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WO2025140636A1 - Crystal form of acid salt of sulfoximine compound, preparation method therefor, and use thereof - Google Patents

Crystal form of acid salt of sulfoximine compound, preparation method therefor, and use thereof Download PDF

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Publication number
WO2025140636A1
WO2025140636A1 PCT/CN2024/143407 CN2024143407W WO2025140636A1 WO 2025140636 A1 WO2025140636 A1 WO 2025140636A1 CN 2024143407 W CN2024143407 W CN 2024143407W WO 2025140636 A1 WO2025140636 A1 WO 2025140636A1
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another preferred
compound
formula
hydrochloride
salt form
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French (fr)
Chinese (zh)
Inventor
常少华
雷四军
陈晓飞
李学强
胡剑
丁克
马大为
任小梅
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Kinoteck Therapeutics Co Ltd
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Kinoteck Therapeutics Co Ltd
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

  • Fibroblast growth factor receptor is a receptor for fibroblast growth factor (FGF) signal transduction, and its family is composed of four members (FGFR1, FGFR2, FGFR3, FGFR4), which is a glycoprotein composed of an extracellular immunoglobulin (Ig)-like domain, a hydrophobic transmembrane region, and an intracellular part including a tyrosine kinase region.
  • FGF fibroblast growth factor
  • the purpose of the present invention is to develop a pharmaceutically acceptable salt form, a crystal form and a preparation method thereof of a sulfoximine FGFR inhibitor compound.
  • the TGA spectrum of the crystal form A of the compound of formula I-1 is shown in FIG3 .
  • the maleate crystalline form A of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2 ⁇ angles: 8.44 ⁇ 0.2°, 11.59 ⁇ 0.2°, 12.00 ⁇ 0.2°, 12.34 ⁇ 0.2°, 14.16 ⁇ 0.2°, 15.50 ⁇ 0.2°, 16.50 ⁇ 0.2°, 16.74 ⁇ 0.2°, 18.38 ⁇ 0.2°, 18.81 ⁇ 0.2°, 19.79 ⁇ 0.2°, 20.44 ⁇ 0.2°, 21.32 ⁇ 0.2°, 21.53 ⁇ 0.2°.
  • the maleate salt form A of the compound of formula I-1 has an XRPD pattern as shown in FIG4 .
  • the present invention also provides a method for preparing the A crystal form of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and maleic acid to acetonitrile and dichloromethane, and recrystallizing or slurrying to obtain the crystal form, wherein the ratio of the compound of formula I-1 to maleic acid is selected from: 0.8 to 1.2.
  • the monomaleate crystalline form B of the compound of formula I-1 has a DSC spectrum as shown in FIG6 .
  • the monomaleate crystalline form B of the compound of formula I-1 has a thermogravimetric analysis curve with two weight loss steps at 24.00°C ⁇ 2°C and 180.00°C ⁇ 2°C, and starts to decompose after 250.00°C ⁇ 2°C.
  • the monomaleate crystalline form B of the compound of formula I-1 has a TGA spectrum as shown in FIG7 .
  • the XRPD spectrum of the fumarate crystalline form A of the compound of formula I-1 is shown in FIG8 .
  • the present invention also provides a method for preparing the fumarate crystalline form A of the compound of formula I-1, comprising adding the compound of formula I-1 and fumaric acid to acetonitrile and dichloromethane, and recrystallizing or slurrying to obtain the compound, wherein the ratio of the compound of formula I-1 to fumaric acid is selected from: 0.8 to 1.2.
  • the present invention also provides a hemi-fumarate crystalline form B of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2 ⁇ angles: 5.12 ⁇ 0.2°, 10.20 ⁇ 0.2°, 10.53 ⁇ 0.2°, 14.24 ⁇ 0.2°, 16.99 ⁇ 0.2°, 18.81 ⁇ 0.2°, 19.45 ⁇ 0.2°, 20.22 ⁇ 0.2°, 20.43 ⁇ 0.2°, 20.84 ⁇ 0.2°, 27.04 ⁇ 0.2°, 27.904 ⁇ 0.2°, 28.254 ⁇ 0.2°, 28.754 ⁇ 0.2°.
  • the hemi-fumarate crystalline form B of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2 ⁇ angles: 5.12 ⁇ 0.2°, 7.27 ⁇ 0.2°, 7.48 ⁇ 0.2°, 8.77 ⁇ 0.2°, 9.18 ⁇ 0.2°, 9.74 ⁇ 0.2°, 10.20 ⁇ 0.2°, 10.53 ⁇ 0.2°, 14.24 ⁇ 0.2°, 14.96 ⁇ 0.2°, 16.09 ⁇ 0.2°, 16.99 ⁇ 0.2°, 17.61 ⁇ 0.2°, 17.95 ⁇ 0.2°, 18.81 ⁇ 0.2°, 19.45 ⁇ 0.2 °, 20.22 ⁇ 0.2°, 20.43 ⁇ 0.2°, 20.84 ⁇ 0.2°, 22.51 ⁇ 0.2°, 23.11 ⁇ 0.2°, 23.76 ⁇ 0.2°, 24.19 ⁇ 0.2°, 25.24 ⁇ 0.2°, 27.04 ⁇ 0.2°, 27.90 ⁇ 0.2°, 28.25 ⁇ 0.2°, 28.75 ⁇ 0.2°, 29.73 ⁇ 0.2°, 30.14 ⁇ 0.2°, 30.77 ⁇
  • the XRPD spectrum of the hemi-fumarate crystalline form B of the compound of formula I-1 is shown in FIG9 .
  • the DSC spectrum of the hemi-fumarate crystalline form B of the compound of formula I-1 is shown in FIG10 .
  • the hemi-fumarate form B of the compound of formula I-1 has a thermogravimetric analysis curve with three weight loss steps at three temperatures: 31.90°C ⁇ 2°C, 90.00°C ⁇ 2°C and 190.00°C ⁇ 2°C, and begins to decompose after 270.00°C ⁇ 2°C.
  • the present invention also provides a method for preparing the hemi-fumarate crystal form B of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and fumaric acid to tetrahydrofuran, and recrystallizing or slurrying to obtain the hemi-fumarate, wherein the ratio of the compound of formula I-1 to fumaric acid is selected from: 1.6 to 2.4.
  • the present invention also provides a monoethanolate crystalline form A of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2 ⁇ angles: 6.37 ⁇ 0.2°, 10.37 ⁇ 0.2°, 12.69 ⁇ 0.2°, 13.55 ⁇ 0.2°, 14.06 ⁇ 0.2°, 18.22 ⁇ 0.2°, 18.47 ⁇ 0.2°, 21.25 ⁇ 0.2°, 22.83 ⁇ 0.2°, 23.49 ⁇ 0.2°, 26.41 ⁇ 0.2°, 30.96 ⁇ 0.2°.
  • the monoglycolic acid salt form A of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2 ⁇ angles: 6.37 ⁇ 0.2°, 10.37 ⁇ 0.2°, 11.09 ⁇ 0.2°, 11.70 ⁇ 0.2°, 12.69 ⁇ 0.2°, 13.55 ⁇ 0.2°, 14.06 ⁇ 0.2°, 15.97 ⁇ 0.2°, 17.34 ⁇ 0.2°, 18.22 ⁇ 0.2°, 18.47 ⁇ 0.2°, 19.09 ⁇ 0.2°, 2 0.41 ⁇ 0.2°, 20.71 ⁇ 0.2°, 21.25 ⁇ 0.2°, 22.06 ⁇ 0.2°, 22.43 ⁇ 0.2°, 22.83 ⁇ 0.2°, 23.49 ⁇ 0.2°, 24.09 ⁇ 0.2°, 24.79 ⁇ 0.2°, 25.21 ⁇ 0.2°, 26.41 ⁇ 0.2°, 27.23 ⁇ 0.2°, 28.00 ⁇ 0.2°, 29.59 ⁇ 0.2°, 30.44 ⁇ 0.2°, 30.96 ⁇ 0.2°, 38.67 ⁇ 0.2°.
  • the XRPD spectrum of the monoglycolic acid salt form A of the compound of formula I-1 is shown in FIG12 .
  • the monoethanolate crystalline form A of the compound of formula I-1 has a differential scanning calorimetry curve having two starting points of endothermic peaks at 109.66°C ⁇ 2°C and 198.83°C ⁇ 2°C.
  • the DSC spectrum of the monoglycolic acid salt form A of the compound of formula I-1 is shown in FIG13 .
  • the monoethanolate crystalline form A of the compound of formula I-1 has a thermogravimetric analysis curve with three weight loss steps at 33.00°C ⁇ 2°C, 100.00°C ⁇ 2°C and 165.00°C ⁇ 2°C, and begins to decompose after 200.00°C ⁇ 2°C.
  • the TGA spectrum of the monoglycolic acid salt form A of the compound of formula I-1 is shown in Figure 14.
  • the present invention also provides a method for preparing the monoethanolate crystalline form A of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and glycolic acid to acetonitrile, and recrystallizing or slurrying to obtain the monoethanolate crystalline form A, wherein the ratio of the compound of formula I-1 to glycolic acid is selected from: 0.8 to 1.2.
  • the present invention also provides a method for preparing the hydrochloride crystal form C2 of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and hydrochloric acid to 2-methyltetrahydrofuran, and preparing the product by recrystallization or slurrying, wherein the ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2, the hydrochloride crystal form C2 of the compound of formula I-1 is a 2-methyltetrahydrofuran solvent and a hydrate crystal form, the 2-methyltetrahydrofuran content is 0.21 equivalents, and the water content is 2.8 equivalents.
  • the present invention also provides the hydrochloride form D of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2 ⁇ angles: 6.60 ⁇ 0.2°, 7.79 ⁇ 0.2°, 9.84 ⁇ 0.2°, 13.31 ⁇ 0.2°, 15.23 ⁇ 0.2°, 15.93 ⁇ 0.2°, 20.09 ⁇ 0.2°, 20.41 ⁇ 0.2°, 21.23 ⁇ 0.2°, 21.80 ⁇ 0.2°.
  • the hydrochloride crystal form D of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2 ⁇ angles: 6.60 ⁇ 0.2°, 7.26 ⁇ 0.2°, 7.79 ⁇ 0.2°, 8.48 ⁇ 0.2°, 9.84 ⁇ 0.2°, 11.18 ⁇ 0.2°, 13.31 ⁇ 0.2°, 13.89 ⁇ 0.2°, 14.64 ⁇ 0.2°, 14.9 8 ⁇ 0.2°, 15.23 ⁇ 0.2°, 15.93 ⁇ 0.2°, 16.27 ⁇ 0.2°, 17.04 ⁇ 0.2°, 18.21 ⁇ 0.2°, 19.33 ⁇ 0.2°, 20.09 ⁇ 0.2°, 20.41 ⁇ 0.2°, 21.23 ⁇ 0.2°, 21.80 ⁇ 0.2°, 23.49 ⁇ 0.2°, 24.79 ⁇ 0.2°, 28.43 ⁇ 0.2°.
  • the DSC spectrum of the hydrochloride form D of the compound of formula I-1 is shown in Figure 36.
  • the hydrochloride crystal form D of the compound of formula I-1 has two weight loss steps at 36.24°C ⁇ 2°C and 110.00°C ⁇ 2°C in its thermogravimetric analysis curve.
  • the TGA spectrum of the hydrochloride crystal form D of the compound of formula I-1 is shown in Figure 37.
  • the hydrochloride form E1 of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2 ⁇ angles: 6.15 ⁇ 0.2°, 7.66 ⁇ 0.2°, 7.90 ⁇ 0.2°, 8.41 ⁇ 0.2°, 9.49 ⁇ 0.2°, 9.91 ⁇ 0.2°, 10.88 ⁇ 0.2°, 11.42 ⁇ 0.2°, 13.06 ⁇ 0.2°, 13.66 ⁇ 0.2°, 14.06 ⁇ 0.2°, 14.69 ⁇ 0.2°, 15.32 ⁇ 0.2°, 15.52 ⁇ 0.2°, 15.88 ⁇ 0.2°, 16.25 ⁇ 0.2°, 16.81 ⁇ 0.2°, 17.35 ⁇ 0.2° , 18.37 ⁇ 0.2°, 19.01 ⁇ 0.2°, 19.75 ⁇ 0.2°, 20.19 ⁇ 0.2°, 21.15 ⁇ 0.2°, 21.51 ⁇ 0.2°, 21.81 ⁇ 0.2°, 22.50 ⁇ 0.2°, 22.87 ⁇ 0.2°, 23.56 ⁇ 0.2°, 24.95 ⁇ 0.2°, 25.18 ⁇ 0.2°, 25.63 ⁇ 0.2°, 26.71 ⁇ 0.2°,
  • the present invention also provides the hydrochloride form E2 of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2 ⁇ angles: 7.88 ⁇ 0.2°, 10.90 ⁇ 0.2°, 13.10 ⁇ 0.2°, 14.14 ⁇ 0.2°, 16.30 ⁇ 0.2°, 19.01 ⁇ 0.2°, 19.75 ⁇ 0.2°, 21.54 ⁇ 0.2°, 21.84 ⁇ 0.2°, 23.63 ⁇ 0.2°, 24.96 ⁇ 0.2°, 26.78 ⁇ 0.2°, 29.91 ⁇ 0.2°.
  • the hydrochloride crystal form E2 of the compound of formula I-1 above has an XRPD spectrum as shown in FIG. 41 .
  • the hydrochloride form E2 of the compound of formula I-1 has a differential scanning calorimetry curve with two starting points of endothermic peaks at 14.99°C ⁇ 2°C and 174.19°C ⁇ 2°C, and the sample begins to decompose at 213.17°C ⁇ 2°C.
  • the hydrochloride crystal form E2 of the compound of formula I-1 above has a DSC spectrum as shown in FIG42 .
  • the hydrochloride crystal form E2 of the compound of formula I-1 has three weight loss steps at 33.18°C ⁇ 2°C, 90.00°C ⁇ 2°C and 140.00°C ⁇ 2°C in its thermogravimetric analysis curve.
  • the hydrochloride crystal form E2 of the compound of formula I-1 above has a TGA spectrum as shown in FIG43 .
  • the present invention also provides a method for preparing the hydrochloride crystal form E2 of the above-mentioned compound of formula I-1, which is prepared by drying the hydrochloride crystal form F of the compound of formula I-1 at 25°C vacuum, 50°C vacuum or 100°C, wherein the ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2, and the hydrochloride crystal form E2 of the compound of formula I-1 is a hydrate crystal form with a water content of 1.8 equivalents.
  • the present invention also provides the hydrochloride form F of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2 ⁇ angles: 7.65 ⁇ 0.2°, 11.47 ⁇ 0.2°, 13.93 ⁇ 0.2°, 14.80 ⁇ 0.2°, 15.25 ⁇ 0.2°, 19.84 ⁇ 0.2°, 20.09 ⁇ 0.2°, 21.51 ⁇ 0.2°, 23.22 ⁇ 0.2°, 25.06 ⁇ 0.2°, 26.68 ⁇ 0.2°, 28.87 ⁇ 0.2°, 32.45 ⁇ 0.2°, 33.59 ⁇ 0.2°.
  • the hydrochloride form F of the compound of formula I-1 has an X-ray powder diffraction pattern with special diffraction peaks at the following 2 ⁇ angles: 6.85 ⁇ 0.2°, 7.65 ⁇ 0.2°, 10.21 ⁇ 0.2°, 10.70 ⁇ 0.2°, 11.47 ⁇ 0.2°, 13.93 ⁇ 0.2°, 14.80 ⁇ 0.2°, 15.25 ⁇ 0.2°, 16.60 ⁇ 0.2°, 16.88 ⁇ 0.2°, 17.84 ⁇ 0.2°, 19.00 ⁇ 0.2°, 19.
  • the hydrochloride form F of the compound of formula I-1 has a differential scanning calorimetry curve with two starting points of endothermic peaks at 36.03°C ⁇ 2°C and 172.45°C ⁇ 2°C, and the sample begins to decompose at 212.66°C ⁇ 2°C.
  • the present invention also provides a method for preparing the hydrochloride crystal form F of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and hydrochloric acid to ethanol, acetone, ethyl acetate, acetonitrile, tetrahydrofuran or a methyl isobutyl ketone/trifluoroethanol mixed solvent, and recrystallizing or slurrying at 50°C, wherein the ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2, and the hydrochloride crystal form F of the compound of formula I-1 is a hydrate crystal form, and the water content is 2.0 equivalents.
  • the DSC spectrum of the hydrochloride form G of the compound of formula I-1 is shown in Figure 48.
  • the XRPD spectrum of the hydrochloride form H of the compound of formula I-1 is shown in Figure 50.
  • the hydrochloride form H of the compound of formula I-1 has a differential scanning calorimetry curve with two starting points of endothermic peaks at 51.49°C ⁇ 2°C and 153.61°C ⁇ 2°C, and the sample begins to decompose at 211.73°C ⁇ 2°C.
  • the hydrochloride crystal form H of the compound of formula I-1 above has a DSC spectrum as shown in FIG51 .
  • the hydrochloride crystal form H of the compound of formula I-1 has three weight loss steps at 26.12°C ⁇ 2°C, 110.00°C ⁇ 2°C and 150.00°C ⁇ 2°C in its thermogravimetric analysis curve.
  • the present invention also provides a method for preparing the hydrochloride form H of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and hydrochloric acid to a methanol/water mixed solvent and suspending and recrystallizing or slurrying at 25% or 50% of the solvent, wherein the ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2, and the hydrochloride form H of the compound of formula I-1 is a hydrate form with a water content of 3.9 equivalents.
  • the hydrochloride form I of the compound of formula I-1 has an X-ray powder diffraction pattern with special diffraction peaks at the following 2 ⁇ angles: 6.68 ⁇ 0.2°, 9.50 ⁇ 0.2°, 12.31 ⁇ 0.2°, 12.54 ⁇ 0.2°, 13.34 ⁇ 0.2°, 14.05 ⁇ 0.2°, 14.96 ⁇ 0.2°, 15.38 ⁇ 0.2°, 17.18 ⁇ 0.2°, 17.92 ⁇ 0.2°, 19.03 ⁇ 0.2°, 19.74 ⁇ 0.2°, 19.99 ⁇ 0.2°, 20.96 ⁇ 0.2°, 21.
  • the hydrochloride crystal form I of the compound of formula I-1 has a differential scanning calorimetry curve having two starting points of endothermic peaks at 18.15°C ⁇ 2°C and 194.49°C ⁇ 2°C, and the sample begins to decompose at 215.51°C ⁇ 2°C.
  • the DSC spectrum of the hydrochloride form I of the compound of formula I-1 is shown in Figure 54.
  • the hydrochloride form I of the compound of formula I-1 has three weight loss steps at 28.31°C ⁇ 2°C, 70.00°C ⁇ 2°C and 173.00°C ⁇ 2°C in its thermogravimetric analysis curve.
  • the hydrochloride crystal form I of the compound of formula I-1 has a TGA spectrum as shown in Figure 55.
  • the present invention also provides a method for preparing the hydrochloride crystal form I of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and hydrochloric acid to methanol or a methanol/methyl tert-butyl ether mixed solvent, suspending and recrystallizing or slurrying at 25% tert-butyl, wherein the ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2, and the hydrochloride crystal form I of the compound of formula I-1 is an anhydrous crystalline form.
  • the present invention also provides the hydrochloride form J1 of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2 ⁇ angles: 6.80 ⁇ 0.2°, 11.69 ⁇ 0.2°, 14.87 ⁇ 0.2°, 15.98 ⁇ 0.2°, 18.05 ⁇ 0.2°, 19.49 ⁇ 0.2°, 20.41 ⁇ 0.2°, 21.55 ⁇ 0.2°, 21.70 ⁇ 0.2°, 22.06 ⁇ 0.2°, 23.69 ⁇ 0.2°, 24.92 ⁇ 0.2°, 25.13 ⁇ 0.2°, 29.07 ⁇ 0.2°, and 30.16 ⁇ 0.2°.
  • the hydrochloride form J1 of the compound of formula I-1 has a special diffraction peak at the following 2 ⁇ angles in its X-ray powder diffraction pattern: 6.80 ⁇ 0.2°, 7.82 ⁇ 0.2°, 7.95 ⁇ 0.2°, 10.08 ⁇ 0.2°, 11.69 ⁇ 0.2°, 12.30 ⁇ 0.2°, 12.60 ⁇ 0.2°, 13.60 ⁇ 0.2°, 14.87 ⁇ 0.2°, 15.98 ⁇ 0.2°, 16.25 ⁇ 0.2°, 18.05 ⁇ 0.2°, 18.60 ⁇ 0.2°.
  • the hydrochloride crystal form J1 of the compound of formula I-1 has an XRPD spectrum as shown in FIG56 .
  • the hydrochloride form J1 of the compound of formula I-1 has a differential scanning calorimetry curve with two starting points of endothermic peaks at 70.82°C ⁇ 2°C and 165.48°C ⁇ 2°C, and the sample begins to decompose at 212.96°C ⁇ 2°C.
  • the hydrochloride crystal form J1 of the compound of formula I-1 has two weight loss steps at 33.94°C ⁇ 2°C and 110.00°C ⁇ 2°C in its thermogravimetric analysis curve.
  • the hydrochloride crystal form J1 of the compound of formula I-1 has a TGA spectrum as shown in Figure 58.
  • the present invention also provides a method for preparing the hydrochloride crystal form J1 of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and hydrochloric acid to 2-methyltetrahydrofuran, suspending at 50°0 or heating and cooling to recrystallize or slurry to obtain the compound, wherein the ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2, and the hydrochloride crystal form J1 of the compound of formula I-1 is a solvate of 2-methyltetrahydrofuran and water, wherein the 2-methyltetrahydrofuran content is 0.75 equivalents and the water content is 0.98 equivalents.
  • the hydrochloride crystal form J2 of the above-mentioned compound of formula I-1 has an XRPD spectrum as shown in Figure 59.
  • the hydrochloride form J2 of the compound of formula I-1 has a differential scanning calorimetry curve with two starting points of endothermic peaks at 77.60°C ⁇ 2°C and 163.47°C ⁇ 2°C, and the sample begins to decompose at 211.78°C ⁇ 2°C.
  • the hydrochloride crystal form J2 of the compound of formula I-1 above has a DSC spectrum as shown in FIG60 .
  • the present invention also provides a method for preparing the hydrochloride crystal form L of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and hydrochloric acid to toluene, suspending or heating and cooling to recrystallize or slurry at 25°C or 50°C, wherein the ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2, and the hydrochloride crystal form L of the compound of formula I-1 is a solvate of toluene, and the toluene content is 0.46 equivalents.
  • the present invention also provides the hydrochloride form M of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2 ⁇ angles: 6.84 ⁇ 0.2°, 7.21 ⁇ 0.2°, 14.17 ⁇ 0.2°, 14.90 ⁇ 0.2°, 18.94 ⁇ 0.2°, 19.46 ⁇ 0.2°, 19.71 ⁇ 0.2°, 19.96 ⁇ 0.2°, 20.82 ⁇ 0.2°, 22.60 ⁇ 0.2°, 24.17 ⁇ 0.2°, 25.17 ⁇ 0.2°, 25.45 ⁇ 0.2°, 27.17 ⁇ 0.2°, 28.09 ⁇ 0.2°, 28.88 ⁇ 0.2°.
  • the hydrochloride form M of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2 ⁇ angles: 6.84 ⁇ 0.2°, 7.21 ⁇ 0.2°, 8.92 ⁇ 0.2°, 10.07 ⁇ 0.2°, 10.69 ⁇ 0.2°, 10.89 ⁇ 0.2°, 11.24 ⁇ 0.2°, 13.23 ⁇ 0.2°, 14.17 ⁇ 0.2°, 14.90 ⁇ 0.2°, 15.59 ⁇ 0.2°, 16.74 ⁇ 0.2°, 17.67 ⁇ 0.2°, 18.29 ⁇ 0.2°, 18.94 ⁇ 0.2°, 19.46 ⁇ 0.2 °, 19.71 ⁇ 0.2°, 19.96 ⁇ 0.2°, 20.82 ⁇ 0.2°, 21.49 ⁇ 0.2°, 21.83 ⁇ 0.2°, 22.60 ⁇ 0.2°, 23.14 ⁇ 0.2°, 23.54 ⁇ 0.2°, 24.17 ⁇ 0.2°, 25.17 ⁇ 0.2°, 25.45 ⁇ 0.2°, 26.10 ⁇ 0.2°, 27.17 ⁇ 0.2°, 27.61 ⁇ 0.2°, 28.09 ⁇ 0.2°, 28.88 ⁇ 0.2
  • the hydrochloride form M of the compound of formula I-1 has a differential scanning calorimetry curve with endothermic peak starting points at 31.74°C ⁇ 2°C and 150.05°C ⁇ 2°C, and the sample begins to decompose at 215.09°C ⁇ 2°C.
  • the hydrochloride form M of the compound of formula I-1 above has a DSC spectrum as shown in FIG69 .
  • the hydrochloride form M of the compound of formula I-1 has two weight loss steps at 32.98°C ⁇ 2°C and 115.00°C ⁇ 2°C in its thermogravimetric analysis curve.
  • the hydrochloride form M of the compound of formula I-1 has a TGA spectrum as shown in Figure 70.
  • the present invention also provides a method for preparing the hydrochloride crystal form M of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and hydrochloric acid to a mixed solvent of isopropanol/dimethyl sulfoxide, isopropyl acetate/dimethyl sulfoxide, and water/dimethyl sulfoxide, and suspending, recrystallizing, or slurrying at 25°C or 50°C, wherein the ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2, and the hydrochloride crystal form M of the compound of formula I-1 is a solvate of dimethyl sulfoxide and water, wherein the dimethyl sulfoxide content is 3.4 equivalents, and the water content is 13.7 equivalents.
  • the present invention also provides the hydrochloride form N of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2 ⁇ angles: 6.61 ⁇ 0.2°, 7.80 ⁇ 0.2°, 13.17 ⁇ 0.2°, 15.24 ⁇ 0.2°, 16.02 ⁇ 0.2°, 16.19 ⁇ 0.2°, 20.10 ⁇ 0.2°, 21.57 ⁇ 0.2°, 21.95 ⁇ 0.2°, 28.42 ⁇ 0.2°.
  • the hydrochloride form N of the compound of formula I-1 has an X-ray powder diffraction pattern with special diffraction peaks at the following 2 ⁇ angles: 6.61 ⁇ 0.2°, 7.80 ⁇ 0.2°, 9.75 ⁇ 0.2°, 11.19 ⁇ 0.2°, 12.53 ⁇ 0.2°, 13.17 ⁇ 0.2°, 14.61 ⁇ 0.2°, 15.24 ⁇ 0.2 °, 16.02 ⁇ 0.2°, 16.19 ⁇ 0.2°, 18.51 ⁇ 0.2°, 19.36 ⁇ 0.2°, 20.10 ⁇ 0.2°, 21.57 ⁇ 0.2°, 21.95 ⁇ 0.2°, 23.47 ⁇ 0.2°, 25.60 ⁇ 0.2°, 27.32 ⁇ 0.2°, 28.42 ⁇ 0.2°, 29.12 ⁇ 0.2°.
  • the XRPD spectrum of the hydrochloride form N of the compound of formula I-1 is shown in Figure 71.
  • the hydrochloride form N of the compound of formula I-1 has a differential scanning calorimetry curve with endothermic peak starting points at 47.38°C ⁇ 2°C and 167.91°C ⁇ 2°C, and the sample begins to decompose at 212.57°C ⁇ 2°C.
  • the DSC spectrum of the hydrochloride form N of the compound of formula I-1 is shown in Figure 72.
  • the hydrochloride form N of the compound of formula I-1 has a TGA spectrum as shown in Figure 73.
  • the hydrochloride crystal form O of the compound of formula I-1 above has a TGA spectrum as shown in Figure 76.
  • Another aspect of the present invention provides a method for preparing a crystalline form of a pharmaceutically acceptable salt of the compound of formula (I), characterized in that it comprises the following steps:
  • FIG4 is an XRPD spectrum of Compound I-1 maleate salt Form A.
  • FIG5 is an XRPD spectrum of Compound I-1 monomaleate salt Form B.
  • FIG6 is a DSC spectrum of Compound I-1 monomaleate crystal form B.
  • FIG. 7 is a TGA spectrum of Compound I-1 monomaleate salt Form B.
  • FIG8 is an XRPD spectrum of Compound I-1 fumarate salt Form A.
  • FIG9 is an XRPD spectrum of compound I-1 hemifumarate form B.
  • FIG10 is a DSC spectrum of compound I-1 hemifumarate form B.
  • FIG11 is a TGA spectrum of compound I-1 hemifumarate form B.
  • FIG12 is an XRPD spectrum of Compound I-1 monoglycolic acid salt Form A.
  • FIG13 is a DSC spectrum of Compound I-1 monoglycolic acid salt Form A.
  • FIG15 is an XRPD spectrum of Compound I-1 glycolate Form B.
  • FIG16 is an XRPD spectrum of Compound I-1 mono L-malate Form A.
  • FIG18 is a TGA spectrum of Compound I-1 mono L-malate Form A.
  • FIG19 is an XRPD spectrum of Compound I-1 monosuccinate Form A.
  • Figure 21 is the TGA spectrum of Compound I-1 monosuccinate form A.
  • FIG31 is a TGA spectrum of Compound I-1 hydrochloride salt form C1.
  • Figure 44 is the XRPD spectrum of Compound I-1 hydrochloride Form F.
  • Figure 60 is the DSC spectrum of Compound I-1 hydrochloride salt form J2.
  • Figure 62 is the XRPD spectrum of Compound I-1 hydrochloride Form K.
  • Figure 63 is the DSC spectrum of Compound I-1 hydrochloride form K.
  • Figure 64 is the TGA spectrum of Compound I-1 hydrochloride form K.
  • Figure 66 is the DSC spectrum of Compound I-1 hydrochloride form L.
  • Figure 67 is the TGA spectrum of Compound I-1 hydrochloride form L.
  • Figure 68 is the XRPD spectrum of Compound I-1 hydrochloride form M.
  • FIG69 is a DSC spectrum of Compound I-1 hydrochloride salt form M.
  • Figure 70 is the TGA spectrum of Compound I-1 hydrochloride form M.
  • Figure 71 is the XRPD spectrum of Compound I-1 hydrochloride form N.
  • Figure 72 is the DSC spectrum of Compound I-1 hydrochloride form N.
  • Figure 74 is the XRPD spectrum of Compound I-1 hydrochloride form O.
  • Figure 75 is the DSC spectrum of Compound I-1 hydrochloride form O.
  • the inventors have conducted in-depth research on the different forms of the compound of formula (I), and developed a variety of crystal forms and acid salt crystal forms of the compound of formula (I), especially the hydrochloride, which greatly improved the physical and chemical properties of the compound of formula (I), such as solubility, hygroscopicity and chemical stability.
  • the raw materials of the crystalline acid salt compound meet the requirements of industrial production, can meet the needs of clinical drug preparation development, have very important clinical application value, and are expected to accelerate the development of a new generation of FGFR2 inhibitors. On this basis, the present invention was completed.
  • n or more 2 ⁇ values selected from the following group refers to any positive integer greater than n (e.g., n, n+1, ...), including n and n, wherein the upper limit Nup is the number of all 2 ⁇ peaks in the group.
  • “1 or more” includes not only 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, ... each positive integer of the upper limit Nup, but also includes “2 or more", “3 or more”, “4 or more”, “5 or more”, “6 or more”, “7 or more”, “8 or more”, “9 or more", “10 or more”, etc.
  • "3 or more” not only includes 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, ... the upper limit Nup, each positive integer, but also includes “4 or more”, “5 or more”, “6 or more”, “7 or more”, “8 or more”, “9 or more", “10 or more” and other ranges.
  • solvent includes but is not limited to acetonitrile, alcohol solvents, ester solvents, ether solvents, or a mixed solvent of an alcohol solvent and water.
  • the intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the embodiments of the present invention.
  • test items and methods used in the present invention are as follows:
  • 10.2 Weigh about 20 mg of the compound of formula I-1 and 1.0 equivalent of succinic acid into a 2 mL glass bottle, add 0.15 mL of dichloromethane and perform a screening experiment by suspension method. The obtained sample is suspended at 50°C for 2 hours, then naturally cooled to 25°C, and suspended at 25°C for at least 48 hours. The obtained suspension is centrifuged at 14,000 rpm through a 0.45 ⁇ m nylon filter membrane, and the obtained solid is vacuum dried at 50°C for 2 hours to obtain a monosuccinate crystalline form A sample of the compound of formula I-1.
  • the compound of formula I-1 (16.5 g) was added to ethyl acetate (165) mL, cooled to about 0°C, and 1.0 equivalent of 4M hydrogen chloride dioxane solution was added dropwise. After addition, the mixture was returned to room temperature and stirred overnight. The mixture was filtered and dried to obtain a hydrochloride crystal form C1 sample of the compound of formula I-1 (18.3 g) as a white solid.
  • hydrochloride crystal form J1 sample of the compound of formula I-1 is heated to 110° C. to obtain a solid which is the hydrochloride crystal form J2 sample of the compound of formula I-1.
  • 29.1 Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of methyl tert-butyl ether, and suspend under magnetic stirring at 50° C. at a speed of 300-400 rpm. The resulting suspension is centrifuged and filtered at 14,000 rpm using a 0.45 ⁇ m nylon filter centrifuge tube to obtain a solid sample of the hydrochloride crystal form K of the compound of formula I-1.
  • 29.3 Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of toluene, and perform 10 heating and cooling cycles between 5°C and 50°C at a rate of 0.1°C/min, while suspending under magnetic stirring at a rate of 300-400 rpm, and the temperature during sampling is 10°C.
  • the resulting suspension is centrifuged and filtered at 14,000 rpm at 10°C using a 0.45 ⁇ m nylon filter centrifuge tube, and the resulting solid is the hydrochloride crystal form K sample of the compound of formula I-1.
  • 31.2 Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of isopropyl acetate/dimethyl sulfoxide (9/1, v/v), and suspend under magnetic stirring at 300-400 rpm at 25° C. The resulting suspension is centrifuged at 14,000 rpm using a 0.45 ⁇ m nylon filter centrifuge tube to obtain a solid sample of the hydrochloride crystal form M of the compound of formula I-1.

