F晶型的差示扫描量热曲线(DSC)在98.9±3℃处具有吸热峰。本申请的一些方案中，上述F晶型的差示扫描量热曲线(DSC)在229.9±3℃、和/或188.6±3℃、和/或98.9±3℃处具有吸热峰。
本申请的一些方案中，上述F晶型的DSC图谱如图16所示。
本申请的一些方案中，上述F晶型是式(I)化合物的水合物晶型。本申请的一些方案中，F晶型 中式(I)化合物与水分子个数比例选自1：0.8～1.2；优选1：1。
另一方面，本申请提供上述F晶型的制备方法，包括：1)将式(I)化合物溶于DMF中；2)将上述所得溶液与水混合；3)析出固体，得到F晶型。本申请的一些方案中，F晶型的制备方法中，以式(I)化合物的A晶型加入到DMF中。本申请的一些方案中，F晶型的制备方法中，步骤2)中，所述溶液与水混合的方式选自将溶液滴加到水中。
本申请提供式(I)化合物的G晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.03±0.20°、8.31±0.20°、19.18±0.20°和25.99±0.20°。本申请的一些方案中，上述G晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.03±0.20°、8.31±0.20°、15.86±0.20°、19.18±0.20°、21.05±0.20°和25.99±0.20°。本申请的一些方案中，上述G晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.03±0.20°、8.31±0.20°、11.62±0.20°、12.91±0.20°、15.86±0.20°、19.18±0.20°、21.05±0.20°、24.67±0.20°和25.99±0.20°。本申请的一些方案中，上述G晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.03±0.20°、8.31±0.20°、11.62±0.20°、12.91±0.20°、15.86±0.20°、17.17±0.20°、18.20±0.20°、19.18±0.20°、19.74±0.20°、21.05±0.20°、21.30±0.20°、24.67±0.20°和25.99±0.20°。
本申请的一些方案中，上述G晶型的XRPD图谱如图17所示。
本申请的一些方案中，上述G晶型的XRPD图谱在下列2θ角处具有特征衍射峰，如表7所示：
表7：G晶型的XRPD图谱数据
Figure PCTCN2020130612-appb-000007
本申请的一些方案中，上述G晶型的热重分析曲线在升温至150.0±3℃时失重达7.39％。
本申请的一些方案中，上述G晶型的TGA图谱如图18所示。
本申请的一些方案中，上述G晶型的差示扫描量热曲线(DSC)在235.7±3℃处具有吸热峰。本申请的一些方案中，上述G晶型的差示扫描量热曲线(DSC)在177.8±3℃处具有放热峰。本申请的一些方案中，上述G晶型的差示扫描量热曲线(DSC)在235.7±3℃处有吸热峰、和/或在177.8±3℃处有放热峰。
本申请的一些方案中，上述G晶型的DSC图谱如图19所示。
另一方面，本申请提供上述G晶型的制备方法，包括：1)将式(I)化合物加入到CHCl 3和THF混合溶剂中；2)析出固体，分离得到G晶型。本申请的一些方案中，以式(I)化合物的A晶型加入 到CHCl 3和THF混合溶剂中。
本申请提供式(I)化合物的H晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.05±0.20°、9.10±0.20°、10.78±0.20°和22.90±0.20°。本申请的一些方案中，上述H晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.05±0.20°、9.10±0.20°、10.78±0.20°、21.24±0.20°、21.74±0.20°和22.90±0.20°。本申请的一些方案中，上述H晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.05±0.20°、9.10±0.20°、10.78±0.20°、13.07±0.20°、19.57±0.20°、21.24±0.20°、21.74±0.20°、22.24±0.20°和22.90±0.20°。本申请的一些方案中，上述H晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.05±0.20°、9.10±0.20°、10.78±0.20°、11.34±0.20°、13.07±0.20°、14.07±0.20°、14.99±0.20°、15.86±0.20°、16.17±0.20°、18.60±0.20°、19.57±0.20°、21.24±0.20°、21.46±0.20°、21.74±0.20°、22.24±0.20°、22.72±0.20°和22.90±0.20°。
本申请的一些方案中，上述H晶型的XRPD图谱如图20所示。
本申请的一些方案中，上述H晶型的XRPD图谱在下列2θ角处具有特征衍射峰，如表8所示：
表8：H晶型的XRPD图谱数据
Figure PCTCN2020130612-appb-000008
本申请的一些方案中，上述H晶型的热重分析曲线在升温至160.0±3℃时失重达11.77％。
本申请的一些方案中，上述H晶型的TGA图谱如图21所示。
本申请的一些方案中，上述H晶型的差示扫描量热曲线(DSC)在140.4±3℃处具有吸热峰。本申请的一些方案中，上述H晶型的差示扫描量热曲线(DSC)在236.9±3℃处具有吸热峰。本申请的一些方案中，上述H晶型的差示扫描量热曲线(DSC)在140.4±3℃、和/或236.9±3℃处具有吸热峰。
本申请的一些方案中，上述H晶型的DSC图谱如图22所示。
本申请的一些方案中，上述H晶型是式(I)化合物的DMF合物晶型。本申请的一些方案中，H 晶型中式(I)化合物与DMF分子个数比例选自1：0.6～1.0；优选1：0.8。
另一方面，本申请提供上述H晶型的制备方法，包括：1)将式(I)化合物加入到EtOH和DMF混合溶剂中；2)析出固体，分离得到H晶型。本申请的一些方案中，H晶型的制备方法中，以式(I)化合物的A晶型加入到EtOH和DMF混合溶剂中。
本申请提供式(I)化合物的I晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.56±0.20°、11.25±0.20°和14.09±0.20°。本申请的一些方案中，上述I晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.56±0.20°、7.54±0.20°、11.25±0.20、14.09±0.20°和19.64±0.20°。本申请的一些方案中，上述I晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.56±0.20°、7.54±0.20°、11.25±0.20°、14.09±0.20°、18.07±0.20°、19.64±0.20°和20.33±0.20°。本申请的一些方案中，上述I晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.56±0.20°、7.54±0.20°、11.25±0.20°、14.09±0.20°、18.07±0.20°、19.64±0.20°、20.33±0.20°、21.65±0.20°、22.31±0.20°。
本申请的一些方案中，上述I晶型的XRPD图谱如图23所示。
本申请的一些方案中，上述I晶型的XRPD图谱在下列2θ角处具有特征衍射峰，如表9所示：
表9：I晶型的XRPD图谱数据
Figure PCTCN2020130612-appb-000009
本申请的一些方案中，上述I晶型的热重分析曲线在升温至100.0±3℃时失重达3.52％。
本申请的一些方案中，上述I晶型的TGA图谱如图24所示。
本申请的一些方案中，上述I晶型的差示扫描量热曲线(DSC)在94.7±3℃处具有吸热峰。本申请的一些方案中，上述I晶型的差示扫描量热曲线(DSC)在234.4±3℃处具有吸热峰。本申请的一些方案中，上述I晶型的差示扫描量热曲线(DSC)在185.2±3℃处具有放热峰。本申请的一些方案中，上述I晶型的差示扫描量热曲线(DSC)在94.7±3℃、和/或234.4±3℃处具有吸热峰、和/或在185.2±3℃处具有放热峰。
本申请的一些方案中，上述I晶型的DSC图谱如图25所示。
本申请的一些方案中，上述I晶型是式(I)化合物的水合物晶型。本申请的一些方案中，I晶型中式(I)化合物与水分子个数比例选自1：1.0～1.2；优选1：1.1。
另一方面，本申请提供上述I晶型的制备方法，包括：1)将式(I)化合物加入到水中；2)悬浮 搅拌，分离得到I晶型。本申请的一些方案中，上述I晶型的制备方法中，以式(I)化合物的A晶型加入水中。本申请的一些方案中，上述I晶型的制备方法中，需在加热条件下搅拌。本申请的一些方案中，上述I晶型的制备方法中，加热温度选自45～60℃；或者55℃。
本申请提供式(I)化合物的J晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.28±0.20°、10.34±0.20°、22.66±0.20°和26.12±0.20°。本申请的一些方案中，上述J晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.28±0.20°、10.34±0.20°、19.45±0.20°、20.93±0.20°、22.66±0.20°和26.12±0.20°。本申请的一些方案中，上述J晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.28±0.20°、10.34±0.20°、12.35±0.20°、14.95±0.20°、17.88±0.20°、19.45±0.20°、20.93±0.20°、22.66±0.20°和26.12±0.20°。本申请的一些方案中，上述J晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.47±0.20°、9.28±0.20°、10.34±0.20°、10.92±0.20°、12.35±0.20°、14.95±0.20°、、17.62±0.20°、17.88±0.20°、19.09±0.20°、19.45±0.20°、20.08±0.20°、20.93±0.20°、22.66±0.20°、23.98±0.20°、26.12±0.20°和28.63±0.20°。
本申请的一些方案中，上述J晶型的XRPD图谱如图26所示。
本申请的一些方案中，上述J晶型的XRPD图谱在下列2θ角处具有特征衍射峰，如表10所示：
表10：J晶型的XRPD图谱数据
Figure PCTCN2020130612-appb-000010
本申请的一些方案中，上述J晶型的热重分析曲线在升温至140.0±3℃时失重达27.46％。
本申请的一些方案中，上述J晶型的TGA图谱如图27所示。
本申请的一些方案中，上述J晶型的差示扫描量热曲线(DSC)在86.7±3℃处具有吸热峰。本申请的一些方案中，上述J晶型的差示扫描量热曲线(DSC)在229.4±3℃处具有吸热峰。本申请的一些方案中，上述J晶型的差示扫描量热曲线(DSC)在150.0±3℃处具有吸热峰。本申请的一些方案中，上述J晶型的差示扫描量热曲线(DSC)在148.6±3℃处具有放热峰。本申请的一些方案中，上述 J晶型的差示扫描量热曲线(DSC)在86.7±3℃、和/或150.0±3℃、和/或229.4±3℃处具有吸热峰、和/或在148.6±3℃处具有放热峰。
本申请的一些方案中，上述J晶型的DSC图谱如图28所示。
另一方面，本申请提供上述J晶型的制备方法，包括：1)将上述式(I)化合物加入到2-MeTHF中；2)悬浮搅拌，分离得到J晶型。本申请的一些方案中，J晶型的制备方法中，以式(I)化合物的A晶型加入到2-MeTHF中。本申请的一些方案中，所述J晶型的制备方法需加热条件下进行搅拌；本申请的一些方案中，所述加热温度选自45～60℃；或者50℃。
本申请提供式(I)化合物的K晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.49±0.20°、8.46±0.20°、15.99±0.20°和17.02±0.20°。本申请的一些方案中，上述K晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.49±0.20°、8.46±0.20°、13.18±0.20°、14.43±0.20°、15.99±0.20°和17.02±0.20°。本申请的一些方案中，上述K晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.49±0.20°、8.46±0.20°、9.91±0.20°、13.18±0.20°、14.43±0.20°、15.99±0.20°、17.02±0.20°、20.97±0.20°和24.20±0.20°。本申请的一些方案中，上述K晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.49±0.20°、8.46±0.20°、9.12±0.20°、9.91±0.20°、10.67±0.20°、13.18±0.20°、14.43±0.20°、15.99±0.20°、17.02±0.20°、18.34±0.20°、19.95±0.20°、20.29±0.20°、20.97±0.20°、21.66±0.20°、23.03±0.20°、24.20±0.20°、24.94±0.20°和25.69±0.20°。
本申请的一些方案中，上述K晶型的XRPD图谱如图29所示。
本申请的一些方案中，上述K晶型的XRPD图谱在下列2θ角处具有特征衍射峰，如表11所示：
表11：K晶型的XRPD图谱数据
Figure PCTCN2020130612-appb-000011
本申请的一些方案中，上述K晶型的热重分析曲线在升温至150.0±3℃时失重达1.35％。
本申请的一些方案中，上述K晶型的TGA图谱如图30所示。
本申请的一些方案中，上述K晶型的差示扫描量热曲线(DSC)在231.2±3℃处具有吸热峰。本申请的一些方案中，上述K晶型的差示扫描量热曲线(DSC)在164.1±3℃处具有放热峰。本申请的一些方案中，上述K晶型的差示扫描量热曲线(DSC)在160.6±3℃处具有吸热峰。本申请的一些方案中，上述K晶型的差示扫描量热曲线(DSC)在231.2±3℃、和/或160.6±3℃处具有吸热峰、和/或在164.1±3℃处具有放热峰。
本申请的一些方案中，上述K晶型的DSC图谱如图31所示。
另一方面，本申请提供上述K晶型的制备方法，包括：1)将上述式(I)化合物溶解在DCM和MeOH混合溶剂中；2)析出固体，分离得到K晶型。本申请的一些方案中，上述K晶型的制备方法中，以式(I)化合物的A晶型加入到DCM和MeOH混合溶剂中。本申请的一些方案中，所述K晶型的制备方法中，需在加热条件下溶解。本申请的一些方案中，所述K晶型的制备方法中，所述加热温度选自45～60℃；或者50℃。本申请的一些方案中，所述K晶型的制备方法中，步骤2)中，采用降温方法析出固体。
本申请提供式(I)化合物的L晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.53±0.20°、11.09±0.20°、22.34±0.20°和23.12±0.20°。本申请的一些方案中，上述L晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.53±0.20°、11.09±0.20°、15.00±0.20°、20.76±0.20°、22.34±0.20°和23.12±0.20°。本申请的一些方案中，上述L晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.03±0.20°、8.53±0.20°、11.09±0.20°、14.14±0.20°、15.00±0.20°、20.76±0.20°、22.34±0.20°、23.12±0.20°和26.85±0.20°。本申请的一些方案中，上述L晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.03±0.20°、8.53±0.20°、10.50±0.20°、11.09±0.20°、14.14±0.20°、15.00±0.20°、20.76±0.20°、22.34±0.20°、23.12±0.20°和26.85±0.20°。
本申请的一些方案中，上述L晶型的XRPD图谱如图32所示。
本申请的一些方案中，上述L晶型的XRPD图谱在下列2θ角处具有特征衍射峰，如表12所示：
表12：L晶型的XRPD图谱数据
Figure PCTCN2020130612-appb-000012
本申请的一些方案中，上述L晶型的热重分析曲线在升温至160.0±3℃时失重达10.37％。
本申请的一些方案中，上述L晶型的TGA图谱如图33所示。