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Abstract

The present invention relates to a crystal form of a sulfoximine compound, a preparation method therefor, and a use thereof. Specifically, disclosed are a crystal form of a compound as shown in a formula (I), a preparation method therefor, and a use thereof. The crystal form has excellent stability, and can be widely applied to the preparation of drugs for preventing and/or treating diseases related to increased FGFR2 activity and expression level. The crystal form is preferably a hydrochloride crystal form I of the compound represented by formula I, and the X-ray powder diffraction pattern of the hydrochloride crystal form I has a 2θ angle selected from the following group: 6.68 +/-0.2 degrees, 13.34 +/-0.2 degrees, and 21.42 +/-0.2 degrees.

Description

一种亚砜亚胺类化合物的酸式盐的晶型及其制备方法和用途A crystalline form of an acid salt of a sulfoximine compound, and a preparation method and use thereof 技术领域Technical Field

本发明属于药物开发领域，具体涉及一种亚砜亚胺类化合物的酸式盐的晶型及其制备方法和用途。The invention belongs to the field of drug development, and specifically relates to a crystal form of an acid salt of a sulfoximine compound, a preparation method and use thereof.

背景技术Background Art

纤维母细胞生长因子受体(FGFR)是成纤维母细胞生长因子(FGF)信号传导的受体，其家族由四个成员(FGFR1、FGFR2、FGFR3、FGFR4)组成，为由细胞外免疫球蛋白(Ig)样结构域、疏水性跨膜区域和包括酪氨酸激酶区域的细胞内部分所组成的糖蛋白。FGF配体的结合引起受体二聚合和胞内域构形变化，从而引起激酶域和细胞内尾部发生分子间转磷酸化。磷酸化残基充当接附蛋白的对接位点，其促进下游信号级联，从而产生细胞行为，包括增殖、存活、分化、迁移和血管生成。FGFRs信号异常涉及多种癌症类型，包括肝癌、肝内胆管癌、膀胱癌、子宫内膜癌、乳腺癌和肺癌，并通过过表达、点突变和/或染色体易位发生疾病进展。Fibroblast growth factor receptor (FGFR) is a receptor for fibroblast growth factor (FGF) signal transduction, and its family is composed of four members (FGFR1, FGFR2, FGFR3, FGFR4), which is a glycoprotein composed of an extracellular immunoglobulin (Ig)-like domain, a hydrophobic transmembrane region, and an intracellular part including a tyrosine kinase region. The binding of FGF ligands causes receptor dimerization and intracellular domain conformational changes, thereby causing intermolecular transphosphorylation between the kinase domain and the intracellular tail. The phosphorylated residues serve as docking sites for attached proteins, which promote downstream signal cascades, thereby producing cell behaviors, including proliferation, survival, differentiation, migration, and angiogenesis. FGFRs signal abnormalities are involved in a variety of cancer types, including liver cancer, intrahepatic bile duct cancer, bladder cancer, endometrial cancer, breast cancer, and lung cancer, and disease progression occurs through overexpression, point mutations, and/or chromosomal translocations.

随着研究的不断深入，泛FGFR1-3抑制剂已对FGFR改变的多种癌症产生临床应答，但也表现出靶点限制性的毒性，导致不良副作用，如高磷酸盐血症和组织矿化，这源自磷酸盐的再吸收的调控是由FGFR1和FGFR3介导。一些研究概述了在14％的肝内胆管癌中出现FGFR2易位；FGFR2突变在12-14％的子宫内膜癌和5％的鳞状非小细胞肺癌中出现；FGFR2在12-14％的胃癌和4％的乳腺癌中扩增。FGFR2在促进人类表皮生长因子受体2(HER2)靶向治疗获得性耐药性中发挥作用，通过间接过度激活肿瘤相关成纤维细胞中的FGFR2。As research continues to deepen, pan-FGFR1-3 inhibitors have produced clinical responses to a variety of cancers with FGFR alterations, but they also show target-restricted toxicity, leading to adverse side effects such as hyperphosphatemia and tissue mineralization, which originates from the regulation of phosphate reabsorption mediated by FGFR1 and FGFR3. Some studies have outlined the presence of FGFR2 translocations in 14% of intrahepatic cholangiocarcinomas; FGFR2 mutations in 12-14% of endometrial cancers and 5% of squamous non-small cell lung cancers; FGFR2 amplification in 12-14% of gastric cancers and 4% of breast cancers. FGFR2 plays a role in promoting acquired resistance to human epidermal growth factor receptor 2 (HER2) targeted therapy by indirectly overactivating FGFR2 in tumor-associated fibroblasts.

因此，基于未满足的临床需求，开发FGFR2选择性抑制剂用于治疗具有极大的价值和前景。Therefore, based on unmet clinical needs, the development of FGFR2 selective inhibitors for treatment has great value and prospects.

发明内容Summary of the invention

本发明的目的是开发一种亚砜亚胺类FGFR抑制剂化合物的药用盐型、晶型及其制备方法。The purpose of the present invention is to develop a pharmaceutically acceptable salt form, a crystal form and a preparation method thereof of a sulfoximine FGFR inhibitor compound.

本发明的一个方面，提供了一种式(I)化合物，
One aspect of the present invention provides a compound of formula (I),

的无定形或晶体形态或其溶剂合物；an amorphous or crystalline form or a solvate thereof;

其中，m为1、2、3、4、5、6、7、8或9；wherein m is 1, 2, 3, 4, 5, 6, 7, 8 or 9;

n为0、0.5、1、1.5、2、2.5或3；且X选自下组：盐酸、氢溴酸、氢氟酸、硫酸、硝酸或磷酸，甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘磺酸、马尿酸、乙醇酸或戊二酸。n is 0, 0.5, 1, 1.5, 2, 2.5 or 3; and X is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid or phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, hippuric acid, glycolic acid or glutaric acid.

在另一优选例中，所述式I-1化合物的结构如下：
In another preferred embodiment, the structure of the compound of formula I-1 is as follows:

本发明提供了式I-1化合物的A晶型，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：11.59±0.2°，12.00±0.2°，14.16±0.2°，15.50±0.2°，16.74±0.2°，18.38±0.2°，18.81±0.2°，21.32±0.2°，21.80±0.2°，23.01±0.2°，24.37±0.2°，26.50±0.2°，28.90±0.2°。The present invention provides a crystalline form A of a compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 11.59±0.2°, 12.00±0.2°, 14.16±0.2°, 15.50±0.2°, 16.74±0.2°, 18.38±0.2°, 18.81±0.2°, 21.32±0.2°, 21.80±0.2°, 23.01±0.2°, 24.37±0.2°, 26.50±0.2°, 28.90±0.2°.

本发明的一些方案中，上述式I-1化合物的A晶型，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：8.44±0.2°，11.59±0.2°，12.00±0.2°，12.34±0.2°，14.16±0.2°，15.50±0.2°，16.50±0.2°，16.74±0.2°，18.38±0.2°，18.81±0.2°，19.79±0.2°，20.44±0.2°，21.32±0.2°，21.53±0.2°，21.80±0.2°，22.24±0.2°，23.01±0.2°，24.37±0.2°，25.43±0.2°，26.50±0.2°，27.13±0.2°，27.74±0.2°，28.90±0.2°，29.72±0.2°，29.93±0.2°，30.83±0.2°，31.56±0.2°，32.47±0.2°，33.64±0.2°，34.12±0.2°，35.03±0.2°，36.17±0.2°。In some embodiments of the present invention, the A crystal form of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 8.44±0.2°, 11.59±0.2°, 12.00±0.2°, 12.34±0.2°, 14.16±0.2°, 15.50±0.2°, 16.50±0.2°, 16.74±0.2°, 18.38±0.2°, 18.81±0.2°, 19.79±0.2°, 20.44±0.2°, 21.32±0.2°, 21.53±0.2° °, 21.80±0.2°, 22.24±0.2°, 23.01±0.2°, 24.37±0.2°, 25.43±0.2°, 26.50±0.2°, 27.13±0.2°, 27.74±0.2°, 28.90±0.2°, 29.72±0.2°, 29.93±0.2°, 30.83±0.2°, 31.56±0.2°, 32.47±0.2°, 33.64±0.2°, 34.12±0.2°, 35.03±0.2°, 36.17±0.2°.

本发明的一些方案中，上述式I-1化合物的A晶型，其XRPD图谱如图1所示。In some embodiments of the present invention, the XRPD pattern of Form A of the compound of Formula I-1 is shown in FIG1 .

表1：式I-1化合物的A晶型XRPD解析数据

Table 1: XRPD analysis data of Form A of the compound of formula I-1

本发明的一些方案中，上述式I-1化合物的A晶型，其差示扫描量热曲线在26.10℃±2℃和223.34℃±2℃两处具有吸热峰的起始点。In some embodiments of the present invention, the differential scanning calorimetry curve of the above-mentioned crystal form A of the compound of formula I-1 has two starting points of endothermic peaks at 26.10°C±2°C and 223.34°C±2°C.

本发明的一些方案中，上述式I-1化合物的A晶型，其DSC图谱如图2所示。In some embodiments of the present invention, the DSC spectrum of the crystal form A of the compound of formula I-1 is shown in FIG2 .

本发明的一些方案中，上述式I-1化合物的A晶型，其热重分析曲线在24.00℃±2℃，110.00℃±2℃和200.00℃±2℃三处，有三个较小的失重台阶，250.00℃±2℃之后开始分解。In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned crystal form A of the compound of formula I-1 has three smaller weight loss steps at 24.00℃±2℃, 110.00℃±2℃ and 200.00℃±2℃, and begins to decompose after 250.00℃±2℃.

本发明的一些方案中，上述式I-1化合物的A晶型，其TGA图谱如图3所示。In some embodiments of the present invention, the TGA spectrum of the crystal form A of the compound of formula I-1 is shown in FIG3 .

本发明还提供了上述式I-1化合物的A晶型的制备方法，包括将式I-1化合物加入到乙腈，醇类溶剂，酯类溶剂，醚类溶剂，醇类溶剂与水的混合溶剂中，重结晶或打浆制得，其中醇类溶剂选自甲醇，乙醇，异丙醇等，酯类溶剂选自乙酸乙酯，乙酸异丙酯，甲酸甲酸，甲酸乙酯，甲酸异丙酯等，醚类溶剂选自甲基叔丁基醚，四氢呋喃，乙二醇二甲醚等，所述醇类溶剂与水的混合溶剂选自甲醇与水的混合溶剂，乙醇与水的混合溶剂或异丙醇与水的混合溶剂，所述醇类溶剂与水的混合溶剂中，醇类溶剂和水的体积比选自：1：0.1～1.5。The present invention also provides a method for preparing the A crystal form of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 to acetonitrile, an alcohol solvent, an ester solvent, an ether solvent, or a mixed solvent of an alcohol solvent and water, and recrystallizing or beating to obtain the crystal form, wherein the alcohol solvent is selected from methanol, ethanol, isopropanol, etc., the ester solvent is selected from ethyl acetate, isopropyl acetate, formic acid, ethyl formate, isopropyl formate, etc., the ether solvent is selected from methyl tert-butyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, etc., the mixed solvent of the alcohol solvent and water is selected from a mixed solvent of methanol and water, a mixed solvent of ethanol and water, or a mixed solvent of isopropanol and water, and in the mixed solvent of the alcohol solvent and water, the volume ratio of the alcohol solvent to water is selected from: 1:0.1 to 1.5.

本发明还提供了上述式I-1化合物的马来酸盐晶型A，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：5.82±0.2°，9.86±0.2°，11.29±0.2°，12.72±0.2°，13.04±0.2°，15.17±0.2°，17.88±0.2°，18.11±0.2°，22.28±0.2°，23.02±0.2°，24.42±0.2°，25.34±0.2°，26.77±0.2°。The present invention also provides a maleate crystalline form A of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 5.82±0.2°, 9.86±0.2°, 11.29±0.2°, 12.72±0.2°, 13.04±0.2°, 15.17±0.2°, 17.88±0.2°, 18.11±0.2°, 22.28±0.2°, 23.02±0.2°, 24.42±0.2°, 25.34±0.2°, 26.77±0.2°.

本发明的一些方案中，上述式I-1化合物的马来酸盐晶型A，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：8.44±0.2°，11.59±0.2°，12.00±0.2°，12.34±0.2°，14.16±0.2°，15.50±0.2°，16.50±0.2°，16.74±0.2°，18.38±0.2°，18.81±0.2°，19.79±0.2°，20.44±0.2°，21.32±0.2°，21.53±0.2°，21.80±0.2°，22.24±0.2°，23.01±0.2°，24.37±0.2°，25.43±0.2°，26.50±0.2°，27.13±0.2°，27.74±0.2°，28.90±0.2°，29.72±0.2°，29.93±0.2°，30.83±0.2°，31.56±0.2°，32.47±0.2°，33.64±0.2°，34.12±0.2°，35.03±0.2°，36.17±0.2°。In some embodiments of the present invention, the maleate crystalline form A of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 8.44±0.2°, 11.59±0.2°, 12.00±0.2°, 12.34±0.2°, 14.16±0.2°, 15.50±0.2°, 16.50±0.2°, 16.74±0.2°, 18.38±0.2°, 18.81±0.2°, 19.79±0.2°, 20.44±0.2°, 21.32±0.2°, 21.53±0.2°. .2°, 21.80±0.2°, 22.24±0.2°, 23.01±0.2°, 24.37±0.2°, 25.43±0.2°, 26.50±0.2°, 27.13±0.2°, 27.74±0.2°, 28.90±0.2°, 29.72±0.2°, 29.93±0.2°, 30.83±0.2°, 31.56±0.2°, 32.47±0.2°, 33.64±0.2°, 34.12±0.2°, 35.03±0.2°, 36.17±0.2°.

本发明的一些方案中，上述式I-1化合物的马来酸盐晶型A，其XRPD图谱如图4所示。In some embodiments of the present invention, the maleate salt form A of the compound of formula I-1 has an XRPD pattern as shown in FIG4 .

表2式I-1化合物的马来酸盐晶型A的XRPD解析数据

Table 2 XRPD analysis data of maleate salt form A of compound of formula I-1

本发明还提供了上述式I-1化合物的A晶型的制备方法，包括将式I-1化合物和马来酸加入到乙腈，二氯甲烷中，重结晶或打浆制得，式I-1化合物与马来酸的比例选自：0.8～1.2。The present invention also provides a method for preparing the A crystal form of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and maleic acid to acetonitrile and dichloromethane, and recrystallizing or slurrying to obtain the crystal form, wherein the ratio of the compound of formula I-1 to maleic acid is selected from: 0.8 to 1.2.

本发明还提供了上述式I-1化合物的单马来酸盐晶型B，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：7.98±0.2°，8.29±0.2°，11.61±0.2°，13.21±0.2°，13.99±0.2°，15.25±0.2°，15.95±0.2°，16.57±0.2°，17.38±0.2°，18.06±0.2°，20.39±0.2°，21.25±0.2°，21.61±0.2°，22.17±0.2°，23.54±0.2°，24.70±0.2°，25.91±0.2°，27.24±0.2°，29.47±0.2°，29.71±0.2°，32.64±0.2°。The present invention also provides a monomaleate crystalline form B of the compound of formula I-1, whose X-ray powder diffraction spectrum has special diffraction peaks at the following 2θ angles: 7.98±0.2°, 8.29±0.2°, 11.61±0.2°, 13.21±0.2°, 13.99±0.2°, 15.25±0.2°, 15.95±0.2°, 16.57±0.2°, 17. 38±0.2°, 18.06±0.2°, 20.39±0.2°, 21.25±0.2°, 21.61±0.2°, 22.17±0.2°, 23.54±0.2°, 24.70±0.2°, 25.91±0.2°, 27.24±0.2°, 29.47±0.2°, 29.71±0.2°, 32.64±0.2°.

本发明的一些方案中，上述式I-1化合物的单马来酸盐晶型B，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：7.98±0.2°，8.29±0.2°，10.27±0.2°，11.61±0.2°，13.21±0.2°，13.99±0.2°，14.52±0.2°，15.25±0.2°，15.95±0.2°，16.57±0.2°，16.89±0.2°，17.38±0.2°，18.06±0.2°，20.39±0.2°，20.61±0.2°，21.25±0.2°，21.61±0.2°，22.17±0.2°，23.31±0.2°，23.54±0.2°，23.98±0.2°，24.70±0.2°，24.93±0.2°，25.32±0.2°，25.91±0.2°，26.55±0.2°，27.24±0.2°，28.23±0.2°，28.54±0.2°，29.00±0.2°，29.47±0.2°，29.71±0.2°，32.64±0.2°，35.12±0.2°。In some embodiments of the present invention, the monomaleate crystalline form B of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 7.98±0.2°, 8.29±0.2°, 10.27±0.2°, 11.61±0.2°, 13.21±0.2°, 13.99±0.2°, 14.52±0.2°, 15.25±0.2°, 15.95±0.2°, 16.57±0.2°, 16.89±0.2°, 17.38±0.2°, 18.06±0.2°, 20.39±0.2°, 20.61±0.2°. .2°, 21.25±0.2°, 21.61±0.2°, 22.17±0.2°, 23.31±0.2°, 23.54±0.2°, 23.98±0.2°, 24.70±0.2°, 24.93±0.2°, 25.32±0.2°, 25.91±0.2°, 26.55±0.2°, 27.24±0.2°, 28.23±0.2°, 28.54±0.2°, 29.00±0.2°, 29.47±0.2°, 29.71±0.2°, 32.64±0.2°, 35.12±0.2°.

本发明的一些方案中，上述式I-1化合物的单马来酸盐晶型B，其XRPD图谱如图5所示。In some embodiments of the present invention, the XRPD spectrum of the monomaleate crystalline form B of the compound of formula I-1 is shown in FIG5 .

表3式I-1化合物的单马来酸盐晶型B的XRPD解析数据

Table 3 XRPD analysis data of the monomaleate salt form B of the compound of formula I-1

本发明的一些方案中，上述式I-1化合物的单马来酸盐晶型B，其差示扫描量热曲线在213.92℃±2℃处具有吸热峰的起始点。In some embodiments of the present invention, the monomaleate crystalline form B of the compound of formula I-1 has a differential scanning calorimetry curve having an endothermic peak starting point at 213.92°C±2°C.

本发明的一些方案中，上述式I-1化合物的单马来酸盐晶型B，其DSC图谱如图6所示。In some embodiments of the present invention, the monomaleate crystalline form B of the compound of formula I-1 has a DSC spectrum as shown in FIG6 .

本发明的一些方案中，上述式I-1化合物的单马来酸盐晶型B，其热重分析曲线在24.00℃±2℃和180.00℃±2℃两处有两个失重台阶，250.00℃±2℃之后开始分解。In some embodiments of the present invention, the monomaleate crystalline form B of the compound of formula I-1 has a thermogravimetric analysis curve with two weight loss steps at 24.00°C±2°C and 180.00°C±2°C, and starts to decompose after 250.00°C±2°C.

本发明的一些方案中，上述式I-1化合物的单马来酸盐晶型B，其TGA图谱如图7所示。In some embodiments of the present invention, the monomaleate crystalline form B of the compound of formula I-1 has a TGA spectrum as shown in FIG7 .

本发明还提供了上述式I-1化合物的单马来酸盐晶型B的制备方法，包括将式I-1化合物和马来酸加入到四氢呋喃中，重结晶或打浆制得，式I-1化合物与马来酸的比例选自：0.8～1.2。The present invention also provides a method for preparing the monomaleate crystal form B of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and maleic acid to tetrahydrofuran, and recrystallizing or slurrying to obtain the monomaleate crystal form B, wherein the ratio of the compound of formula I-1 to maleic acid is selected from: 0.8 to 1.2.

本发明还提供了上述式I-1化合物的富马酸盐晶型A，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：5.11±0.2°，10.20±0.2°，14.23±0.2°，17.03±0.2°，18.79±0.2°，28.85±0.2°，29.46±0.2°。The present invention also provides a fumarate crystalline form A of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 5.11±0.2°, 10.20±0.2°, 14.23±0.2°, 17.03±0.2°, 18.79±0.2°, 28.85±0.2°, 29.46±0.2°.

本发明的一些方案中，上述式I-1化合物的富马酸盐晶型A，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：5.11±0.2°，7.26±0.2°，10.20±0.2°，10.51±0.2°，14.23±0.2°，14.47±0.2°，14.93±0.2°，16.17±0.2°，17.03±0.2°，17.90±0.2°，18.79±0.2°，19.44±0.2°，20.19±0.2°，20.80±0.2°，22.48±0.2°，23.07±0.2°，23.74±0.2°，24.07±0.2°，27.06±0.2°，27.85±0.2°，28.30±0.2°，28.85±0.2°，29.46±0.2°，38.24±0.2°。In some embodiments of the present invention, the fumarate salt form A of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 5.11±0.2°, 7.26±0.2°, 10.20±0.2°, 10.51±0.2°, 14.23±0.2°, 14.47±0.2°, 14.93±0.2°, 16.17±0.2°, 17.03±0.2°, 17.90±0.2°. .2°, 18.79±0.2°, 19.44±0.2°, 20.19±0.2°, 20.80±0.2°, 22.48±0.2°, 23.07±0.2°, 23.74±0.2°, 24.07±0.2°, 27.06±0.2°, 27.85±0.2°, 28.30±0.2°, 28.85±0.2°, 29.46±0.2°, 38.24±0.2°.

本发明的一些方案中，上述式I-1化合物的富马酸盐晶型A，其XRPD图谱如图8所示。In some embodiments of the present invention, the XRPD spectrum of the fumarate crystalline form A of the compound of formula I-1 is shown in FIG8 .

表4式I-1化合物的富马酸盐晶型A的XRPD解析数据

Table 4 XRPD analysis data of the fumarate salt form A of the compound of formula I-1

本发明还提供了上述式I-1化合物的富马酸盐晶型A的制备方法，包括将式I-1化合物和富马酸加入到乙腈，二氯甲烷中，重结晶或打浆制得，式I-1化合物与富马酸的比例选自：0.8～1.2。The present invention also provides a method for preparing the fumarate crystalline form A of the compound of formula I-1, comprising adding the compound of formula I-1 and fumaric acid to acetonitrile and dichloromethane, and recrystallizing or slurrying to obtain the compound, wherein the ratio of the compound of formula I-1 to fumaric acid is selected from: 0.8 to 1.2.

本发明还提供了上述式I-1化合物的半富马酸盐晶型B，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：5.12±0.2°，10.20±0.2°，10.53±0.2°，14.24±0.2°，16.99±0.2°，18.81±0.2°，19.45±0.2°，20.22±0.2°，20.43±0.2°，20.84±0.2°，27.04±0.2：°，27.904±0.2°，28.254±0.2°，28.754±0.2°。The present invention also provides a hemi-fumarate crystalline form B of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 5.12±0.2°, 10.20±0.2°, 10.53±0.2°, 14.24±0.2°, 16.99±0.2°, 18.81±0.2°, 19.45±0.2°, 20.22±0.2°, 20.43±0.2°, 20.84±0.2°, 27.04±0.2°, 27.904±0.2°, 28.254±0.2°, 28.754±0.2°.

本发明的一些方案中，上述式I-1化合物的半富马酸盐晶型B，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：5.12±0.2°，7.27±0.2°，7.48±0.2°，8.77±0.2°，9.18±0.2°，9.74±0.2°，10.20±0.2°，10.53±0.2°，14.24±0.2°，14.96±0.2°，16.09±0.2°，16.99±0.2°，17.61±0.2°，17.95±0.2°，18.81±0.2°，19.45±0.2°，20.22±0.2°，20.43±0.2°，20.84±0.2°，22.51±0.2°，23.11±0.2°，23.76±0.2°，24.19±0.2°，25.24±0.2°，27.04±0.2°，27.90±0.2°，28.25±0.2°，28.75±0.2°，29.73±0.2°，30.14±0.2°，30.77±0.2°，31.28±0.2°，33.95±0.2°，34.52±0.2°，37.07±0.2°，38.26±0.2°。In some embodiments of the present invention, the hemi-fumarate crystalline form B of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 5.12±0.2°, 7.27±0.2°, 7.48±0.2°, 8.77±0.2°, 9.18±0.2°, 9.74±0.2°, 10.20±0.2°, 10.53±0.2°, 14.24±0.2°, 14.96±0.2°, 16.09±0.2°, 16.99±0.2°, 17.61±0.2°, 17.95±0.2°, 18.81±0.2°, 19.45±0.2 °, 20.22±0.2°, 20.43±0.2°, 20.84±0.2°, 22.51±0.2°, 23.11±0.2°, 23.76±0.2°, 24.19±0.2°, 25.24±0.2°, 27.04±0.2°, 27.90±0.2°, 28.25±0.2°, 28.75±0.2°, 29.73±0.2°, 30.14±0.2°, 30.77±0.2°, 31.28±0.2°, 33.95±0.2°, 34.52±0.2°, 37.07±0.2°, 38.26±0.2°.

本发明的一些方案中，上述式I-1化合物的半富马酸盐晶型B，其XRPD图谱如图9所示。In some embodiments of the present invention, the XRPD spectrum of the hemi-fumarate crystalline form B of the compound of formula I-1 is shown in FIG9 .

表5式I-1化合物半富马酸盐晶型B的XRPD解析数据

Table 5 XRPD analysis data of hemifumarate crystal form B of the compound of formula I-1

本发明的一些方案中，上述式I-1化合物的半富马酸盐晶型B，其差示扫描量热曲线在21.34℃±2℃，172.21℃±2℃，234.34℃±2℃三处具有吸热峰的起始点。In some embodiments of the present invention, the hemi-fumarate crystalline form B of the compound of formula I-1 has a differential scanning calorimetry curve having endothermic peak starting points at 21.34°C±2°C, 172.21°C±2°C, and 234.34°C±2°C.

本发明的一些方案中，上述式I-1化合物的半富马酸盐晶型B，其DSC图谱如图10所示。In some embodiments of the present invention, the DSC spectrum of the hemi-fumarate crystalline form B of the compound of formula I-1 is shown in FIG10 .

本发明的一些方案中，上述式I-1化合物的半富马酸盐晶型B，其热重分析曲线在31.90℃±2℃，90.00℃±2℃和190.00℃±2℃三个温度处有三个失重台阶，270.00℃±2℃之后开始分解。In some embodiments of the present invention, the hemi-fumarate form B of the compound of formula I-1 has a thermogravimetric analysis curve with three weight loss steps at three temperatures: 31.90°C±2°C, 90.00°C±2°C and 190.00°C±2°C, and begins to decompose after 270.00°C±2°C.

本发明的一些方案中，上述式I-1化合物的半富马酸盐晶型B，其TGA图谱如图11所示。In some embodiments of the present invention, the hemi-fumarate crystalline form B of the compound of formula I-1 has a TGA spectrum as shown in FIG11 .

本发明还提供了上述式I-1化合物的半富马酸盐晶型B的制备方法，包括将式I-1化合物和富马酸加入到四氢呋喃中，重结晶或打浆制得，式I-1化合物与富马酸的比例选自：1.6～2.4。The present invention also provides a method for preparing the hemi-fumarate crystal form B of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and fumaric acid to tetrahydrofuran, and recrystallizing or slurrying to obtain the hemi-fumarate, wherein the ratio of the compound of formula I-1 to fumaric acid is selected from: 1.6 to 2.4.

本发明还提供了上述式I-1化合物的单乙醇酸盐晶型A，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：6.37±0.2°，10.37±0.2°，12.69±0.2°，13.55±0.2°，14.06±0.2°，18.22±0.2°，18.47±0.2°，21.25±0.2°，22.83±0.2°，23.49±0.2°，26.41±0.2°，30.96±0.2°。The present invention also provides a monoethanolate crystalline form A of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 6.37±0.2°, 10.37±0.2°, 12.69±0.2°, 13.55±0.2°, 14.06±0.2°, 18.22±0.2°, 18.47±0.2°, 21.25±0.2°, 22.83±0.2°, 23.49±0.2°, 26.41±0.2°, 30.96±0.2°.

本发明的一些方案中，上述式I-1化合物的单乙醇酸盐晶型A，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：6.37±0.2°，10.37±0.2°，11.09±0.2°，11.70±0.2°，12.69±0.2°，13.55±0.2°，14.06±0.2°，15.97±0.2°，17.34±0.2°，18.22±0.2°，18.47±0.2°，19.09±0.2°，20.41±0.2°，20.71±0.2°，21.25±0.2°，22.06±0.2°，22.43±0.2°，22.83±0.2°，23.49±0.2°，24.09±0.2°，24.79±0.2°，25.21±0.2°，26.41±0.2°，27.23±0.2°，28.00±0.2°，29.59±0.2°，30.44±0.2°，30.96±0.2°，38.67±0.2°。In some embodiments of the present invention, the monoglycolic acid salt form A of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 6.37±0.2°, 10.37±0.2°, 11.09±0.2°, 11.70±0.2°, 12.69±0.2°, 13.55±0.2°, 14.06±0.2°, 15.97±0.2°, 17.34±0.2°, 18.22±0.2°, 18.47±0.2°, 19.09±0.2°, 2 0.41±0.2°, 20.71±0.2°, 21.25±0.2°, 22.06±0.2°, 22.43±0.2°, 22.83±0.2°, 23.49±0.2°, 24.09±0.2°, 24.79±0.2°, 25.21±0.2°, 26.41±0.2°, 27.23±0.2°, 28.00±0.2°, 29.59±0.2°, 30.44±0.2°, 30.96±0.2°, 38.67±0.2°.

本发明的一些方案中，上述式I-1化合物的单乙醇酸盐晶型A，其XRPD图谱如图12所示。In some embodiments of the present invention, the XRPD spectrum of the monoglycolic acid salt form A of the compound of formula I-1 is shown in FIG12 .

表6式I-1化合物单乙醇酸盐晶型A的XRPD解析数据

Table 6 XRPD analysis data of monoglycolic acid salt of formula I-1 compound Form A

本发明的一些方案中，上述式I-1化合物的单乙醇酸盐晶型A，其差示扫描量热曲线在109.66℃±2℃，198.83℃±2℃两处具有吸热峰的起始点。In some embodiments of the present invention, the monoethanolate crystalline form A of the compound of formula I-1 has a differential scanning calorimetry curve having two starting points of endothermic peaks at 109.66°C±2°C and 198.83°C±2°C.

本发明的一些方案中，上述式I-1化合物的单乙醇酸盐晶型A，其DSC图谱如图13所示。In some embodiments of the present invention, the DSC spectrum of the monoglycolic acid salt form A of the compound of formula I-1 is shown in FIG13 .

本发明的一些方案中，上述式I-1化合物的单乙醇酸盐晶型A，其热重分析曲线在33.00℃±2℃，100.00℃±2℃和165.00℃±2℃三处有三个失重台阶，200.00℃±2℃之后开始分解。In some embodiments of the present invention, the monoethanolate crystalline form A of the compound of formula I-1 has a thermogravimetric analysis curve with three weight loss steps at 33.00℃±2℃, 100.00℃±2℃ and 165.00℃±2℃, and begins to decompose after 200.00℃±2℃.

本发明的一些方案中，上述式I-1化合物的单乙醇酸盐晶型A，其TGA图谱如图14所示。In some embodiments of the present invention, the TGA spectrum of the monoglycolic acid salt form A of the compound of formula I-1 is shown in Figure 14.

本发明还提供了上述式I-1化合物的单乙醇酸盐晶型A的制备方法，包括将式I-1化合物和乙醇酸加入到乙腈中，重结晶或打浆制得，式I-1化合物与乙醇酸的比例选自：0.8～1.2。The present invention also provides a method for preparing the monoethanolate crystalline form A of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and glycolic acid to acetonitrile, and recrystallizing or slurrying to obtain the monoethanolate crystalline form A, wherein the ratio of the compound of formula I-1 to glycolic acid is selected from: 0.8 to 1.2.

本发明还提供了上述式I-1化合物的乙醇酸盐晶型B，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：5.95±0.2°，12.20±0.2°，13.87±0.2°，15.79±0.2°，15.97±0.2°，16.44±0.2°，16.63±0.2°，16.79±0.2°，17.30±0.2°，19.49±0.2°，23.50±0.2°，26.68±0.2°。The present invention also provides a crystalline form B of the glycolate of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 5.95±0.2°, 12.20±0.2°, 13.87±0.2°, 15.79±0.2°, 15.97±0.2°, 16.44±0.2°, 16.63±0.2°, 16.79±0.2°, 17.30±0.2°, 19.49±0.2°, 23.50±0.2°, 26.68±0.2°.

本发明的一些方案中，上述式I-1化合物的乙醇酸盐晶型B，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：5.95±0.2°，11.06±0.2°，12.20±0.2°，13.87±0.2°，15.01±0.2°，15.79±0.2°，15.97±0.2°，16.44±0.2°，16.63±0.2°，16.79±0.2°，17.30±0.2°，17.90±0.2°，18.33±0.2°，18.91±0.2°，19.49±0.2°，21.59±0.2°，22.18±0.2°，22.80±0.2°，23.16±0.2°，23.50±0.2°，23.93±0.2°，24.49±0.2°，25.13±0.2°，26.68±0.2°，27.95±0.2°，30.49±0.2°，31.62±0.2°，32.27±0.2°。In some embodiments of the present invention, the glycolate crystalline form B of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 5.95±0.2°, 11.06±0.2°, 12.20±0.2°, 13.87±0.2°, 15.01±0.2°, 15.79±0.2°, 15.97±0.2°, 16.44±0.2°, 16.63±0.2°, 16.79±0.2°, 17.30±0.2°, 17.90±0.2°. .2°, 18.33±0.2°, 18.91±0.2°, 19.49±0.2°, 21.59±0.2°, 22.18±0.2°, 22.80±0.2°, 23.16±0.2°, 23.50±0.2°, 23.93±0.2°, 24.49±0.2°, 25.13±0.2°, 26.68±0.2°, 27.95±0.2°, 30.49±0.2°, 31.62±0.2°, 32.27±0.2°.

本发明的一些方案中，上述式I-1化合物的乙醇酸盐晶型B，其XRPD图谱如图15所示。In some embodiments of the present invention, the glycolate crystalline form B of the compound of formula I-1 has an XRPD pattern as shown in FIG15 .

表7式I-1化合物乙醇酸盐晶型B的XRPD解析数据
Table 7 XRPD analysis data of the glycolate crystal form B of the compound of formula I-1

本发明还提供了上述式I-1化合物的乙醇酸盐晶型B的制备方法，包括将式I-1化合物和乙醇酸加入到四氢呋喃，二氯甲烷中，重结晶或打浆制得，式I-1化合物与乙醇酸的比例选自：0.8～1.2。The present invention also provides a method for preparing the glycolate crystal form B of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and glycolic acid to tetrahydrofuran or dichloromethane, and recrystallizing or slurrying to obtain the glycolate, wherein the ratio of the compound of formula I-1 to glycolic acid is selected from: 0.8 to 1.2.

本发明还提供了上述式I-1化合物的单L-苹果酸盐晶型A，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：6.01±0.2°，15.15±0.2°，17.27±0.2°，17.99±0.2°，18.58±0.2°，22.58±0.2°，24.00±0.2°，24.50±0.2°，25.00±0.2°，29.40±0.2°，30.53±0.2°。The present invention also provides a mono L-malate crystalline form A of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 6.01±0.2°, 15.15±0.2°, 17.27±0.2°, 17.99±0.2°, 18.58±0.2°, 22.58±0.2°, 24.00±0.2°, 24.50±0.2°, 25.00±0.2°, 29.40±0.2°, 30.53±0.2°.

本发明的一些方案中，上述式I-1化合物的单L-苹果酸盐晶型A，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：6.01±0.2°，10.06±0.2°，11.04±0.2°，11.98±0.2°，12.66±0.2°，12.86±0.2°，13.39±0.2°，15.15±0.2°，15.62±0.2°，16.46±0.2°，17.27±0.2°，17.99±0.2°，18.58±0.2°，19.53±0.2°，19.77±0.2°，20.25±0.2°，21.01±0.2°，21.57±0.2°，22.04±0.2°，22.58±0.2°，23.67±0.2°，24.00±0.2°，24.50±0.2°，25.00±0.2°，27.34±0.2°，28.54±0.2°，28.91±0.2°，29.40±0.2°，29.89±0.2°，30.53±0.2°，31.33±0.2°，33.67±0.2°，36.16±0.2°。In some embodiments of the present invention, the mono L-malate crystalline form A of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 6.01±0.2°, 10.06±0.2°, 11.04±0.2°, 11.98±0.2°, 12.66±0.2°, 12.86±0.2°, 13.39±0.2°, 15.15±0.2°, 15.62±0.2°, 16.46±0.2°, 17.27±0.2°, 17.99±0.2°, 18.58±0.2°, 19.53±0.2°, 19.77±0.2°, 20.25±0.2°, 21.01±0.2°, 21.57±0.2°, 22.04±0.2°, 22.58±0.2°, 23.67±0.2°, 24.00±0.2°, 24.50±0.2°, 25.00±0.2°, 27.34±0.2°, 28.54±0.2°, 28.91±0.2°, 29.40±0.2°, 29.89±0.2°, 30.53±0.2°, 31.33±0.2°, 33.67±0.2°, 36.16±0.2°.

本发明的一些方案中，上述式I-1化合物的单L-苹果酸盐晶型A，其XRPD图谱如图16所示。In some embodiments of the present invention, the XRPD spectrum of the mono L-malate crystalline form A of the compound of formula I-1 is shown in FIG16 .

表8式I-1化合物单L-苹果酸盐晶型A的XRPD解析数据

Table 8 XRPD analysis data of the mono-L-malate crystal form A of the compound of formula I-1

本发明的一些方案中，上述式I-1化合物的单L-苹果酸盐晶型A，其差示扫描量热曲线在204.74℃±2℃处具有吸热峰的起始点。In some embodiments of the present invention, the mono L-malate crystalline form A of the compound of formula I-1 has a differential scanning calorimetry curve having an endothermic peak starting point at 204.74°C±2°C.

本发明的一些方案中，上述式I-1化合物的单L-苹果酸盐晶型A，其DSC图谱如图17所示。In some embodiments of the present invention, the DSC spectrum of the mono L-malate crystalline form A of the compound of formula I-1 is shown in FIG17 .

本发明的一些方案中，上述式I-1化合物的单L-苹果酸盐晶型A，其热重分析曲线在33.00℃±2℃和185.00℃±2℃两处有两个失重台阶，250.00℃±2℃之后开始分解。In some embodiments of the present invention, the mono L-malate crystalline form A of the compound of formula I-1 has a thermogravimetric analysis curve with two weight loss steps at 33.00℃±2℃ and 185.00℃±2℃, and starts to decompose after 250.00℃±2℃.

本发明的一些方案中，上述式I-1化合物的单L-苹果酸盐晶型A，其TGA图谱如图18所示。In some embodiments of the present invention, the TGA spectrum of the mono L-malate crystalline form A of the compound of formula I-1 is shown in FIG18 .

本发明还提供了上述式I-1化合物的单L-苹果酸盐晶型A的制备方法，包括将式I-1化合物和L-苹果酸加入到乙腈，四氢呋喃，二氯甲烷中，重结晶或打浆制得，式I-1化合物与L-苹果酸的比例选自：0.8～1.2。The present invention also provides a method for preparing the mono L-malate crystal form A of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and L-malic acid to acetonitrile, tetrahydrofuran, or dichloromethane, and recrystallizing or slurrying the mixture, wherein the ratio of the compound of formula I-1 to L-malic acid is selected from the range of 0.8 to 1.2.

本发明还提供了上述式I-1化合物的单琥珀酸盐晶型A，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：6.15±0.2°，12.26±0.2°，17.59±0.2°，18.40±0.2°，18.89±0.2°，19.11±0.2°，19.73±0.2°，20.90±0.2°，23.12±0.2°，23.83±0.2°，24.09±0.2°，24.35±0.2°，24.62±0.2°，24.93±0.2°，25.17±0.2°。The present invention also provides a monosuccinate crystalline form A of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 6.15±0.2°, 12.26±0.2°, 17.59±0.2°, 18.40±0.2°, 18.89±0.2°, 19.11±0.2°, 19.73±0.2°, 20.90±0.2°, 23.12±0.2°, 23.83±0.2°, 24.09±0.2°, 24.35±0.2°, 24.62±0.2°, 24.93±0.2°, 25.17±0.2°.

本发明的一些方案中，上述式I-1化合物的单琥珀酸盐晶型A，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：6.15±0.2°，9.64±0.2°，9.95±0.2°，11.19±0.2°，12.26±0.2°，12.70±0.2°，13.30±0.2°，14.95±0.2°，15.25±0.2°，16.18±0.2°，17.59±0.2°，18.40±0.2°，18.89±0.2°，19.11±0.2°，19.73±0.2°，20.28±0.2°，20.90±0.2°，21.27±0.2°，21.64±0.2°，22.12±0.2°，23.12±0.2°，23.83±0.2°，24.09±0.2°，24.35±0.2°，24.62±0.2°，24.93±0.2°，25.17±0.2°，26.05±0.2°，27.00±0.2°，28.27±0.2°，28.72±0.2°，30.12±0.2°，31.20±0.2°，33.57±0.2°，34.13±0.2°，34.58±0.2°，35.60±0.2°，38.23±0.2°。In some embodiments of the present invention, the monosuccinate crystalline form A of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 6.15±0.2°, 9.64±0.2°, 9.95±0.2°, 11.19±0.2°, 12.26±0.2°, 12.70±0.2°, 13.30±0.2°, 14.95±0.2°, 15.25±0.2°, 16.18±0.2°, 17.59±0.2°, 18.40±0.2°, 18.89±0.2°, 19.11±0.2°, 19.73±0.2°, 20.28±0.2°, 20.90±0.2°. .2°, 21.27±0.2°, 21.64±0.2°, 22.12±0.2°, 23.12±0.2°, 23.83±0.2°, 24.09±0.2°, 24.35±0.2°, 24.62±0.2°, 24.93±0.2°, 25.17±0.2°, 26.05±0.2°, 27.00±0.2°, 28.27±0.2°, 28.72±0.2°, 30.12±0.2°, 31.20±0.2°, 33.57±0.2°, 34.13±0.2°, 34.58±0.2°, 35.60±0.2°, 38.23±0.2°.

本发明的一些方案中，上述式I-1化合物的单琥珀酸盐晶型A，其XRPD图谱如图19所示。In some embodiments of the present invention, the XRPD spectrum of the monosuccinate crystalline form A of the compound of formula I-1 is shown in FIG19 .

表9式I-1化合物单琥珀酸盐晶型A的XRPD解析数据


Table 9 XRPD analysis data of the monosuccinate salt of the compound of formula I-1, Form A


本发明的一些方案中，上述式I-1化合物的单琥珀酸盐晶型A，其差示扫描量热曲线在72.75℃±2℃，146.41℃±2℃，175.72℃±2℃三处具有吸热峰的起始点。In some embodiments of the present invention, the monosuccinate crystalline form A of the compound of formula I-1 has a differential scanning calorimetry curve having endothermic peak starting points at 72.75°C±2°C, 146.41°C±2°C, and 175.72°C±2°C.

本发明的一些方案中，上述式I-1化合物的单琥珀酸盐晶型A，其DSC图谱如图20所示。In some embodiments of the present invention, the DSC spectrum of the monosuccinate crystalline form A of the compound of formula I-1 is shown in FIG20 .

本发明的一些方案中，上述式I-1化合物的单琥珀酸盐晶型A，其热重分析曲线在33.00℃±2℃，90.00℃±2℃和160.00℃±2℃三处有三个失重台阶，260.00℃±2℃之后开始分解。In some embodiments of the present invention, the monosuccinate crystalline form A of the compound of formula I-1 has a thermogravimetric analysis curve with three weight loss steps at 33.00℃±2℃, 90.00℃±2℃ and 160.00℃±2℃, and starts to decompose after 260.00℃±2℃.

本发明的一些方案中，上述式I-1化合物的单琥珀酸盐晶型A，其TGA图谱如图21所示。In some embodiments of the present invention, the TGA spectrum of the monosuccinate crystalline form A of the compound of formula I-1 is shown in Figure 21.

本发明还提供了上述式I-1化合物的单琥珀酸盐晶型A的制备方法，包括将式I-1化合物和琥珀酸加入到乙腈，四氢呋喃，二氯甲烷中，重结晶或打浆制得，式I-1化合物与琥珀酸的比例选自：0.8～1.2。The present invention also provides a method for preparing the monosuccinate crystalline form A of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and succinic acid to acetonitrile, tetrahydrofuran, or dichloromethane, and recrystallizing or slurrying the mixture, wherein the ratio of the compound of formula I-1 to succinic acid is selected from the range of 0.8 to 1.2.

本发明还提供了上述式I-1化合物的硫酸盐晶型A，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：6.74±0.2°，9.56±0.2°，12.89±0.2°，13.78±0.2°，14.97±0.2°，15.70±0.2°，18.68±0.2°，19.87±0.2°，20.21±0.2°，21.54±0.2°，21.76±0.2°，22.58±0.2°，23.75±0.2°，24.11±0.2°，24.50±0.2°，25.25±0.2°，25.86±0.2°，27.73±0.2°，28.41±0.2°，29.70±0.2°，30.21±0.2°，30.99±0.2°。The present invention also provides a sulfate crystalline form A of the compound of formula I-1, whose X-ray powder diffraction spectrum has special diffraction peaks at the following 2θ angles: 6.74±0.2°, 9.56±0.2°, 12.89±0.2°, 13.78±0.2°, 14.97±0.2°, 15.70±0.2°, 18.68±0.2°, 19.87±0.2°, 20.21±0.2 °, 21.54±0.2°, 21.76±0.2°, 22.58±0.2°, 23.75±0.2°, 24.11±0.2°, 24.50±0.2°, 25.25±0.2°, 25.86±0.2°, 27.73±0.2°, 28.41±0.2°, 29.70±0.2°, 30.21±0.2°, 30.99±0.2°.

本发明的一些方案中，上述式I-1化合物的硫酸盐晶型A，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：6.74±0.2°，9.56±0.2°，12.89±0.2°，13.78±0.2°，14.68±0.2°，14.97±0.2°，15.49±0.2°，15.70±0.2°，16.41±0.2°，16.90±0.2°，18.47±0.2°，18.68±0.2°，18.86±0.2°，19.33±0.2°，19.87±0.2°，20.21±0.2°，20.70±0.2°，21.54±0.2°，21.76±0.2°，22.25±0.2°，22.58±0.2°，23.75±0.2°，24.11±0.2°，24.50±0.2°，25.25±0.2°，25.86±0.2°，26.10±0.2°，26.71±0.2°，26.96±0.2°，27.73±0.2°，28.41±0.2°，28.90±0.2°，29.70±0.2°，30.21±0.2°，30.99±0.2°。In some embodiments of the present invention, the sulfate crystalline form A of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 6.74±0.2°, 9.56±0.2°, 12.89±0.2°, 13.78±0.2°, 14.68±0.2°, 14.97±0.2°, 15.49±0.2°, 15.70±0.2°, 16.41±0.2°, 16.90±0.2°, 18.47±0.2°, 18.68±0.2°, 18.86±0.2°, 19.33±0.2°, 19.87±0.2°, 20 .21±0.2°, 20.70±0.2°, 21.54±0.2°, 21.76±0.2°, 22.25±0.2°, 22.58±0.2°, 23.75±0.2°, 24.11±0.2°, 24.50±0.2°, 25.25±0.2°, 25.86±0.2°, 26.10±0.2°, 26.71±0.2°, 26.96±0.2°, 27.73±0.2°, 28.41±0.2°, 28.90±0.2°, 29.70±0.2°, 30.21±0.2°, 30.99±0.2°.

本发明的一些方案中，上述式I-1化合物的硫酸盐晶型A，其XRPD图谱如图22所示。In some embodiments of the present invention, the XRPD spectrum of the sulfate crystalline form A of the compound of formula I-1 is shown in FIG. 22 .

表10式I-1化合物硫酸盐晶型A的XRPD解析数据

Table 10 XRPD analysis data of sulfate crystal form A of the compound of formula I-1

本发明还提供了上述式I-1化合物硫酸盐晶型A的制备方法，包括将式I-1化合物和硫酸加入到乙腈中，重结晶或打浆制得，式I-1化合物与硫酸的比例选自：0.8～1.2。The present invention also provides a method for preparing the sulfate crystal form A of the compound of formula I-1, comprising adding the compound of formula I-1 and sulfuric acid to acetonitrile, and recrystallizing or slurrying to obtain the sulfate crystal form A, wherein the ratio of the compound of formula I-1 to sulfuric acid is selected from: 0.8 to 1.2.

本发明还提供了上述式I-1化合物的L-酒石酸盐晶型A，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：5.53±0.2°，8.90±0.2°，9.35±0.2°，11.05±0.2°，12.54±0.2°，12.90±0.2°，14.35±0.2°，14.64±0.2°，16.95±0.2°，18.70±0.2°，19.45±0.2°，19.74±0.2°，20.38±0.2°，20.79±0.2°，21.45±0.2°，21.94±0.2°，22.88±0.2°，23.80±0.2°，25.01±0.2°，25.77±0.2°，27.33±0.2°，27.80±0.2°，28.65±0.2°，29.41±0.2°，30.00±0.2°，31.09±0.2°。The present invention also provides L-tartrate crystalline form A of the compound of formula I-1, whose X-ray powder diffraction spectrum has special diffraction peaks at the following 2θ angles: 5.53±0.2°, 8.90±0.2°, 9.35±0.2°, 11.05±0.2°, 12.54±0.2°, 12.90±0.2°, 14.35±0.2°, 14.64±0.2°, 16.95±0.2°, 18.70±0.2°, 19.45±0. 2°, 19.74±0.2°, 20.38±0.2°, 20.79±0.2°, 21.45±0.2°, 21.94±0.2°, 22.88±0.2°, 23.80±0.2°, 25.01±0.2°, 25.77±0.2°, 27.33±0.2°, 27.80±0.2°, 28.65±0.2°, 29.41±0.2°, 30.00±0.2°, 31.09±0.2°.

本发明的一些方案中，上述式I-1化合物的L-酒石酸盐晶型A，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：5.53±0.2°，8.90±0.2°，9.35±0.2°，11.05±0.2°，12.54±0.2°，12.90±0.2°，14.35±0.2°，14.64±0.2°，16.95±0.2°，18.70±0.2°，19.45±0.2°，19.74±0.2°，20.38±0.2°，20.79±0.2°，21.45±0.2°，21.94±0.2°，22.88±0.2°，23.80±0.2°，25.01±0.2°，25.77±0.2°，27.33±0.2°，27.80±0.2°，28.65±0.2°，29.41±0.2°，30.00±0.2°，31.09±0.2°。In some embodiments of the present invention, the L-tartrate salt form A of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 5.53±0.2°, 8.90±0.2°, 9.35±0.2°, 11.05±0.2°, 12.54±0.2°, 12.90±0.2°, 14.35±0.2°, 14.64±0.2°, 16.95±0.2°, 18.70±0.2°, 19.45±0.2°. .2°, 19.74±0.2°, 20.38±0.2°, 20.79±0.2°, 21.45±0.2°, 21.94±0.2°, 22.88±0.2°, 23.80±0.2°, 25.01±0.2°, 25.77±0.2°, 27.33±0.2°, 27.80±0.2°, 28.65±0.2°, 29.41±0.2°, 30.00±0.2°, 31.09±0.2°.

本发明的一些方案中，上述式I-1化合物的L-酒石酸盐晶型A，其XRPD图谱如图23所示。In some embodiments of the present invention, the XRPD spectrum of the L-tartrate salt form A of the compound of formula I-1 is shown in FIG23 .

表11式I-1化合物的L-酒石酸盐晶型A的XRPD解析数据
Table 11 XRPD analysis data of L-tartrate salt form A of the compound of formula I-1

本发明还提供了上述式I-1化合物的L-酒石酸盐晶型A的制备方法，包括将式I-1化合物和L-酒石酸加入到乙腈中，重结晶或打浆制得，式I-1化合物与L-酒石酸的比例选自：0.8～1.2。The present invention also provides a method for preparing the L-tartrate salt form A of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and L-tartaric acid to acetonitrile, and recrystallizing or slurrying to obtain the L-tartrate salt form A, wherein the ratio of the compound of formula I-1 to L-tartaric acid is selected from: 0.8 to 1.2.

本发明还提供了上述式I-1化合物马尿酸盐晶型A，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：6.17±0.2°，6.52±0.2°，12.30±0.2°，14.18±0.2°，15.62±0.2°，16.06±0.2°，16.78±0.2°，17.64±0.2°，18.78±0.2°，20.42±0.2°，21.15±0.2°，21.29±0.2°，21.79±0.2°，24.42±0.2°，26.45±0.2°。The present invention also provides the hippurate crystalline form A of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 6.17±0.2°, 6.52±0.2°, 12.30±0.2°, 14.18±0.2°, 15.62±0.2°, 16.06±0.2°, 16.78±0.2°, 17.64±0.2°, 18.78±0.2°, 20.42±0.2°, 21.15±0.2°, 21.29±0.2°, 21.79±0.2°, 24.42±0.2°, 26.45±0.2°.

本发明的一些方案中，上述式I-1化合物马尿酸盐晶型A，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：6.17±0.2°，6.52±0.2°，8.77±0.2°，10.74±0.2°，11.16±0.2°，12.30±0.2°，14.18±0.2°，14.70±0.2°，15.62±0.2°，16.06±0.2°，16.78±0.2°，17.64±0.2°，18.78±0.2°，20.42±0.2°，21.15±0.2°，21.29±0.2°，21.79±0.2°，23.03±0.2°，24.05±0.2°，24.42±0.2°，25.32±0.2°，26.45±0.2°，26.87±0.2°，28.85±0.2°。In some embodiments of the present invention, the hippurate crystalline form A of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 6.17±0.2°, 6.52±0.2°, 8.77±0.2°, 10.74±0.2°, 11.16±0.2°, 12.30±0.2°, 14.18±0.2°, 14.70±0.2°, 15.62±0.2°, 16.06±0. 2°, 16.78±0.2°, 17.64±0.2°, 18.78±0.2°, 20.42±0.2°, 21.15±0.2°, 21.29±0.2°, 21.79±0.2°, 23.03±0.2°, 24.05±0.2°, 24.42±0.2°, 25.32±0.2°, 26.45±0.2°, 26.87±0.2°, 28.85±0.2°.

本发明的一些方案中，上述式I-1化合物马尿酸盐晶型A，其XRPD图谱如图24所示。In some embodiments of the present invention, the hippurate salt form A of the compound of formula I-1 has an XRPD spectrum as shown in FIG24 .

表12式I-1化合物马尿酸盐晶型A的XRPD解析数据
Table 12 XRPD analysis data of hippurate salt form A of compound of formula I-1

本发明还提供了上述式I-1化合物马尿酸盐晶型A的制备方法，包括将式I-1化合物和马尿酸加入到四氢呋喃中，重结晶或打浆制得，式I-1化合物与马尿酸的比例选自：0.8～1.2。The present invention also provides a method for preparing the hippurate crystalline form A of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and hippuric acid to tetrahydrofuran, and recrystallizing or slurrying to obtain the compound, wherein the ratio of the compound of formula I-1 to hippuric acid is selected from: 0.8 to 1.2.

本发明还提供了上述式I-1化合物戊二酸盐晶型A，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：11.82±0.2°，12.75±0.2°，13.19±0.2°，14.87±0.2°，15.10±0.2°，17.10±0.2°，17.82±0.2°，18.35±0.2°，19.75±0.2°，20.14±0.2°，20.70±0.2°，22.23±0.2°，23.20±0.2°，24.26±0.2°，24.47±0.2°，29.92±0.2°。The present invention also provides the above-mentioned glutaric acid salt form A of the compound of formula I-1, whose X-ray powder diffraction spectrum has special diffraction peaks at the following 2θ angles: 11.82±0.2°, 12.75±0.2°, 13.19±0.2°, 14.87±0.2°, 15.10±0.2°, 17.10±0.2°, 17.82±0.2°, 18.35±0.2°, 19.75±0.2°, 20.14±0.2°, 20.70±0.2°, 22.23±0.2°, 23.20±0.2°, 24.26±0.2°, 24.47±0.2°, 29.92±0.2°.

本发明的一些方案中，上述式I-1化合物戊二酸盐晶型A，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：9.86±0.2°，10.97±0.2°，11.82±0.2°，12.29±0.2°，12.75±0.2°，13.19±0.2°，14.87±0.2°，15.10±0.2°，15.37±0.2°，16.33±0.2°，17.10±0.2°，17.82±0.2°，18.35±0.2°，19.17±0.2°，19.75±0.2°，20.14±0.2°，20.70±0.2°，21.14±0.2°，22.23±0.2°，23.20±0.2°，24.26±0.2°，24.47±0.2°，24.86±0.2°，25.28±0.2°，29.92±0.2°。In some embodiments of the present invention, the glutaric acid salt form A of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 9.86±0.2°, 10.97±0.2°, 11.82±0.2°, 12.29±0.2°, 12.75±0.2°, 13.19±0.2°, 14.87±0.2°, 15.10±0.2°, 15.37±0.2°, 16.33±0.2°, 17 .10±0.2°, 17.82±0.2°, 18.35±0.2°, 19.17±0.2°, 19.75±0.2°, 20.14±0.2°, 20.70±0.2°, 21.14±0.2°, 22.23±0.2°, 23.20±0.2°, 24.26±0.2°, 24.47±0.2°, 24.86±0.2°, 25.28±0.2°, 29.92±0.2°.