本申请的一些方案中，上述L晶型的差示扫描量热曲线(DSC)在150.1±3℃处具有吸热峰。本申请的一些方案中，上述L晶型的差示扫描量热曲线(DSC)在210.7±3℃处具有吸热峰。本申请的一些方案中，上述L晶型的差示扫描量热曲线(DSC)在150.1±3℃和/或210.7±3℃处具有吸热峰。
本申请的一些方案中，上述L晶型的DSC图谱如图34所示。
本申请的一些方案中，上述L晶型是式(I)化合物的NMP合物晶型。本申请的一些方案中，L晶型中式(I)化合物与NMP分子个数比例选自1：0.5～1.0；优选1：0.8。
另一方面，本申请提供上述L晶型的制备方法，包括：1)将式(I)化合物溶解在NMP中；2)往NMP溶液加入EtOAc中；3)析出固体，分离得到L晶型。本申请的一些方案中，L晶型的制备方法中，以式(I)化合物的A晶型加入到NMP中。本申请的一些方案中，L晶型的制备方法中，步骤2)中，采用挥发EtOAc入NMP的方法往NMP加入EtOAc。
本申请提供式(I)化合物的M晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.32±0.20°、10.43±0.20°、12.46±0.20°和19.62±0.20°。本申请的一些方案中，上述M晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.32±0.20°、10.43±0.20°、10.81±0.20°、12.46±0.20°、19.62±0.20°和21.03±0.20°。本申请的一些方案中，上述M晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.32±0.20°、10.43±0.20°、10.81±0.20°、12.46±0.20°、17.55±0.20°、17.99±0.20°、19.62±0.20°、21.03±0.20°和22.90±0.20°。本申请的一些方案中，上述M晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.32±0.20°、10.43±0.20°、10.81±0.20°、12.46±0.20°、13.00±0.20°、15.06±0.20°、17.55±0.20°、17.99±0.20°、19.62±0.20°、21.03±0.20°和22.90±0.20°。
本申请的一些方案中，上述M晶型的XRPD图谱如图35所示。
本申请的一些方案中，上述M晶型的XRPD图谱在下列2θ角处具有特征衍射峰，如表13所示：
表13：M晶型的XRPD图谱数据
Figure PCTCN2020130612-appb-000013
本申请的一些方案中，上述M晶型的热重分析曲线在升温至130.0±3℃时失重达10.98％。
本申请的一些方案中，上述M晶型的TGA图谱如图36所示。
本申请的一些方案中，上述M晶型的差示扫描量热曲线(DSC)在109.7±3℃处具有吸热峰。本 申请的一些方案中，上述M晶型的差示扫描量热曲线(DSC)在235.9±3℃处具有吸热峰。本申请的一些方案中，上述M晶型的差示扫描量热曲线(DSC)在109.7±3℃和/或235.9±3℃处具有吸热峰。
本申请的一些方案中，上述M晶型的DSC图谱如图37所示。
本申请的一些方案中，上述M晶型是式(I)化合物的THF合物晶型。本申请的一些方案中，M晶型中式(I)化合物与TMF分子个数比例选自1：0.6～1.0；优选1：0.8。
另一方面，本申请提供上述M晶型的制备方法，包括：1)将式(I)化合物溶解在THF中；2)析出固体，分离得到M晶型。本申请的一些方案中，M晶型的制备方法中，以式(I)化合物的A晶型加入到THF中。
本申请提供式(I)化合物的N晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.47°±0.20°、12.62±0.20°、15.70±0.20°和18.41±0.20°。本申请的一些方案中，上述N晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.47±0.20°、11.23±0.20°、12.62±0.20°、15.70±0.20°、18.41±0.20°和21.49±0.20°。本申请的一些方案中，上述N晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.04±0.20°、8.47±0.20°、10.01±0.20°、11.23±0.20°、12.62±0.20°、15.70±0.20°、18.41±0.20°、21.49±0.20°和22.53±0.20°。本申请的一些方案中，上述N晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.04±0.20°、8.47±0.20°、10.01±0.20°、11.23±0.20°、12.62±0.20°、15.70±0.20°、17.32±0.20°、18.41±0.20°、20.31±0.20°、21.49±0.20°、22.53±0.20°和26.34±0.20°。
本申请的一些方案中，上述N晶型的XRPD图谱如图38所示。
本申请的一些方案中，上述N晶型的XRPD图谱在下列2θ角处具有特征衍射峰，如表14所示：
表14：N晶型的XRPD图谱数据
Figure PCTCN2020130612-appb-000014
本申请的一些方案中，上述N晶型的热重分析曲线在升温至200.0±3℃时失重达1.99％。
本申请的一些方案中，上述N晶型的TGA图谱如图39所示。
本申请的一些方案中，上述N晶型的差示扫描量热曲线(DSC)在236.3±3℃处具有吸热峰。
本申请的一些方案中，上述N晶型的DSC图谱如图40所示。
另一方面，本申请提供上述N晶型的制备方法，包括：1)将式(I)化合物溶解在EtOH中；2)析出固体，分离得到N晶型。本申请的一些方案中，N晶型的制备方法中，以式(I)化合物的A晶 型加入到EtOH中。
本申请提供式(I)化合物的O晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.50±0.20°、10.65±0.20°和11.10±0.20°。本申请的一些方案中，上述O晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.18±0.20°、7.50±0.20°、10.65±0.20°、11.10±0.20°、14.04±0.20°和21.48±0.20°。本申请的一些方案中，上述O晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.18±0.20°、7.50±0.20°、10.65±0.20°、11.10±0.20°、14.04±0.20°、21.48±0.20°、22.79±0.20°和27.02±0.20°。本申请的一些方案中，上述O晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.18±0.20°、7.50±0.20°、10.65±0.20°、11.10±0.20°、14.04±0.20°、15.67±0.20°、19.16±0.20°、21.48±0.20°、22.79±0.20°、23.39±0.20°、26.28±0.20°和27.02±0.20°。
本申请的一些方案中，上述O晶型的XRPD图谱如图41所示。
本申请的一些方案中，上述O晶型的XRPD图谱在下列2θ角处具有特征衍射峰，如表15所示：
表15：O晶型的XRPD图谱数据
Figure PCTCN2020130612-appb-000015
本申请的一些方案中，上述O晶型的热重分析曲线在升温至140.0±3℃时失重达2.23％。
本申请的一些方案中，上述O晶型的TGA图谱如图42所示。
本申请的一些方案中，上述O晶型的差示扫描量热曲线(DSC)在123.3±3℃处具有吸热峰。本申请的一些方案中，上述O晶型的差示扫描量热曲线(DSC)在128.5±3℃处具有放热峰。本申请的一些方案中，上述O晶型的差示扫描量热曲线(DSC)在231.1±3℃处具有吸热峰。本申请的一些方案中，上述O晶型的差示扫描量热曲线(DSC)在237.1±3℃处具有吸热峰。本申请的一些方案中，上述O晶型的差示扫描量热曲线(DSC)在123.3±3℃、和/或231.1±3℃、和/或237.1±3℃处具有吸热峰、和/或在128.5±3℃处具有放热峰。
本申请的一些方案中，上述O晶型的DSC图谱如图43所示。
本申请的一些方案中，上述O晶型是式(I)化合物的水合物晶型。本申请的一些方案中，O晶型中式(I)化合物与水分子个数比例选自1：0.6～1.0；优选1：0.7。
另一方面，本申请提供上述O晶型的制备方法，包括：将上述D晶型在真空、室温条件下干燥，得到O晶型。
本申请提供式(I)化合物的P晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰： 7.08±0.20°和21.48±0.20°。本申请的一些方案中，上述P晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.08±0.20°、21.25±0.20°和21.48±0.20°。本申请的一些方案中，上述P晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.08±0.20°、20.39±0.20°、21.25±0.20°、21.48±0.20°、26.74±0.20°和27.46±0.20°。本申请的一些方案中，上述P晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.08±0.20°、20.39±0.20°、21.48±0.20°、26.74±0.20°和27.46±0.20°。本申请的一些方案中，上述P晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.08±0.20°、12.92±0.20°、18.61±0.20°、20.39±0.20°、21.48±0.20°、22.71±0.20°、26.74±0.20°、27.46±0.20°和27.83±0.20°。本申请的一些方案中，上述P晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.08±0.20°、12.92±0.20°、18.61±0.20°、20.39±0.20°、21.25±0.20°、21.48±0.20°、22.71±0.20°、25.01±0.20°、26.74±0.20°、27.46±0.20°和27.83±0.20°。
本申请的一些方案中，所述P晶型X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.08±0.20°、15.36±0.20°、21.25±0.20°、21.48±0.20°和22.71±0.20°。本申请的一些方案中，所述P晶型X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.08±0.20°、12.92±0.20°、15.36±0.20°、21.25±0.20°、21.48±0.20°、22.71±0.20°和27.46±0.20°。本申请的一些方案中，所述P晶型X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.08±0.20°、12.92±0.20°、15.36±0.20°、20.39±0.20°、21.25±0.20°、21.48±0.20°、22.71±0.20°、26.74±0.20°和27.46±0.20°。本申请的一些方案中，所述P晶型X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.08±0.20°、12.92±0.20°、15.36±0.20°、18.61±0.20°、20.39±0.20°、21.25±0.20°、21.48±0.20°、22.71±0.20°、26.74±0.20°27.46±0.20°和27.83±0.20°。
本申请的一些方案中，所述P晶型X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.08±0.20°、11.61±0.20°、12.92±0.20°、15.36±0.20°、15.89±0.20°、18.61±0.20°、20.39±0.20°、21.25±0.20°、21.48±0.20°、22.71±0.20°、26.74±0.20°、27.46±0.20°和27.83±0.20°。本申请的一些方案中，所述P晶型X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.08±0.20°、11.61±0.20°、12.92±0.20°、15.36±0.20°、15.89±0.20°、18.61±0.20°、19.89±0.20°、20.39±0.20°、21.25±0.20°、21.48±0.20°、22.71±0.20°、26.05±0.20°、26.74±0.20°、27.46±0.20°和27.83±0.20°
本申请的一些方案中，上述P晶型的XRPD图谱如图44A、或图44B所示。
本申请的一些方案中，上述P晶型的XRPD图谱在下列2θ角处具有特征衍射峰，如表16A所示：
表16A：P晶型的XRPD图谱数据
Figure PCTCN2020130612-appb-000016
Figure PCTCN2020130612-appb-000017
本申请的一些方案中，上述P晶型的XRPD图谱在下列2θ角处具有特征衍射峰，如表16B所示：
表16B：P晶型的XRPD图谱数据
Figure PCTCN2020130612-appb-000018
本申请的一些方案中，上述P晶型的热重分析曲线在升温至150.0±3℃时失重达2.76％。
本申请的一些方案中，上述P晶型的TGA图谱如图45所示。
本申请的一些方案中，上述P晶型的差示扫描量热曲线(DSC)在236.1±3℃处具有吸热峰。
本申请的一些方案中，上述P晶型的DSC图谱如图46所示。
本申请的另一些方案中，所述P晶型X射线粉末衍射图谱在下列2θ角处具有特征衍射峰： 7.12±0.20°和21.46±0.20°。本申请的一些方案中，上述P晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°、21.28±0.20°和21.46±0.20°。本申请的一些方案中，上述P晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°、20.38±0.20°、21.28±0.20°、21.46±0.20°、26.72±0.20°和27.48±0.20°。本申请的一些方案中，上述P晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°、20.38±0.20°、21.46±0.20°、26.72±0.20°和27.48±0.20°。本申请的一些方案中，上述P晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°、12.96±0.20°、18.66±0.20°、20.38±0.20°、21.46±0.20°、22.74±0.20°、26.72±0.20°、27.48±0.20°和27.82±0.20°。本申请的一些方案中，上述P晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°、12.96±0.20°、18.66±0.20°、20.38±0.20°、21.28±0.20°、21.46±0.20°、22.74±0.20°、24.84±0.20°、26.72±0.20°、27.48±0.20°和27.82±0.20°。
本申请的另一些方案中，所述P晶型X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°、15.40±0.20°、21.28±0.20°、21.46±0.20°和22.74±0.20°。本申请的一些方案中，上述P晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°、12.96±0.20°、15.40±0.20°、21.28±0.20°、21.46±0.20°、22.74±0.20°和27.48±0.20°。本申请的一些方案中，上述P晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°、12.96±0.20°、15.40±0.20°、20.38±0.20°、21.28±0.20°、21.46±0.20°、22.74±0.20°、26.72±0.20°和27.48±0.20°。本申请的一些方案中，上述P晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°、12.96±0.20°、15.40±0.20°、18.66±0.20°、20.38±0.20°、21.28±0.20°、21.46±0.20°、22.74±0.20°、26.72±0.20°、27.48±0.20°和27.82±0.20°。
本申请的另一些方案中，上述P晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°、8.74±0.20°、12.96±0.20°、15.40±0.20°、15.92±0.20°、18.66±0.20°、20.38±0.20°、21.28±0.20°、21.46±0.20°、22.74±0.20°、26.72±0.20°和27.48±0.20°。本申请的一些方案中，上述P晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°、8.74±0.20°、11.66±0.20°、12.96±0.20°、15.40±0.20°、15.92±0.20°、16.22±0.20°、18.66±0.20°、20.38±0.20°、21.28±0.20°、21.46±0.20°、22.74±0.20°、26.72±0.20°、27.48±0.20°和27.82±0.20°。本申请的一些方案中，上述P晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°、8.74±0.20°、9.29±0.20°、11.66±0.20°、12.96±0.20°、15.40±0.20°、15.92±0.20°、16.22±0.20°、17.54±0.20°、18.66±0.20°、20.38±0.20°、21.28±0.20°、21.46±0.20°、22.74±0.20°、26.72±0.20°、27.48±0.20°和27.82±0.20°。
本申请的一些方案中，上述P晶型的XRPD图谱如图59所示。
本申请的一些方案中，上述P晶型的XRPD图谱在下列2θ角处具有特征衍射峰，如表16C所示：
表16C：P晶型的XRPD图谱数据
Figure PCTCN2020130612-appb-000019
本申请另一些实施方案中，上述P晶型，晶体属于三斜晶系，空间群为P-1，晶胞参数为
Figure PCTCN2020130612-appb-000020
Figure PCTCN2020130612-appb-000021
α＝66.982(8)°，β＝75.337(8)°，γ＝68.492(8)°，晶胞体积
Figure PCTCN2020130612-appb-000022
晶胞内不对称单位数Z＝2。
本申请提供式(I)化合物的P晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°和21.46±0.20°。本申请的一些方案中，上述P晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°、21.28±0.20°和21.46±0.20°。本申请的一些方案中，上述P晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°、20.38±0.20°、21.28±0.20°、21.46±0.20°、26.72±0.20°和27.48±0.20°。本申请的一些方案中，上述P晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°、20.38±0.20°、21.46±0.20°、26.72±0.20°和27.48±0.20°。本申请的一些方 案中，上述P晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°、12.96±0.20°、18.66±0.20°、20.38±0.20°、21.46±0.20°、22.74±0.20°、26.72±0.20°、27.48±0.20°和27.82±0.20°。本申请的一些方案中，上述P晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°、12.96±0.20°、18.66±0.20°、20.38±0.20°、21.28±0.20°、21.46±0.20°、22.74±0.20°、24.84±0.20°、26.72±0.20°、27.48±0.20°和27.82±0.20°。
本申请提供式(I)化合物的P晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°、15.40±0.20°、21.28±0.20°、21.46±0.20°和22.74±0.20°。本申请的一些方案中，上述P晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°、12.96±0.20°、15.40±0.20°、21.28±0.20°、21.46±0.20°、22.74±0.20°和27.48±0.20°。本申请的一些方案中，上述P晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°、12.96±0.20°、15.40±0.20°、20.38±0.20°、21.28±0.20°、21.46±0.20°、22.74±0.20°、26.72±0.20°和27.48±0.20°。本申请的一些方案中，上述P晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°、12.96±0.20°、15.40±0.20°、18.66±0.20°、20.38±0.20°、21.28±0.20°、21.46±0.20°、22.74±0.20°、26.72±0.20°、27.48±0.20°和27.82±0.20°。
本申请提供式(I)化合物的P晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°、8.74±0.20°、12.96±0.20°、15.40±0.20°、15.92±0.20°、18.66±0.20°、20.38±0.20°、21.28±0.20°、21.46±0.20°、22.74±0.20°、26.72±0.20°和27.48±0.20°。本申请的一些方案中，上述P晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°、8.74±0.20°、11.66±0.20°、12.96±0.20°、15.40±0.20°、15.92±0.20°、16.22±0.20°、18.66±0.20°、20.38±0.20°、21.28±0.20°、21.46±0.20°、22.74±0.20°、26.72±0.20°、27.48±0.20°和27.82±0.20°。本申请的一些方案中，上述P晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°、8.74±0.20°、9.29±0.20°、11.66±0.20°、12.96±0.20°、15.40±0.20°、15.92±0.20°、16.22±0.20°、17.54±0.20°、18.66±0.20°、20.38±0.20°、21.28±0.20°、21.46±0.20°、22.74±0.20°、26.72±0.20°、27.48±0.20°和27.82±0.20°。
本申请的一些方案中，上述P晶型的XRPD图谱如图59所示。
本申请的一些方案中，上述P晶型的XRPD图谱在下列2θ角处具有特征衍射峰，如表16D所示：
表16D：P晶型的XRPD图谱数据
Figure PCTCN2020130612-appb-000023
Figure PCTCN2020130612-appb-000024
本申请提供式(I)化合物的P晶型，其晶体属于三斜晶系，空间群为P-1，晶胞参数为
Figure PCTCN2020130612-appb-000025
Figure PCTCN2020130612-appb-000026
α＝66.982(8)°，β＝75.337(8)°，γ＝68.492(8)°，晶胞体积
Figure PCTCN2020130612-appb-000027
晶胞内不对称单位数Z＝2。
另一方面，本申请提供上述P晶型的制备方法，包括：1)将式(I)化合物溶解在MTBE和MeOH混合溶剂中；2)析出固体后，分离得到P晶型。本申请的一些方案中，在P晶型的制备方法中，以式(I)化合物的A晶型加入到MTBE和MeOH混合溶剂中。本申请的一些方案中，在P晶型的制备方法中，MTBE与MeOH体积比为3:2。本申请的一些方案中，在P晶型的制备方法中，式(I)化合物与MTBE及MeOH的质量体积比选自1mg:0.01～0.4mL:0.005～0.3mL；或者，选自1mg:0.02～0.1mL:0.01～0.1mL；或者，选自1mg:0.04mL:0.027mL。
另一方面，本申请提供上述P晶型的制备方法，包括：1)将式将式(I)化合物溶解在甲醇或丙酮中；2)析出固体后，分离得到P晶型。
本申请提供式(I)化合物的Q晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.03±0.20°、8.22±0.20°和14.10±0.20°。本申请的一些方案中，上述Q晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.03±0.20°、8.22±0.20°、10.34±0.20°、14.10±0.20°、14.66±0.20°和 21.61±0.20°。本申请的一些方案中，上述Q晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.03±0.20°、8.22±0.20°、8.53±0.20°、10.34±0.20°、14.10±0.20°、14.66±0.20°、16.47±0.20°、17.07±0.20°、和21.61±0.20°。本申请的一些方案中，上述Q晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.03±0.20°、8.22±0.20°、8.53±0.20°、8.95±0.20°、10.34±0.20°、14.10±0.20°、14.66±0.20°、15.90±0.20°、16.47±0.20°、17.07±0.20°、19.45±0.20°、21.61±0.20°、22.89±0.20°和23.36±0.20°。
本申请的一些方案中，上述Q晶型的XRPD图谱如图47所示。
本申请的一些方案中，上述Q晶型的XRPD图谱在下列2θ角处具有特征衍射峰，如表17所示：
表17：Q晶型的XRPD图谱数据
Figure PCTCN2020130612-appb-000028
本申请的一些方案中，上述Q晶型的热重分析曲线在升温至140.0±3℃时失重达9.29％。
本申请的一些方案中，上述Q晶型的TGA图谱如图48所示。
本申请的一些方案中，上述Q晶型的差示扫描量热曲线(DSC)在162.9±3℃处具有吸热峰。本申请的一些方案中，上述Q晶型的差示扫描量热曲线(DSC)在235.6±3℃处具有吸热峰。本申请的一些方案中，上述Q晶型的差示扫描量热曲线(DSC)在168.5±3℃处具有放热峰。本申请的一些方案中，上述Q晶型的差示扫描量热曲线(DSC)在162.9±3℃、和/或235.6±3℃处具有吸热峰、和/或在168.5±3℃处具有放热峰。
本申请的一些方案中，上述Q晶型的DSC图谱如图49所示。
本申请的一些方案中，上述Q晶型是式(I)化合物的水合物晶型。本申请的一些方案中，Q晶型中式(I)化合物与水分子个数比例选自1：2.5～3.5；优选1：3.1。
另一方面，本申请提供上述Q晶型的制备方法，包括：1)将式(I)化合物溶解在MeOH中，滴加ACN，2)析固体后，分离得到Q晶型。本申请的一些方案中，Q晶型的制备方法中，以式(I)化合物的A晶型加入到MeOH中。
本申请提供式(I)化合物的R晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.60±0.20°、8.55±0.20°和15.21±0.20°。本申请的一些方案中，上述R晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.60±0.20°、8.55±0.20°、11.67±0.20°、15.21±0.20°、17.60±0.20°、和24.56±0.20°。本申请的一些方案中，上述R晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射 峰：6.60±0.20°、8.55±0.20°、11.67±0.20°、15.21±0.20°、17.12±0.20°、17.60±0.20°、23.25±0.20°、24.56±0.20°和27.31±0.20°。
本申请的一些方案中，上述R晶型的XRPD图谱如图50所示。
本申请的一些方案中，上述R晶型的XRPD图谱在下列2θ角处具有特征衍射峰，如表18所示：
表18：R晶型的XRPD图谱数据
Figure PCTCN2020130612-appb-000029
另一方面，本申请提供上述R晶型的制备方法，包括：将上述O晶型加热至120～180℃，冷却至室温，得到R晶型。本申请的一些方案中，在R晶型的制备方法中，O晶型加热至150℃。
本申请提供式(I)化合物的S晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.15±0.20°、8.43±0.20°、21.57±0.20°和23.90±0.20°。本申请的一些方案中，上述S晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.15±0.20°、8.43±0.20°、14.94±0.20°、16.29±0.20°、16.84±0.20°、21.57±0.20°和23.90±0.20°。本申请的一些方案中，上述S晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.15±0.20°、6.57±0.20°、8.43±0.20°、11.27±0.20°、14.94±0.20°、16.29±0.20°、16.84±0.20°、17.71±0.20°、21.57±0.20°和23.90±0.20°。本申请的一些方案中，上述S晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.15±0.20°、6.57±0.20°、8.43±0.20°、8.83±0.20°、11.27±0.20°、13.97±0.20°、14.23±0.20°、14.94±0.20°、16.29±0.20°、16.84±0.20°、17.20±0.20°、17.71±0.20°、18.48±0.20°、19.19±0.20°、20.36±0.20°、20.74±0.20°、21.57±0.20°、22.61±0.20°、23.02±0.20°、23.90±0.20°、26.16±0.20°、26.67±0.20°和27.74±0.20°。本申请的一些方案中，上述S晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.15±0.20°、6.57±0.20°、8.43±0.20°、8.83±0.20°、9.90±0.20°、11.27±0.20°、11.54±0.20°、13.13±0.20°、13.97±0.20°、14.23±0.20°、14.94±0.20°、16.29±0.20°、16.84±0.20°、17.20±0.20°、17.71±0.20°、18.48±0.20°、19.19±0.20°、20.36±0.20°、20.74±0.20°、21.57±0.20°、22.20±0.20°、22.61±0.20°、23.02±0.20°、23.90±0.20°、24.92±0.20°、25.58±0.20°、26.16±0.20°、26.67±0.20°、27.74±0.20°、28.25±0.20°、和31.28±0.20°。
本申请的一些方案中，上述S晶型的XRPD图谱如图51所示。
本申请的一些方案中，上述S晶型的XRPD图谱在下列2θ角处具有特征衍射峰，如表19所示：
表19：S晶型的XRPD图谱数据
Figure PCTCN2020130612-appb-000030
另一方面，本申请提供上述S晶型的制备方法，包括：将上述E晶型加热至180～240℃，得到S晶型。本申请的一些方案中，S晶型的制备方法中，加热至210℃。
本申请提供式(I)化合物的T晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.23±0.20°、8.45±0.20°、16.18±0.20°和26.35±0.20°。本申请的一些方案中，上述T晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.23±0.20°、8.45±0.20°、12.85±0.20°、16.18±0.20°、19.41±0.20°和26.35±0.20°。本申请的一些方案中，上述T晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.23±0.20°、8.45±0.20°、12.85±0.20°、16.18±0.20°、18.46±0.20°、19.41±0.20°、19.97±0.20°、21.46±0.20°和26.35±0.20°。本申请的一些方案中，上述T晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.23±0.20°、8.45±0.20°、9.72±0.20°、12.85±0.20°、14.41±0.20°、16.18±0.20°、18.46±0.20°、19.41±0.20°、19.97±0.20°、21.46±0.20°、24.95±0.20°和26.35±0.20°。