本发明的一些方案中，上述式I-1化合物戊二酸盐晶型A，其XRPD图谱如图25所示。In some embodiments of the present invention, the XRPD spectrum of the glutaric acid salt form A of the compound of formula I-1 is shown in Figure 25.

表13式I-1化合物戊二酸盐晶型A的XRPD解析数据

Table 13 XRPD analysis data of glutaric acid salt form A of compound of formula I-1

本发明还提供了上述式I-1化合物戊二酸盐晶型A的制备方法，包括将式I-1化合物和戊二酸加入到乙腈，二氯甲烷中，重结晶或打浆制得，式I-1化合物与戊二酸的比例选自：0.8～1.2。The present invention also provides a method for preparing the above-mentioned glutaric acid salt form A of the compound of formula I-1, comprising adding the compound of formula I-1 and glutaric acid to acetonitrile and dichloromethane, and recrystallizing or slurrying to obtain the glutaric acid salt form A, wherein the ratio of the compound of formula I-1 to glutaric acid is selected from: 0.8 to 1.2.

本发明还提供了上述式I-1化合物对甲苯磺酸盐晶型A，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：7.08±0.2°，10.23±0.2°，13.36±0.2°，14.16±0.2°，17.77±0.2°，18.10±0.2°，18.90±0.2°，19.12±0.2°，20.11±0.2°，20.53±0.2°，20.91±0.2°，24.41±0.2°，25.51±0.2°，28.28±0.2°，29.95±0.2°，30.98±0.2°，35.22±0.2°。The present invention also provides the p-toluenesulfonate crystalline form A of the compound of formula I-1, whose X-ray powder diffraction spectrum has special diffraction peaks at the following 2θ angles: 7.08±0.2°, 10.23±0.2°, 13.36±0.2°, 14.16±0.2°, 17.77±0.2°, 18.10±0.2°, 18.90±0.2°, 19.12±0.2°, 20.11±0.2°, 20.53±0.2°, 20.91±0.2°, 24.41±0.2°, 25.51±0.2°, 28.28±0.2°, 29.95±0.2°, 30.98±0.2°, 35.22±0.2°.

本发明的一些方案中，上述式I-1化合物对甲苯磺酸盐晶型A，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：7.08±0.2°，8.00±0.2°，9.39±0.2°，10.23±0.2°，13.36±0.2°，14.16±0.2°，14.81±0.2°，15.77±0.2°，16.21±0.2°，17.77±0.2°，18.10±0.2°，18.90±0.2°，19.12±0.2°，20.11±0.2°，20.53±0.2°，20.91±0.2°，21.29±0.2°，22.49±0.2°，23.11±0.2°，24.41±0.2°，25.51±0.2°，26.77±0.2°，28.28±0.2°，28.81±0.2°，29.22±0.2°，29.95±0.2°，30.98±0.2°，35.22±0.2°。In some embodiments of the present invention, the p-toluenesulfonate crystalline form A of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 7.08±0.2°, 8.00±0.2°, 9.39±0.2°, 10.23±0.2°, 13.36±0.2°, 14.16±0.2°, 14.81±0.2°, 15.77±0.2°, 16.21±0.2°, 17.77±0.2°, 18.10±0.2°, 18.90±0.2°. .2°, 19.12±0.2°, 20.11±0.2°, 20.53±0.2°, 20.91±0.2°, 21.29±0.2°, 22.49±0.2°, 23.11±0.2°, 24.41±0.2°, 25.51±0.2°, 26.77±0.2°, 28.28±0.2°, 28.81±0.2°, 29.22±0.2°, 29.95±0.2°, 30.98±0.2°, 35.22±0.2°.

本发明的一些方案中，上述式I-1化合物对甲苯磺酸盐晶型A，其XRPD图谱如图26所示。In some embodiments of the present invention, the XRPD spectrum of the p-toluenesulfonate crystalline form A of the compound of formula I-1 is shown in FIG26 .

表14式I-1化合物对甲苯磺酸盐晶型A的XRPD解析数据

Table 14 XRPD analysis data of p-toluenesulfonate salt of formula I-1 compound Form A

本发明还提供了上述式I-1化合物对甲苯磺酸盐晶型A的制备方法，包括将式I-1化合物和对甲苯磺酸加入到乙腈中，重结晶或打浆制得，式I-1化合物与对甲苯磺酸的比例选自：0.8～1.2。The present invention also provides a method for preparing the above-mentioned p-toluenesulfonate crystalline form A of the compound of formula I-1, comprising adding the compound of formula I-1 and p-toluenesulfonic acid to acetonitrile, and recrystallizing or slurrying to obtain the compound, wherein the ratio of the compound of formula I-1 to p-toluenesulfonic acid is selected from: 0.8 to 1.2.

本发明还提供了上述式I-1化合物对甲苯磺酸盐晶型B，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：8.27±0.2°，13.69±0.2°，13.95±0.2°，16.15±0.2°，17.72±0.2°，19.52±0.2°，21.05±0.2°，22.45±0.2°，23.91±0.2°，25.40±0.2°，27.33±0.2°，29.25±0.2°。The present invention also provides the p-toluenesulfonate crystalline form B of the compound of formula I-1, whose X-ray powder diffraction spectrum has special diffraction peaks at the following 2θ angles: 8.27±0.2°, 13.69±0.2°, 13.95±0.2°, 16.15±0.2°, 17.72±0.2°, 19.52±0.2°, 21.05±0.2°, 22.45±0.2°, 23.91±0.2°, 25.40±0.2°, 27.33±0.2°, 29.25±0.2°.

本发明的一些方案中，上述式I-1化合物对甲苯磺酸盐晶型B，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：8.27±0.2°，12.59±0.2°，13.69±0.2°，13.95±0.2°，14.63±0.2°，16.15±0.2°，17.72±0.2°，18.68±0.2°，19.52±0.2°，20.75±0.2°，21.05±0.2°，21.92±0.2°，22.45±0.2°，23.23±0.2°，23.91±0.2°，25.40±0.2°，27.33±0.2°，29.25±0.2°。In some embodiments of the present invention, the p-toluenesulfonate crystalline form B of the above-mentioned formula I-1 compound has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 8.27±0.2°, 12.59±0.2°, 13.69±0.2°, 13.95±0.2°, 14.63±0.2°, 16.15±0.2°, 17.72±0.2°, 18.68±0.2°, 19.52±0.2°, 20.75±0.2°, 21.05±0.2°, 21.92±0.2°, 22.45±0.2°, 23.23±0.2°, 23.91±0.2°, 25.40±0.2°, 27.33±0.2°, 29.25±0.2°.

本发明的一些方案中，上述式I-1化合物对甲苯磺酸盐晶型B，其XRPD图谱如图27所示。In some embodiments of the present invention, the XRPD spectrum of the p-toluenesulfonate crystalline form B of the compound of formula I-1 is shown in FIG. 27 .

表15式I-1化合物对甲苯磺酸盐晶型B的XRPD解析数据

Table 15 XRPD analysis data of p-toluenesulfonate salt of formula I-1 compound Form B

本发明还提供了上述式I-1化合物对甲苯磺酸盐晶型B的制备方法，包括将式I-1化合物和对甲苯磺酸加入到四氢呋喃中，重结晶或打浆制得，式I-1化合物与对甲苯磺酸的比例选自：0.8～1.2。The present invention also provides a method for preparing the above-mentioned p-toluenesulfonate crystalline form B of the compound of formula I-1, comprising adding the compound of formula I-1 and p-toluenesulfonic acid to tetrahydrofuran, and recrystallizing or slurrying to obtain the compound, wherein the ratio of the compound of formula I-1 to p-toluenesulfonic acid is selected from: 0.8 to 1.2.

本发明还提供了上述式I-1化合物甲磺酸盐晶型A，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：6.70±0.2°，9.10±0.2°，9.81±0.2°，10.160.2°，13.34±0.2°，13.87±0.2°，14.27±0.2°，15.37±0.2°，17.21±0.2°，19.57±0.2°，21.16±0.2°，22.09±0.2°，23.86±0.2°，24.30±0.2°，24.99±0.2°，27.18±0.2°。The present invention also provides the above-mentioned mesylate crystalline form A of the compound of formula I-1, whose X-ray powder diffraction spectrum has special diffraction peaks at the following 2θ angles: 6.70±0.2°, 9.10±0.2°, 9.81±0.2°, 10.160.2°, 13.34±0.2°, 13.87±0.2°, 14.27±0.2°, 15.37±0.2°, 17.21±0.2°, 19.57±0.2°, 21.16±0.2°, 22.09±0.2°, 23.86±0.2°, 24.30±0.2°, 24.99±0.2°, 27.18±0.2°.

本发明的一些方案中，上述式I-1化合物甲磺酸盐晶型A，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：6.70±0.2°，9.10±0.2°，9.81±0.2°，10.16±0.2°，13.34±0.2°，13.87±0.2°，14.27±0.2°，15.37±0.2°，15.79±0.2°，17.21±0.2°，18.75±0.2°，19.57±0.2°，21.16±0.2°，22.09±0.2°，23.31±0.2°，23.86±0.2°，24.30±0.2°，24.99±0.2°，27.18±0.2°，28.04±0.2°，28.83±0.2°。In some embodiments of the present invention, the above-mentioned mesylate crystalline form A of the compound of formula I-1 has an X-ray powder diffraction pattern with special diffraction peaks at the following 2θ angles: 6.70±0.2°, 9.10±0.2°, 9.81±0.2°, 10.16±0.2°, 13.34±0.2°, 13.87±0.2°, 14.27±0.2°, 15.37±0.2°, 15. 79±0.2°, 17.21±0.2°, 18.75±0.2°, 19.57±0.2°, 21.16±0.2°, 22.09±0.2°, 23.31±0.2°, 23.86±0.2°, 24.30±0.2°, 24.99±0.2°, 27.18±0.2°, 28.04±0.2°, 28.83±0.2°.

本发明的一些方案中，上述式I-1化合物甲磺酸盐晶型A，其XRPD图谱如图28所示。In some embodiments of the present invention, the XRPD spectrum of the mesylate crystal form A of the compound of formula I-1 is shown in FIG28 .

表16式I-1化合物甲磺酸盐晶型A的XRPD解析数据

Table 16 XRPD analysis data of the mesylate salt form A of the compound of formula I-1

本发明还提供了上述式I-1化合物甲磺酸盐晶型A的制备方法,包括将式I-1化合物和甲磺酸加入到四氢呋喃中，重结晶或打浆制得，式I-1化合物与甲磺酸的比例选自：0.8～1.2。The present invention also provides a method for preparing the above-mentioned mesylate crystal form A of the compound of formula I-1, comprising adding the compound of formula I-1 and methanesulfonic acid to tetrahydrofuran, and recrystallizing or slurrying to obtain the compound, wherein the ratio of the compound of formula I-1 to methanesulfonic acid is selected from: 0.8 to 1.2.

本发明还提供了上述式I-1化合物盐酸盐晶型C1，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：7.47±0.2°，7.73±0.2°，12.2500.2°，13.1800.2°，13.51±0.2°，14.96±0.2°，15.46±0.2°，17.31±0.2°，18.56±0.2°，19.34±0.2°，19.57±0.2°，19.78±0.2°，20.01±0.2°，20.41±0.2°，20.76±0.2°，24.36±0.2°，25.63±0.2°，26.47±0.2°，27.51±0.2°。The present invention also provides the hydrochloride crystal form C1 of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 7.47±0.2°, 7.73±0.2°, 12.2500.2°, 13.1800.2°, 13.51±0.2°, 14.96±0.2°, 15.46±0.2°, 17.31±0.2°, 18.56±0.2°, 19.34±0.2°, 19.57±0.2°, 19.78±0.2°, 20.01±0.2°, 20.41±0.2°, 20.76±0.2°, 24.36±0.2°, 25.63±0.2°, 26.47±0.2°, and 27.51±0.2°.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型C1，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：7.47±0.2°，7.73±0.2°，9.63±0.2°，11.4600.2°，12.2500.2°，13.1800.2°，13.51±0.2°，14.96±0.2°，15.46±0.2°，16.79±0.2°，17.04±0.2°，17.31±0.2°，17.72±0.2°，18.56±0.2°，19.34±0.2°，19.57±0.2°，19.78±0.2°，20.01±0.2°，20.41±0.2°，20.76±0.2°，22.60±0.2°，23.09±0.2°，23.80±0.2°，24.36±0.2°，25.63±0.2°，26.47±0.2°，27.51±0.2°，29.09±0.2°，30.76±0.2°，31.99±0.2°，36.24±0.2°。In some embodiments of the present invention, the hydrochloride crystal form C1 of the compound of formula I-1 has a special diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern: 7.47±0.2°, 7.73±0.2°, 9.63±0.2°, 11.4600.2°, 12.2500.2°, 13.1800.2°, 13.51±0.2°, 14.96±0.2°, 15.46±0.2°, 16.79±0.2°, 17.04±0.2°, 17.31±0.2°, 17.72±0.2°, 18. 56±0.2°, 19.34±0.2°, 19.57±0.2°, 19.78±0.2°, 20.01±0.2°, 20.41±0.2°, 20.76±0.2°, 22.60±0.2°, 23.09±0.2°, 23.80±0.2°, 24.36±0.2°, 25.63±0.2°, 26.47±0.2°, 27.51±0.2°, 29.09±0.2°, 30.76±0.2°, 31.99±0.2°, 36.24±0.2°.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型C1，其XRPD图谱如图29所示。In some embodiments of the present invention, the XRPD spectrum of the hydrochloride crystal form C1 of the compound of formula I-1 is shown in Figure 29.

表17式I-1化合物盐酸盐晶型C1的XRPD解析数据

Table 17 XRPD analysis data of the hydrochloride salt form C1 of the compound of formula I-1

本发明的一些方案中，上述式I-1化合物盐酸盐晶型C1，其差示扫描量热曲线在39.76℃±2℃，153.80℃±2℃两处具有吸热峰的起始点，样品在214.75℃±2℃处分解。In some embodiments of the present invention, the hydrochloride crystal form C1 of the compound of formula I-1 has a differential scanning calorimetry curve with two starting points of endothermic peaks at 39.76°C±2°C and 153.80°C±2°C, and the sample decomposes at 214.75°C±2°C.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型C1，其DSC图谱如图30所示。In some embodiments of the present invention, the hydrochloride crystal form C1 of the compound of formula I-1 has a DSC spectrum as shown in FIG30 .

本发明的一些方案中，上述式I-1化合物盐酸盐晶型C1，其热重分析曲线在26.03℃±2℃，100.00℃±2℃，150.00℃±2℃三处有三个失重台阶。In some embodiments of the present invention, the thermogravimetric analysis curve of the hydrochloride crystal form C1 of the compound of formula I-1 has three weight loss steps at 26.03℃±2℃, 100.00℃±2℃, and 150.00℃±2℃.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型C1，其TGA图谱如图31所示。In some embodiments of the present invention, the hydrochloride crystal form C1 of the compound of formula I-1 has a TGA spectrum as shown in FIG31 .

本发明还提供了上述式I-1化合物盐酸盐晶型C1的制备方法，包括将式I-1化合物和盐酸加入到乙酸乙酯中，重结晶或打浆制得，式I-1化合物与盐酸的比例选自：0.8～1.2，式I-1化合物的盐酸盐晶型C1为乙酸乙酯溶剂和水合物晶型，乙酸乙酯含量为0.62当量，水含量为3.0当量。The present invention also provides a method for preparing the hydrochloride crystal form C1 of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and hydrochloric acid to ethyl acetate, and recrystallizing or slurrying to obtain the compound, wherein the ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2, and the hydrochloride crystal form C1 of the compound of formula I-1 is an ethyl acetate solvent and a hydrate crystal form, the ethyl acetate content is 0.62 equivalents, and the water content is 3.0 equivalents.

本发明还提供了上述式I-1化合物盐酸盐晶型C2，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：7.56±0.2°，7.79±0.2°，12.32±0.2°，13.21±0.2°，13.63±0.2°，15.10±0.2°，15.56±0.2°，18.58±0.2°，19.36±0.2°，19.66±0.2°，19.82±0.2°，20.91±0.2°，24.35±0.2°，26.56±0.2°，30.74±0.2°。The present invention also provides the hydrochloride form C2 of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 7.56±0.2°, 7.79±0.2°, 12.32±0.2°, 13.21±0.2°, 13.63±0.2°, 15.10±0.2°, 15.56±0.2°, 18.58±0.2°, 19.36±0.2°, 19.66±0.2°, 19.82±0.2°, 20.91±0.2°, 24.35±0.2°, 26.56±0.2°, and 30.74±0.2°.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型C2，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：7.56±0.2°，7.79±0.2°，9.65±0.2°，11.48±0.2°，12.32±0.2°，13.21±0.2°，13.63±0.2°，15.10±0.2°，15.56±0.2°，16.86±0.2°，17.16±0.2°，17.41±0.2°，17.77±0.2°，18.58±0.2°，19.36±0.2°，19.66±0.2°，19.82±0.2°，20.32±0.2°，20.91±0.2°，22.71±0.2°，23.21±0.2°，23.80±0.2°，24.35±0.2°，25.71±0.2°，26.56±0.2°，27.53±0.2°，27.80±0.2°，28.20±0.2°，29.15±0.2°，30.74±0.2°，32.06±0.2°，36.30±0.2°，38.22±0.2°。In some embodiments of the present invention, the hydrochloride crystal form C2 of the compound of formula I-1 has a special diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern: 7.56±0.2°, 7.79±0.2°, 9.65±0.2°, 11.48±0.2°, 12.32±0.2°, 13.21±0.2°, 13.63±0.2°, 15.10±0.2°, 15.56±0.2°, 16.86±0.2°, 17.16±0.2°, 17.41±0.2°, 17.77±0.2°, 18.58±0.2°, 19. 36±0.2°, 19.66±0.2°, 19.82±0.2°, 20.32±0.2°, 20.91±0.2°, 22.71±0.2°, 23.21±0.2°, 23.80±0.2°, 24.35±0.2°, 25.71±0.2°, 26.56±0.2°, 27.53±0.2°, 27.80±0.2°, 28.20±0.2°, 29.15±0.2°, 30.74±0.2°, 32.06±0.2°, 36.30±0.2°, 38.22±0.2°.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型C2，其XRPD图谱如图32所示。In some embodiments of the present invention, the hydrochloride crystal form C2 of the compound of formula I-1 above has an XRPD spectrum as shown in FIG32 .

表18式I-1化合物盐酸盐晶型C2的XRPD解析数据

Table 18 XRPD analysis data of the hydrochloride salt form C2 of the compound of formula I-1

本发明的一些方案中，上述式I-1化合物盐酸盐晶型C2，其差示扫描量热曲线在33.27℃±2℃，155.72℃±2℃两处具有吸热峰的起始点，样品在212.45℃±2℃处开始分解。In some embodiments of the present invention, the hydrochloride crystal form C2 of the above-mentioned compound of formula I-1 has a differential scanning calorimetry curve with two starting points of endothermic peaks at 33.27℃±2℃ and 155.72℃±2℃, and the sample begins to decompose at 212.45℃±2℃.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型C2，其DSC图谱如图33所示。In some embodiments of the present invention, the hydrochloride crystal form C2 of the compound of formula I-1 above has a DSC spectrum as shown in FIG33 .

本发明的一些方案中，上述式I-1化合物盐酸盐晶型C2，其热重分析曲线在28.19℃±2℃，115.00℃±2℃，150.00℃±2℃三处有三个失重台阶。In some embodiments of the present invention, the hydrochloride crystal form C2 of the above-mentioned compound of formula I-1 has three weight loss steps at 28.19℃±2℃, 115.00℃±2℃, and 150.00℃±2℃ in its thermogravimetric analysis curve.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型C2，其TGA图谱如图34所示。In some embodiments of the present invention, the hydrochloride crystal form C2 of the compound of formula I-1 has a TGA spectrum as shown in FIG34 .

本发明还提供了上述式I-1化合物盐酸盐晶型C2的制备方法，包括将式I-1化合物和盐酸加入到2-甲基四氢呋喃中，重结晶或打浆制得，式I-1化合物与盐酸的比例选自：0.8～1.2，式I-1化合物的盐酸盐晶型C2为2-甲基四氢呋喃溶剂和水合物晶型，2-甲基四氢呋喃含量为0.21当量，水含量为2.8当量。The present invention also provides a method for preparing the hydrochloride crystal form C2 of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and hydrochloric acid to 2-methyltetrahydrofuran, and preparing the product by recrystallization or slurrying, wherein the ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2, the hydrochloride crystal form C2 of the compound of formula I-1 is a 2-methyltetrahydrofuran solvent and a hydrate crystal form, the 2-methyltetrahydrofuran content is 0.21 equivalents, and the water content is 2.8 equivalents.

本发明还提供了上述式I-1化合物盐酸盐晶型D，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：6.60±0.2°，7.79±0.2°，9.84±0.2°，13.31±0.2°，15.23±0.2°，15.93±0.2°，20.09±0.2°，20.41±0.2°，21.23±0.2°，21.80±0.2°。The present invention also provides the hydrochloride form D of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 6.60±0.2°, 7.79±0.2°, 9.84±0.2°, 13.31±0.2°, 15.23±0.2°, 15.93±0.2°, 20.09±0.2°, 20.41±0.2°, 21.23±0.2°, 21.80±0.2°.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型D，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：6.60±0.2°，7.26±0.2°，7.79±0.2°，8.48±0.2°，9.84±0.2°，11.18±0.2°，13.31±0.2°，13.89±0.2°，14.64±0.2°，14.98±0.2°，15.23±0.2°，15.93±0.2°，16.27±0.2°，17.04±0.2°，18.21±0.2°，19.33±0.2°，20.09±0.2°，20.41±0.2°，21.23±0.2°，21.80±0.2°，23.49±0.2°，24.79±0.2°，28.43±0.2°。In some embodiments of the present invention, the hydrochloride crystal form D of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 6.60±0.2°, 7.26±0.2°, 7.79±0.2°, 8.48±0.2°, 9.84±0.2°, 11.18±0.2°, 13.31±0.2°, 13.89±0.2°, 14.64±0.2°, 14.9 8±0.2°, 15.23±0.2°, 15.93±0.2°, 16.27±0.2°, 17.04±0.2°, 18.21±0.2°, 19.33±0.2°, 20.09±0.2°, 20.41±0.2°, 21.23±0.2°, 21.80±0.2°, 23.49±0.2°, 24.79±0.2°, 28.43±0.2°.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型D，其XRPD图谱如图35所示。In some embodiments of the present invention, the XRPD spectrum of the hydrochloride form D of the compound of formula I-1 is shown in FIG35 .

表19式I-1化合物盐酸盐晶型D的XRPD解析数据

Table 19 XRPD analysis data of the hydrochloride salt form D of the compound of formula I-1

本发明的一些方案中，上述式I-1化合物盐酸盐晶型D，其差示扫描量热曲线在55.20℃±2℃，164.37℃±2℃两处具有吸热峰的起始点，样品在211.35℃±2℃处开始分解。In some embodiments of the present invention, the hydrochloride form D of the compound of formula I-1 has a differential scanning calorimetry curve with two starting points of endothermic peaks at 55.20°C±2°C and 164.37°C±2°C, and the sample begins to decompose at 211.35°C±2°C.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型D，其DSC图谱如图36所示。In some embodiments of the present invention, the DSC spectrum of the hydrochloride form D of the compound of formula I-1 is shown in Figure 36.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型D，其热重分析曲线在36.24℃±2℃，110.00℃±2℃两处有两个失重台阶。In some embodiments of the present invention, the hydrochloride crystal form D of the compound of formula I-1 has two weight loss steps at 36.24°C±2°C and 110.00°C±2°C in its thermogravimetric analysis curve.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型D，其TGA图谱如图37所示。In some embodiments of the present invention, the TGA spectrum of the hydrochloride crystal form D of the compound of formula I-1 is shown in Figure 37.

本发明还提供了上述式I-1化合物盐酸盐晶型D的制备方法，包括将式I-1化合物和盐酸加入到丁酮中，重结晶或打浆制得，式I-1化合物与盐酸的比例选自：0.8～1.2，式I-1化合物的盐酸盐晶型D为无水晶型。The present invention also provides a method for preparing the hydrochloride crystal form D of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and hydrochloric acid to butanone, and recrystallizing or slurrying to obtain the compound, wherein the ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2, and the hydrochloride crystal form D of the compound of formula I-1 is an anhydrous crystal form.

本发明还提供了上述式I-1化合物盐酸盐晶型E1，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：6.15±0.2°，7.66±0.2°，7.90±0.2°，13.06±0.2°，14.06±0.2°，16.25±0.2°，18.37±0.2°，19.01±0.2°，19.75±0.2°，20.19±0.2°，21.81±0.2°，23.56±0.2°，24.95±0.2°，25.18±0.2°，25.63±0.2°，26.71±0.2°，27.10±0.2°，27.91±0.2°，29.81±0.2°，32.93±0.2°。The present invention also provides the hydrochloride crystal form E1 of the compound of formula I-1, whose X-ray powder diffraction spectrum has special diffraction peaks at the following 2θ angles: 6.15±0.2°, 7.66±0.2°, 7.90±0.2°, 13.06±0.2°, 14.06±0.2°, 16.25±0.2°, 18.37±0.2°, 19.01±0.2° , 19.75±0.2°, 20.19±0.2°, 21.81±0.2°, 23.56±0.2°, 24.95±0.2°, 25.18±0.2°, 25.63±0.2°, 26.71±0.2°, 27.10±0.2°, 27.91±0.2°, 29.81±0.2°, 32.93±0.2°.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型E1，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：6.15±0.2°，7.66±0.2°，7.90±0.2°，8.41±0.2°，9.49±0.2°，9.91±0.2°，10.88±0.2°，11.42±0.2°，13.06±0.2°，13.66±0.2°，14.06±0.2°，14.69±0.2°，15.32±0.2°，15.52±0.2°，15.88±0.2°，16.25±0.2°，16.81±0.2°，17.35±0.2°，18.37±0.2°，19.01±0.2°，19.75±0.2°，20.19±0.2°，21.15±0.2°，21.51±0.2°，21.81±0.2°，22.50±0.2°，22.87±0.2°，23.56±0.2°，24.95±0.2°，25.18±0.2°，25.63±0.2°，26.71±0.2°，27.10±0.2°，27.91±0.2°，28.47±0.2°，29.30±0.2°，29.81±0.2°，30.12±0.2°，32.93±0.2°，34.96±0.2°。In some embodiments of the present invention, the hydrochloride form E1 of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 6.15±0.2°, 7.66±0.2°, 7.90±0.2°, 8.41±0.2°, 9.49±0.2°, 9.91±0.2°, 10.88±0.2°, 11.42±0.2°, 13.06±0.2°, 13.66±0.2°, 14.06±0.2°, 14.69±0.2°, 15.32±0.2°, 15.52±0.2°, 15.88±0.2°, 16.25±0.2°, 16.81±0.2°, 17.35±0.2° , 18.37±0.2°, 19.01±0.2°, 19.75±0.2°, 20.19±0.2°, 21.15±0.2°, 21.51±0.2°, 21.81±0.2°, 22.50±0.2°, 22.87±0.2°, 23.56±0.2°, 24.95±0.2°, 25.18±0.2°, 25.63±0.2°, 26.71±0.2°, 27.10±0.2°, 27.91±0.2°, 28.47±0.2°, 29.30±0.2°, 29.81±0.2°, 30.12±0.2°, 32.93±0.2°, 34.96±0.2°.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型E1，其XRPD图谱如图38所示。In some embodiments of the present invention, the hydrochloride crystal form E1 of the compound of formula I-1 has an XRPD spectrum as shown in FIG. 38 .

表20式I-1化合物盐酸盐晶型E1的XRPD解析数据

Table 20 XRPD analysis data of the hydrochloride salt form E1 of the compound of formula I-1

本发明的一些方案中，上述式I-1化合物盐酸盐晶型E1，其差示扫描量热曲线在13.36℃±2℃，174.06℃±2℃两处具有吸热峰的起始点，样品在211.29℃±2℃处开始分解。In some embodiments of the present invention, the hydrochloride crystal form E1 of the compound of formula I-1 has a differential scanning calorimetry curve with two starting points of endothermic peaks at 13.36°C±2°C and 174.06°C±2°C, and the sample begins to decompose at 211.29°C±2°C.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型E1，其DSC图谱如图39所示。In some embodiments of the present invention, the hydrochloride crystal form E1 of the compound of formula I-1 has a DSC spectrum as shown in FIG39 .

本发明的一些方案中，上述式I-1化合物盐酸盐晶型E1，其热重分析曲线在25.81℃±2℃，120.00℃±2℃和160.00℃±2℃三处有三个失重台阶。In some embodiments of the present invention, the hydrochloride crystal form E1 of the compound of formula I-1 has three weight loss steps at 25.81°C±2°C, 120.00°C±2°C and 160.00°C±2°C in its thermogravimetric analysis curve.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型E1，其TGA图谱如图40所示。In some embodiments of the present invention, the hydrochloride crystal form E1 of the compound of formula I-1 has a TGA spectrum as shown in FIG40 .

本发明还提供了上述式I-1化合物盐酸盐晶型E1的制备方法，包括将式I-1化合物和盐酸加入到乙醇中，重结晶或打浆制得，式I-1化合物与盐酸的比例选自：0.8～1.2，式I-1化合物的盐酸盐晶型E1为水合物晶型，水含量为1.7当量。The present invention also provides a method for preparing the hydrochloride crystal form E1 of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and hydrochloric acid to ethanol, and recrystallizing or slurrying to obtain the compound, wherein the ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2, and the hydrochloride crystal form E1 of the compound of formula I-1 is a hydrate crystal form, and the water content is 1.7 equivalents.