本申请的一些方案中，上述T晶型的XRPD图谱如图52所示。
本申请的一些方案中，上述T晶型的XRPD图谱在下列2θ角处具有特征衍射峰，如表20所示：
表20：T晶型的XRPD图谱数据
Figure PCTCN2020130612-appb-000031
本申请的一些方案中，上述T晶型的热重分析曲线在升温至150.0±3℃时失重达0.47％。
本申请的一些方案中，上述T晶型的TGA图谱如图53所示。
本申请的一些方案中，上述T晶型的差示扫描量热曲线(DSC)在235.3±3℃处具有吸热峰。本申请的一些方案中，上述T晶型的差示扫描量热曲线(DSC)在178.1±3℃处具有放热峰。本申请的一些方案中，上述T晶型的差示扫描量热曲线(DSC)在235.3±3℃处具有吸热峰、和/或在178.1±3℃处具有放热峰。
本申请的一些方案中，上述T晶型的DSC图谱如图54所示。
另一方面，本申请提供上述T晶型的制备方法，包括：将上述G晶型加热至120～180℃，冷却至室温，得到T晶型。本申请的一些方案中，T晶型的制备方法中，G晶型加热至150℃。
本申请提供式(I)化合物的U晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.50±0.20°、6.97±0.20°、9.51±0.20°和19.13±0.20°。本申请的一些方案中，上述U晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.50±0.20°、6.97±0.20°、9.51±0.20°、11.55±0.20°、17.53±0.20°、19.13±0.20°和19.62±0.20°。本申请的一些方案中，上述U晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.50±0.20°、6.97±0.20°、9.51±0.20°、10.29±0.20°、11.55±0.20°、14.00±0.20°、17.53±0.20°、19.13±0.20°、19.62±0.20°和21.09±0.20°。本申请的一些方案中，上述U晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.50±0.20°、6.97±0.20°、9.51±0.20°、9.98±0.20°、10.29±0.20°、11.55±0.20°、14.00±0.20°、17.53±0.20°、19.13±0.20°、19.62±0.20°、20.71±0.20°、21.09±0.20°、21.41±0.20°、22.32±0.20°、24.35±0.20°、26.98±0.20°、35.53±0.20°。
本申请的一些方案中，上述U晶型的XRPD图谱如图55所示。
本申请的一些方案中，上述U晶型的XRPD图谱在下列2θ角处具有特征衍射峰，如表21所示：
表21：U晶型的XRPD图谱数据
Figure PCTCN2020130612-appb-000032
Figure PCTCN2020130612-appb-000033
另一方面，本申请提供上述U晶型的制备方法，包括：1)将上述式(I)化合物溶解在DMAc中；2)往DMAc溶液中加入甲苯；3)析出固体后，分离得到U晶型。本申请的一些方案中，U晶型的制备方法中，以式(I)化合物的A晶型溶解在DMAc中。本申请的一些方案中，U晶型的制备方法中，往DMAc溶液中加入甲苯采用挥发甲苯至DMAc溶液的方法。
本申请提供式(I)化合物的V晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.17±0.20°、9.44±0.20°、19.06±0.20°和19.56±0.20°。本申请的一些方案中，上述V晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.17±0.20°、9.44±0.20°、10.22±0.20°、11.48±0.20°、19.06±0.20°、19.56±0.20°和21.35±0.20°。本申请的一些方案中，上述V晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.90±0.20°、7.17±0.20°、8.99±0.20°、9.44±0.20°、9.91±0.20°、10.22±0.20°、11.48±0.20°、19.06±0.20°、19.56±0.20°和21.35±0.20°。本申请的一些方案中，上述V晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.90±0.20°、7.17±0.20°、8.99±0.20°、9.44±0.20°、9.91±0.20°、10.22±0.20°、11.48±0.20°、14.50±0.20°、17.46±0.20°、19.06±0.20°、19.56±0.20°、21.01±0.20°、21.35±0.20°、21.85±0.20°、22.25±0.20°和24.27±0.20°。本申请的一些方案中，上述V晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.90±0.20°、7.17±0.20°、8.99±0.20°、9.44±0.20°、9.91±0.20°、10.22±0.20°、10.41±0.20°、10.57±0.20°、11.48±0.20°、13.93±0.20°、14.50±0.20°、17.46±0.20°、19.06±0.20°、19.56±0.20°、20.64±0.20°、21.01±0.20°、21.35±0.20°、21.85±0.20°、22.25±0.20°、24.27±0.20°、26.88±0.20°和29.30±0.20°。
本申请的一些方案中，上述V晶型的XRPD图谱如图56所示。
本申请的一些方案中，上述V晶型的XRPD图谱在下列2θ角处具有特征衍射峰，如表22所示：
表22：V晶型的XRPD图谱数据
Figure PCTCN2020130612-appb-000034
Figure PCTCN2020130612-appb-000035
本申请的一些方案中，上述V晶型的热重分析曲线在升温至110.0±3℃时失重达14.05％。本申请的一些方案中，上述V晶型的热重分析曲线在由110.0±3℃升温至160.0±3℃时失重达16.46％。本申请的一些方案中，上述V晶型的热重分析曲线在升温至110.0±3℃时失重达14.05％、和/或在由110.0±3℃升温至160.0±3℃时失重达16.46％。
本申请的一些方案中，上述V晶型的TGA图谱如图57所示。
本申请的一些方案中，上述V晶型的差示扫描量热曲线(DSC)在231.1±3℃处具有吸热峰。本申请的一些方案中，上述V晶型的差示扫描量热曲线(DSC)在153.9±3℃处具有吸热峰。本申请的一些方案中，上述V晶型的差示扫描量热曲线(DSC)在231.1±3℃和/或153.9±3℃处具有吸热峰。
本申请的一些方案中，上述V晶型的DSC图谱如图58所示。
另一方面，本申请提供上述V晶型的制备方法，包括：将上述U晶型于50℃、真空条件下干燥，得到V晶型。
又一方面，本申请提供包含所述上述晶型的晶型组合物，其中，所述晶型占晶型组合物重量的50％以上，较好为80％以上，更好是90％以上，最好是95％以上。
又一方面，本申请提供一种药物组合物，该药物组合物中包含治疗有效量的本申请所述晶型、或其晶型组合物。本申请的药物组合物中可含有或不含有药学上可接受的辅料。此外，本申请的药物组合物可进一步包括一种或多种其他治疗剂。
本申请还提供上述晶型、其晶型组合物、或其药物组合物在制备抑制核蛋白的药物中的应用。
本申请还提供一种抑制核蛋白的方法，包括对需要该治疗或预防的哺乳动物，优选人类，给予治疗有效量的上述晶型、其晶型组合物、或其药物组合物。
本申请还提供用作核蛋白抑制剂的上述晶型、其晶型组合物、或其药物组合物。
本申请还提供上述晶型、其晶型组合物、或其药物组合物在抑制核蛋白中的应用。
本申请的一些方案中，上述应用或方法，其特征在于，核蛋白抑制剂的药物是治疗或预防HBV感染相关疾病的药物。
本申请还提供上述晶型、其晶型组合物、或其药物组合物在制备治疗或预防HBV感染相关疾病的药物中的应用。
本申请还提供上述晶型、其晶型组合物、或其药物组合物在治疗或预防HBV感染相关疾病中的应用。
本申请还提供用于治疗或预防HBV感染相关疾病的上述晶型、其晶型组合物、或其药物组合物。
本申请还提供上述晶型、其晶型组合物、或其药物组合物在治疗或预防HBV感染相关疾病中的应用。
技术效果
本申请式(I)化合物具有良好的体内给药药效且其各晶型稳定、受光热湿度影响小、溶解性好，成药前景广阔。本申请的晶型具有良好的药代动力学性质，适合作为药物使用，其中所述药代动力学性质可以在临床前的例如SD大鼠、比格犬的动物试验中测得，也可以在临床的人体试验中测得。本申请的晶型为化合物的固体形式作出了贡献。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在含有下列含义。一个特定的短语或术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文出现商品名时，旨在指代其对应的商品或其活性成分。
需要说明的是，在粉末X-射线衍射光谱中，峰的位置或峰的相对强度可能会因为测定仪器、测定方法/条件等因素而产生差异。对任何特定的晶型，峰的位置可能存在误差，2θ值的测定误差可以为±0.2°。因此，在确定每种晶型时，应该将此误差考虑在内，在误差内也属于本申请的范围。
晶体内一些晶粒的点阵平面或晶棱占优势地沿着某些方向和平面排列的现象称为择优取向。在粉末法中，线条相对强度的计算要求粉末样品中晶体呈完全无规则取向，若在样品中，取向晶体增多，必将引起强度增加。这就使得衍射线强度与取向度之间具有一定的对应关系。(《X射线结构分析》，祁景玉主编，同济大学出版社，2003年4月第1版)。
试样中的晶粒显著倾向于某一晶体学方向称为择优取向，对于强解理的物质，目视都可很容易地发现择优取向现象。对于这类材料，例如片状或针状晶体，在制做测试样品时，容易发生择优取向。如板状晶体，在圆柱体样品管中，片状晶面的发现趋向于与样品管的轴重合。在衍射仪的平板样品架中，片状晶面的法线趋向于与样品架的基面垂直。用标准的θ-2θ连动的布拉格-布伦塔诺型衍射仪收集衍射数据时，择优取向晶面的衍射强度将异常增强。即使经过多次制作样品，虽可得到一些改善，但仍难以完全克服择优取向现象(《粉末衍射法测定晶体结构》，梁敬魁编著，科学出版社，2003年4月第1版)。
择优取向会影响粉末衍射法测定晶体结构的检测结果。晶型的不同批次的XRPD检测结果存在 差异，但这不阻碍本领域技术人员对是否是相同晶型作出判断。
需要说明的是，对于同种晶型，DSC的吸热峰出现位置可能会因为测定仪器、测定方法/条件等因素而产生差异。对任何特定的晶型，吸热峰的位置可能存在误差，误差可以为±5℃，可以为±3℃。因此，在确定每种晶型时，应该将此误差考虑在内，在误差内也属于本申请的范围。
术语“溶剂合物”是指本申请式(I)化合物与药学上可接受的溶剂结合形成的物质，本申请不包括水。药学上可接受的溶剂包括，乙醇，乙酸等。溶剂化物包括化学计算量的溶剂合物和非化学计算量的溶剂合物。
所述“词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。“药学上可接受的辅料”是指与活性成份一同给药的、有利于活性成份给药的惰性物质，包括但不限于国家食品药品监督管理局许可的可接受的用于人或动物(例如家畜)的任何助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味增强剂、表面活性剂、润湿剂、分散剂、崩解剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。所述辅料的非限制性实例包括碳酸钙、磷酸钙、各种糖和各类淀粉、纤维素衍生物、明胶、植物油和聚乙二醇。
术语“药物组合物”是指一种或多种本申请的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本申请的化合物。
本申请的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
给予本申请所述晶型或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
本申请的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合，来配制该药物组合物。这些辅料能使本申请的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。
本申请化合物的治疗剂量可根据例如以下而定：治疗的具体用途、给予化合物的方式、患者的健康和状态，以及签处方医师的判断。本申请化合物在药用组合物中的比例或浓度可不固定，取决于多种因素，它们包括剂量、化学特性(例如疏水性)和给药途径。
术语“治疗”意为将本申请所述化合物或制剂进行给药以改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：
(i)抑制疾病或疾病状态，即遏制其发展；
(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
术语“预防”意为将本申请所述化合物或制剂进行给药以预防疾病或与所述疾病相关的一个或多个症状，且包括：预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时。
针对药物或药理学活性剂而言，术语“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
本申请所述晶型的治疗有效量为从约0.0001到20mg/Kg体重/天，例如从0.001到10mg/Kg体重/天。
本申请所述晶型的剂量频率由患者个体的需求决定，例如，每天1次或2次，或每天更多次。给药可以是间歇性的，例如，其中在若干天的期间内，患者接受晶型的每日剂量，接着在若干天或更多天的期间，患者不接受晶型的每日剂量。
本申请的中间体化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本申请的实施例。
本申请具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本申请的化学变化及其所需的试剂和物料。为了获得本申请的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
下面会通过实施例具体描述本申请，这些实施例并不意味着对本申请的任何限制。
本申请所使用的所有溶剂是市售的，无需进一步纯化即可使用。
本申请所使用的溶剂可经市售获得。本申请采用下述缩略词：DCM代表二氯甲烷；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOH代表乙醇；MeOH代表甲醇；TFA代表三氟乙酸；ATP代表三磷酸腺苷；HEPES代表4-羟乙基哌嗪乙磺酸；EGTA代表乙二醇双(2-氨基乙基醚)四乙酸；MgCl 2代表二氯化镁；NMP代表N-甲基吡咯烷酮；THF代表四氢呋喃；2-MeTHF代表2-甲基四氢呋喃；MTBE代表甲基叔丁基醚；DMAc代表二甲基乙酰胺；ACN代表乙腈。
XRPD、DSC、TGA的具体方法(包括设备型号以及各参数)
本申请粉末X-射线衍射(X-ray powder diffractometer,XRPD)方法
仪器型号：PANalytical(帕纳科)公司的X’Pert 3/Empyrean型X-射线衍射仪
测试方法：大约10mg样品用于XRPD检测。
详细的XRPD参数如下：
射线源：Cu,kα(
Figure PCTCN2020130612-appb-000036
Kα2/Kα1强度比例：0.5)
光管电压：45kV，光管电流：40mA
发散狭缝：固定1/8deg
第一索拉狭缝：0.04rad,第二索拉狭缝：0.04rad
接收狭缝：无，防散射狭缝：7.5mm
测量时间：5min
扫描角度范围：3-40deg
步宽角度：0.0263deg(X’Pert 3)/0.0167deg(Empyrean)
步长：46.665秒(X’Pert 3)/17.780秒(Empyrean)
样品盘转速：15rpm
本申请差示扫描量热(Differential Scanning Calorimeter,DSC)方法
仪器型号：TA Q2000/Discovery DSC 2500差示扫描量热仪
测试方法：取样品(～1-5mg)置于DSC铝盘内进行测试,在50mL/min N 2条件下,以10℃/min的升温速率,加热样品从25℃(室温)到样品分解前。