本发明还提供了上述式I-1化合物盐酸盐晶型E2，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：7.88±0.2°，10.90±0.2°，13.10±0.2°，14.14±0.2°，16.30±0.2°，19.01±0.2°，19.75±0.2°，21.54±0.2°，21.84±0.2°，23.63±0.2°，24.96±0.2°，26.78±0.2°，29.91±0.2°。The present invention also provides the hydrochloride form E2 of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 7.88±0.2°, 10.90±0.2°, 13.10±0.2°, 14.14±0.2°, 16.30±0.2°, 19.01±0.2°, 19.75±0.2°, 21.54±0.2°, 21.84±0.2°, 23.63±0.2°, 24.96±0.2°, 26.78±0.2°, 29.91±0.2°.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型E2，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：7.88±0.2°，9.51±0.2°，10.90±0.2°，11.49±0.2°，13.10±0.2°，13.64±0.2°，14.14±0.2°，14.76±0.2°，15.39±0.2°，15.75±0.2°，16.30±0.2°，16.93±0.2°，19.01±0.2°，19.75±0.2°，20.69±0.2°，21.54±0.2°，21.84±0.2°，22.19±0.2°，22.57±0.2°，23.01±0.2°，23.63±0.2°，24.96±0.2°，25.90±0.2°，26.32±0.2°，26.78±0.2°，27.19±0.2°，27.48±0.2°，27.94±0.2°，28.68±0.2°，29.07±0.2°，29.50±0.2°，29.91±0.2°，31.74±0.2°，32.96±0.2°，33.66±0.2°。In some embodiments of the present invention, the hydrochloride form E2 of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 7.88±0.2°, 9.51±0.2°, 10.90±0.2°, 11.49±0.2°, 13.10±0.2°, 13.64±0.2°, 14.14±0.2°, 14.76±0.2°, 15.39±0.2°, 15.75±0.2°, 16.30±0.2°, 16.93±0.2°, 19.01±0.2°, 19.75±0.2°, 20.69±0.2°, 21. .54±0.2°, 21.84±0.2°, 22.19±0.2°, 22.57±0.2°, 23.01±0.2°, 23.63±0.2°, 24.96±0.2°, 25.90±0.2°, 26.32±0.2°, 26.78±0.2°, 27.19±0.2°, 27.48±0.2°, 27.94±0.2°, 28.68±0.2°, 29.07±0.2°, 29.50±0.2°, 29.91±0.2°, 31.74±0.2°, 32.96±0.2°, 33.66±0.2°.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型E2，其XRPD图谱如图41所示。In some embodiments of the present invention, the hydrochloride crystal form E2 of the compound of formula I-1 above has an XRPD spectrum as shown in FIG. 41 .

表21式I-1化合物盐酸盐晶型E2的XRPD解析数据

Table 21 XRPD analysis data of the hydrochloride salt form E2 of the compound of formula I-1

本发明的一些方案中，上述式I-1化合物盐酸盐晶型E2，其差示扫描量热曲线在14.99℃±2℃，174.19℃±2℃两处具有吸热峰的起始点，样品在213.17℃±2℃处开始分解。In some embodiments of the present invention, the hydrochloride form E2 of the compound of formula I-1 has a differential scanning calorimetry curve with two starting points of endothermic peaks at 14.99°C±2°C and 174.19°C±2°C, and the sample begins to decompose at 213.17°C±2°C.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型E2，其DSC图谱如图42所示。In some embodiments of the present invention, the hydrochloride crystal form E2 of the compound of formula I-1 above has a DSC spectrum as shown in FIG42 .

本发明的一些方案中，上述式I-1化合物盐酸盐晶型E2，其热重分析曲线在33.18℃±2℃，90.00℃±2℃和140.00℃±2℃三处有三个失重台阶。In some embodiments of the present invention, the hydrochloride crystal form E2 of the compound of formula I-1 has three weight loss steps at 33.18°C±2°C, 90.00°C±2°C and 140.00°C±2°C in its thermogravimetric analysis curve.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型E2，其TGA图谱如图43所示。In some embodiments of the present invention, the hydrochloride crystal form E2 of the compound of formula I-1 above has a TGA spectrum as shown in FIG43 .

本发明还提供了上述式I-1化合物盐酸盐晶型E2的制备方法，是将式I-1化合物的盐酸盐晶型F在25℃真空，50℃真空或100℃干燥制得，式I-1化合物与盐酸的比例选自：0.8～1.2，式I-1化合物的盐酸盐晶型E2为水合物晶型，水含量为1.8当量。The present invention also provides a method for preparing the hydrochloride crystal form E2 of the above-mentioned compound of formula I-1, which is prepared by drying the hydrochloride crystal form F of the compound of formula I-1 at 25°C vacuum, 50°C vacuum or 100°C, wherein the ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2, and the hydrochloride crystal form E2 of the compound of formula I-1 is a hydrate crystal form with a water content of 1.8 equivalents.

本发明还提供了上述式I-1化合物盐酸盐晶型F，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：7.65±0.2°，11.47±0.2°，13.93±0.2°，14.80±0.2°，15.25±0.2°，19.84±0.2°，20.09±0.2°，21.51±0.2°，23.22±0.2°，25.06±0.2°，26.68±0.2°，28.87±0.2°，32.45±0.2°，33.59±0.2°。The present invention also provides the hydrochloride form F of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 7.65±0.2°, 11.47±0.2°, 13.93±0.2°, 14.80±0.2°, 15.25±0.2°, 19.84±0.2°, 20.09±0.2°, 21.51±0.2°, 23.22±0.2°, 25.06±0.2°, 26.68±0.2°, 28.87±0.2°, 32.45±0.2°, 33.59±0.2°.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型F，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：6.85±0.2°，7.65±0.2°，10.21±0.2°，10.70±0.2°，11.47±0.2°，13.93±0.2°，14.80±0.2°，15.25±0.2°，16.60±0.2°，16.88±0.2°，17.84±0.2°，19.00±0.2°，19.16±0.2°，19.84±0.2°，20.09±0.2°，20.34±0.2°，21.51±0.2°，22.35±0.2°，23.22±0.2°，23.86±0.2°，25.06±0.2°，25.31±0.2°，25.63±0.2°，26.68±0.2°，28.10±0.2°，28.87±0.2°，30.53±0.2°，32.45±0.2°，33.59±0.2°。In some embodiments of the present invention, the hydrochloride form F of the compound of formula I-1 has an X-ray powder diffraction pattern with special diffraction peaks at the following 2θ angles: 6.85±0.2°, 7.65±0.2°, 10.21±0.2°, 10.70±0.2°, 11.47±0.2°, 13.93±0.2°, 14.80±0.2°, 15.25±0.2°, 16.60±0.2°, 16.88±0.2°, 17.84±0.2°, 19.00±0.2°, 19. 16±0.2°, 19.84±0.2°, 20.09±0.2°, 20.34±0.2°, 21.51±0.2°, 22.35±0.2°, 23.22±0.2°, 23.86±0.2°, 25.06±0.2°, 25.31±0.2°, 25.63±0.2°, 26.68±0.2°, 28.10±0.2°, 28.87±0.2°, 30.53±0.2°, 32.45±0.2°, 33.59±0.2°.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型F，其XRPD图谱如图44所示。In some embodiments of the present invention, the XRPD spectrum of the hydrochloride form F of the compound of formula I-1 is shown in FIG. 44 .

表22式I-1化合物盐酸盐晶型F的XRPD解析数据

Table 22 XRPD analysis data of the hydrochloride salt form F of the compound of formula I-1

本发明的一些方案中，上述式I-1化合物盐酸盐晶型F，其差示扫描量热曲线在36.03℃±2℃，172.45℃±2℃两处具有吸热峰的起始点，样品在212.66℃±2℃处开始分解。In some embodiments of the present invention, the hydrochloride form F of the compound of formula I-1 has a differential scanning calorimetry curve with two starting points of endothermic peaks at 36.03°C±2°C and 172.45°C±2°C, and the sample begins to decompose at 212.66°C±2°C.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型F，其DSC图谱如图45所示。In some embodiments of the present invention, the DSC spectrum of the hydrochloride form F of the compound of formula I-1 is shown in Figure 45.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型F，其热重分析曲线在33.35℃±2℃，100.00℃±2℃和150.00℃±2℃三处有三个失重台阶。In some embodiments of the present invention, the hydrochloride form F of the compound of formula I-1 has three weight loss steps at 33.35°C±2°C, 100.00°C±2°C and 150.00°C±2°C in its thermogravimetric analysis curve.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型F，其TGA图谱如图46所示。In some embodiments of the present invention, the hydrochloride crystal form F of the compound of formula I-1 above has a TGA spectrum as shown in FIG. 46 .

本发明还提供了上述式I-1化合物盐酸盐晶型F的制备方法，包括将式I-1化合物和盐酸加入到乙醇、丙酮、乙酸乙酯、乙腈、四氢呋喃或甲基异丁基酮/三氟乙醇混合溶剂中，50℃重结晶或打浆制得，式I-1化合物与盐酸的比例选自：0.8～1.2，式I-1化合物的盐酸盐晶型F为水合物晶型，水含量为2.0当量。The present invention also provides a method for preparing the hydrochloride crystal form F of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and hydrochloric acid to ethanol, acetone, ethyl acetate, acetonitrile, tetrahydrofuran or a methyl isobutyl ketone/trifluoroethanol mixed solvent, and recrystallizing or slurrying at 50°C, wherein the ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2, and the hydrochloride crystal form F of the compound of formula I-1 is a hydrate crystal form, and the water content is 2.0 equivalents.

本发明还提供了上述式I-1化合物盐酸盐晶型G，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：5.83±0.2°，9.97±0.2°，13.26±0.2°，14.17±0.2°，15.52±0.2°，16.77±0.2°，18.37±0.2°，20.27±0.2°，20.48±0.2°，21.35±0.2°，21.82±0.2°，22.65±0.2°，23.04±0.2°，24.43±0.2°，26.24±0.2°，26.54±0.2°，28.94±0.2°，30.18±0.2°。The present invention also provides the hydrochloride form G of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 5.83±0.2°, 9.97±0.2°, 13.26±0.2°, 14.17±0.2°, 15.52±0.2°, 16.77±0.2°, 18.37±0.2°, 20.27±0.2°, 20.48±0.2°, 21.35±0.2°, 21.82±0.2°, 22.65±0.2°, 23.04±0.2°, 24.43±0.2°, 26.24±0.2°, 26.54±0.2°, 28.94±0.2°, and 30.18±0.2°.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型G，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：5.83±0.2°，7.18±0.2°，9.97±0.2°，11.63±0.2°，12.00±0.2°，12.35±0.2°，13.26±0.2°，13.58±0.2°，14.17±0.2°，14.60±0.2°，15.52±0.2°，16.77±0.2°，17.64±0.2°，18.37±0.2°，18.81±0.2°，19.14±0.2°，19.80±0.2°，20.27±0.2°，20.48±0.2°，21.35±0.2°，21.82±0.2°，22.65±0.2°，23.04±0.2°，23.35±0.2°，24.43±0.2°，25.47±0.2°，26.24±0.2°，26.54±0.2°，26.84±0.2°，27.92±0.2°，28.94±0.2°，29.31±0.2°，30.18±0.2°。In some embodiments of the present invention, the hydrochloride form G of the compound of formula I-1 has a X-ray powder diffraction pattern with special diffraction peaks at the following 2θ angles: 5.83±0.2°, 7.18±0.2°, 9.97±0.2°, 11.63±0.2°, 12.00±0.2°, 12.35±0.2°, 13.26±0.2°, 13.58±0.2°, 14.17±0.2°, 14.60±0.2°, 15.52±0.2°, 16.77±0.2°, 17.64±0.2°, 18.37±0.2°, 18. 81±0.2°, 19.14±0.2°, 19.80±0.2°, 20.27±0.2°, 20.48±0.2°, 21.35±0.2°, 21.82±0.2°, 22.65±0.2°, 23.04±0.2°, 23.35±0.2°, 24.43±0.2°, 25.47±0.2°, 26.24±0.2°, 26.54±0.2°, 26.84±0.2°, 27.92±0.2°, 28.94±0.2°, 29.31±0.2°, 30.18±0.2°.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型G，其XRPD图谱如图47所示。In some embodiments of the present invention, the XRPD spectrum of the hydrochloride form G of the compound of formula I-1 is shown in FIG. 47 .

表23式I-1化合物盐酸盐晶型G的XRPD解析数据

Table 23 XRPD analysis data of the hydrochloride salt form G of the compound of formula I-1

本发明的一些方案中，上述式I-1化合物盐酸盐晶型G，其差示扫描量热曲线在59.42℃±2℃，151.02℃±2℃和166.01℃±2℃三处具有吸热峰的起始点。In some embodiments of the present invention, the hydrochloride form G of the compound of formula I-1 has a differential scanning calorimetry curve having three starting points of endothermic peaks at 59.42°C±2°C, 151.02°C±2°C and 166.01°C±2°C.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型G，其DSC图谱如图48所示。In some embodiments of the present invention, the DSC spectrum of the hydrochloride form G of the compound of formula I-1 is shown in Figure 48.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型G，其热重分析曲线在26.28℃±2℃，120.00℃±2℃和150.00℃±2℃三处有三个失重台阶。In some embodiments of the present invention, the hydrochloride crystal form G of the compound of formula I-1 has three weight loss steps at 26.28°C±2°C, 120.00°C±2°C and 150.00°C±2°C in its thermogravimetric analysis curve.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型G，其TGA图谱如图49所示。In some embodiments of the present invention, the hydrochloride crystal form G of the compound of formula I-1 above has a TGA spectrum as shown in FIG. 49 .

本发明还提供了上述式I-1化合物盐酸盐晶型G的制备方法，包括将式I-1化合物和盐酸加入到水中，25℃，50℃或升降温混悬重结晶或打浆制得，式I-1化合物与盐酸的比例选自：0.8～1.2，式I-1化合物的盐酸盐晶型G为水合物晶型，水含量为3.0当量。The present invention also provides a preparation method of the hydrochloride crystal form G of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and hydrochloric acid to water, suspending and recrystallizing or slurrying at 25°C, 50°C or raising or lowering the temperature, wherein the ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2, and the hydrochloride crystal form G of the compound of formula I-1 is a hydrate crystal form with a water content of 3.0 equivalents.

本发明还提供了上述式I-1化合物盐酸盐晶型H，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：5.83±0.2°，7.16±0.2°，10.02±0.2°，11.64±0.2°，13.23±0.2°，14.58±0.2°，16.67±0.2°，18.40±0.2°，18.62±0.2°，20.23±0.2°，20.54±0.2°，21.40±0.2°，22.62±0.2°，22.78±0.2°，23.36±0.2°，24.73±0.2°，26.23±0.2°，26.57±0.2°，26.91±0.2°，29.30±0.2°，30.21±0.2°。The present invention also provides the hydrochloride crystal form H of the compound of formula I-1, whose X-ray powder diffraction spectrum has special diffraction peaks at the following 2θ angles: 5.83±0.2°, 7.16±0.2°, 10.02±0.2°, 11.64±0.2°, 13.23±0.2°, 14.58±0.2°, 16.67±0.2°, 18.40±0.2°, 18.6 2±0.2°, 20.23±0.2°, 20.54±0.2°, 21.40±0.2°, 22.62±0.2°, 22.78±0.2°, 23.36±0.2°, 24.73±0.2°, 26.23±0.2°, 26.57±0.2°, 26.91±0.2°, 29.30±0.2°, 30.21±0.2°.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型H，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：5.83±0.2°，7.16±0.2°，10.02±0.2°，11.64±0.2°，12.35±0.2°，13.23±0.2°，13.59±0.2°，14.58±0.2°，15.51±0.2°，15.97±0.2°，16.67±0.2°，17.63±0.2°，18.40±0.2°，18.62±0.2°，19.11±0.2°，20.23±0.2°，20.54±0.2°，21.40±0.2°，22.07±0.2°，22.62±0.2°，22.78±0.2°，23.36±0.2°，24.73±0.2°，24.98±0.2°，26.23±0.2°，26.57±0.2°，26.91±0.2°，27.88±0.2°，29.01±0.2°，29.30±0.2°，29.61±0.2°，30.21±0.2°，31.21±0.2°，32.12±0.2°，34.66±0.2°。In some embodiments of the present invention, the hydrochloride form H of the compound of formula I-1 has a X-ray powder diffraction pattern with special diffraction peaks at the following 2θ angles: 5.83±0.2°, 7.16±0.2°, 10.02±0.2°, 11.64±0.2°, 12.35±0.2°, 13.23±0.2°, 13.59±0.2°, 14.58±0.2°, 15.51±0.2°, 15.97±0.2°, 16.67±0.2°, 17.63±0.2°, 18.40±0.2°, 18.62±0.2°, 19.11±0.2°, 20. : 23±0.2°, 20.54±0.2°, 21.40±0.2°, 22.07±0.2°, 22.62±0.2°, 22.78±0.2°, 23.36±0.2°, 24.73±0.2°, 24.98±0.2°, 26.23±0.2°, 26.57±0.2°, 26.91±0.2°, 27.88±0.2°, 29.01±0.2°, 29.30±0.2°, 29.61±0.2°, 30.21±0.2°, 31.21±0.2°, 32.12±0.2°, 34.66±0.2°.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型H，其XRPD图谱如图50所示。In some embodiments of the present invention, the XRPD spectrum of the hydrochloride form H of the compound of formula I-1 is shown in Figure 50.

表24式I-1化合物盐酸盐晶型H的XRPD解析数据

Table 24 XRPD analysis data of the hydrochloride salt form H of the compound of formula I-1

本发明的一些方案中，上述式I-1化合物盐酸盐晶型H，其差示扫描量热曲线在51.49℃±2℃和153.61℃±2℃两处具有吸热峰的起始点，样品在211.73℃±2℃处开始分解。In some embodiments of the present invention, the hydrochloride form H of the compound of formula I-1 has a differential scanning calorimetry curve with two starting points of endothermic peaks at 51.49°C±2°C and 153.61°C±2°C, and the sample begins to decompose at 211.73°C±2°C.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型H，其DSC图谱如图51所示。In some embodiments of the present invention, the hydrochloride crystal form H of the compound of formula I-1 above has a DSC spectrum as shown in FIG51 .

本发明的一些方案中，上述式I-1化合物盐酸盐晶型H，其热重分析曲线在26.12℃±2℃，110.00℃±2℃和150.00℃±2℃三处有三个失重台阶。In some embodiments of the present invention, the hydrochloride crystal form H of the compound of formula I-1 has three weight loss steps at 26.12°C±2°C, 110.00°C±2°C and 150.00°C±2°C in its thermogravimetric analysis curve.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型H，其TGA图谱如图52所示。In some embodiments of the present invention, the hydrochloride crystal form H of the compound of formula I-1 above has a TGA spectrum as shown in Figure 52.

本发明还提供了上述式I-1化合物盐酸盐晶型H的制备方法，包括将式I-1化合物和盐酸加入甲醇/水混合溶剂中通过在25合溶或50合溶下混悬重结晶或打浆制得，式I-1化合物与盐酸的比例选自：0.8～1.2，式I-1化合物的盐酸盐晶型H为水合物晶型，水含量为3.9当量。The present invention also provides a method for preparing the hydrochloride form H of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and hydrochloric acid to a methanol/water mixed solvent and suspending and recrystallizing or slurrying at 25% or 50% of the solvent, wherein the ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2, and the hydrochloride form H of the compound of formula I-1 is a hydrate form with a water content of 3.9 equivalents.

本发明还提供了上述式I-1化合物盐酸盐晶型I，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：6.68±0.2°，12.31±0.2°，12.54±0.2°，13.34±0.2°，14.05±0.2°，14.96±0.2°，17.92±0.2°，19.03±0.2°，19.74±0.2°，19.99±0.2°，20.96±0.2°，21.42±0.2°，21.62±0.2°，26.81±0.2°，27.21±0.2°，27.60±0.2°，27.78±0.2°，30.07±0.2°，31.00±0.2°，34.83±0.2°。The present invention also provides the hydrochloride crystal form I of the compound of formula I-1, whose X-ray powder diffraction spectrum has special diffraction peaks at the following 2θ angles: 6.68±0.2°, 12.31±0.2°, 12.54±0.2°, 13.34±0.2°, 14.05±0.2°, 14.96±0.2°, 17.92±0.2°, 19.03±0.2 °, 19.74±0.2°, 19.99±0.2°, 20.96±0.2°, 21.42±0.2°, 21.62±0.2°, 26.81±0.2°, 27.21±0.2°, 27.60±0.2°, 27.78±0.2°, 30.07±0.2°, 31.00±0.2°, 34.83±0.2°.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型I，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：6.68±0.2°，9.50±0.2°，12.31±0.2°，12.54±0.2°，13.34±0.2°，14.05±0.2°，14.96±0.2°，15.38±0.2°，17.18±0.2°，17.92±0.2°，19.03±0.2°，19.74±0.2°，19.99±0.2°，20.96±0.2°，21.42±0.2°，21.62±0.2°，21.99±0.2°，22.98±0.2°，23.52±0.2°，23.80±0.2°，24.38±0.2°，25.92±0.2°，26.81±0.2°，27.21±0.2°，27.60±0.2°，27.78±0.2°，28.26±0.2°，28.74±0.2°，30.07±0.2°，31.00±0.2°，32.69±0.2°，34.02±0.2°，34.83±0.2°。In some embodiments of the present invention, the hydrochloride form I of the compound of formula I-1 has an X-ray powder diffraction pattern with special diffraction peaks at the following 2θ angles: 6.68±0.2°, 9.50±0.2°, 12.31±0.2°, 12.54±0.2°, 13.34±0.2°, 14.05±0.2°, 14.96±0.2°, 15.38±0.2°, 17.18±0.2°, 17.92±0.2°, 19.03±0.2°, 19.74±0.2°, 19.99±0.2°, 20.96±0.2°, 21. 42±0.2°, 21.62±0.2°, 21.99±0.2°, 22.98±0.2°, 23.52±0.2°, 23.80±0.2°, 24.38±0.2°, 25.92±0.2°, 26.81±0.2°, 27.21±0.2°, 27.60±0.2°, 27.78±0.2°, 28.26±0.2°, 28.74±0.2°, 30.07±0.2°, 31.00±0.2°, 32.69±0.2°, 34.02±0.2°, 34.83±0.2°.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型I，其XRPD图谱如图53所示。In some embodiments of the present invention, the XRPD spectrum of the hydrochloride form I of the compound of formula I-1 is shown in Figure 53.

表25式I-1化合物盐酸盐晶型I的XRPD解析数据

Table 25 XRPD analysis data of the hydrochloride salt form I of the compound of formula I-1

本发明的一些方案中，上述式I-1化合物盐酸盐晶型I，其差示扫描量热曲线在18.15℃±2℃和194.49℃±2℃两处具有吸热峰的起始点，样品在215.51℃±2℃处开始分解In some embodiments of the present invention, the hydrochloride crystal form I of the compound of formula I-1 has a differential scanning calorimetry curve having two starting points of endothermic peaks at 18.15°C ± 2°C and 194.49°C ± 2°C, and the sample begins to decompose at 215.51°C ± 2°C.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型I，其DSC图谱如图54所示。In some embodiments of the present invention, the DSC spectrum of the hydrochloride form I of the compound of formula I-1 is shown in Figure 54.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型I，其热重分析曲线在28.31℃±2℃，70.00℃±2℃和173.00℃±2℃三处有三个失重台阶。In some embodiments of the present invention, the hydrochloride form I of the compound of formula I-1 has three weight loss steps at 28.31°C±2°C, 70.00°C±2°C and 173.00°C±2°C in its thermogravimetric analysis curve.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型I，其TGA图谱如图55所示。In some embodiments of the present invention, the hydrochloride crystal form I of the compound of formula I-1 has a TGA spectrum as shown in Figure 55.

本发明还提供了上述式I-1化合物盐酸盐晶型I的制备方法，包括将式I-1化合物和盐酸加入甲醇或甲醇/甲基叔丁基醚混合溶剂中在25叔丁混悬重结晶或打浆制得，式I-1化合物与盐酸的比例选自：0.8～1.2，式I-1化合物的盐酸盐晶型I为无水晶型。The present invention also provides a method for preparing the hydrochloride crystal form I of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and hydrochloric acid to methanol or a methanol/methyl tert-butyl ether mixed solvent, suspending and recrystallizing or slurrying at 25% tert-butyl, wherein the ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2, and the hydrochloride crystal form I of the compound of formula I-1 is an anhydrous crystalline form.

本发明还提供了上述式I-1化合物盐酸盐晶型J1，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：6.80±0.2°，11.69±0.2°，14.87±0.2°，15.98±0.2°，18.05±0.2°，19.49±0.2°，20.41±0.2°，21.55±0.2°，21.70±0.2°，22.06±0.2°，23.69±0.2°，24.92±0.2°，25.13±0.2°，29.07±0.2°，30.16±0.2°。The present invention also provides the hydrochloride form J1 of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 6.80±0.2°, 11.69±0.2°, 14.87±0.2°, 15.98±0.2°, 18.05±0.2°, 19.49±0.2°, 20.41±0.2°, 21.55±0.2°, 21.70±0.2°, 22.06±0.2°, 23.69±0.2°, 24.92±0.2°, 25.13±0.2°, 29.07±0.2°, and 30.16±0.2°.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型J1，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：6.80±0.2°，7.82±0.2°，7.95±0.2°，10.08±0.2°，11.69±0.2°，12.30±0.2°，12.60±0.2°，13.60±0.2°，14.87±0.2°，15.98±0.2°，16.25±0.2°，18.05±0.2°，18.60±0.2°，18.79±0.2°，19.49±0.2°，20.41±0.2°，20.82±0.2°，21.55±0.2°，21.70±0.2°，22.06±0.2°，22.88±0.2°，23.69±0.2°，24.92±0.2°，25.13±0.2°，26.19±0.2°，26.57±0.2°，29.07±0.2°，30.16±0.2°，31.85±0.2°，32.80±0.2°。In some embodiments of the present invention, the hydrochloride form J1 of the compound of formula I-1 has a special diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern: 6.80±0.2°, 7.82±0.2°, 7.95±0.2°, 10.08±0.2°, 11.69±0.2°, 12.30±0.2°, 12.60±0.2°, 13.60±0.2°, 14.87±0.2°, 15.98±0.2°, 16.25±0.2°, 18.05±0.2°, 18.60±0.2°. 2°, 18.79±0.2°, 19.49±0.2°, 20.41±0.2°, 20.82±0.2°, 21.55±0.2°, 21.70±0.2°, 22.06±0.2°, 22.88±0.2°, 23.69±0.2°, 24.92±0.2°, 25.13±0.2°, 26.19±0.2°, 26.57±0.2°, 29.07±0.2°, 30.16±0.2°, 31.85±0.2°, 32.80±0.2°.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型J1，其XRPD图谱如图56所示。In some embodiments of the present invention, the hydrochloride crystal form J1 of the compound of formula I-1 has an XRPD spectrum as shown in FIG56 .

表26式I-1化合物盐酸盐晶型J1的XRPD解析数据

Table 26 XRPD analysis data of the hydrochloride salt form J1 of the compound of formula I-1

本发明的一些方案中，上述式I-1化合物盐酸盐晶型J1，其差示扫描量热曲线在70.82℃±2℃和165.48℃±2℃两处具有吸热峰的起始点，样品在212.96℃±2℃处开始分解。In some embodiments of the present invention, the hydrochloride form J1 of the compound of formula I-1 has a differential scanning calorimetry curve with two starting points of endothermic peaks at 70.82°C±2°C and 165.48°C±2°C, and the sample begins to decompose at 212.96°C±2°C.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型J1，其DSC图谱如图57所示。In some embodiments of the present invention, the hydrochloride crystal form J1 of the compound of formula I-1 above has a DSC spectrum as shown in FIG57 .

本发明的一些方案中，上述式I-1化合物盐酸盐晶型J1，其热重分析曲线在33.94℃±2℃和110.00℃±2℃两处有两个失重台阶。In some embodiments of the present invention, the hydrochloride crystal form J1 of the compound of formula I-1 has two weight loss steps at 33.94°C±2°C and 110.00°C±2°C in its thermogravimetric analysis curve.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型J1，其TGA图谱如图58所示。In some embodiments of the present invention, the hydrochloride crystal form J1 of the compound of formula I-1 has a TGA spectrum as shown in Figure 58.

本发明还提供了上述式I-1化合物盐酸盐晶型J1的制备方法，包括将式I-1化合物和盐酸加入2-甲基四氢呋喃中，在50°0混悬或升降温重结晶或打浆制得，式I-1化合物与盐酸的比例选自：0.8～1.2，式I-1化合物的盐酸盐晶型J1为2-甲基四氢呋喃和水的溶剂合物，2-甲基四氢呋喃含量为0.75当量，水含量为0.98当量。The present invention also provides a method for preparing the hydrochloride crystal form J1 of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and hydrochloric acid to 2-methyltetrahydrofuran, suspending at 50°0 or heating and cooling to recrystallize or slurry to obtain the compound, wherein the ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2, and the hydrochloride crystal form J1 of the compound of formula I-1 is a solvate of 2-methyltetrahydrofuran and water, wherein the 2-methyltetrahydrofuran content is 0.75 equivalents and the water content is 0.98 equivalents.

本发明还提供了上述式I-1化合物盐酸盐晶型J2，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：6.78±0.2°，11.59±0.2°，12.24±0.2°，13.56±0.2°，14.69±0.2°，17.45±0.2°，18.12±0.2°，18.89±0.2°，19.51±0.2°，21.28±0.2°，21.46±0.2°，22.23±0.2°，24.09±0.2°，24.86±0.2°，24.99±0.2°，29.00±0.2°。The present invention also provides the hydrochloride form J2 of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 6.78±0.2°, 11.59±0.2°, 12.24±0.2°, 13.56±0.2°, 14.69±0.2°, 17.45±0.2°, 18.12±0.2°, 18.89±0.2°, 19.51±0.2°, 21.28±0.2°, 21.46±0.2°, 22.23±0.2°, 24.09±0.2°, 24.86±0.2°, 24.99±0.2°, 29.00±0.2°.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型J2，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：6.78±0.2°，7.96±0.2°，8.31±0.2°，11.59±0.2°，12.24±0.2°，13.56±0.2°，14.69±0.2°，16.44±0.2°，16.63±0.2°，17.45±0.2°，18.12±0.2°，18.89±0.2°，19.51±0.2°，20.12±0.2°，20.35±0.2°，20.49±0.2°，21.28±0.2°，21.46±0.2°，22.23±0.2°，22.75±0.2°，23.27±0.2°，24.09±0.2°，24.86±0.2°，24.99±0.2°，25.37±0.2°，25.65±0.2°，26.54±0.2°，27.62±0.2°，28.61±0.2°，29.00±0.2°，30.43±0.2°，32.10±0.2°，33.01±0.2°，36.96±0.2°。In some embodiments of the present invention, the hydrochloride form J2 of the compound of formula I-1 has a special diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern: 6.78±0.2°, 7.96±0.2°, 8.31±0.2°, 11.59±0.2°, 12.24±0.2°, 13.56±0.2°, 14.69±0.2°, 16.44±0.2°, 16.63±0.2°, 17.45±0.2°, 18.12±0.2°, 18.89±0.2°, 19.51±0.2°, 20.12±0.2°, 20.35±0.2°. 2°, 20.49±0.2°, 21.28±0.2°, 21.46±0.2°, 22.23±0.2°, 22.75±0.2°, 23.27±0.2°, 24.09±0.2°, 24.86±0.2°, 24.99±0.2°, 25.37±0.2°, 25.65±0.2°, 26.54±0.2°, 27.62±0.2°, 28.61±0.2°, 29.00±0.2°, 30.43±0.2°, 32.10±0.2°, 33.01±0.2°, 36.96±0.2°.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型J2，其XRPD图谱如图59所示。In some embodiments of the present invention, the hydrochloride crystal form J2 of the above-mentioned compound of formula I-1 has an XRPD spectrum as shown in Figure 59.

表27式I-1化合物盐酸盐晶型J2的XRPD解析数据

Table 27 XRPD analysis data of the hydrochloride salt form J2 of the compound of formula I-1

本发明的一些方案中，上述式I-1化合物盐酸盐晶型J2，其差示扫描量热曲线在77.60℃±2℃和163.47℃±2℃两处具有吸热峰的起始点，样品在211.78℃±2℃处开始分解。In some embodiments of the present invention, the hydrochloride form J2 of the compound of formula I-1 has a differential scanning calorimetry curve with two starting points of endothermic peaks at 77.60°C±2°C and 163.47°C±2°C, and the sample begins to decompose at 211.78°C±2°C.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型J2，其DSC图谱如图60所示。In some embodiments of the present invention, the hydrochloride crystal form J2 of the compound of formula I-1 above has a DSC spectrum as shown in FIG60 .

本发明的一些方案中，上述式I-1化合物盐酸盐晶型J2，其热重分析曲线在28.73℃±2℃和120.00℃±2℃两处有两个失重台阶。In some embodiments of the present invention, the hydrochloride crystal form J2 of the compound of formula I-1 has two weight loss steps at 28.73°C±2°C and 120.00°C±2°C in its thermogravimetric analysis curve.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型J2，其TGA图谱如图61所示。In some embodiments of the present invention, the hydrochloride crystal form J2 of the compound of formula I-1 above has a TGA spectrum as shown in Figure 61.

本发明还提供了上述式I-1化合物盐酸盐晶型J2的制备方法，包括将式I-1化合物的盐酸盐晶型J1加热至110°0制得，式I-1化合物与盐酸的比例选自：0.8～1.2，式I-1化合物的盐酸盐晶型J2为2-甲基四氢呋喃和水的溶剂合物，2-甲基四氢呋喃含量为0.39当量，水含量为0.94当量。The present invention also provides a method for preparing the hydrochloride crystal form J2 of the above-mentioned compound of formula I-1, comprising heating the hydrochloride crystal form J1 of the compound of formula I-1 to 110°0, wherein the ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2, and the hydrochloride crystal form J2 of the compound of formula I-1 is a solvate of 2-methyltetrahydrofuran and water, the 2-methyltetrahydrofuran content is 0.39 equivalents, and the water content is 0.94 equivalents.

本发明还提供了上述式I-1化合物盐酸盐晶型K，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：6.79±0.2°，11.61±0.2°，14.93±0.2°，16.08±0.2°，18.05±0.2°，18.63±0.2°，20.49±0.2°，20.64±0.2°，21.52±0.2°，21.72±0.2°，21.93±0.2°，23.68±0.2°，25.19±0.2°，26.25±0.2°，26.57±0.2°，29.91±0.2°，32.56±0.2°。The present invention also provides the hydrochloride form K of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 6.79±0.2°, 11.61±0.2°, 14.93±0.2°, 16.08±0.2°, 18.05±0.2°, 18.63±0.2°, 20.49±0.2°, 20.64±0.2°, 21.52±0.2°, 21.72±0.2°, 21.93±0.2°, 23.68±0.2°, 25.19±0.2°, 26.25±0.2°, 26.57±0.2°, 29.91±0.2°, and 32.56±0.2°.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型K，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：6.79±0.2°，7.83±0.2°，8.04±0.2°，10.00±0.2°，10.74±0.2°，11.61±0.2°，12.25±0.2°，12.64±0.2°，13.57±0.2°，14.93±0.2°，16.08±0.2°，18.05±0.2°，18.63±0.2°，19.43±0.2°，20.15±0.2°，20.49±0.2°，20.64±0.2°，21.52±0.2°，21.72±0.2°，21.93±0.2°，23.27±0.2°，23.68±0.2°，24.73±0.2°，25.19±0.2°，26.25±0.2°，26.57±0.2°，27.42±0.2°，28.02±0.2°，28.67±0.2°，29.13±0.2°，29.91±0.2°，32.56±0.2°。In some embodiments of the present invention, the hydrochloride form K of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 6.79±0.2°, 7.83±0.2°, 8.04±0.2°, 10.00±0.2°, 10.74±0.2°, 11.61±0.2°, 12.25±0.2°, 12.64±0.2°, 13.57±0.2°, 14.93±0.2°, 16.08±0.2°, 18.05±0.2°, 18.63±0.2°, 19.43±0.2 °, 20.15±0.2°, 20.49±0.2°, 20.64±0.2°, 21.52±0.2°, 21.72±0.2°, 21.93±0.2°, 23.27±0.2°, 23.68±0.2°, 24.73±0.2°, 25.19±0.2°, 26.25±0.2°, 26.57±0.2°, 27.42±0.2°, 28.02±0.2°, 28.67±0.2°, 29.13±0.2°, 29.91±0.2°, 32.56±0.2°.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型K，其XRPD图谱如图62所示。In some embodiments of the present invention, the XRPD spectrum of the hydrochloride form K of the compound of formula I-1 is shown in Figure 62.

表28式I-1化合物盐酸盐晶型K的XRPD解析数据

Table 28 XRPD analysis data of the hydrochloride salt form K of the compound of formula I-1

本发明的一些方案中，上述式I-1化合物盐酸盐晶型K，其差示扫描量热曲线在80.73℃±2℃和171.74℃±2℃两处具有吸热峰的起始点，样品在211.42℃±2℃处开始分解。In some embodiments of the present invention, the hydrochloride form K of the compound of formula I-1 has a differential scanning calorimetry curve with two starting points of endothermic peaks at 80.73°C±2°C and 171.74°C±2°C, and the sample begins to decompose at 211.42°C±2°C.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型K，其DSC图谱如图63所示。In some embodiments of the present invention, the DSC spectrum of the hydrochloride form K of the compound of formula I-1 is shown in Figure 63.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型K，其热重分析曲线在33.39℃±2℃，125.00℃±2℃和155.00℃±2℃三处有三个失重台阶。In some embodiments of the present invention, the hydrochloride form K of the compound of formula I-1 has three weight loss steps at 33.39°C±2°C, 125.00°C±2°C and 155.00°C±2°C in its thermogravimetric analysis curve.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型K，其TGA图谱如图64所示。In some embodiments of the present invention, the hydrochloride form K of the compound of formula I-1 has a TGA spectrum as shown in FIG64 .

本发明还提供了上述式I-1化合物盐酸盐晶型K的制备方法，包括将式I-1化合物和盐酸加入甲基叔丁基醚中，在50°0混悬或升降温重结晶或打浆制得，式I-1化合物与盐酸的比例选自：0.8～1.2，式I-1化合物的盐酸盐晶型K为甲基叔丁基醚和水的溶剂合物，甲基叔丁基醚含量为0.5当量，水含量为0.93当量。The present invention also provides a preparation method of the hydrochloride crystal form K of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and hydrochloric acid to methyl tert-butyl ether, suspending at 50°0 or heating and cooling to recrystallize or slurry to obtain the compound, wherein the ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2, and the hydrochloride crystal form K of the compound of formula I-1 is a solvate of methyl tert-butyl ether and water, wherein the methyl tert-butyl ether content is 0.5 equivalents and the water content is 0.93 equivalents.

本发明还提供了上述式I-1化合物盐酸盐晶型L，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：8.15±0.2°，12.72±0.2°，13.59±0.2°，15.07±0.2°，15.56±0.2°，16.60±0.2°，16.89±0.2°，17.56±0.2°，19.74±0.2°，20.52±0.2°，21.69±0.2°，22.60±0.2°，25.57±0.2°，27.48±0.2°，29.54±0.2°，29.80±0.2°。The present invention also provides the hydrochloride form L of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 8.15±0.2°, 12.72±0.2°, 13.59±0.2°, 15.07±0.2°, 15.56±0.2°, 16.60±0.2°, 16.89±0.2°, 17.56±0.2°, 19.74±0.2°, 20.52±0.2°, 21.69±0.2°, 22.60±0.2°, 25.57±0.2°, 27.48±0.2°, 29.54±0.2°, 29.80±0.2°.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型L，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：7.70±0.2°，8.15±0.2°，8.82±0.2°，9.85±0.2°，11.25±0.2°，12.72±0.2°，13.59±0.2°，14.68±0.2°，15.07±0.2°，15.56±0.2°，16.60±0.2°，16.89±0.2°，17.56±0.2°，18.53±0.2°，18.98±0.2°，19.74±0.2°，20.29±0.2°，20.52±0.2°，21.30±0.2°，21.69±0.2°，22.60±0.2°，22.79±0.2°，24.38±0.2°，25.57±0.2°，26.21±0.2°，26.50±0.2°，26.97±0.2°，27.48±0.2°，28.17±0.2°，28.60±0.2°，29.54±0.2°，29.80±0.2°，31.17±0.2°，33.28±0.2°。In some embodiments of the present invention, the hydrochloride form L of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 7.70±0.2°, 8.15±0.2°, 8.82±0.2°, 9.85±0.2°, 11.25±0.2°, 12.72±0.2°, 13.59±0.2°, 14.68±0.2°, 15.07±0.2°, 15.56±0.2°, 16.60±0.2°, 16.89±0.2°, 17.56±0.2°, 18.53±0.2°, 18.98±0.2°. °, 19.74±0.2°, 20.29±0.2°, 20.52±0.2°, 21.30±0.2°, 21.69±0.2°, 22.60±0.2°, 22.79±0.2°, 24.38±0.2°, 25.57±0.2°, 26.21±0.2°, 26.50±0.2°, 26.97±0.2°, 27.48±0.2°, 28.17±0.2°, 28.60±0.2°, 29.54±0.2°, 29.80±0.2°, 31.17±0.2°, 33.28±0.2°.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型L，其XRPD图谱如图65所示。In some embodiments of the present invention, the XRPD spectrum of the hydrochloride form L of the compound of formula I-1 is shown in Figure 65.

表29式I-1化合物盐酸盐晶型L的XRPD解析数据

Table 29 XRPD analysis data of the hydrochloride form L of the compound of formula I-1

本发明的一些方案中，上述式I-1化合物盐酸盐晶型L，其差示扫描量热曲线在180.17℃±2℃处具有吸热峰的起始点，样品在212.43℃±2℃处开始分解。In some embodiments of the present invention, the hydrochloride crystal form L of the compound of formula I-1 has a differential scanning calorimetry curve with an endothermic peak starting point at 180.17°C±2°C, and the sample begins to decompose at 212.43°C±2°C.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型L，其DSC图谱如图66所示。In some embodiments of the present invention, the DSC spectrum of the hydrochloride form L of the compound of formula I-1 is shown in Figure 66.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型L，其热重分析曲线在33.53℃±2℃和140.00℃±2℃两处有两个失重台阶。In some embodiments of the present invention, the hydrochloride crystal form L of the compound of formula I-1 has two weight loss steps at 33.53°C±2°C and 140.00°C±2°C in its thermogravimetric analysis curve.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型L，其TGA图谱如图67所示。In some embodiments of the present invention, the hydrochloride crystal form L of the above-mentioned compound of formula I-1 has a TGA spectrum as shown in Figure 67.

本发明还提供了上述式I-1化合物盐酸盐晶型L的制备方法，包括将式I-1化合物和盐酸加入甲苯中，在，25°盐或50°0混悬或升降温重结晶或打浆制得，式I-1化合物与盐酸的比例选自：0.8～1.2，式I-1化合物的盐酸盐晶型L为甲苯的溶剂合物，甲苯含量为0.46当量。The present invention also provides a method for preparing the hydrochloride crystal form L of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and hydrochloric acid to toluene, suspending or heating and cooling to recrystallize or slurry at 25°C or 50°C, wherein the ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2, and the hydrochloride crystal form L of the compound of formula I-1 is a solvate of toluene, and the toluene content is 0.46 equivalents.

本发明还提供了上述式I-1化合物盐酸盐晶型M，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：6.84±0.2°，7.21±0.2°，14.17±0.2°，14.90±0.2°，18.94±0.2°，19.46±0.2°，19.71±0.2°，19.96±0.2°，20.82±0.2°，22.60±0.2°，24.17±0.2°，25.17±0.2°，25.45±0.2°，27.17±0.2°，28.09±0.2°，28.88±0.2°。The present invention also provides the hydrochloride form M of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 6.84±0.2°, 7.21±0.2°, 14.17±0.2°, 14.90±0.2°, 18.94±0.2°, 19.46±0.2°, 19.71±0.2°, 19.96±0.2°, 20.82±0.2°, 22.60±0.2°, 24.17±0.2°, 25.17±0.2°, 25.45±0.2°, 27.17±0.2°, 28.09±0.2°, 28.88±0.2°.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型M，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：6.84±0.2°，7.21±0.2°，8.92±0.2°，10.07±0.2°，10.69±0.2°，10.89±0.2°，11.24±0.2°，13.23±0.2°，14.17±0.2°，14.90±0.2°，15.59±0.2°，16.74±0.2°，17.67±0.2°，18.29±0.2°，18.94±0.2°，19.46±0.2°，19.71±0.2°，19.96±0.2°，20.82±0.2°，21.49±0.2°，21.83±0.2°，22.60±0.2°，23.14±0.2°，23.54±0.2°，24.17±0.2°，25.17±0.2°，25.45±0.2°，26.10±0.2°，27.17±0.2°，27.61±0.2°，28.09±0.2°，28.88±0.2°，29.42±0.2°，30.12±0.2°，32.48±0.2°，35.22±0.2°。In some embodiments of the present invention, the hydrochloride form M of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 6.84±0.2°, 7.21±0.2°, 8.92±0.2°, 10.07±0.2°, 10.69±0.2°, 10.89±0.2°, 11.24±0.2°, 13.23±0.2°, 14.17±0.2°, 14.90±0.2°, 15.59±0.2°, 16.74±0.2°, 17.67±0.2°, 18.29±0.2°, 18.94±0.2°, 19.46±0.2 °, 19.71±0.2°, 19.96±0.2°, 20.82±0.2°, 21.49±0.2°, 21.83±0.2°, 22.60±0.2°, 23.14±0.2°, 23.54±0.2°, 24.17±0.2°, 25.17±0.2°, 25.45±0.2°, 26.10±0.2°, 27.17±0.2°, 27.61±0.2°, 28.09±0.2°, 28.88±0.2°, 29.42±0.2°, 30.12±0.2°, 32.48±0.2°, 35.22±0.2°.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型M，其XRPD图谱如图68所示。In some embodiments of the present invention, the hydrochloride form M of the compound of formula I-1 above has an XRPD spectrum as shown in FIG68 .

表30式I-1化合物盐酸盐晶型M的XRPD解析数据

Table 30 XRPD analysis data of the hydrochloride form M of the compound of formula I-1

本发明的一些方案中，上述式I-1化合物盐酸盐晶型M，其差示扫描量热曲线在31.74℃±2℃和150.05℃±2℃处具有吸热峰的起始点，样品在215.09℃±2℃处开始分解。In some embodiments of the present invention, the hydrochloride form M of the compound of formula I-1 has a differential scanning calorimetry curve with endothermic peak starting points at 31.74°C±2°C and 150.05°C±2°C, and the sample begins to decompose at 215.09°C±2°C.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型M，其DSC图谱如图69所示。In some embodiments of the present invention, the hydrochloride form M of the compound of formula I-1 above has a DSC spectrum as shown in FIG69 .

本发明的一些方案中，上述式I-1化合物盐酸盐晶型M，其热重分析曲线在32.98℃±2℃和115.00℃±2℃两处有两个失重台阶。In some embodiments of the present invention, the hydrochloride form M of the compound of formula I-1 has two weight loss steps at 32.98°C±2°C and 115.00°C±2°C in its thermogravimetric analysis curve.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型M，其TGA图谱如图70所示。In some embodiments of the present invention, the hydrochloride form M of the compound of formula I-1 has a TGA spectrum as shown in Figure 70.

本发明还提供了上述式I-1化合物盐酸盐晶型M的制备方法，包括将式I-1化合物和盐酸加入异丙醇/二甲基亚砜、乙酸异丙酯/二甲基亚砜、水/二甲基亚砜混合溶剂中，在25°甲或50°0混悬重结晶或打浆制得，式I-1化合物与盐酸的比例选自：0.8～1.2，式I-1化合物的盐酸盐晶型M为二甲基亚砜和水的溶剂合物，二甲基亚砜含量为3.4当量，水的含量为13.7当量。The present invention also provides a method for preparing the hydrochloride crystal form M of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and hydrochloric acid to a mixed solvent of isopropanol/dimethyl sulfoxide, isopropyl acetate/dimethyl sulfoxide, and water/dimethyl sulfoxide, and suspending, recrystallizing, or slurrying at 25°C or 50°C, wherein the ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2, and the hydrochloride crystal form M of the compound of formula I-1 is a solvate of dimethyl sulfoxide and water, wherein the dimethyl sulfoxide content is 3.4 equivalents, and the water content is 13.7 equivalents.

本发明还提供了上述式I-1化合物盐酸盐晶型N，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：6.61±0.2°，7.80±0.2°，13.17±0.2°，15.24±0.2°，16.02±0.2°，16.19±0.2°，20.10±0.2°，21.57±0.2°，21.95±0.2°，28.42±0.2°。The present invention also provides the hydrochloride form N of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 6.61±0.2°, 7.80±0.2°, 13.17±0.2°, 15.24±0.2°, 16.02±0.2°, 16.19±0.2°, 20.10±0.2°, 21.57±0.2°, 21.95±0.2°, 28.42±0.2°.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型N，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：6.61±0.2°，7.80±0.2°，9.75±0.2°，11.19±0.2°，12.53±0.2°，13.17±0.2°，14.61±0.2°，15.24±0.2°，16.02±0.2°，16.19±0.2°，18.51±0.2°，19.36±0.2°，20.10±0.2°，21.57±0.2°，21.95±0.2°，23.47±0.2°，25.60±0.2°，27.32±0.2°，28.42±0.2°，29.12±0.2°。In some embodiments of the present invention, the hydrochloride form N of the compound of formula I-1 has an X-ray powder diffraction pattern with special diffraction peaks at the following 2θ angles: 6.61±0.2°, 7.80±0.2°, 9.75±0.2°, 11.19±0.2°, 12.53±0.2°, 13.17±0.2°, 14.61±0.2°, 15.24±0.2 °, 16.02±0.2°, 16.19±0.2°, 18.51±0.2°, 19.36±0.2°, 20.10±0.2°, 21.57±0.2°, 21.95±0.2°, 23.47±0.2°, 25.60±0.2°, 27.32±0.2°, 28.42±0.2°, 29.12±0.2°.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型N，其XRPD图谱如图71所示。In some embodiments of the present invention, the XRPD spectrum of the hydrochloride form N of the compound of formula I-1 is shown in Figure 71.

表31式I-1化合物盐酸盐晶型N的XRPD解析数据
Table 31 XRPD analysis data of the hydrochloride salt form N of the compound of formula I-1

本发明的一些方案中，上述式I-1化合物盐酸盐晶型N，其差示扫描量热曲线在47.38℃±2℃和167.91℃±2℃处具有吸热峰的起始点，样品在212.57℃±2℃处开始分解。In some embodiments of the present invention, the hydrochloride form N of the compound of formula I-1 has a differential scanning calorimetry curve with endothermic peak starting points at 47.38°C±2°C and 167.91°C±2°C, and the sample begins to decompose at 212.57°C±2°C.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型N，其DSC图谱如图72所示。In some embodiments of the present invention, the DSC spectrum of the hydrochloride form N of the compound of formula I-1 is shown in Figure 72.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型N，其热重分析曲线在33.22℃±2℃，75.00℃±2℃和150.00℃±2℃三处有三个失重台阶。In some embodiments of the present invention, the hydrochloride form N of the compound of formula I-1 has three weight loss steps at 33.22°C±2°C, 75.00°C±2°C and 150.00°C±2°C in its thermogravimetric analysis curve.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型N，其TGA图谱如图73所示。In some embodiments of the present invention, the hydrochloride form N of the compound of formula I-1 has a TGA spectrum as shown in Figure 73.

本发明还提供了上述式I-1化合物盐酸盐晶型N的制备方法，包括将式I-1化合物和盐酸加入甲醇中，在25°盐混悬重结晶或打浆制得，式I-1化合物与盐酸的比例选自：0.8～1.2，式I-1化合物的盐酸盐晶型N为水合物晶型，水的含量为3.0当量。The present invention also provides a method for preparing the hydrochloride form N of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and hydrochloric acid to methanol, and preparing the salt by suspension recrystallization or slurrying at 25°, wherein the ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2, and the hydrochloride form N of the compound of formula I-1 is a hydrate form, and the water content is 3.0 equivalents.

本发明还提供了上述式I-1化合物盐酸盐晶型O，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：6.14±0.2°，9.90±0.2°，13.54±0.2°，14.40±0.2°，15.33±0.2°，15.51±0.2°，15.87±0.2°，16.79±0.2°，18.36±0.2°，20.17±0.2°，21.14±0.2°，22.51±0.2°，22.84±0.2°，24.59±0.2°，25.28±0.2°，26.82±0.2°，27.07±0.2°，27.93±0.2°。The present invention also provides the hydrochloride form O of the compound of formula I-1, whose X-ray powder diffraction pattern has special diffraction peaks at the following 2θ angles: 6.14±0.2°, 9.90±0.2°, 13.54±0.2°, 14.40±0.2°, 15.33±0.2°, 15.51±0.2°, 15.87±0.2°, 16.79±0.2°, 18.36±0.2°, 20.17±0.2°, 21.14±0.2°, 22.51±0.2°, 22.84±0.2°, 24.59±0.2°, 25.28±0.2°, 26.82±0.2°, 27.07±0.2°, 27.93±0.2°.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型O，其X射线粉末衍射图谱在下列2θ角处具有特殊衍射峰：6.14±0.2°，8.39±0.2°，9.90±0.2°，11.28±0.2°，13.19±0.2°，13.54±0.2°，14.40±0.2°，15.33±0.2°，15.51±0.2°，15.87±0.2°，16.79±0.2°，17.32±0.2°，18.36±0.2°，19.03±0.2°，19.38±0.2°，19.84±0.2°，20.17±0.2°，20.39±0.2°，21.14±0.2°，21.82±0.2°，22.51±0.2°，22.84±0.2°，23.77±0.2°，24.59±0.2°，25.28±0.2°，26.21±0.2°，26.82±0.2°，27.07±0.2°，27.93±0.2°，28.45±0.2°，29.24±0.2°，29.70±0.2°，30.12±0.2°，30.91±0.2°，31.32±0.2°，32.02±0.2°，32.81±0.2°，33.99±0.2°，35.51±0.2°，37.27±0.2°。In some embodiments of the present invention, the hydrochloride form O of the compound of formula I-1 has an X-ray powder diffraction pattern having special diffraction peaks at the following 2θ angles: 6.14±0.2°, 8.39±0.2°, 9.90±0.2°, 11.28±0.2°, 13.19±0.2°, 13.54±0.2°, 14.40±0.2°, 15.33±0.2°, 15.51±0.2°, 15.87±0.2°, 16.79±0.2°, 17.32±0.2°, 18.36±0.2°, 19.03±0.2°, 19.38±0.2°, 19.84±0.2°, 20.17±0.2°, 20.39±0.2° °, 21.14±0.2°, 21.82±0.2°, 22.51±0.2°, 22.84±0.2°, 23.77±0.2°, 24.59±0.2°, 25.28±0.2°, 26.21±0.2°, 26.82±0.2°, 27.07±0.2°, 27.93±0.2°, 28.45±0.2°, 29.24±0.2°, 29.70±0.2°, 30.12±0.2°, 30.91±0.2°, 31.32±0.2°, 32.02±0.2°, 32.81±0.2°, 33.99±0.2°, 35.51±0.2°, 37.27±0.2°.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型O，其XRPD图谱如图74所示。In some embodiments of the present invention, the hydrochloride form O of the compound of formula I-1 above has an XRPD spectrum as shown in FIG. 74 .

表32式I-1化合物盐酸盐晶型O的XRPD解析数据

Table 32 XRPD analysis data of the hydrochloride form O of the compound of formula I-1

本发明的一些方案中，上述式I-1化合物盐酸盐晶型O，其差示扫描量热曲线在12.36℃±2℃和174.87℃±2℃处具有吸热峰的起始点，样品在212.00℃±2℃处开始分解。In some embodiments of the present invention, the hydrochloride form O of the compound of formula I-1 has a differential scanning calorimetry curve with endothermic peak starting points at 12.36°C±2°C and 174.87°C±2°C, and the sample begins to decompose at 212.00°C±2°C.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型O，其DSC图谱如图75所示。In some embodiments of the present invention, the hydrochloride crystal form O of the compound of formula I-1 above has a DSC spectrum as shown in Figure 75.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型O，其热重分析曲线在27.70℃±2℃，115.00℃±2℃和160.00℃±2℃三处有三个失重台阶。In some embodiments of the present invention, the hydrochloride crystal form O of the compound of formula I-1 has three weight loss steps at 27.70℃±2℃, 115.00℃±2℃ and 160.00℃±2℃ in its thermogravimetric analysis curve.

本发明的一些方案中，上述式I-1化合物盐酸盐晶型O，其TGA图谱如图76所示。In some embodiments of the present invention, the hydrochloride crystal form O of the compound of formula I-1 above has a TGA spectrum as shown in Figure 76.

本发明还提供了上述式I-1化合物盐酸盐晶型O的制备方法，包括将式I-1化合物和盐酸加入二氯甲烷中，在25°盐混悬重结晶或打浆制得，式I-1化合物与盐酸的比例选自：0.8～1.2，式I-1化合物的盐酸盐晶型O为水合物晶型，水的含量为0.9当量。The present invention also provides a method for preparing the hydrochloride form O of the above-mentioned compound of formula I-1, comprising adding the compound of formula I-1 and hydrochloric acid to dichloromethane, and suspending and recrystallizing or slurrying the salt at 25°, wherein the ratio of the compound of formula I-1 to hydrochloric acid is selected from: 0.8 to 1.2, and the hydrochloride form O of the compound of formula I-1 is a hydrate form, and the water content is 0.9 equivalents.

本发明的另一方面，提供了一种制备上述的式(I)化合物的药学上可接受的盐的晶型的方法，其特征在于，包括如下步骤：Another aspect of the present invention provides a method for preparing a crystalline form of a pharmaceutically acceptable salt of the compound of formula (I), characterized in that it comprises the following steps:

a.将式(I)化合物和酸按1:(0.8-3)的摩尔比溶解到或分散到1～20倍体积的溶剂A中；a. dissolving or dispersing the compound of formula (I) and the acid in a molar ratio of 1:(0.8-3) into 1 to 20 times the volume of solvent A;

b.混悬、重结晶或打浆；b. Suspension, recrystallization or slurrying;

其中，所述酸不选自盐酸(优选地，所述酸选自下组：马来酸、富马酸、乙醇酸、L-苹果酸、琥珀酸、硫酸、L-酒石酸、马尿酸、戊二酸、对甲苯磺酸或甲磺酸)；wherein the acid is not selected from hydrochloric acid (preferably, the acid is selected from the group consisting of maleic acid, fumaric acid, glycolic acid, L-malic acid, succinic acid, sulfuric acid, L-tartaric acid, hippuric acid, glutaric acid, p-toluenesulfonic acid or methanesulfonic acid);

所述溶剂A选自下组：乙腈、二氯甲烷、四氢呋喃、或其组合；The solvent A is selected from the group consisting of acetonitrile, dichloromethane, tetrahydrofuran, or a combination thereof;

或所述酸为盐酸或氯化氢二氧六环；且所述溶剂A选自下组：乙酸乙酯、2-甲基四氢呋喃、丁酮、乙醇、丙酮、乙酸乙酯、乙腈、四氢呋喃、甲基异丁基酮、三氟乙醇、水、甲醇、甲基叔丁基醚、甲苯、异丙醇、二甲基亚砜、乙酸异丙酯、二氯甲烷、或其组合。Or the acid is hydrochloric acid or hydrochloric acid dioxane; and the solvent A is selected from the following group: ethyl acetate, 2-methyltetrahydrofuran, butanone, ethanol, acetone, ethyl acetate, acetonitrile, tetrahydrofuran, methyl isobutyl ketone, trifluoroethanol, water, methanol, methyl tert-butyl ether, toluene, isopropanol, dimethyl sulfoxide, isopropyl acetate, dichloromethane, or a combination thereof.

在另一优选例中，所述溶剂A选自下组：甲基异丁基酮/三氟乙醇、甲醇/水、甲醇/甲基叔丁基醚、异丙醇/二甲基亚砜、乙酸异丙酯/二甲基亚砜、水/二甲基亚砜。In another preferred embodiment, the solvent A is selected from the following group: methyl isobutyl ketone/trifluoroethanol, methanol/water, methanol/methyl tert-butyl ether, isopropanol/dimethyl sulfoxide, isopropyl acetate/dimethyl sulfoxide, water/dimethyl sulfoxide.

在另一优选例中，所述混悬包括如下步骤：In another preferred embodiment, the suspending comprises the following steps:

a.将式(I)化合物、酸和溶剂在45～65℃下混悬1～3h；a. suspending the compound of formula (I), the acid and the solvent at 45 to 65 ° C for 1 to 3 hours;

b.自然降温至20～30℃，并继续混悬至少48h；b. Cool naturally to 20-30°C and continue to suspend for at least 48 hours;

c.将所得混悬液通过0.4～0.5μm滤膜以12000～16000rpm转速离心；c. The resulting suspension was centrifuged at 12000-16000 rpm through a 0.4-0.5 μm filter membrane;

d.将所得固体在45～65℃下真空干燥。d. The obtained solid was dried under vacuum at 45-65°C.