本申请热重分析(Thermal Gravimetric Analyzer,TGA)方法
仪器型号：TA Discovery TGA 5500热重分析仪
测试方法：取样品(～1-5mg)置于TGA铝盘内进行测试,在10mL/min N 2条件下,以10℃/min的升温速率,加热样品从室温到350℃。
本申请单晶检测方法
用Bruker D8 venture衍射仪收集衍射强度数据，光源为Cukα辐射，扫描方式：
Figure PCTCN2020130612-appb-000037
扫描。
附图说明
图1：A晶型的XRPD图谱。
图2：A晶型的TGA图谱。
图3：A晶型的DSC图谱。
图4：B晶型的XRPD图谱。
图5：B晶型的TGA图谱。
图6：B晶型的DSC图谱。
图7：C晶型的XRPD图谱。
图8：C晶型的TGA图谱。
图9：C晶型的DSC图谱。
图10：D晶型的XRPD图谱。
图11：E晶型的XRPD图谱。
图12：E晶型的TGA图谱。
图13：E晶型的DSC图谱。
图14：F晶型的XRPD图谱。
图15：F晶型的TGA图谱。
图16：F晶型的DSC图谱。
图17：G晶型的XRPD图谱。
图18：G晶型的TGA图谱。
图19：G晶型的DSC图谱。
图20：H晶型的XRPD图谱。
图21：H晶型的TGA图谱。
图22：H晶型的DSC图谱。
图23：I晶型的XRPD图谱。
图24：I晶型的TGA图谱。
图25：I晶型的DSC图谱。
图26：J晶型的XRPD图谱。
图27：J晶型的TGA图谱。
图28：J晶型的DSC图谱。
图29：K晶型的XRPD图谱。
图30：K晶型的TGA图谱。
图31：K晶型的DSC图谱。
图32：L晶型的XRPD图谱。
图33：L晶型的TGA图谱。
图34：L晶型的DSC图谱。
图35：M晶型的XRPD图谱。
图36：M晶型的TGA图谱。
图37：M晶型的DSC图谱。
图38：N晶型的XRPD图谱。
图39：N晶型的TGA图谱。
图40：N晶型的DSC图谱。
图41：O晶型的XRPD图谱。
图42：O晶型的TGA图谱。
图43：O晶型的DSC图谱。
图44A：P晶型的XRPD图谱1。
图44B：P晶型的XRPD图谱2。
图45：P晶型的TGA图谱1。
图46：P晶型的DSC图谱1。
图47：Q晶型的XRPD图谱。
图48：Q晶型的TGA图谱。
图49：Q晶型的DSC图谱。
图50：R晶型的XRPD图谱。
图51：S晶型的XRPD图谱。
图52：T晶型的XRPD图谱。
图53：T晶型的TGA图谱。
图54：T晶型的DSC图谱。
图55：U晶型的XRPD图谱。
图56：V晶型的XRPD图谱。
图57：V晶型的TGA图谱。
图58：V晶型的DSC图谱。
图59：P晶型的XRPD图谱3。
图60：P晶型的DSC图谱2。
图61：通过单晶数据计算得到的P晶型的XRPD图。
图62：P晶型的偏光显微镜(PLM)图片。
图63：图44B(上方的图)、图59(中间的图)、图61(下方的图)的叠合图。
具体实施方式
为了更好的理解本申请的内容，下面结合具体实施例来做进一步的说明但具体的实施方式并不是对本申请的内容所做的限制。
实施例1：式(I)化合物
Figure PCTCN2020130612-appb-000038
合成路线：
Figure PCTCN2020130612-appb-000039
Figure PCTCN2020130612-appb-000040
第一步
Figure PCTCN2020130612-appb-000041
在单口瓶中将化合物13-1(1g,4.40mmol,1eq)溶于四氢呋喃(20mL)，氮气保护0℃下加入钠氢(615.93mg,60％纯度,3.5eq)，搅拌0.5小时后，加入化合物13-2(2.33g,9.24mmol,2.1eq)，反应在30℃搅拌30分钟。TLC显示反应完毕。反应倒入0.5M稀盐酸中(100mL)，粗品经柱层析分离纯化(石油醚：乙酸乙酯＝50:1至20:1)得到化合物13-3。
1H NMR(400MHz,CDCl 3)δ＝5.55(s,1H),4.43(s,1H),3.32–3.26(m,1H),2.41–2.38(m,1H),2.30–2.28(m,1H),2.15–2.14(m,1H),2.13–2.04(m,1H),2.03–2.01(m,1H),1.54–1.49(m,2H),1.46(s,9H),1.43(s,9H),1.33(s,3H).
第二步
Figure PCTCN2020130612-appb-000042
在氢化瓶中将湿钯碳(200mg,10％含量)溶于四氢呋喃(40mL)并加入化合物13-3(1.35g,4.15mmol,1eq)，反应在H 2(15Psi)保护下于25℃搅拌2个小时。TLC显示反应完毕。反应液过滤浓缩得到化合物13-4。
第三步
Figure PCTCN2020130612-appb-000043
在一个干燥的单口瓶中将化合物13-4(1.3g,3.97mmol,1eq)溶于乙酸乙酯(30mL)并加入盐酸/乙酸乙酯(4M,10mL,10.08eq)，反应在30℃搅拌16个小时。反应液直接浓缩得到化合物13-5。
1H NMR(400MHz,MeOH-d 4)δ＝1.85–1.83(m,4H),1.77–1.76(m,2H),1.63–1.60(m,3H),1.45(s,9H),1.35–1.31(m,5H).
第四步
Figure PCTCN2020130612-appb-000044
在一个干燥的单口瓶中将化合物13-5(250mg,861.77μmol,1eq)溶于二氯甲烷(10mL)并加入三乙胺(261.61mg,2.59mmol,359.85μL,3eq)，氮气保护0℃下滴加化合物11-7(293.88mg,1.29mmol,1.5eq)的二氯甲烷(10mL)溶液，反应在30℃搅拌1个小时。LCMS显示反应完毕。反应液倒入水中(50mL)，然后水相用二氯甲烷萃取(20mL*3)，有机相用0.5M稀盐酸洗涤(20mL*3)，有机相用无水硫酸钠干燥过滤并减压浓缩得到化合物13-6。
MS(ESI)m/s:425.2[M+H-(t-Bu)] +
1H NMR(400MHz,CDCl 3)δ＝5.99(s,1H),4.32(t,J＝7.6Hz,2H),3.84(s,2H),3.14(t,J＝7.6Hz,2H),2.52–2.48(m,2H),2.31–2.28(m,2H),2.14–2.12(m,2H),1.68–1.65(m,2H),1.45–1.42(m,2H),1.39–1.36(m,12H),1.24–1.22(m,2H),1.18–1.14(m,2H).
将化合物13-6经SFC分离(色谱柱:DAICELCHIRALCELOJ(250mm*30mm,10μm)；流动相[Neu-ETOH]；B％:30％-30％,9min)。得到化合物1-1(SFC保留时间1.7min)，SFC分析条件(色谱柱:大赛璐OJ-3型手性柱,规格0.46cm id x 5cm；流动相:[A:二氧化碳,B:色谱乙醇(0.05％异丙胺)]；B％:5％-40％；流速:4毫升/分钟；4分钟；系统背压:100bar)。
化合物1-1： 1H NMR(400MHz,CDCl 3)δ＝6.08(s,1H),4.31(t,J＝7.4Hz,2H),3.83(s,3H),3.12(t,J＝7.6Hz,2H),2.51-2.47(m,2H),2.17–2.15(m,2H),2.14–2.00(m,2H),1.83-1.70(m,6H),1.48(s,3H),1.47-1.45(m,11H),1.45-1.26(m,3H)。
第五步
在一个单口瓶中将化合物1-1(550.00mg,1.14mmol,1eq)溶于四氢呋喃(10mL)，水(10mL)和甲醇(10mL)并加入一水合氢氧化锂(239.91mg,5.72mmol,5eq)，反应在30℃继续搅拌16个小时。LCMS显示反应完全。反应液用0.5M稀盐酸调至pH＝1，水相用乙酸乙酯萃取(20mL*3)，有机相用无水硫酸钠干燥过滤并减压浓缩，得到化合物1-2。
第六步
将化合物1-2(500mg,1.07mmol,1eq)溶于二氯甲烷(20mL)，氮气保护0℃下滴加草酰氯(271.83mg,2.14mmol,187.47μL,2eq)和N,N-二甲基甲酰胺(7.83mg,107.08μmol,8.24μL,0.1eq)，反应在25℃搅拌1个小时。取两滴反应液加甲醇淬灭，LCMS显示反应完毕。反应液减压浓缩得到化合物1-3。
第七步
将化合物1-3溶于二氯甲烷(15mL)并加入TEA(312.70mg,3.09mmol,430.12μL,3eq)，氮气保护0℃下滴加化合物1-4(500.00mg,1.03mmol,1eq)溶于二氯甲烷(5mL)的溶液，反应在25℃搅拌1个小时。LCMS显示反应完毕。反应液倒入0.5mol/L稀盐酸(50mL)，水相用二氯甲烷萃取(20mL*3)，有机相用无水硫酸钠干燥过滤并减压浓缩。粗品经柱层析分离纯化(100-200目硅胶，石油醚：乙酸乙酯＝10:1至4:1，V/V)得到化合物1-5。MS(ESI)m/s:540.1[M+H-(t-Bu)] +。
1H NMR(400MHz,CDCl 3)δ＝8.47(s,1H),7.38-7.34(m,2H),6.23(s,1H),4.35-4.31(m,2H),3.28-3.23(m,2H),2.52-2.49(m,2H),2.18-2.14(m,2H),2.05-2.00(m,2H),1.93-1.81(m,3H),1.80-1.71(m,2H),1.55(s,3H),1.50-1.45(m,9H),1.32-1.26(m,2H).
第八步
将化合物1-5(100.00mg,167.78μmol,1eq)溶于二氯甲烷(1mL)并加入三氟乙酸(382.59mg,3.36mmol,248.44μL,20eq)，反应在25℃搅拌1个小时。LCMS和HPLC显示反应完毕。反应液减压浓缩。粗品经制备型HPLC分离纯化(中性体系，色谱柱:Xtimate C18 150mm*25mm*5μm；流动相:[水(10mM碳酸氢铵)-乙腈]；乙腈％:10％-50％,20min)得到式(I)化合物。MS(ESI)m/s:540.2[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ＝9.99(s,1H),8.29(s,1H),7.65-7.57(m,2H),4.30-4.26(m,2H),3.09-3.05(m,2H),2.47-2.43(m,2H),2.16-2.12(m,2H),1.85-1.80(m,2H),1.75-1.61(m,5H),1.35(s,3H),1.21-1.16(m,2H).
实施例2：晶型的制备方法
A晶型制备方法：将7.5克化合物1-5，溶解二氯甲烷(80mL)中，随后加入三氟乙酸(40mL)，反应在15℃搅拌1个小时。HPLC显示反应完毕，将反应液直接减压浓缩。粗品经甲基叔丁基醚(100mL)打浆纯化，过滤浓缩，经冻干得到白色固体产物，分离测试XRPD，即为A晶型。
B晶型制备方法：将约15毫克A晶型样品溶解在0.04毫升DMSO中，滴加水直至固体析出，悬浮搅拌过夜，分离测试XRPD，即为B晶型。
C晶型制备方法：将约15毫克晶型A样品溶解在0.18毫升THF中，滴加MTBE直至固体析出，悬浮搅拌过夜，分离测试XRPD，即为晶型C。
D晶型制备方法：将约15毫克A晶型样品溶解在0.13毫升THF中，滴加DCM直至固体析出，悬浮搅拌过夜，分离测试XRPD，即为D晶型。
E晶型制备方法：将约15毫克晶型A样品溶解在0.6毫升1,4-Dioxane(1,4-二氧六环)中，将上述溶液放置在3毫升玻璃瓶中，再将装有上述溶液的3毫升玻璃瓶放置在装有3毫升ACN(乙腈)的20 毫升玻璃瓶中，使ACN(乙腈)缓慢挥发至1,4-Dioxane(1,4-二氧六环)溶液中，以在1,4-Dioxane(1,4-二氧六环)溶液中产生固体，得到固体后，分离固体测试XRPD，即为晶型E。
F晶型制备方法：将约15毫克晶型A样品溶解在0.3毫升DMF中得到澄清溶液，将澄清溶液滴加至3毫升H 2O中，室温悬浮搅拌过夜后，分离固体测试XRPD，即为晶型F。
G晶型制备方法：将约15毫克A晶型样品分散在0.1毫升CHCl 3/THF(9:1，v/v)中，室温悬浮搅拌约2周，分离测试XRPD，即为G晶型。
H晶型制备方法：将约15毫克A晶型样品分散在0.1毫升EtOH/DMF(19:1，v/v)中，室温悬浮搅拌约2周，分离测试XRPD，即为H晶型。
I晶型制备方法：将约15毫克A晶型样品分散在0.1毫升水中，50℃下悬浮搅拌约2周，分离测试XRPD，即为I晶型。
J晶型制备方法：将约15毫克A晶型样品分散在0.1毫升2-MeTHF中，50℃下悬浮搅拌约2周，分离测试XRPD，即为J晶型。
K晶型制备方法：将约15毫克A晶型样品50℃下溶解在0.2毫升DCM/MeOH(4:1，v/v)中，直接降温至5℃，分离测试XRPD，即为K晶型。
L晶型制备方法：将约15毫克晶型A样品溶解在0.1毫升NMP(N-甲基吡咯烷酮)中，将上述溶液放置在3毫升玻璃瓶中，再将装有上述溶液的3毫升玻璃瓶放置在装有3毫升EtOAc(乙酸乙酯)的20毫升玻璃瓶中，使EtOAc(乙酸乙酯)缓慢挥发至NMP(N-甲基吡咯烷酮)溶液中，以在NMP(N-甲基吡咯烷酮)溶液中产生固体，得到固体后，分离固体测试XRPD，即为晶型L。
M晶型制备方法：将约15毫克A晶型样品溶解在0.4毫升THF中，室温下缓慢挥发得到固体，分离测试XRPD，即为M晶型。
N晶型制备方法：将约15毫克A晶型样品50℃下溶解在1.5毫升EtOH中，直接降温至5℃，分离测试XRPD，即为N晶型。
O晶型制备方法：将D晶型室温真空干燥约1小时，测试XRPD，即为O晶型。
P晶型制备方法1：将约15毫克A晶型样品溶解在1.0毫升MTBE/MeOH(3:2，v/v)中，室温下缓慢挥发得到固体，分离测试XRPD，即为P晶型。所得P晶型的XRPD检测结果如图44A、图44B，TGA和DSC检测结果分别如图45和图46所示。
Q晶型制备方法：将约15毫克A晶型样品溶解在1.5毫升MeOH中，滴加ACN约3毫升后得到澄清溶液，转至-20℃悬浮搅拌，分离固体测试XRPD，即为Q晶型。
R晶型制备方法：将O晶型加热至150℃后将至室温，测试XRPD，即为R晶型。
S晶型制备方法：将E晶型加热至210℃，原位测试XRPD，即为S晶型。
T晶型制备方法：将G晶型加热至150℃后将至室温，即为T晶型。
U晶型制备方法：将约15毫克A晶型样品溶解在0.7毫升DMAc中，室温下缓慢挥发甲苯至DMAc溶液中，得到澄清溶液，转至室温挥发，分离测试XRPD，即为U晶型。
V晶型制备方法：将U晶型在50℃真空干燥2～3小时，测试XRPD，即为V晶型。
实施例3：P晶型的制备方法2
将丙酮(10.06L)加入反应釜中，控制温度在10～25℃，然后加入A晶型样品(1342.02g，2.49mol)，反应随后在40℃搅拌16～24个小时。停止反应，反应液直接过滤，滤饼在45℃减压浓缩得到式(I)化合物粗品1142.51g。重复上述操作，样品二次匀浆，反应液直接过滤，滤饼在45℃减压浓缩得到式(I)化合物989.01g，收率为73.44％。取样进行XRPD检测，结果如图59所示，其DSC检测结果如图60。
实施例4：P晶型的单晶制备方法
将式(I)化合物溶于甲醇中，采用溶剂挥发法，在室温经过10天培养以后获得。
式(I)化合物的P晶型的单晶的晶胞参数，其晶体学数据和原子坐标等如下表23、24所示。
表23 晶体学数据和结构精修
Figure PCTCN2020130612-appb-000045
Figure PCTCN2020130612-appb-000046
表24 原子坐标(×10 4)和等效各向同性位移参数
Figure PCTCN2020130612-appb-000047
Figure PCTCN2020130612-appb-000048
Figure PCTCN2020130612-appb-000049
Figure PCTCN2020130612-appb-000050
根据单晶数据通过软件模拟计算得到的XRPD图如图61所示。
实验例1：P晶型的固定稳定性研究
为评估P晶型的固体稳定性，对P晶型进行了影响因素(高温、高湿及光照)、加速条件稳定性及中间条件稳定性的考察。将P晶型在高温(60℃，闭口)、高湿(室温，92.5％RH，封口膜包裹并扎5～10个小孔)下放置5天、10天，按照ICH条件(可见光照度达到1.2E+06Lux·hrs，紫外光照度达到200W·hrs/m)闭口放置在可见光及紫外光下(遮光对照组用锡箔纸包裹)，同时在加速条件稳定性(60℃/75％RH，封口膜包裹并扎5～10个小孔)下放置10天及1、2个月。对放置后的样品进行XRPD及HPLC表征，以检测晶型及纯度的变化；结果表25显示：P晶型在所有稳定性条件下，晶型未发生变化。
表25：P晶型的固体稳定性评估结果
Figure PCTCN2020130612-appb-000051
注：“ #”表示ICH条件。*相对纯度＝稳定性样品纯度与起始样品纯度的比值。
上述结果说明P晶型具有良好的稳定性。
实验例2：HBV体外测试定量qPCR试验
1实验目的：
通过实时定量qPCR试验(real time-qPCR)检测HepG2.2.15细胞内的HBV DNA含量，以化合物的EC 50值为指标，来评价化合物对HBV的抑制作用。
2实验材料:
2.1细胞系：HepG2.2.15细胞
HepG2.2.15细胞培养基(DMEM/F12，Invitrogen-11330057；10％血清，Invitrogen-10099141；100units/ml青霉素和10μg/ml链霉素，Invitrogen-15140122；1％非必需氨基酸，Invitrogen-11140076；2mM左旋谷氨酰胺，Invitrogen-25030081；300μg/ml遗传霉素，Invitrogen-10131027)
2.2试剂：
胰酶(Invitrogen-25300062)
DPBS(Hyclone-SH30028.01B)
DMSO(Sigma-D2650-100ML)
高通量DNA纯化试剂盒(QIAamp 96DNA Blood Kit，Qiagen-51162)
定量快速启动通用探针试剂(FastStart Universal Probe Master，Roche-04914058001)
2.3耗材与仪器：
96孔细胞培养板(Corning-3599)
CO 2培养箱(HERA-CELL-240)
光学封板膜(ABI-4311971)
定量PCR 96孔板(Applied Biosystems-4306737)
荧光定量PCR仪(Applied Biosystems-7500real time PCR system)
3.实验步骤和方法：
3.1种HepG2.2.15细胞(4x10 4细胞/孔)到96孔板，在37℃，5％CO 2培养过夜。
3.2第二天，稀释化合物，共8个浓度，3倍梯度稀释。加不同浓度化合物到培养孔中，双复孔。培养液中DMSO的终浓度为1％。1μM GLS4作为100％抑制对照(WO2008154817A1公开了GLS4的结构如下：
Figure PCTCN2020130612-appb-000052
)；1％的DMSO作为0％抑制对照。
3.3第五天，更换含有化合物的新鲜培养液。
3.4第八天收取培养孔中的培养液，使用高通量DNA纯化试剂盒(Qiagen-51162)提取DNA，具体步骤参照该产品说明书。
3.5 PCR反应液的配制如表26所示：
表26.PCR反应液的配制
Figure PCTCN2020130612-appb-000053
Figure PCTCN2020130612-appb-000054
上游引物序列：GTGTCTGCGGCGTTTTATCA
下游引物序列：GACAAACGGGCAACATACCTT
探针序列：5'+FAM+CCTCTKCATCCTGCTGCTATGCCTCATC+TAMRA-3'
3.6在96孔PCR板中每孔加入15μL的反应混合液，然后每孔加入10μL的样品DNA或HBV DNA的标准品。
3.7PCR的反应条件为：95℃加热10分钟；然后95℃变性15秒，60℃延伸1分钟，共40个循环。
3.8数据分析：
3.8.1计算抑制百分比：％Inh.＝【1-(样品中DNA拷贝数–1μM GLS4中DNA拷贝数)/(DMSO对照中DNA拷贝数–1μM GLS4中DNA拷贝数)】×100。
3.8.2计算EC 50：使用GraphPad Prism软件计算化合物对HBV的50％抑制浓度(EC 50)值。
3.8.3实验结果如表27所示：
表27.qPCR实验检测EC 50测试结果
Figure PCTCN2020130612-appb-000055
实验例3：hERG钾离子通道的抑制试验
1.实验目的：
用全自动膜片钳的方法检测待测本申请化合物对hERG钾离子通道的影响。
2.实验方法
2.1.细胞培养
实验所用的稳定表达hERG钾离子通道的细胞来自于Aviva Biosciences的CHO-hERE，CHO-hERG培养于5％CO 2，37℃的环境下。CHO hERG培养液见表28。
表28.CHO hERG培养液
试剂 供应商 体积(mL)
F12培养基 Invitrogen 500
胎牛血清 Invitrogen 50
G418/遗传毒素 Invitrogen 1
潮霉素B Invitrogen 1
2.2.细胞的前期准备
准备用于实验的CHO-hERG细胞至少培养两天以上，且细胞密度达到75％以上。实验开始之前，用TrypLE消化细胞，然后用细胞外液重悬收集细胞。
2.3.细胞内外液的配制
细胞外液需每个月配制一次。细胞内液须分装冻存在-20℃。细胞内外液成分见表29。
表29.细胞内外液成分
组成成分 细胞外液(mM) 细胞内液(mM)
NaCl 145 -
KCl 4 120
KOH - 31.25
CaCl 2 2 5.374
MgCl 2 1 1.75
Glucose 10 -
Na 2ATP - 4
HEPES 10 10
EGTA - 10
pH 氢氧化钠调节pH为7.4 氢氧化钾调节pH为7.4
渗透压 295mOsm 285mOsm
。
2.4.化合物的配制
将待测化合物和阳性对照阿米替林用DMSO溶解成一定浓度的储备液，然后按照不同的梯度稀释，最后按一定的比例加入细胞外液中，稀释成待测浓度。在实验开始前用肉眼检查看有无沉淀。最后，待测溶液和阳性对照阿米替林中，DMSO的浓度最高不能超过0.3％。
2.5.电压刺激方案
保持钳制电位在-80mv，首先是给予-50mv的电压刺激，持续80ms以记录细胞漏电流值，随后去极化至+20mv，维持4800ms，打开hERG的通道，然后复极化至-50mv维持5000ms，引出hERG尾电流并记录，最后，电压恢复至钳制电位-80mv，维持3100ms。以上电压刺激，每15000ms重复一次。
2.6.QPatch HTX全细胞膜片钳记录
hERG QPatch HTX实验是在室温下进行的。在QPatch Assay Software 5.2(Sophion Bioscience)的软件上建立全细胞方案，电压刺激方案和化合物检测方案。
首先进行30次重复设定电压刺激，该区段为后续分析的基线区域，随后加入5μl细胞外液，重复三次。依次加入各个化合物的作用浓度，仍旧以5μl加入体积重复三次。每一测试浓度孵育细胞至少不低于5mins。整个记录过程中，各项指标需达到数据分析接收标准，若未达到该标准，则该细胞不计入分析范围，化合物将重新进行测试，以上记录过程由均由Qpatch分析软件自动化操作。每一化合物测试浓度依次为0.24μM、1.20μM、6.00μM、30.00μM，每一浓度至少重复两个细胞。
2.7.数据分析
在每一个完整电流记录中，基于峰值电流在阴性对照中所占的百分比，可以计算出每一化合物作用浓度的抑制百分比。利用标准希式方程拟合得到量效关系曲线，具体方程如下：
I (C)＝I b+(I fr-I b)*c n/(IC 50 n+c n)
C为化合物测试浓度，n为斜率，I为电流
曲线拟合和抑制率计算均由Qpatch分析软件分析完成，若最低浓度下抑制率超过半数抑制或最高浓度下抑制率未达到半数抑制，则该化合物相应的IC 50低于最低浓度或IC 50值大于最高浓度。
2.8.测试结果
实施例化合物hERG IC50值结果见表30。
表30.实施例化合物hERG IC50值结果
供试样品 hERG IC50(μM)
式(I)化合物 >40
。
实验例4：细胞色素P450同工酶抑制性研究
实验目的：测定受试化合物对对人肝微粒体细胞色素P450同工酶(CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4)活性的抑制作用。
实验操作：首先将受试化合物(10mM)进行梯度，制备工作液(100×最终浓度)，工作液浓度分别为：5,1.5,0.5,0.15,0.05,0.015,0.005mM，同时准备P450同工酶(CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4)各阳性抑制剂及其特异性底物混合物的工作液；将冷冻于–80℃冰箱的人肝微粒体置于冰上解冻，待人肝微粒体全部溶解，用PB(磷酸缓冲液)进行稀释，制备一定浓度工作液(0.253mg/ml)；并将20μl底物混合液加至反应板中(Blank孔中加入20μl PB)同时将158μl人肝微粒体工作液加入反应板中，将反应板置于冰上，待用；此时将2μl各个浓度的受试化合物(N＝1)及特异性抑制剂(N＝2)加入对应孔中，无抑制剂(受试化合物或阳性抑制剂)组加入对应的有机溶剂，作为对照组样品(受试化合物对照样品为1:1DMSO:MeOH,阳性对照样品为1:9DMSO:MeOH,)；在37℃水浴预孵育10min后，将20μl辅酶因子(NADPH)溶液加入反应板中，置于37℃水浴孵育10min；加入400μL冷的乙腈溶液(内标为200ng/mL Tolbutamide和Labetalol)终止反应；将反应板置于摇床，振荡10min；4,000rpm离心20min；取200μL上清加至100μL水中，进行样品稀释；最后封板，振荡，摇匀，进行LC/MS/MS检测。实验结果如表31所示：
表31.受试化合物对对人肝微粒体细胞色素P450同工酶活性的抑制作用结果
Figure PCTCN2020130612-appb-000056
实验例5：细胞毒性测试实验步骤
1.将化合物用DMSO(二甲基亚砜)以3倍梯度稀释9个点，双复孔，加入96孔板中。化合 物浓度为最终测试浓度的200倍。
2.将细胞用PBS(磷酸盐缓冲液)润洗一遍，加入0.25％的胰酶在37℃、5％CO 2培养箱中消化约2-5分钟后，用细胞培养基终止消化，并用枪吹打将细胞分散成单细胞。
3.用细胞计数仪计数细胞密度，并用培养基将细胞密度调整到所需要的密度。
4.将细胞加入到已经加好化合物的96孔板中，每孔中DMSO的终浓度为0.5％。以含0.5％DMSO的细胞孔为无毒性阴性对照，以细胞培养液孔为100％细胞毒性对照。然后将细胞板放置于37℃、5％CO 2细胞培养箱内培养3天。
5.用细胞活力检测试剂盒CellTiter-Glo，按试剂盒说明书，用多功能酶标仪Envision检测细胞板中各孔的化学发光信号(RLU，相对化学发光单位)。
6.将原始数据(RLU)代入下面的公式，计算测试各孔的细胞活力(细胞活力％)：
细胞活力％＝(RLU Sample-AverageRLU Mediumcontrol)/(AverageRLU Cellcontrol-A verageRLU Mediumcontrol)×100％
RLU Sample为样品孔的信号值；AverageRLU Cellcontrol为细胞对照孔信号平均值；AverageRLU Mediumcontrol为培养基对照孔信号平均值。
7.用GraphPad Prism软件，将细胞活力数据非线性拟合绘制剂量效应曲线，并得出化合物的半数细胞毒性浓度(CC 50)值，结果如表32。
表32.半数细胞毒性浓度(CC 50)值测试结果
化合物 CC 50(μM)
式(I)化合物 >50
。
实验例6：体外微粒体稳定性研究
化合物在CD-1小鼠和人肝微粒体中的代谢稳定性
实验目的：评定受试化合物分别在CD-1小鼠和人肝微粒体中的代谢稳定性
实验操作：首先将受试化合物(10mM)进行两步稀释，中间浓度为100％甲醇稀释到100μM，工作液浓度为磷酸钾盐缓冲液稀释到10μM；准备8块96孔孵育板，分别命名为T0、T5、T10、T20、T30、T60、Blank和NCF60；前6块孵育板对应的反应时间点分别为0、5、10、20、30和60分钟，Blank板中不加入受试化合物或对照化合物，NCF60板中用磷酸钾盐缓冲液代替NADPH再生体系溶液进行孵育60分钟；在T0、T5、T10、T20、T30、T60和NCF60板上分别加入10μL受试化合物工作液和80μL微粒体工作液(肝微粒体蛋白浓度为0.625mg/mL)，在Blank板中只添加微粒体工作液，然后将上述孵育板放置于37℃水浴锅中预孵育大约10分钟；预孵育结束后，除NCF60板和T0板外，每个样品孔内添加10μL NADPH再生体系工作液以启动反应，在NCF60板上每孔添加10μL磷酸钾盐缓冲液；因此，在受试化合物或对照化合物的样品中，化合物、睾酮、双氯芬酸和普罗帕酮的反应终浓度为1μM，肝微粒体的浓度为0.5mg/mL，DMSO和乙腈在反应体系中的终浓度分别为0.01％(v/v)和0.99％(v/v)；孵育适当时间(如5、10、20、30和60分钟)后，分别在每个样品孔中加入300μL的终止液(含100ng/mL tolbutamide和100ng/mL labetalol的乙腈溶液)以终止反应；在T0板 中先加入300μL终止液然后再加入10μL NADPH工作液；所有样品板摇匀并在离心机(3220×g)离心20分钟，然后每孔取100μL上清液稀释到300μL纯水中用于液相色谱串联质谱分析。
实验结果如表33所示：
表33.受试化合物分别在CD-1小鼠和人肝微粒体中的代谢稳定性结果
Figure PCTCN2020130612-appb-000057
化合物在SD大鼠、比格犬和食蟹猴肝微粒体中的代谢稳定性
实验目的：评定受试式(I)化合物分别在大鼠、比格犬和食蟹猴肝微粒体中的代谢稳定性
实验操作：首先将受试化合物(10mM)进行两步稀释，中间浓度为100％甲醇稀释到100μM，工作液浓度为磷酸钾盐缓冲液稀释到10μM；准备8块96孔孵育板，分别命名为T0、T5、T10、T20、T30、T60、Blank和NCF60；前6块孵育板对应的反应时间点分别为0、5、10、20、30和60分钟，空白板中不加入受试化合物或对照化合物，NCF60板中用磷酸钾盐缓冲液代替NADPH再生体系溶液进行孵育60分钟；在T0、T5、T10、T20、T30、T60和NCF60板上分别加入10μL受试化合物工作液和80μL微粒体工作液(肝微粒体蛋白浓度为0.625mg/mL)，在Blank板中只添加微粒体工作液，然后将上述孵育板放置于37℃水浴锅中预孵育大约10分钟；预孵育结束后，除NCF60板和T0板外，每个样品孔内添加10μL NADPH再生体系工作液以启动反应，在NCF60板上每孔添加10μL磷酸钾盐缓冲液；因此，在受试化合物或对照化合物的样品中，化合物、睾酮、双氯芬酸和普罗帕酮的反应终浓度为1μM，肝微粒体的浓度为0.5mg/mL，DMSO和乙腈在反应体系中的终浓度分别为0.01％(v/v)和0.99％(v/v)；孵育适当时间(如5、10、20、30和60分钟)后，分别在每个样品孔中加入300μL的终止液(含100ng/mL甲苯磺丁脲和100ng/mL拉贝洛尔的乙腈溶液)以终止反应；在T0板中先加入300μL终止液然后再加入10μL NADPH工作液；所有样品板摇匀并在离心机(3220×g)离心20分钟，然后每孔取100μL上清液稀释到300μL纯水中用于液相色谱串联质谱分析。
实验结果如表34所示：
表34.受试化合物分别在SD大鼠、比格犬和食蟹猴肝微粒体中的代谢稳定性结果
Figure PCTCN2020130612-appb-000058
实验例7：药代动力学研究
Balb/c小鼠口服及静脉注射受试化合物的药代动力学研究：
受试化合物与10％二甲基亚砜/60％聚乙二醇400/30％水溶液混合，涡旋并超声，制备得到0.2mg/mL澄清溶液，微孔滤膜过滤后备用。选取7至10周龄的Balb/c雌性小鼠，静脉注射给予候选化合物溶液，剂量为1mg/kg。
受试化合物与10％聚乙二醇硬脂酸酯水溶液混合，涡旋并超声，制备得到0.3mg/mL澄清溶液备用。选取7至10周龄的Balb/c雌性小鼠，口服给予候选化合物溶液，剂量为3mg/kg。
收集全血，制备得到血浆，以LC-MS/MS方法分析药物浓度，并用Phoenix WinNonlin软件计算药代参数，结果如表35所示。
表35.受试化合物的药代动力学结果
Figure PCTCN2020130612-appb-000059
实验例8：小鼠体内肝血比研究
Balb/c小鼠口服受试化合物的肝血比研究
式(I)化合物与10％聚乙二醇-15羟基硬脂酸酯水溶液混合，涡旋并超声，制备得到0.3mg/mL澄清溶液备用。选取7至10周龄的Balb/c雌性小鼠，口服给予候选化合物溶液，剂量为3mg/kg。
收集一定时间的全血，制备得到血浆，收集相应时间的肝脏组织，制备得组织均浆液，以LC-MS/MS方法分析药物浓度，并用Phoenix WinNonlin软件计算药代参数，结果如表36所示。
表36受试化合物的肝血比结果
Figure PCTCN2020130612-appb-000060
实验例9：体内药效研究
HDI/HBV模型
实验目的：通过HDI/HBV小鼠模型检测化合物在小鼠体内抗乙肝病毒效果。
化合物配制：溶剂为10％的聚乙二醇-15羟基硬脂酸酯；将一定量的受试式(I)化合物分别溶解于10％聚乙二醇-15羟基硬脂酸酯水溶液，涡旋并超声，制备得到均一的混悬液，保存在4℃备用。
小鼠尾静脉高压注射HBV质粒DNA溶液：将注射质粒当天定为第0天，注射后1天为第1天，依此类推。在第0天所有动物按体重8％的体积通过尾静脉注射含有10μg质粒DNA的生理盐水溶液，5秒内完成注射。
给药：第1-6天所有动物每天灌胃给药两次(间隔时间8/16小时)，第7天给药一次，所有动物在第7天下午安乐死。每天监控小鼠体重，整个实验过程中小鼠体重保持平稳。
样品收集：所有动物在第1、3和5天，分别在当天早上第一次给药后四小时颌下静脉采血收集血浆，所有血样收集于K 2-EDTA抗凝管中，4℃，7000g离心10分钟，以制备约40μL血浆。第7天所有动物在早上给药后四小时经CO 2安乐死，心脏采血，血浆制备方法同上。收集两份肝脏组织，每份70-100mg，液氮速冻。样品全部收集后保存在-80℃冰箱进行HBV DNA含量的检测。
样品分析：所有的血浆样品和肝脏样品用qPCR法检测HBV DNA。
实验结果：实验结果如表37。
表37
Figure PCTCN2020130612-appb-000061