本发明的另一方面，提供了一种上述式(I)化合物的药学上可接受的盐的晶型的方法，其特征在于，所述方法为通过晶型转化的方法，将式(I)化合物的药学上可接受的盐的一种晶型转化为该盐的另外一种晶型；Another aspect of the present invention provides a method for obtaining a crystalline form of a pharmaceutically acceptable salt of the compound of formula (I), characterized in that the method is a method of converting a crystalline form of a pharmaceutically acceptable salt of the compound of formula (I) into another crystalline form of the salt by a crystalline form conversion method;

其中，晶型转化的方法包括以下步骤：Wherein, the method for crystal form transformation comprises the following steps:

a.将式(I)化合物的药学上可接受的盐的一种晶型溶解到或分散到1～20倍体积的溶剂A中；a. dissolving or dispersing a crystalline form of a pharmaceutically acceptable salt of a compound of formula (I) into 1 to 20 times the volume of solvent A;

b.混悬；b. Suspension;

c.将所得混悬液通过0.4～0.5μm滤膜以12000～16000rpm转速离心过滤；c. The resulting suspension was centrifuged through a 0.4-0.5 μm filter membrane at a speed of 12000-16000 rpm;

其中，溶剂A选自下组：乙醇、丙酮、乙酸乙酯、乙腈、四氢呋喃、甲基异丁基酮、三氟乙醇、甲醇、2-甲基四氢呋喃、甲基叔丁基醚、甲苯、异丙醇、二甲基亚砜、乙酸异丙酯、二甲基亚砜、甲醇、二氯甲烷、水或其组合。Wherein, solvent A is selected from the following group: ethanol, acetone, ethyl acetate, acetonitrile, tetrahydrofuran, methyl isobutyl ketone, trifluoroethanol, methanol, 2-methyltetrahydrofuran, methyl tert-butyl ether, toluene, isopropanol, dimethyl sulfoxide, isopropyl acetate, dimethyl sulfoxide, methanol, dichloromethane, water or a combination thereof.

在另一优选例中，所述溶剂A选自下组：甲基异丁基酮/三氟乙醇、甲醇/水、异丙醇/二甲基亚砜、乙酸异丙酯/二甲基亚砜、二甲基亚砜/水。In another preferred embodiment, the solvent A is selected from the following group: methyl isobutyl ketone/trifluoroethanol, methanol/water, isopropanol/dimethyl sulfoxide, isopropyl acetate/dimethyl sulfoxide, and dimethyl sulfoxide/water.

在另一优选例中，所述混悬包括步骤：在20～30℃下，以300-400rpm速率搅拌。In another preferred embodiment, the suspending comprises the steps of: stirring at a rate of 300-400 rpm at 20-30°C.

在另一优选例中，所述混悬包括步骤：在40～60℃下，以300-400rpm速率搅拌。In another preferred embodiment, the suspending comprises the steps of: stirring at 40-60°C and at a rate of 300-400 rpm.

在另一优选例中，所述混悬包括步骤：在5～50℃之间以0.05～0.2℃/min的速率进行8～12个升降温循环，同时以300-400rpm速率搅拌，混悬液的终温度为10～15℃。In another preferred embodiment, the suspension comprises the steps of: performing 8 to 12 temperature rise and fall cycles at a rate of 0.05 to 0.2°C/min between 5 and 50°C, while stirring at a rate of 300-400 rpm, and the final temperature of the suspension is 10 to 15°C.

在另一优选例中，所述混悬包括步骤：利用0.4～0.5μm滤膜过滤得到澄清溶液，以1:(8～12)的比例添加甲基叔丁基醚后混悬。In another preferred embodiment, the suspending comprises the steps of: filtering with a 0.4-0.5 μm filter membrane to obtain a clear solution, adding methyl tert-butyl ether in a ratio of 1:(8-12) and then suspending.

本发明的另一方面，还提供了一种药物组合物，包括上述的式(I)化合物，上述的晶型A，或上述的式(I)化合物的晶型；Another aspect of the present invention provides a pharmaceutical composition, comprising the compound of formula (I), the crystalline form A, or the crystalline form of the compound of formula (I);

和and

一种或多种可药用的载体、赋形剂、佐剂、辅料和/或稀释剂。One or more pharmaceutically acceptable carriers, excipients, adjuvants, auxiliary materials and/or diluents.

在另一优选例中，所述药物组合物还包括其他治疗剂。In another preferred embodiment, the pharmaceutical composition further comprises other therapeutic agents.

在另一优选例中，所述其他治疗剂选自下组：化疗药物、激酶抑制剂、靶向表观遗传调节剂、抗体药物、免疫检查点抑制剂，或其组合。在另一优选例中，所述化疗药物选自下组：顺铂、多柔比星、紫杉醇、依托泊苷、伊立替康、环磷酰胺、吉西他滨、异环磷酰胺、他莫昔芬、托瑞米芬、氟维司群、阿那曲唑、依西美坦、戈舍瑞林、亮丙瑞林、美法仑、苯丁酸氮芥、白消安、氟尿苷、阿糖胞苷、奥沙利铂、亚叶酸、喷司他丁、己烯雌酚。In another preferred embodiment, the other therapeutic agent is selected from the group consisting of chemotherapeutic drugs, kinase inhibitors, targeted epigenetic regulators, antibody drugs, immune checkpoint inhibitors, or combinations thereof. In another preferred embodiment, the chemotherapeutic drug is selected from the group consisting of cisplatin, doxorubicin, paclitaxel, etoposide, irinotecan, cyclophosphamide, gemcitabine, ifosfamide, tamoxifen, toremifene, fulvestrant, anastrozole, exemestane, goserelin, leuprorelin, melphalan, chlorambucil, busulfan, floxuridine, cytarabine, oxaliplatin, folinic acid, pentostatin, diethylstilbestrol.

在另一优选例中，所述激酶抑制剂选自下组：Akt、TGF-βR、Pim、PKA、PKG、PKC、CaM激酶、CDK2、CDK4、CDK4/6、MEK、ERK、MAPK、mTOR、EGFR、HER2、HER3、HER4、PDGFαR、PDGFβR、CSFIR、KIT、c-Met、TRKA、TRKB、TRKC、FLT3、VEGFR、BTK、FAK、SYK、FRK、JAK、HPK1、AXL、ALK、B-Raf抑制剂。在另一优选例中，所述靶向表观遗传调节剂选自下组：溴结构域抑制剂、组蛋白赖氨酸甲基转移酶、组蛋白精氨酸甲基转移酶、组蛋白脱甲基酶、组蛋白脱乙酰酶、组蛋白乙酰化酶、DNA甲基转移酶。在另一优选例中，所述抗体药物选自下组：抗HER 2抗体、抗VEGFR抗体、抗EGFR抗体、抗c-MET抗体、抗CD20抗体。In another preferred embodiment, the kinase inhibitor is selected from the group consisting of Akt, TGF-βR, Pim, PKA, PKG, PKC, CaM kinase, CDK2, CDK4, CDK4/6, MEK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, PDGFαR, PDGFβR, CSFIR, KIT, c-Met, TRKA, TRKB, TRKC, FLT3, VEGFR, BTK, FAK, SYK, FRK, JAK, HPK1, AXL, ALK, B-Raf inhibitor. In another preferred embodiment, the targeted epigenetic regulator is selected from the group consisting of bromodomain inhibitors, histone lysine methyltransferases, histone arginine methyltransferases, histone demethylases, histone deacetylases, histone acetylases, and DNA methyltransferases. In another preferred embodiment, the antibody drug is selected from the following group: anti-HER 2 antibody, anti-VEGFR antibody, anti-EGFR antibody, anti-c-MET antibody, and anti-CD20 antibody.

在另一优选例中，所述免疫检查点抑制剂选自下组：CD27、CD28、CD40、CD122、CD96、CD73、CD47、OX40、GITR、A2AR、B7-H3、B7-H4、BTLA、CTLA-4、LAG3、TIM3、VISTA、PD-1、PD-L1、PD-L2。In another preferred embodiment, the immune checkpoint inhibitor is selected from the following group: CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1, PD-L1, and PD-L2.

本发明的另一方面，还提供了一种上述的式(I)化合物，上述的晶型A，上述的式(I)化合物的晶型，和上述的药物组合物在制备预防和/或治疗FGFR2的活性或表达量增加相关的疾病的药物中的用途。Another aspect of the present invention provides a use of the above-mentioned compound of formula (I), the above-mentioned crystalline form A, the above-mentioned crystalline form of the compound of formula (I), and the above-mentioned pharmaceutical composition in the preparation of a drug for preventing and/or treating diseases related to increased activity or expression of FGFR2.

在另一优选例中，所述FGFR2的活性或表达量增加选自下组：FGFR2扩增、FGFR2基因突变、FGFR2基因融合/重排、FGFR2基因易位、FGFR2基因激活。In another preferred embodiment, the increased activity or expression of FGFR2 is selected from the group consisting of: FGFR2 amplification, FGFR2 gene mutation, FGFR2 gene fusion/rearrangement, FGFR2 gene translocation, and FGFR2 gene activation.

在另一优选例中，所述FGFR2的活性或表达量增加相关的疾病选自下组：胆管癌、肝癌、乳腺癌、前列腺癌、肺癌、甲状腺癌、胃癌、卵巢癌、食管癌、胰腺癌、宫颈癌、结直肠癌、唾液腺癌、子宫内膜癌和尿道上皮癌等。In another preferred embodiment, the disease associated with increased activity or expression of FGFR2 is selected from the following group: bile duct cancer, liver cancer, breast cancer, prostate cancer, lung cancer, thyroid cancer, gastric cancer, ovarian cancer, esophageal cancer, pancreatic cancer, cervical cancer, colorectal cancer, salivary gland cancer, endometrial cancer and urothelial cancer, etc.

在另一优选例中，所述胆管癌为肝内胆管癌。In another preferred embodiment, the bile duct cancer is intrahepatic bile duct cancer.

在另一优选例中，所述肝癌为肝细胞癌。In another preferred embodiment, the liver cancer is hepatocellular carcinoma.

在另一优选例中，所述肺癌是肺鳞状细胞癌或非小细胞肺癌。In another preferred embodiment, the lung cancer is squamous cell lung carcinoma or non-small cell lung cancer.

附图说明BRIEF DESCRIPTION OF THE DRAWINGS

图1为化合物I-1晶型A的XRPD图谱。FIG1 is an XRPD spectrum of Compound I-1 Form A.

图2为化合物I-1晶型A的DSC图谱。FIG2 is a DSC spectrum of Compound I-1 Form A.

图3为化合物I-1晶型A的TGA图谱。FIG3 is a TGA spectrum of Compound I-1 Form A.

图4为化合物I-1马来酸盐晶型A的XRPD图谱。FIG4 is an XRPD spectrum of Compound I-1 maleate salt Form A.

图5为化合物I-1单马来酸盐晶型B的XRPD图谱。FIG5 is an XRPD spectrum of Compound I-1 monomaleate salt Form B.

图6为化合物I-1单马来酸盐晶型B的DSC图谱。FIG6 is a DSC spectrum of Compound I-1 monomaleate crystal form B.

图7为化合物I-1单马来酸盐晶型B的TGA图谱。FIG. 7 is a TGA spectrum of Compound I-1 monomaleate salt Form B.

图8为化合物I-1富马酸盐晶型A的XRPD图谱。FIG8 is an XRPD spectrum of Compound I-1 fumarate salt Form A.

图9为化合物I-1半富马酸盐晶型B的XRPD图谱。FIG9 is an XRPD spectrum of compound I-1 hemifumarate form B.

图10为化合物I-1半富马酸盐晶型B的DSC图谱。FIG10 is a DSC spectrum of compound I-1 hemifumarate form B.

图11为化合物I-1半富马酸盐晶型B的TGA图谱。FIG11 is a TGA spectrum of compound I-1 hemifumarate form B.

图12为化合物I-1单乙醇酸盐晶型A的XRPD图谱。FIG12 is an XRPD spectrum of Compound I-1 monoglycolic acid salt Form A.

图13为化合物I-1单乙醇酸盐晶型A的DSC图谱。FIG13 is a DSC spectrum of Compound I-1 monoglycolic acid salt Form A.

图14为化合物I-1单乙醇酸盐晶型A的TGA图谱。FIG14 is a TGA spectrum of Compound I-1 monoglycolic acid salt Form A.

图15为化合物I-1乙醇酸盐晶型B的XRPD图谱。FIG15 is an XRPD spectrum of Compound I-1 glycolate Form B.

图16为化合物I-1单L-苹果酸盐晶型A的XRPD图谱。FIG16 is an XRPD spectrum of Compound I-1 mono L-malate Form A.

图17为化合物I-1单L-苹果酸盐晶型A的DSC图谱。FIG17 is a DSC spectrum of Compound I-1 mono L-malate Form A.

图18为化合物I-1单L-苹果酸盐晶型A的TGA图谱。FIG18 is a TGA spectrum of Compound I-1 mono L-malate Form A.

图19为化合物I-1单琥珀酸盐晶型A的XRPD图谱。FIG19 is an XRPD spectrum of Compound I-1 monosuccinate Form A.

图20为化合物I-1单琥珀酸盐晶型A的DSC图谱。FIG20 is a DSC spectrum of Compound I-1 monosuccinate Form A.

图21为化合物I-1单琥珀酸盐晶型A的TGA图谱。Figure 21 is the TGA spectrum of Compound I-1 monosuccinate form A.

图22为化合物I-1硫酸盐晶型A的XRPD图谱。FIG. 22 is an XRPD spectrum of Compound I-1 sulfate salt Form A.

图23为化合物I-1L-酒石酸盐晶型A的XRPD图谱。FIG. 23 is an XRPD spectrum of Compound I-1 L-tartrate Form A.

图24为化合物I-1马尿酸盐晶型A的XRPD图谱。FIG. 24 is an XRPD spectrum of Form A of the hippurate salt of Compound I-1.

图25为化合物I-1戊二酸盐晶型A的XRPD图谱。Figure 25 is the XRPD spectrum of Compound I-1 glutaric acid salt Form A.

图26为化合物I-1对甲苯磺酸盐晶型A的XRPD图谱。FIG26 is an XRPD spectrum of Compound I-1 p-toluenesulfonate Form A.

图27为化合物I-1对甲苯磺酸盐晶型B的XRPD图谱。FIG27 is an XRPD spectrum of Compound I-1 p-toluenesulfonate Form B.

图28为化合物I-1甲磺酸盐晶型A的XRPD图谱。FIG28 is an XRPD spectrum of Compound I-1 mesylate Form A.

图29为化合物I-1盐酸盐晶型C1的XRPD图谱。FIG29 is an XRPD spectrum of Compound I-1 hydrochloride salt form C1.

图30为化合物I-1盐酸盐晶型C1的DSC图谱。FIG30 is a DSC spectrum of Compound I-1 hydrochloride salt form C1.

图31为化合物I-1盐酸盐晶型C1的TGA图谱。FIG31 is a TGA spectrum of Compound I-1 hydrochloride salt form C1.

图32为化合物I-1盐酸盐晶型C2的XRPD图谱。Figure 32 is the XRPD spectrum of Compound I-1 hydrochloride salt form C2.

图33为化合物I-1盐酸盐晶型C2的DSC图谱。FIG33 is a DSC spectrum of Compound I-1 hydrochloride salt form C2.

图34为化合物I-1盐酸盐晶型C2的TGA图谱。Figure 34 is the TGA spectrum of Compound I-1 hydrochloride salt form C2.

图35为化合物I-1盐酸盐晶型D的XRPD图谱。FIG35 is an XRPD spectrum of Compound I-1 hydrochloride Form D.

图36为化合物I-1盐酸盐晶型D的DSC图谱。FIG36 is a DSC spectrum of Compound I-1 hydrochloride Form D.

图37为化合物I-1盐酸盐晶型D的TGA图谱。FIG37 is a TGA spectrum of Compound I-1 hydrochloride Form D.

图38为化合物I-1盐酸盐晶型E1的XRPD图谱。FIG38 is an XRPD spectrum of Compound I-1 hydrochloride salt Form E1.

图39为化合物I-1盐酸盐晶型E1的DSC图谱。FIG39 is a DSC spectrum of Compound I-1 hydrochloride form E1.

图40为化合物I-1盐酸盐晶型E1的TGA图谱。FIG40 is a TGA spectrum of Compound I-1 hydrochloride salt form E1.

图41为化合物I-1盐酸盐晶型E2的XRPD图谱。Figure 41 is the XRPD spectrum of Compound I-1 hydrochloride form E2.

图42为化合物I-1盐酸盐晶型E2的DSC图谱。FIG42 is a DSC spectrum of Compound I-1 hydrochloride form E2.

图43为化合物I-1盐酸盐晶型E2的TGA图谱。Figure 43 is the TGA spectrum of Compound I-1 hydrochloride form E2.

图44为化合物I-1盐酸盐晶型F的XRPD图谱。Figure 44 is the XRPD spectrum of Compound I-1 hydrochloride Form F.

图45为化合物I-1盐酸盐晶型F的DSC图谱。FIG45 is a DSC spectrum of Compound I-1 hydrochloride Form F.

图46为化合物I-1盐酸盐晶型F的TGA图谱。Figure 46 is the TGA spectrum of Compound I-1 hydrochloride form F.

图47为化合物I-1盐酸盐晶型G的XRPD图谱。Figure 47 is the XRPD spectrum of Compound I-1 hydrochloride Form G.

图48为化合物I-1盐酸盐晶型G的DSC图谱。FIG48 is a DSC spectrum of Compound I-1 hydrochloride Form G.

图49为化合物I-1盐酸盐晶型G的TGA图谱。FIG49 is a TGA spectrum of Compound I-1 hydrochloride Form G.

图50为化合物I-1盐酸盐晶型H的XRPD图谱。Figure 50 is the XRPD spectrum of Compound I-1 hydrochloride salt Form H.

图51为化合物I-1盐酸盐晶型H的DSC图谱。Figure 51 is the DSC spectrum of Compound I-1 hydrochloride form H.

图52为化合物I-1盐酸盐晶型H的TGA图谱。Figure 52 is the TGA spectrum of Compound I-1 hydrochloride form H.

图53为化合物I-1盐酸盐晶型I的XRPD图谱。Figure 53 is the XRPD spectrum of Compound I-1 hydrochloride salt Form I.

图54为化合物I-1盐酸盐晶型I的DSC图谱。Figure 54 is the DSC spectrum of Compound I-1 hydrochloride salt Form I.

图55为化合物I-1盐酸盐晶型I的TGA图谱。Figure 55 is the TGA spectrum of Compound I-1 hydrochloride salt form I.

图56为化合物I-1盐酸盐晶型J1的XRPD图谱。Figure 56 is the XRPD spectrum of Compound I-1 hydrochloride salt form J1.

图57为化合物I-1盐酸盐晶型J1的DSC图谱。Figure 57 is the DSC spectrum of Compound I-1 hydrochloride salt form J1.

图58为化合物I-1盐酸盐晶型J1的TGA图谱。Figure 58 is the TGA spectrum of Compound I-1 hydrochloride salt form J1.

图59为化合物I-1盐酸盐晶型J2的XRPD图谱。Figure 59 is the XRPD spectrum of Compound I-1 hydrochloride salt form J2.

图60为化合物I-1盐酸盐晶型J2的DSC图谱。Figure 60 is the DSC spectrum of Compound I-1 hydrochloride salt form J2.

图61为化合物I-1盐酸盐晶型J2的TGA图谱。Figure 61 is the TGA spectrum of Compound I-1 hydrochloride salt form J2.

图62为化合物I-1盐酸盐晶型K的XRPD图谱。Figure 62 is the XRPD spectrum of Compound I-1 hydrochloride Form K.

图63为化合物I-1盐酸盐晶型K的DSC图谱。Figure 63 is the DSC spectrum of Compound I-1 hydrochloride form K.

图64为化合物I-1盐酸盐晶型K的TGA图谱。Figure 64 is the TGA spectrum of Compound I-1 hydrochloride form K.

图65为化合物I-1盐酸盐晶型L的XRPD图谱。Figure 65 is the XRPD spectrum of Compound I-1 hydrochloride form L.

图66为化合物I-1盐酸盐晶型L的DSC图谱。Figure 66 is the DSC spectrum of Compound I-1 hydrochloride form L.

图67为化合物I-1盐酸盐晶型L的TGA图谱。Figure 67 is the TGA spectrum of Compound I-1 hydrochloride form L.

图68为化合物I-1盐酸盐晶型M的XRPD图谱。Figure 68 is the XRPD spectrum of Compound I-1 hydrochloride form M.

图69为化合物I-1盐酸盐晶型M的DSC图谱。FIG69 is a DSC spectrum of Compound I-1 hydrochloride salt form M.

图70为化合物I-1盐酸盐晶型M的TGA图谱。Figure 70 is the TGA spectrum of Compound I-1 hydrochloride form M.

图71为化合物I-1盐酸盐晶型N的XRPD图谱。Figure 71 is the XRPD spectrum of Compound I-1 hydrochloride form N.

图72为化合物I-1盐酸盐晶型N的DSC图谱。Figure 72 is the DSC spectrum of Compound I-1 hydrochloride form N.

图73为化合物I-1盐酸盐晶型N的TGA图谱。Figure 73 is the TGA spectrum of Compound I-1 hydrochloride form N.

图74为化合物I-1盐酸盐晶型O的XRPD图谱。Figure 74 is the XRPD spectrum of Compound I-1 hydrochloride form O.

图75为化合物I-1盐酸盐晶型O的DSC图谱。Figure 75 is the DSC spectrum of Compound I-1 hydrochloride form O.

图76为化合物I-1盐酸盐晶型O的TGA图谱。Figure 76 is the TGA spectrum of Compound I-1 hydrochloride form O.

具体实施方式DETAILED DESCRIPTION

为解决现有技术存在的问题，发明人深入研究了式(I)化合物的不同形态，开发出式(I)化合物的多种晶型和酸式盐的晶型，尤其是盐酸盐，大大改善了式(I)化合物的溶解性、吸湿性和化学稳定性等物化性能，所述结晶型酸式盐化合物原料符合工业生产要求，能够满足临床药物制剂开发需要，具有非常重要的临床应用价值，有望加速开发成新一代FGFR2抑制剂。在此基础上，完成了本发明。In order to solve the problems existing in the prior art, the inventors have conducted in-depth research on the different forms of the compound of formula (I), and developed a variety of crystal forms and acid salt crystal forms of the compound of formula (I), especially the hydrochloride, which greatly improved the physical and chemical properties of the compound of formula (I), such as solubility, hygroscopicity and chemical stability. The raw materials of the crystalline acid salt compound meet the requirements of industrial production, can meet the needs of clinical drug preparation development, have very important clinical application value, and are expected to accelerate the development of a new generation of FGFR2 inhibitors. On this basis, the present invention was completed.

定义definition

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。Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient.

如本文所用，术语“n个或n个以上选自下组的2θ值”指包括n以及大于n的任意正整数(例如n、n+1、…….)，其中上限Nup为该组中所有2θ峰值的个数。例如“1个或1个以上”不仅包括1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、……上限Nup各个正整数，还包括“2个或2个以上”、“3个或3个以上”、“4个或4个以上”、“5个或5个以上”、“6个或6个以上”、“7个或7个以上”、“8个或8个以上”、“9个或9个以上”、“10个或10个以上”等范围。例如“3个或3个以上”不仅包括3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、…上限Nup各个正整数，还包括“4个或4个以上”、“5个或5个以上”、“6个或6个以上”、“7个或7个以上”、“8个或8个以上”、“9个或9个以上”、“10个或10个以上”等范围。As used herein, the term "n or more 2θ values selected from the following group" refers to any positive integer greater than n (e.g., n, n+1, ...), including n and n, wherein the upper limit Nup is the number of all 2θ peaks in the group. For example, "1 or more" includes not only 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, ... each positive integer of the upper limit Nup, but also includes "2 or more", "3 or more", "4 or more", "5 or more", "6 or more", "7 or more", "8 or more", "9 or more", "10 or more", etc. For example, "3 or more" not only includes 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, ... the upper limit Nup, each positive integer, but also includes "4 or more", "5 or more", "6 or more", "7 or more", "8 or more", "9 or more", "10 or more" and other ranges.

如本文所用，“将式(I)化合物溶解或分散到1～5倍体积的溶剂中”是指将1克式(I)化合物溶解或分散到1～5毫升溶剂中，其中溶剂包括但不限于乙腈、醇类溶剂、酯类溶剂、醚类溶剂或醇类溶剂与水的混合溶剂。As used herein, "dissolving or dispersing the compound of formula (I) in 1 to 5 volumes of a solvent" means dissolving or dispersing 1 gram of the compound of formula (I) in 1 to 5 milliliters of a solvent, wherein the solvent includes but is not limited to acetonitrile, alcohol solvents, ester solvents, ether solvents, or a mixed solvent of an alcohol solvent and water.

本发明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、其与其它化学合成方法的结合所形成的实施方式以及本领域技术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发明的实施例。The intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the embodiments of the present invention.

本发明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发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物，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。The chemical reactions of the specific embodiments of the present invention are carried out in a suitable solvent, which must be suitable for the chemical changes of the present invention and the reagents and materials required. In order to obtain the compounds of the present invention, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction processes based on the existing embodiments.

下面会通过实施例具体描述本发明，这些实施例并不意味着本发明的任何限制。The present invention will be described in detail below by way of examples, which are not intended to limit the present invention in any way.

本发明所使用的所有溶剂是市售的，无需进一步纯化即可使用。All solvents used in the present invention were commercially available and used without further purification.

本发明中使用的常用缩写如下：
Common abbreviations used in the present invention are as follows:

本发明所用测试项目及方法如下：


The test items and methods used in the present invention are as follows:


为了更好的理解本发明的内容，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发明的内容所做的限制。In order to better understand the content of the present invention, further description is given below in conjunction with specific embodiments, but the specific implementation methods are not intended to limit the content of the present invention.

实施例1：式(I-1)化合物的制备
Example 1: Preparation of the compound of formula (I-1)

第一步：first step:

将化合物a(5.0g,26.3mmol)、三乙胺(8.0g,11ml)溶于DCM(50ml)，0℃下，逐滴加入2-甲基丙烯酰氯(3.03g,2.8ml)于反应液中，反应搅拌1h。用水(100ml)稀释反应液，DCM(100ml)萃取三次。有机相用饱和食盐水洗涤，无水Na2SO4干燥，减压浓缩所得粗产物通过硅胶柱层析(EA/PE＝1/4)纯化得到化合物b(4.9g,72％)，淡黄白色固体。Compound a (5.0 g, 26.3 mmol) and triethylamine (8.0 g, 11 ml) were dissolved in DCM (50 ml). 2-Methacryloyl chloride (3.03 g, 2.8 ml) was added dropwise to the reaction solution at 0°C and the reaction was stirred for 1 h. The reaction solution was diluted with water (100 ml) and extracted with DCM (100 ml) three times. The organic phase was washed with saturated brine, dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA/PE=1/4) to obtain compound b (4.9 g, 72%) as a pale yellowish white solid.

MS(ESI)m/z 258,260[M+H]+。MS (ESI) m/z 258,260 [M+H] + .

第二步：Step 2:

将化合物b(2.0g,7.75mmol)、频哪醇二硼(3.94g,15.5mmol)、Pd(dppf)Cl2(567mg,0.77mmol),AcOK(2.28g,23.25mmol),1,4-二氧六环(20ml)加入密封管中，氩气置换三次。将混合物在90℃反应5h。用水淬灭反应，用DCM萃取。有机相用饱和食盐水洗涤，经无水Na2SO4干燥，减压浓缩。所得粗产物通过硅胶柱层析(EA/PE＝1/8to 1/4)纯化得到化合物c(1.52g,64％)，黄色固体。Compound b (2.0 g, 7.75 mmol), pinacol diboron (3.94 g, 15.5 mmol), Pd(dppf)Cl 2 (567 mg, 0.77 mmol), AcOK (2.28 g, 23.25 mmol), 1,4-dioxane (20 ml) were added to a sealed tube and replaced with argon three times. The mixture was reacted at 90°C for 5 h. The reaction was quenched with water and extracted with DCM. The organic phase was washed with saturated brine, dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA/PE=1/8 to 1/4) to obtain compound c (1.52 g, 64%) as a yellow solid.

MS(ESI)m/z 306[M+H]+。MS (ESI) m/z 306 [M+H] + .

1H NMR(500MHz,CDCl3)δ7.70-7.65(m,2H),7.53(dd,J＝11.5,1.9Hz,1H),7.20(dd,J＝8.2,1.9Hz,1H),5.78(s,1H),5.48(d,J＝1.7Hz,1H),2.04(s,3H),1.34(s,12H). 1 H NMR (500MHz, CDCl 3 )δ7.70-7.65(m,2H),7.53(dd,J＝11.5,1.9Hz,1H),7.20(dd,J＝8.2,1.9Hz,1H),5.78(s,1H),5.48(d,J＝1.7Hz,1H),2.04(s,3H),1.34(s,12H).

第三步：Step 3:

将化合物d(2.00g,19.6mmol)、氨基甲酸铵(2.29g,29.4mmol)依次加入烧瓶中，然后加入MeOH(40mL)，碘苯二乙酯(13.24g,41.1mmol)，反应液在室温下敞口搅拌30min后减压浓缩除去溶剂得到粗产品，粗品经柱层析(MeOH/DCM＝1/80)纯化得到化合物e(1.62g)，白色固体。Compound d (2.00 g, 19.6 mmol) and ammonium carbamate (2.29 g, 29.4 mmol) were added to a flask in sequence, and then MeOH (40 mL) and diethyl iodophenyl (13.24 g, 41.1 mmol) were added. The reaction solution was stirred at room temperature for 30 min and then concentrated under reduced pressure to remove the solvent to obtain a crude product. The crude product was purified by column chromatography (MeOH/DCM=1/80) to obtain compound e (1.62 g) as a white solid.

MS(ESI)m/z 120[M+H]+。MS (ESI) m/z 120 [M+H] + .

第四步：Step 4:

将化合物e(282mg,2.35mmol)、碳酸艳(892mg,2.74mmol)、1-溴-4-碘苯(552mg,1.96mmol)、Pd2(dba)3(40mg,0.05mmol)及Xantphos(77mg,0.13mmol)加入到1,4-二氧六环(10mL)中，反应液加热至105℃反应13h。反应液经硅藻土过滤，乙酸乙酯(50mL)洗涤滤饼，饱和食盐水(50mL)洗涤，有机相用无水硫酸钠干燥，减压浓缩得到粗产品，粗品经柱层析(PE/EtOAc＝4/1to 1/1)纯化得到化合物f(410mg)，黄色油状液体。Compound e (282 mg, 2.35 mmol), cesium carbonate (892 mg, 2.74 mmol), 1-bromo-4-iodobenzene (552 mg, 1.96 mmol), Pd 2 (dba) 3 (40 mg, 0.05 mmol) and Xantphos (77 mg, 0.13 mmol) were added to 1,4-dioxane (10 mL), and the reaction solution was heated to 105°C for 13 h. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate (50 mL), and saturated brine (50 mL), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE/EtOAc=4/1 to 1/1) to obtain compound f (410 mg), a yellow oily liquid.

MS(ESI)m/z 274[M+H]+。MS (ESI) m/z 274 [M+H] + .