Claims (29)

  1. 式(I)化合物、其水合物、其溶剂合物、或者水与溶剂共合物的晶型
    Figure PCTCN2020130612-appb-100001
  2. 如权利要求1所述的式(I)化合物、其水合物、其溶剂合物、或者水与溶剂共合物的晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.20±0.20°、8.90±0.20°、16.30±0.20°和24.78±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.20±0.20°、8.90±0.20°、14.22±0.20°、16.30±0.20°、22.32±0.20°和24.78±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.20±0.20°、8.90±0.20°、11.26±0.20°、14.22±0.20°、16.30±0.20°、17.89±0.20°、22.32±0.20°和24.78±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.20±0.20°、8.90±0.20°、10.09±0.20°、11.26±0.20°、14.22±0.20°、16.30±0.20°、17.89±0.20°、20.35±0.20°、22.32±0.20°、24.78±0.20°和27.78±0.20°。
  3. 如权利要求1所述的式(I)化合物、其水合物、其溶剂合物、或者水与溶剂共合物的晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.13±0.20°、10.53±0.20°、21.17±0.20°和22.64±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.13±0.20°、10.53±0.20°、11.67±0.20°、20.09±0.20°、21.17±0.20°和22.64±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.13±0.20°、10.53±0.20°、11.67±0.20°、13.52±0.20°、20.09±0.20°、21.17±0.20°和22.64±0.20°。
  4. 如权利要求1所述的式(I)化合物、其水合物、其溶剂合物、或者水与溶剂共合物的晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.94±0.20°、9.83±0.20°和10.99±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.94±0.20°、9.83±0.20°、10.99±0.20°、18.62±0.20°和19.82±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.94±0.20°、9.83±0.20°、10.99±0.20°、13.36±0.20°、17.21±0.20°、18.62±0.20°、19.82±0.20°和21.56±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.94±0.20°、9.39±0.20°、9.83±0.20°、10.48±0.20°±0.20°、10.99±0.20°、13.36±0.20°、14.29±0.20°、17.21±0.20°、18.14±0.20°、18.62±0.20°、19.82±0.20°和21.56±0.20°。
  5. 如权利要求1所述的式(I)化合物、其水合物、其溶剂合物、或者水与溶剂共合物的晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.52±0.20°、11.21±0.20°、12.40±0.20°和 14.41±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.52±0.20°、8.70±0.20°、11.21±0.20°、12.40±0.20°、14.41±0.20°、17.49±0.20°和22.92±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.52±0.20°、8.70±0.20°、11.21±0.20°、12.40±0.20°、14.41±0.20°、16.06±0.20°、17.49±0.20°、20.98±0.20°、21.98±0.20°和22.92±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.17±0.20°、7.52±0.20°、7.99±0.20°、8.70±0.20°、9.99±0.20°、10.74±0.20°、11.21±0.20°、12.40±0.20°、14.41±0.20°、14.88±0.20°、16.06±0.20°、17.05±0.20°、17.49±0.20°、20.98±0.20°、21.98±0.20°、22.48±0.20°、22.92±0.20°、23.50±0.20°、26.47±0.20°、27.05±0.20°和28.04±0.20°。
  6. 如权利要求1所述的式(I)化合物、其水合物、其溶剂合物、或者水与溶剂共合物的晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.72±0.20°、8.53±0.20°、17.76±0.20°和20.38±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.72±0.20°、8.53±0.20°、10.50±0.20°、13.53±0.20°、17.76±0.20°、18.83±0.20°和20.38±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.72±0.20°、8.53±0.20°、10.50±0.20°、13.53±0.20°、17.76±0.20°、18.83±0.20°、20.38±0.20°、21.06±0.20°和24.00±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.72±0.20°、8.53±0.20°、10.50±0.20°、11.41±0.20°、13.53±0.20°、17.76±0.20°、18.83±0.20°、19.99±0.20°、20.38±0.20°、21.06±0.20°、22.23±0.20°、24.00±0.20°、24.42±0.20°和25.90±0.20°。
  7. 如权利要求1所述的式(I)化合物、其水合物、其溶剂合物、或者水与溶剂共合物的晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.18±0.20°、8.35±0.20°、10.58±0.20°和16.86±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.18±0.20°、8.35±0.20°、10.58±0.20°、11.87±0.20°、16.86±0.20°和21.16±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.18±0.20°、8.35±0.20°、10.58±0.20°、11.87±0.20°、12.32±0.20°、16.86±0.20°、21.16±0.20°、25.47±0.20°和29.17±0.20°。
  8. 如权利要求1所述的式(I)化合物、其水合物、其溶剂合物、或者水与溶剂共合物的晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.03±0.20°、8.31±0.20°、19.18±0.20°和25.99±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.03±0.20°、8.31±0.20°、15.86±0.20°、19.18±0.20°、21.05±0.20°和25.99±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.03±0.20°、8.31±0.20°、11.62±0.20°、12.91±0.20°、15.86±0.20°、19.18±0.20°、21.05±0.20°、24.67±0.20°和25.99±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.03±0.20°、8.31±0.20°、11.62±0.20°、12.91±0.20°、15.86±0.20°、17.17±0.20°、18.20±0.20°、19.18±0.20°、19.74±0.20°、21.05±0.20°、 21.30±0.20°、24.67±0.20°和25.99±0.20°。
  9. 如权利要求1所述的式(I)化合物、其水合物、其溶剂合物、或者水与溶剂共合物的晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.05±0.20°、9.10±0.20°、10.78±0.20°和22.90±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.05±0.20°、9.10±0.20°、10.78±0.20°、21.24±0.20°、21.74±0.20°和22.90±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.05±0.20°、9.10±0.20°、10.78±0.20°、13.07±0.20°、19.57±0.20°、21.24±0.20°、21.74±0.20°、22.24±0.20°和22.90±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.05±0.20°、9.10±0.20°、10.78±0.20°、11.34±0.20°、13.07±0.20°、14.07±0.20°、14.99±0.20°、15.86±0.20°、16.17±0.20°、18.60±0.20°、19.57±0.20°、21.24±0.20°、21.46±0.20°、21.74±0.20°、22.24±0.20°、22.72±0.20°和22.90±0.20°。
  10. 如权利要求1所述的式(I)化合物、其水合物、其溶剂合物、或者水与溶剂共合物的晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.56±0.20°、11.25±0.20°和14.09±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.56±0.20°、7.54±0.20°、11.25±0.20、14.09±0.20°和19.64±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.56±0.20°、7.54±0.20°、11.25±0.20°、14.09±0.20°、18.07±0.20°、19.64±0.20°和20.33±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.56±0.20°、7.54±0.20°、11.25±0.20°、14.09±0.20°、18.07±0.20°、19.64±0.20°、20.33±0.20°、21.65±0.20°、22.31±0.20°。
  11. 如权利要求1所述的式(I)化合物、其水合物、其溶剂合物、或者水与溶剂共合物的晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.28±0.20°、10.34±0.20°、22.66±0.20°和26.12±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.28±0.20°、10.34±0.20°、19.45±0.20°、20.93±0.20°、22.66±0.20°和26.12±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.28±0.20°、10.34±0.20°、12.35±0.20°、14.95±0.20°、17.88±0.20°、19.45±0.20°、20.93±0.20°、22.66±0.20°和26.12±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.47±0.20°、9.28±0.20°、10.34±0.20°、10.92±0.20°、12.35±0.20°、14.95±0.20°、、17.62±0.20°、17.88±0.20°、19.09±0.20°、19.45±0.20°、20.08±0.20°、20.93±0.20°、22.66±0.20°、23.98±0.20°、26.12±0.20°和28.63±0.20°。
  12. 如权利要求1所述的式(I)化合物、其水合物、其溶剂合物、或者水与溶剂共合物的晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.49±0.20°、8.46±0.20°、15.99±0.20°和17.02±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.49±0.20°、8.46±0.20°、13.18±0.20°、14.43±0.20°、15.99±0.20°和17.02±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.49±0.20°、8.46±0.20°、9.91±0.20°、 13.18±0.20°、14.43±0.20°、15.99±0.20°、17.02±0.20°、20.97±0.20°和24.20±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.49±0.20°、8.46±0.20°、9.12±0.20°、9.91±0.20°、10.67±0.20°、13.18±0.20°、14.43±0.20°、15.99±0.20°、17.02±0.20°、18.34±0.20°、19.95±0.20°、20.29±0.20°、20.97±0.20°、21.66±0.20°、23.03±0.20°、24.20±0.20°、24.94±0.20°和25.69±0.20°。
  13. 如权利要求1所述的式(I)化合物、其水合物、其溶剂合物、或者水与溶剂共合物的晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.53±0.20°、11.09±0.20°、22.34±0.20°和23.12±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.53±0.20°、11.09±0.20°、15.00±0.20°、20.76±0.20°、22.34±0.20°和23.12±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.03±0.20°、8.53±0.20°、11.09±0.20°、14.14±0.20°、15.00±0.20°、20.76±0.20°、22.34±0.20°、23.12±0.20°和26.85±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.03±0.20°、8.53±0.20°、10.50±0.20°、11.09±0.20°、14.14±0.20°、15.00±0.20°、20.76±0.20°、22.34±0.20°、23.12±0.20°和26.85±0.20°。
  14. 如权利要求1所述的式(I)化合物、其水合物、其溶剂合物、或者水与溶剂共合物的晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.32±0.20°、10.43±0.20°、12.46±0.20°和19.62±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.32±0.20°、10.43±0.20°、10.81±0.20°、12.46±0.20°、19.62±0.20°和21.03±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.32±0.20°、10.43±0.20°、10.81±0.20°、12.46±0.20°、17.55±0.20°、17.99±0.20°、19.62±0.20°、21.03±0.20°和22.90±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.32±0.20°、10.43±0.20°、10.81±0.20°、12.46±0.20°、13.00±0.20°、15.06±0.20°、17.55±0.20°、17.99±0.20°、19.62±0.20°、21.03±0.20°和22.90±0.20°。
  15. 如权利要求1所述的式(I)化合物、其水合物、其溶剂合物、或者水与溶剂共合物的晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.47°±0.20°、12.62±0.20°、15.70±0.20°和18.41±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.47±0.20°、11.23±0.20°、12.62±0.20°、15.70±0.20°、18.41±0.20°和21.49±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.04±0.20°、8.47±0.20°、10.01±0.20°、11.23±0.20°、12.62±0.20°、15.70±0.20°、18.41±0.20°、21.49±0.20°和22.53±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.04±0.20°、8.47±0.20°、10.01±0.20°、11.23±0.20°、12.62±0.20°、15.70±0.20°、17.32±0.20°、18.41±0.20°、20.31±0.20°、21.49±0.20°、22.53±0.20°和26.34±0.20°。
  16. 如权利要求1所述的式(I)化合物、其水合物、其溶剂合物、或者水与溶剂共合物的晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.50±0.20°、10.65±0.20°和11.10±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.18±0.20°、7.50±0.20°、10.65±0.20°、11.10±0.20°、14.04±0.20°和21.48±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.18±0.20°、7.50±0.20°、10.65±0.20°、11.10±0.20°、14.04±0.20°、21.48±0.20°、22.79±0.20°和27.02±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.18±0.20°、7.50±0.20°、10.65±0.20°、11.10±0.20°、14.04±0.20°、15.67±0.20°、19.16±0.20°、21.48±0.20°、22.79±0.20°、23.39±0.20°、26.28±0.20°和27.02±0.20°。
  17. 如权利要求1所述的式(I)化合物、其水合物、其溶剂合物、或者水与溶剂共合物的晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°和21.46±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°、21.28±0.20°和21.46±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°、20.38±0.20°、21.28±0.20°、21.46±0.20°、26.72±0.20°和27.48±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°、20.38±0.20°、21.46±0.20°、26.72±0.20°和27.48±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°、12.96±0.20°、18.66±0.20°、20.38±0.20°、21.46±0.20°、22.74±0.20°、26.72±0.20°、27.48±0.20°和27.82±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°、12.96±0.20°、18.66±0.20°、20.38±0.20°、21.28±0.20°、21.46±0.20°、22.74±0.20°、24.84±0.20°、26.72±0.20°、27.48±0.20°和27.82±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°、15.40±0.20°、21.28±0.20°、21.46±0.20°和22.74±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°、12.96±0.20°、15.40±0.20°、21.28±0.20°、21.46±0.20°、22.74±0.20°和27.48±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°、12.96±0.20°、15.40±0.20°、20.38±0.20°、21.28±0.20°、21.46±0.20°、22.74±0.20°、26.72±0.20°和27.48±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°、12.96±0.20°、15.40±0.20°、18.66±0.20°、20.38±0.20°、21.28±0.20°、21.46±0.20°、22.74±0.20°、26.72±0.20°、27.48±0.20°和27.82±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°、8.74±0.20°、12.96±0.20°、15.40±0.20°、15.92±0.20°、18.66±0.20°、20.38±0.20°、21.28±0.20°、21.46±0.20°、22.74±0.20°、26.72±0.20°和27.48±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°、8.74±0.20°、11.66±0.20°、12.96±0.20°、15.40±0.20°、15.92±0.20°、16.22±0.20°、18.66±0.20°、20.38±0.20°、21.28±0.20°、21.46±0.20°、22.74±0.20°、26.72±0.20°、27.48±0.20°和27.82±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.12±0.20°、8.74±0.20°、9.29±0.20°、11.66±0.20°、12.96±0.20°、15.40±0.20°、15.92±0.20°、16.22±0.20°、17.54±0.20°、18.66±0.20°、20.38±0.20°、21.28±0.20°、21.46±0.20°、22.74±0.20°、26.72±0.20°、27.48±0.20°和27.82±0.20°。
  18. 如权利要求1或17所述的式(I)化合物、其水合物、其溶剂合物、或者水与溶剂共合物的晶型，其特征在于：三斜晶系，空间群为P-1，晶胞参数为
    Figure PCTCN2020130612-appb-100002
    α＝66.982(8)°，β＝75.337(8)°，γ＝68.492(8)°，晶胞体积
    Figure PCTCN2020130612-appb-100003
    晶胞内不对称单位数Z＝2。
  19. 如权利要求1所述的式(I)化合物、其水合物、其溶剂合物、或者水与溶剂共合物的晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.03±0.20°、8.22±0.20°和14.10±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.03±0.20°、8.22±0.20°、10.34±0.20°、14.10±0.20°、14.66±0.20°和21.61±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.03±0.20°、8.22±0.20°、8.53±0.20°、10.34±0.20°、14.10±0.20°、14.66±0.20°、16.47±0.20°、17.07±0.20°、和21.61±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.03±0.20°、8.22±0.20°、8.53±0.20°、8.95±0.20°、10.34±0.20°、14.10±0.20°、14.66±0.20°、15.90±0.20°、16.47±0.20°、17.07±0.20°、19.45±0.20°、21.61±0.20°、22.89±0.20°和23.36±0.20°。
  20. 如权利要求1所述的式(I)化合物、其水合物、其溶剂合物、或者水与溶剂共合物的晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.60±0.20°、8.55±0.20°和15.21±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.60±0.20°、8.55±0.20°、11.67±0.20°、15.21±0.20°、17.60±0.20°、和24.56±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.60±0.20°、8.55±0.20°、11.67±0.20°、15.21±0.20°、17.12±0.20°、17.60±0.20°、23.25±0.20°、24.56±0.20°和27.31±0.20°。
  21. 如权利要求1所述的式(I)化合物、其水合物、其溶剂合物、或者水与溶剂共合物的晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.15±0.20°、8.43±0.20°、21.57±0.20°和23.90±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.15±0.20°、8.43±0.20°、14.94±0.20°、16.29±0.20°、16.84±0.20°、21.57±0.20°和23.90±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.15±0.20°、6.57±0.20°、8.43±0.20°、11.27±0.20°、14.94±0.20°、16.29±0.20°、16.84±0.20°、17.71±0.20°、21.57±0.20°和23.90±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.15±0.20°、6.57±0.20°、8.43±0.20°、8.83±0.20°、11.27±0.20°、13.97±0.20°、14.23±0.20°、14.94±0.20°、16.29±0.20°、16.84±0.20°、17.20±0.20°、17.71±0.20°、18.48±0.20°、19.19±0.20°、20.36±0.20°、20.74±0.20°、21.57±0.20°、22.61±0.20°、23.02±0.20°、23.90±0.20°、26.16±0.20°、26.67±0.20°和27.74±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.15±0.20°、6.57±0.20°、8.43±0.20°、8.83±0.20°、9.90±0.20°、11.27±0.20°、11.54±0.20°、13.13±0.20°、13.97±0.20°、14.23±0.20°、14.94±0.20°、16.29±0.20°、16.84±0.20°、17.20±0.20°、17.71±0.20°、18.48±0.20°、19.19±0.20°、20.36±0.20°、20.74±0.20°、 21.57±0.20°、22.20±0.20°、22.61±0.20°、23.02±0.20°、23.90±0.20°、24.92±0.20°、25.58±0.20°、26.16±0.20°、26.67±0.20°、27.74±0.20°、28.25±0.20°、和31.28±0.20°。
  22. 如权利要求1所述的式(I)化合物、其水合物、其溶剂合物、或者水与溶剂共合物的晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.23±0.20°、8.45±0.20°、16.18±0.20°和26.35±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.23±0.20°、8.45±0.20°、12.85±0.20°、16.18±0.20°、19.41±0.20°和26.35±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.23±0.20°、8.45±0.20°、12.85±0.20°、16.18±0.20°、18.46±0.20°、19.41±0.20°、19.97±0.20°、21.46±0.20°和26.35±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.23±0.20°、8.45±0.20°、9.72±0.20°、12.85±0.20°、14.41±0.20°、16.18±0.20°、18.46±0.20°、19.41±0.20°、19.97±0.20°、21.46±0.20°、24.95±0.20°和26.35±0.20°。
  23. 如权利要求1所述的式(I)化合物、其水合物、其溶剂合物、或者水与溶剂共合物的晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.50±0.20°、6.97±0.20°、9.51±0.20°和19.13±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.50±0.20°、6.97±0.20°、9.51±0.20°、11.55±0.20°、17.53±0.20°、19.13±0.20°和19.62±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.50±0.20°、6.97±0.20°、9.51±0.20°、10.29±0.20°、11.55±0.20°、14.00±0.20°、17.53±0.20°、19.13±0.20°、19.62±0.20°和21.09±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.50±0.20°、6.97±0.20°、9.51±0.20°、9.98±0.20°、10.29±0.20°、11.55±0.20°、14.00±0.20°、17.53±0.20°、19.13±0.20°、19.62±0.20°、20.71±0.20°、21.09±0.20°、21.41±0.20°、22.32±0.20°、24.35±0.20°、26.98±0.20°、35.53±0.20°。
  24. 如权利要求1所述的式(I)化合物、其水合物、其溶剂合物、或者水与溶剂共合物的晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.17±0.20°、9.44±0.20°、19.06±0.20°和19.56±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.17±0.20°、9.44±0.20°、10.22±0.20°、11.48±0.20°、19.06±0.20°、19.56±0.20°和21.35±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.90±0.20°、7.17±0.20°、8.99±0.20°、9.44±0.20°、9.91±0.20°、10.22±0.20°、11.48±0.20°、19.06±0.20°、19.56±0.20°和21.35±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.90±0.20°、7.17±0.20°、8.99±0.20°、9.44±0.20°、9.91±0.20°、10.22±0.20°、11.48±0.20°、14.50±0.20°、17.46±0.20°、19.06±0.20°、19.56±0.20°、21.01±0.20°、21.35±0.20°、21.85±0.20°、22.25±0.20°和24.27±0.20°；
    典型地，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.90±0.20°、7.17±0.20°、8.99±0.20°、9.44±0.20°、9.91±0.20°、10.22±0.20°、10.41±0.20°、10.57±0.20°、11.48±0.20°、13.93±0.20°、14.50±0.20°、17.46±0.20°、19.06±0.20°、19.56±0.20°、20.64±0.20°、21.01±0.20°、21.35±0.20°、 21.85±0.20°、22.25±0.20°、24.27±0.20°、26.88±0.20°和29.30±0.20°。
  25. 如权利要求1-24项任一项所述的晶型的晶型组合物，其中，所述晶型占晶型组合物重量的50％以上，较好为80％以上，更好是90％以上，最好是95％以上。
  26. 药物组合物，该药物组合物中包含治疗有效量的如权利要求1-24项任一项所述的晶型、或权利要求25所述的晶型组合物。
  27. 如权利要求1-24项任一项所述的晶型、如权利要求25所述的晶型组合物、或如权利要求26所述的药物组合物在制备抑制核蛋白的药物中的应用。
  28. 如权利要求27所述的应用，其特征在于，抑制核蛋白的药物是治疗或预防HBV感染相关疾病的药物。
  29. 如权利要求1-24项任一项所述的晶型、如权利要求25所述的晶型组合物、或如权利要求26所述的药物组合物在制备治疗或预防HBV感染相关疾病的药物中的应用。
PCT/CN2020/130612 2019-11-22 2020-11-20 一种核蛋白抑制剂的晶型及其应用 WO2021098850A1 (zh)

Priority Applications (6)

Application Number Priority Date Filing Date Title
CN202080078475.6A CN114728973A (zh) 2019-11-22 2020-11-20 一种核蛋白抑制剂的晶型及其应用
AU2020385518A AU2020385518A1 (en) 2019-11-22 2020-11-20 Crystal form of nucleoprotein inhibitor and use thereof
CA3159096A CA3159096A1 (en) 2019-11-22 2020-11-20 Crystal form of nucleoprotein inhibitor and use thereof
US17/779,035 US20230026869A1 (en) 2019-11-22 2020-11-20 Crystal form of nucleoprotein inhibitor and use thereof
EP20890696.6A EP4063366A4 (en) 2019-11-22 2020-11-20 CRYSTAL FORM OF NUCLEOPROTEIN INHIBITOR AND USE THEREOF
JP2022529375A JP2023502675A (ja) 2019-11-22 2020-11-20 核タンパク質阻害剤の結晶形及びその使用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201911171978.3 2019-11-22
CN201911171978 2019-11-22

Publications (1)

Publication Number Publication Date
WO2021098850A1 true WO2021098850A1 (zh) 2021-05-27

Family

ID=75980397

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/130612 WO2021098850A1 (zh) 2019-11-22 2020-11-20 一种核蛋白抑制剂的晶型及其应用

Country Status (7)

Country Link
US (1) US20230026869A1 (zh)
EP (1) EP4063366A4 (zh)
JP (1) JP2023502675A (zh)
CN (1) CN114728973A (zh)
AU (1) AU2020385518A1 (zh)
CA (1) CA3159096A1 (zh)
WO (1) WO2021098850A1 (zh)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11247965B2 (en) 2017-12-11 2022-02-15 VenatoRx Pharmaceuticals, Inc. Hepatitis B capsid assembly modulators
US11566001B2 (en) 2018-06-11 2023-01-31 VenatoRx Pharmaceuticals, Inc. Hepatitis B capsid assembly modulators

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008154817A1 (fr) 2007-06-18 2008-12-24 Zhang, Zhongneng Thiazolyl-dihydropyrimidines à substitution bromo-phényle
CN107778310A (zh) * 2016-08-31 2018-03-09 上海市第人民医院 乙肝病毒靶向人La蛋白的抑制剂HBSC11及其衍生物和用途
CN108347943A (zh) * 2015-09-15 2018-07-31 组装生物科学股份有限公司 乙肝核心蛋白调节剂
CN109069488A (zh) * 2016-03-07 2018-12-21 英安塔制药有限公司 乙型肝炎抗病毒剂
CN109790168A (zh) * 2016-08-26 2019-05-21 吉利德科学公司 取代的吡咯嗪化合物及其用途
WO2019165374A1 (en) * 2018-02-26 2019-08-29 Gilead Sciences, Inc. Substituted pyrrolizine compounds as hbv replication inhibitors
WO2019223791A1 (zh) * 2018-05-25 2019-11-28 正大天晴药业集团股份有限公司 2,3-二氢-1h-吡咯嗪-7-甲酰胺类衍生物及其应用

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008154817A1 (fr) 2007-06-18 2008-12-24 Zhang, Zhongneng Thiazolyl-dihydropyrimidines à substitution bromo-phényle
CN108347943A (zh) * 2015-09-15 2018-07-31 组装生物科学股份有限公司 乙肝核心蛋白调节剂
CN109069488A (zh) * 2016-03-07 2018-12-21 英安塔制药有限公司 乙型肝炎抗病毒剂
CN109790168A (zh) * 2016-08-26 2019-05-21 吉利德科学公司 取代的吡咯嗪化合物及其用途
CN107778310A (zh) * 2016-08-31 2018-03-09 上海市第人民医院 乙肝病毒靶向人La蛋白的抑制剂HBSC11及其衍生物和用途
WO2019165374A1 (en) * 2018-02-26 2019-08-29 Gilead Sciences, Inc. Substituted pyrrolizine compounds as hbv replication inhibitors
WO2019223791A1 (zh) * 2018-05-25 2019-11-28 正大天晴药业集团股份有限公司 2,3-二氢-1h-吡咯嗪-7-甲酰胺类衍生物及其应用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Measurement of Crystal Structure by Powder Diffraction Method", April 2003, TONGJI UNIVERSITY PRESS
See also references of EP4063366A4

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11247965B2 (en) 2017-12-11 2022-02-15 VenatoRx Pharmaceuticals, Inc. Hepatitis B capsid assembly modulators
US11566001B2 (en) 2018-06-11 2023-01-31 VenatoRx Pharmaceuticals, Inc. Hepatitis B capsid assembly modulators

Also Published As

Publication number Publication date
JP2023502675A (ja) 2023-01-25
CA3159096A1 (en) 2021-05-27
EP4063366A4 (en) 2023-12-20
AU2020385518A1 (en) 2022-06-09
CN114728973A (zh) 2022-07-08
EP4063366A1 (en) 2022-09-28
US20230026869A1 (en) 2023-01-26

Similar Documents

Publication Publication Date Title
US10662198B2 (en) Polymorphic form of compound, preparation method and use thereof
JP6008937B2 (ja) １−（３−シアノ−１−イソプロピル−インドール−５−イル）ピラゾール−４−カルボン酸の結晶形とその製造方法
CN109651359B (zh) 取代的烟酰胺类化合物及药物组合物及其用途
AU2015330554B2 (en) Crystal form of bisulfate of JAK inhibitor and preparation method therefor
WO2021098850A1 (zh) 一种核蛋白抑制剂的晶型及其应用
CN110577533A (zh) 苯甲酰氨基吡啶衍生物的盐及其在药物中的应用
CN110283131A (zh) 一种吉非替尼与香草酸共晶甲醇溶剂合物及其制备方法
EP4036078A1 (en) Crystalline form of capsid protein assembly inhibitor containing n hetero five-membered ring, and application thereof
JP2019526605A (ja) 置換２−ｈ−ピラゾール誘導体の結晶形、塩型及びその製造方法
WO2021143843A1 (zh) 一种pde3/pde4双重抑制剂的结晶及其应用
US20220332684A1 (en) Crystal form of five-membered n heterocyclic compound, and application thereof
WO2023193563A1 (zh) 一种噻吩并吡啶化合物的晶型a、制备方法及其药物组合物
JP2020512379A (ja) （ｓ）−［２−クロロ−４−フルオロ−５−（７−モルホリン−４−イルキナゾリン−４−イル）フェニル］−（６−メトキシ−ピリダジン−３−イル）メタノールの結晶性形態
WO2017157137A1 (zh) 一种新型的无环核苷类似物及其药物组合物
US8859567B2 (en) Hydrate of 1-{(2S)-2-amino-4-[2,4-bis(trifluoromethyl)-5,8-di-hydropyrido[3,4-D]pyrimidin-7(6H)-yl]-4-oxobutyl}-5,5-difluoro-piperidin-2-one tartrate
WO2017148290A1 (zh) 一种取代的腺嘌呤化合物及其药物组合物
JP2010516668A (ja) 抗ウイルス剤のマレイン酸モノ塩及びそれを含有する医薬組成物
TWI830884B (zh) 磷酸二酯酶抑制劑的晶型、其製備方法及其用途
ES2905926T3 (es) Derivados de ftalazinona, método para la preparación de los mismos, composición farmacéutica que los comprende y su uso
WO2019149090A1 (zh) 一种尿酸转运体1抑制剂的晶体及其制备方法和用途
KR20210049130A (ko) 세고리식 화합물의 결정 형태 및 이의 용도
TWI794895B (zh) 雙二氮雜雙環化合物或其鹽的結晶形式或無定形形式
TWI826013B (zh) 咪唑啉酮衍生物的晶型
WO2022206666A1 (zh) 吡咯酰胺化合物的晶型及其制备方法和用途
WO2022218239A1 (zh) 新型噻唑类化合物及其制备方法和用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20890696

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2022529375

Country of ref document: JP

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 3159096

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2020385518

Country of ref document: AU

Date of ref document: 20201120

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2020890696

Country of ref document: EP

Effective date: 20220622