第五步：Step 5:

向100mL圆底烧瓶中依次加入化合物f(1.02g,3.10mmol)，联硼酸频那醇酯(0.973g,3.83mmol)，Pd(dppf)Cl2(0.461mg,0.63mmol),醋酸钾(0.943g,9.61mmol)，1,4-二氧六环(20mL)。升温至100℃反应4h，监测反应完成后，冷却至室温，硅藻土过滤，乙酸乙酯萃取(50mL×3)，合并有机相，饱和食盐水洗涤(50mL)，减压浓缩得到粗产品，粗品经柱层析纯化(PE/EtOAc＝1/1)得化合物g(0.80g)，黄色固体。Compound f (1.02 g, 3.10 mmol), bipyralidin (0.973 g, 3.83 mmol), Pd(dppf)Cl 2 (0.461 mg, 0.63 mmol), potassium acetate (0.943 g, 9.61 mmol), 1,4-dioxane (20 mL) were added to a 100 mL round-bottom flask in sequence. The temperature was raised to 100 °C for 4 h. After the reaction was completed, it was cooled to room temperature, filtered through celite, extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated brine (50 mL), and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (PE/EtOAc = 1/1) to obtain compound g (0.80 g) as a yellow solid.

1H NMR(400MHz,CDCl3)δ7.62(d,J＝8.3Hz,2H),6.98(d,J＝8.3Hz,2H),3.37–3.30(m,1H),3.15–3.08(m,1H),2.20(dd,J＝29.3,6.9Hz,2H),1.26(s,6H). 1 H NMR (400MHz, CDCl 3 )δ7.62(d,J＝8.3Hz,2H),6.98(d,J＝8.3Hz,2H),3.37–3.30(m,1H),3.15–3.08(m,1H),2.20(dd,J＝29.3,6.9Hz,2H),1.26(s,6H).

第六步：Step 6:

将化合物h(10.6g 0.0466mol)溶于二氯甲烷(100mL)和三氟乙酸(26.7g 0.2334mol)，在10℃下搅拌，分批加入N-碘代丁二酰亚胺(10.5g 0.0466mol)，反应4h，反应完成后，在10℃下缓慢滴加饱和碳酸氢钠水溶液150mL，有固体析出，过滤烘干得到化合物i(13.4g)，紫色固体。Compound h (10.6 g 0.0466 mol) was dissolved in dichloromethane (100 mL) and trifluoroacetic acid (26.7 g 0.2334 mol), stirred at 10°C, N-iodosuccinimide (10.5 g 0.0466 mol) was added in batches, and the reaction was continued for 4 h. After the reaction was completed, 150 mL of saturated sodium bicarbonate aqueous solution was slowly added dropwise at 10°C. A solid precipitated, which was filtered and dried to obtain compound i (13.4 g) as a purple solid.

1H NMR(400MHz,CDCl3)δ8.22(s,1H),5.61(s,2H),3.80(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.22(s,1H),5.61(s,2H),3.80(s,3H).

第七步：Step 7:

将化合物i(2g,6.5mmol)、化合物c(2.3g,6.5mmol)、四(三苯基膦)钯(0.65g,0.56mmol)和磷酸钾(3.6g,0.017mol)加入到反应瓶中，氮气置换3次，并加入DMF(35mL)和水(5mL)，50℃下搅拌16h。反应完成后，加入水(150mL)，二氯甲烷(200mL),萃取分液，有机相用饱和食盐水洗涤，有机相浓缩后得到粗品，粗品经柱层析纯化得到化合物j(1.1g)，淡黄色固体。Compound i (2g, 6.5mmol), compound c (2.3g, 6.5mmol), tetrakis(triphenylphosphine)palladium (0.65g, 0.56mmol) and potassium phosphate (3.6g, 0.017mol) were added to a reaction flask, replaced with nitrogen three times, and DMF (35mL) and water (5mL) were added, and stirred at 50°C for 16h. After the reaction was completed, water (150mL) and dichloromethane (200mL) were added, and the liquid was extracted and separated. The organic phase was washed with saturated brine, and the organic phase was concentrated to obtain a crude product, which was purified by column chromatography to obtain compound j (1.1g) as a light yellow solid.

ESI-MS m/z 404.2[M+H]+ ESI-MS m/z 404.2[M+H] +

1H NMR(400MHz,CDCl3)δ8.35(s,1H),7.82(dd,J＝11.7,2.1Hz,1H),7.69(s,1H),7.44–7.33(m,2H),5.87(s,1H),5.66(s,2H),5.58(q,J＝1.5Hz,1H),3.66(d,J＝1.1Hz,3H),2.12(dd,J＝1.6,0.9Hz,3H).1H NMR (400MHz, CDCl 3 )δ8.35(s,1H),7.82(dd,J＝11.7,2.1Hz,1H),7.69(s,1H),7.44–7.33(m,2H),5.87(s,1H ),5.66(s,2H),5.58(q,J＝1.5Hz,1H),3.66(d,J＝1.1Hz,3H),2.12(dd,J＝1.6,0.9Hz,3H).

第八步：Step 8:

向25mL圆底烧瓶中依次加入化合物g(45mg,0.14mmol)，化合物j(50mg,0.12mmol)，Pd(dppf)Cl2(20mg,0.03mmol)，磷酸钾(80mg,0.38mmol)，1,4-二氧六环(5mL)和水(1mL)。升温至80℃反应0.5h，监测反应完成后，冷却至室温，硅藻土过滤，乙酸乙酯萃取(20mL×3),合并有机相，饱和食盐水洗涤(20mL)，减压浓缩得到粗产品，粗品经柱层析纯化(DCM/MeOH＝6/1)得式I-1化合物(22mg)，白色固体。Compound g (45 mg, 0.14 mmol), compound j (50 mg, 0.12 mmol), Pd(dppf)Cl 2 (20 mg, 0.03 mmol), potassium phosphate (80 mg, 0.38 mmol), 1,4-dioxane (5 mL) and water (1 mL) were added to a 25 mL round-bottom flask in sequence. The temperature was raised to 80°C for reaction for 0.5 h. After monitoring the reaction, the mixture was cooled to room temperature, filtered through diatomaceous earth, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated brine (20 mL), and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (DCM/MeOH=6/1) to obtain the compound of formula I-1 (22 mg) as a white solid.

MS(ESI)m/z 519.4[M+H]+ MS (ESI) m/z 519.4 [M+H] +

1H NMR(400MHz,CDCl3)δ8.28(s,1H),7.65–7.61(m,1H),7.48(s,1H),7.05(d,J＝7.7Hz,2H),7.00(t,J＝4.1Hz,2H),6.91(d,J＝8.5Hz,2H),5.73(s,1H),5.45(d,J＝1.3Hz,1H),4.98(s,2H),3.59(d,J＝0.9Hz,3H),3.36(dd,J＝12.6,6.0Hz,2H),3.13(dd,J＝12.8,6.6Hz,2H),2.29–2.19(m,3H),1.99(d,J＝10.1Hz,3H). 1 H NMR (400MHz, CDCl 3 )δ8.28(s,1H),7.65–7.61(m,1H),7.48(s,1H),7.05(d,J＝7.7Hz,2H),7 .00(t,J＝4.1Hz,2H),6.91(d,J＝8.5Hz,2H),5.73(s,1H),5.45(d,J＝1.3H z,1H),4.98(s,2H),3.59(d,J＝0.9Hz,3H),3.36(dd,J＝12.6,6.0Hz,2H),3.13(dd,J＝12.8,6.6Hz,2H),2.29–2.19(m,3H),1.99(d,J＝10.1Hz,3H).

实施例2：式I-1化合物的晶型A制备Example 2: Preparation of Form A of the Compound of Formula I-1

将上述式I-1化合物(61g)加入乙酸乙酯(100)mL中，室温搅拌过夜，过滤，干燥得到式I-1化合物的晶型A样品(58.2g)，白色固体。The above-mentioned compound of formula I-1 (61 g) was added to ethyl acetate (100) mL, stirred at room temperature overnight, filtered, and dried to obtain a crystalline form A sample (58.2 g) of the compound of formula I-1 as a white solid.

实施例3：式I-1化合物的马来酸盐晶型A制备Example 3: Preparation of maleate salt form A of the compound of formula I-1

3.1：称取约20mg式I-1化合物与1.0当量的马来酸置于2mL玻璃瓶中，加入0.15mL乙腈中以混悬法进行筛选实验。所得样品在50℃下混悬2h，之后自然降温至25℃，并在25℃下混悬至少48h。将所得混悬液通过0.45μm尼龙滤膜以14,000rpm转速离心，所得的固体在50℃下真空干燥2h后得到式I-1化合物的马来酸盐晶型A样品。3.1: Weigh about 20 mg of the compound of formula I-1 and 1.0 equivalent of maleic acid into a 2 mL glass bottle, add 0.15 mL of acetonitrile and perform a screening experiment by suspension method. The obtained sample is suspended at 50°C for 2 hours, then naturally cooled to 25°C, and suspended at 25°C for at least 48 hours. The obtained suspension is centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane, and the obtained solid is vacuum dried at 50°C for 2 hours to obtain a maleate crystal form A sample of the compound of formula I-1.

3.2：称取约20mg式I-1化合物与1.0当量的反离子置于2mL玻璃瓶中，加入0.15mL二氯甲烷中以混悬法进行筛选实验。所得样品在50℃下混悬2h，之后自然降温至25℃，并在25℃下混悬至少48h。将所得混悬液通过0.45μm尼龙滤膜以14,000rpm转速离心，所得的固体在50℃下真空干燥2h后得到式I-1化合物的马来酸盐晶型A样品。3.2: Weigh about 20 mg of the compound of formula I-1 and 1.0 equivalent of the counterion into a 2 mL glass bottle, add 0.15 mL of dichloromethane and perform a screening experiment by suspension method. The obtained sample is suspended at 50°C for 2 hours, then naturally cooled to 25°C, and suspended at 25°C for at least 48 hours. The obtained suspension is centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane, and the obtained solid is vacuum dried at 50°C for 2 hours to obtain a maleate salt crystal form A sample of the compound of formula I-1.

实施例4：式I-1化合物的单马来酸盐晶型B制备Example 4: Preparation of Monomaleate Crystal Form B of Compound of Formula I-1

称取约20mg式I-1化合物与1.0当量的马来酸置于2mL玻璃瓶中，加入0.15mL四氢呋喃中以混悬法进行筛选实验。所得样品在50℃下混悬2h，之后自然降温至25℃，并在25℃下混悬至少48h。将所得混悬液通过0.45μm尼龙滤膜以14,000rpm转速离心，所得的固体在50℃下真空干燥2h后得到式I-1化合物的单马来酸盐晶型B样品。About 20 mg of the compound of formula I-1 and 1.0 equivalent of maleic acid were weighed and placed in a 2 mL glass bottle, and 0.15 mL of tetrahydrofuran was added to perform a screening experiment by suspension method. The obtained sample was suspended at 50° C. for 2 hours, then naturally cooled to 25° C., and suspended at 25° C. for at least 48 hours. The obtained suspension was centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane, and the obtained solid was vacuum dried at 50° C. for 2 hours to obtain a monomaleate crystal form B sample of the compound of formula I-1.

实施例5：式I-1化合物的富马酸盐晶型A制备Example 5: Preparation of Fumarate Crystalline Form A of the Compound of Formula I-1

5.1：称取约20mg式I-1化合物与1.0当量的富马酸置于2mL玻璃瓶中，加入0.15mL乙腈中以混悬法进行筛选实验。所得样品在50℃下混悬2h，之后自然降温至25℃，并在25℃下混悬至少48h。将所得混悬液通过0.45μm尼龙滤膜以14,000rpm转速离心，所得的固体在50℃下真空干燥2h后得到式I-1化合物的富马酸盐晶型A样品。5.1: Weigh about 20 mg of the compound of formula I-1 and 1.0 equivalent of fumaric acid into a 2 mL glass bottle, add 0.15 mL of acetonitrile and perform a screening experiment by suspension method. The obtained sample is suspended at 50°C for 2 hours, then naturally cooled to 25°C, and suspended at 25°C for at least 48 hours. The obtained suspension is centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane, and the obtained solid is vacuum dried at 50°C for 2 hours to obtain a fumarate salt crystal form A sample of the compound of formula I-1.

5.2：称取约20mg式I-1化合物与1.0当量的富马酸置于2mL玻璃瓶中，加入0.15mL二氯甲烷中以混悬法进行筛选实验。所得样品在50℃下混悬2h，之后自然降温至25℃，并在25℃下混悬至少48h。将所得混悬液通过0.45μm尼龙滤膜以14,000rpm转速离心，所得的固体在50℃下真空干燥2h后得到式I-1化合物的富马酸盐晶型A样品。5.2: Weigh about 20 mg of the compound of formula I-1 and 1.0 equivalent of fumaric acid into a 2 mL glass bottle, add 0.15 mL of dichloromethane and perform a screening experiment by suspension method. The obtained sample is suspended at 50°C for 2 hours, then naturally cooled to 25°C, and suspended at 25°C for at least 48 hours. The obtained suspension is centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane, and the obtained solid is vacuum dried at 50°C for 2 hours to obtain a fumarate salt crystal form A sample of the compound of formula I-1.

实施例6：式I-1化合物的半富马酸盐晶型B制备Example 6: Preparation of Hemifumarate Form B of the Compound of Formula I-1

称取约20mg式I-1化合物与1.0当量的富马酸置于2mL玻璃瓶中，加入0.15mL四氢呋喃中以混悬法进行筛选实验。所得样品在50℃下混悬2h，之后自然降温至25℃，并在25℃下混悬至少48h。将所得混悬液通过0.45μm尼龙滤膜以14,000rpm转速离心，所得的固体在50℃下真空干燥2h后得到式I-1化合物的半富马酸盐晶型B样品。About 20 mg of the compound of formula I-1 and 1.0 equivalent of fumaric acid were weighed and placed in a 2 mL glass bottle, and 0.15 mL of tetrahydrofuran was added to perform a screening experiment by suspension method. The obtained sample was suspended at 50° C. for 2 hours, then naturally cooled to 25° C., and suspended at 25° C. for at least 48 hours. The obtained suspension was centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane, and the obtained solid was vacuum dried at 50° C. for 2 hours to obtain a hemi-fumarate crystal form B sample of the compound of formula I-1.

实施例7：式I-1化合物的单乙醇酸盐晶型A制备Example 7: Preparation of Monoglycolic Acid Salt Form A of Compound of Formula I-1

称取约20mg式I-1化合物与1.0当量的乙醇酸置于2mL玻璃瓶中，加入0.15mL乙腈中以混悬法进行筛选实验。所得样品在50℃下混悬2h，之后自然降温至25℃，并在25℃下混悬至少48h。将所得混悬液通过0.45μm尼龙滤膜以14,000rpm转速离心，所得的固体在50℃下真空干燥2h后得到式I-1化合物的单乙醇酸盐晶型A样品。About 20 mg of the compound of formula I-1 and 1.0 equivalent of glycolic acid were weighed and placed in a 2 mL glass bottle, and 0.15 mL of acetonitrile was added to perform a screening experiment by suspension method. The obtained sample was suspended at 50° C. for 2 hours, then naturally cooled to 25° C., and suspended at 25° C. for at least 48 hours. The obtained suspension was centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane, and the obtained solid was vacuum dried at 50° C. for 2 hours to obtain a monoglycolic acid salt crystal form A sample of the compound of formula I-1.

实施例8：式I-1化合物的乙醇酸盐晶型B制备Example 8: Preparation of Glycolic Acid Salt Form B of the Compound of Formula I-1

8.1：称取约20mg式I-1化合物与1.0当量的乙醇酸置于2mL玻璃瓶中，加入0.15mL四氢呋喃中以混悬法进行筛选实验。所得样品在50℃下混悬2h，之后自然降温至25℃，并在25℃下混悬至少48h。将所得混悬液通过0.45μm尼龙滤膜以14,000rpm转速离心，所得的固体在50℃下真空干燥2h后得到式I-1化合物的乙醇酸盐晶型B样品。8.1: Weigh about 20 mg of the compound of formula I-1 and 1.0 equivalent of glycolic acid into a 2 mL glass bottle, add 0.15 mL of tetrahydrofuran and perform a screening experiment by suspension method. The obtained sample is suspended at 50°C for 2 hours, then naturally cooled to 25°C, and suspended at 25°C for at least 48 hours. The obtained suspension is centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane, and the obtained solid is vacuum dried at 50°C for 2 hours to obtain a glycolate crystal form B sample of the compound of formula I-1.

8.2：称取约20mg式I-1化合物与1.0当量的乙醇酸置于2mL玻璃瓶中，加入0.15mL二氯甲烷中以混悬法进行筛选实验。所得样品在50℃下混悬2h，之后自然降温至25℃，并在25℃下混悬至少48h。将所得混悬液通过0.45μm尼龙滤膜以14,000rpm转速离心，所得的固体在50℃下真空干燥2h后得到式I-1化合物的乙醇酸盐晶型B样品。8.2: Weigh about 20 mg of the compound of formula I-1 and 1.0 equivalent of glycolic acid into a 2 mL glass bottle, add 0.15 mL of dichloromethane and perform a screening experiment by suspension method. The obtained sample is suspended at 50°C for 2 hours, then naturally cooled to 25°C, and suspended at 25°C for at least 48 hours. The obtained suspension is centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane, and the obtained solid is vacuum dried at 50°C for 2 hours to obtain a glycolate crystal form B sample of the compound of formula I-1.

实施例9：式I-1化合物的单L-苹果酸盐晶型A制备Example 9: Preparation of Mono L-malate Crystalline Form A of the Compound of Formula I-1

9.1：称取约20mg式I-1化合物与1.0当量的L-苹果酸置于2mL玻璃瓶中，加入0.15mL四氢呋喃中以混悬法进行筛选实验。所得样品在50℃下混悬2h，之后自然降温至25℃，并在25℃下混悬至少48h。将所得混悬液通过0.45μm尼龙滤膜以14,000rpm转速离心，所得的固体在50℃下真空干燥2h后得到式I-1化合物的单L-苹果酸盐晶型A样品。9.1: Weigh about 20 mg of the compound of formula I-1 and 1.0 equivalent of L-malic acid into a 2 mL glass bottle, add 0.15 mL of tetrahydrofuran and perform a screening experiment by suspension method. The obtained sample is suspended at 50°C for 2 hours, then naturally cooled to 25°C, and suspended at 25°C for at least 48 hours. The obtained suspension is centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane, and the obtained solid is vacuum dried at 50°C for 2 hours to obtain a sample of the mono L-malate crystalline form A of the compound of formula I-1.

9.2：称取约20mg式I-1化合物与1.0当量的乙醇酸置于2mL玻璃瓶中，加入0.15mL二氯甲烷中以混悬法进行筛选实验。所得样品在50℃下混悬2h，之后自然降温至25℃，并在25℃下混悬至少48h。将所得混悬液通过0.45μm尼龙滤膜以14,000rpm转速离心，所得的固体在50℃下真空干燥2h后得到式I-1化合物的单L-苹果酸盐晶型A样品。9.2: Weigh about 20 mg of the compound of formula I-1 and 1.0 equivalent of glycolic acid into a 2 mL glass bottle, add 0.15 mL of dichloromethane and perform a screening experiment by suspension method. The obtained sample is suspended at 50°C for 2 hours, then naturally cooled to 25°C, and suspended at 25°C for at least 48 hours. The obtained suspension is centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane, and the obtained solid is vacuum dried at 50°C for 2 hours to obtain a sample of the mono L-malate crystalline form A of the compound of formula I-1.

9.3：称取约20mg式I-1化合物与1.0当量的乙醇酸置于2mL玻璃瓶中，加入0.15mL乙腈中以混悬法进行筛选实验。所得样品在50℃下混悬2h，之后自然降温至25℃，并在25℃下混悬至少48h。将所得混悬液通过0.45μm尼龙滤膜以14,000rpm转速离心，所得的固体在50℃下真空干燥2h后得到式I-1化合物的单L-苹果酸盐晶型A样品。9.3: Weigh about 20 mg of the compound of formula I-1 and 1.0 equivalent of glycolic acid into a 2 mL glass bottle, add 0.15 mL of acetonitrile and perform a screening experiment by suspension method. The obtained sample is suspended at 50°C for 2 hours, then naturally cooled to 25°C, and suspended at 25°C for at least 48 hours. The obtained suspension is centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane, and the obtained solid is vacuum dried at 50°C for 2 hours to obtain a sample of the mono L-malate crystalline form A of the compound of formula I-1.

实施例10：式I-1化合物的单琥珀酸盐晶型A制备Example 10: Preparation of Monosuccinate Form A of the Compound of Formula I-1

10.1：称取约20mg式I-1化合物与1.0当量的琥珀酸置于2mL玻璃瓶中，加入0.15mL乙腈中以混悬法进行筛选实验。所得样品在50℃下混悬2h，之后自然降温至25℃，并在25℃下混悬至少48h。将所得混悬液通过0.45μm尼龙滤膜以14,000rpm转速离心，所得的固体在50℃下真空干燥2h后得到式I-1化合物的单琥珀酸盐晶型A样品。10.1: Weigh about 20 mg of the compound of formula I-1 and 1.0 equivalent of succinic acid into a 2 mL glass bottle, add 0.15 mL of acetonitrile and perform a screening experiment by suspension method. The obtained sample is suspended at 50°C for 2 hours, then naturally cooled to 25°C, and suspended at 25°C for at least 48 hours. The obtained suspension is centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane, and the obtained solid is vacuum dried at 50°C for 2 hours to obtain a monosuccinate crystalline form A sample of the compound of formula I-1.

10.2：称取约20mg式I-1化合物与1.0当量的琥珀酸置于2mL玻璃瓶中，加入0.15mL二氯甲烷中以混悬法进行筛选实验。所得样品在50℃下混悬2h，之后自然降温至25℃，并在25℃下混悬至少48h。将所得混悬液通过0.45μm尼龙滤膜以14,000rpm转速离心，所得的固体在50℃下真空干燥2h后得到式I-1化合物的单琥珀酸盐晶型A样品。10.2: Weigh about 20 mg of the compound of formula I-1 and 1.0 equivalent of succinic acid into a 2 mL glass bottle, add 0.15 mL of dichloromethane and perform a screening experiment by suspension method. The obtained sample is suspended at 50°C for 2 hours, then naturally cooled to 25°C, and suspended at 25°C for at least 48 hours. The obtained suspension is centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane, and the obtained solid is vacuum dried at 50°C for 2 hours to obtain a monosuccinate crystalline form A sample of the compound of formula I-1.

实施例11：式I-1化合物的硫酸盐晶型A制备Example 11: Preparation of Sulfate Crystalline Form A of the Compound of Formula I-1

称取约20mg式I-1化合物与1.0当量的硫酸置于2mL玻璃瓶中，加入0.15mL乙腈中以混悬法进行筛选实验。所得样品在50℃下混悬2h，之后自然降温至25℃，并在25℃下混悬至少48h。将所得混悬液通过0.45μm尼龙滤膜以14,000rpm转速离心，所得的固体在50℃下真空干燥2h后得到式I-1化合物的硫酸盐晶型A样品。About 20 mg of the compound of formula I-1 and 1.0 equivalent of sulfuric acid were weighed and placed in a 2 mL glass bottle, and 0.15 mL of acetonitrile was added to perform a screening experiment by suspension method. The obtained sample was suspended at 50°C for 2 hours, then naturally cooled to 25°C, and suspended at 25°C for at least 48 hours. The obtained suspension was centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane, and the obtained solid was vacuum dried at 50°C for 2 hours to obtain a sulfate crystal form A sample of the compound of formula I-1.

实施例12：式I-1化合物的L-酒石酸盐晶型A制备Example 12: Preparation of L-tartrate Form A of the Compound of Formula I-1

称取约20mg式I-1化合物与1.0当量的L-酒石酸置于2mL玻璃瓶中，加入0.15mL乙腈中以混悬法进行筛选实验。所得样品在50℃下混悬2h，之后自然降温至25℃，并在25℃下混悬至少48h。将所得混悬液通过0.45μm尼龙滤膜以14,000rpm转速离心，所得的固体在50℃下真空干燥2h后得到式I-1化合物的L-酒石酸盐晶型A样品。About 20 mg of the compound of formula I-1 and 1.0 equivalent of L-tartaric acid were weighed and placed in a 2 mL glass bottle, and 0.15 mL of acetonitrile was added to perform a screening experiment by suspension method. The obtained sample was suspended at 50° C. for 2 hours, then naturally cooled to 25° C., and suspended at 25° C. for at least 48 hours. The obtained suspension was centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane, and the obtained solid was vacuum dried at 50° C. for 2 hours to obtain a sample of L-tartrate crystalline form A of the compound of formula I-1.

实施例13：式I-1化合物的马尿酸盐晶型A制备Example 13: Preparation of Hippurate Crystalline Form A of the Compound of Formula I-1

称取约20mg式I-1化合物与1.0当量的马尿酸置于2mL玻璃瓶中，加入0.15mL四氢呋喃中以混悬法进行筛选实验。所得样品在50℃下混悬2h，之后自然降温至25℃，并在25℃下混悬至少48h。将所得混悬液通过0.45μm尼龙滤膜以14,000rpm转速离心，所得的固体在50℃下真空干燥2h后得到式I-1化合物的马尿酸盐晶型A样品。About 20 mg of the compound of formula I-1 and 1.0 equivalent of hippuric acid were weighed and placed in a 2 mL glass bottle, and 0.15 mL of tetrahydrofuran was added to perform a screening experiment by suspension method. The obtained sample was suspended at 50° C. for 2 hours, then naturally cooled to 25° C., and suspended at 25° C. for at least 48 hours. The obtained suspension was centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane, and the obtained solid was vacuum dried at 50° C. for 2 hours to obtain a hippurate crystalline form A sample of the compound of formula I-1.

实施例14：式I-1化合物的戊二酸盐晶型A制备Example 14: Preparation of Form A of the Glutarate Salt of the Compound of Formula I-1

14.1：称取约20mg式I-1化合物与1.0当量的戊二酸置于2mL玻璃瓶中，加入0.15mL乙腈中以混悬法进行筛选实验。所得样品在50℃下混悬2h，之后自然降温至25℃，并在25℃下混悬至少48h。将所得混悬液通过0.45μm尼龙滤膜以14,000rpm转速离心，所得的固体在50℃下真空干燥2h后得到式I-1化合物的戊二酸盐晶型A样品。14.1: About 20 mg of the compound of formula I-1 and 1.0 equivalent of glutaric acid were weighed and placed in a 2 mL glass bottle, and 0.15 mL of acetonitrile was added to perform a screening experiment by suspension method. The obtained sample was suspended at 50°C for 2 hours, then naturally cooled to 25°C, and suspended at 25°C for at least 48 hours. The obtained suspension was centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane, and the obtained solid was vacuum dried at 50°C for 2 hours to obtain a sample of the glutaric acid salt form A of the compound of formula I-1.

14.2：称取约20mg式I-1化合物与1.0当量的戊二酸置于2mL玻璃瓶中，加入0.15mL二氯甲烷中以混悬法进行筛选实验。所得样品在50℃下混悬2h，之后自然降温至25℃，并在25℃下混悬至少48h。将所得混悬液通过0.45μm尼龙滤膜以14,000rpm转速离心，所得的固体在50℃下真空干燥2h后得到式I-1化合物的戊二酸盐晶型A样品。14.2: About 20 mg of the compound of formula I-1 and 1.0 equivalent of glutaric acid were weighed and placed in a 2 mL glass bottle, and 0.15 mL of dichloromethane was added to perform a screening experiment by suspension method. The obtained sample was suspended at 50°C for 2 hours, then naturally cooled to 25°C, and suspended at 25°C for at least 48 hours. The obtained suspension was centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane, and the obtained solid was vacuum dried at 50°C for 2 hours to obtain a sample of the glutaric acid salt form A of the compound of formula I-1.

实施例15：式I-1化合物的对甲苯磺酸盐晶型A制备Example 15: Preparation of p-toluenesulfonate Form A of the Compound of Formula I-1

称取约20mg式I-1化合物与1.0当量的对甲苯磺酸置于2mL玻璃瓶中，加入0.15mL乙腈中以混悬法进行筛选实验。所得样品在50℃下混悬2h，之后自然降温至25℃，并在25℃下混悬至少48h。将所得混悬液通过0.45μm尼龙滤膜以14,000rpm转速离心，所得的固体在50℃下真空干燥2h后得到式I-1化合物的对甲苯磺酸盐晶型A样品。About 20 mg of the compound of formula I-1 and 1.0 equivalent of p-toluenesulfonic acid were weighed and placed in a 2 mL glass bottle, and 0.15 mL of acetonitrile was added to perform a screening experiment by suspension method. The obtained sample was suspended at 50° C. for 2 hours, then naturally cooled to 25° C., and suspended at 25° C. for at least 48 hours. The obtained suspension was centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane, and the obtained solid was vacuum dried at 50° C. for 2 hours to obtain a p-toluenesulfonate crystalline form A sample of the compound of formula I-1.

实施例16：式I-1化合物的对甲苯磺酸盐晶型B制备Example 16: Preparation of p-toluenesulfonate Form B of the compound of formula I-1

称取约20mg式I-1化合物与1.0当量的对甲苯磺酸置于2mL玻璃瓶中，加入0.15mL四氢呋喃中以混悬法进行筛选实验。所得样品在50℃下混悬2h，之后自然降温至25℃，并在25℃下混悬至少48h。将所得混悬液通过0.45μm尼龙滤膜以14,000rpm转速离心，所得的固体在50℃下真空干燥2h后得到式I-1化合物的对甲苯磺酸盐晶型B样品。About 20 mg of the compound of formula I-1 and 1.0 equivalent of p-toluenesulfonic acid were weighed and placed in a 2 mL glass bottle, and 0.15 mL of tetrahydrofuran was added to perform a screening experiment by suspension method. The obtained sample was suspended at 50° C. for 2 hours, then naturally cooled to 25° C., and suspended at 25° C. for at least 48 hours. The obtained suspension was centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane, and the obtained solid was vacuum dried at 50° C. for 2 hours to obtain a p-toluenesulfonate crystal form B sample of the compound of formula I-1.

实施例17：式I-1化合物的甲磺酸盐晶型A制备Example 17: Preparation of Methanesulfonate Form A of the Compound of Formula I-1

称取约20mg式I-1化合物与1.0当量的甲磺酸置于2mL玻璃瓶中，加入0.15mL四氢呋喃中以混悬法进行筛选实验。所得样品在50℃下混悬2h，之后自然降温至25℃，并在25℃下混悬至少48h。将所得混悬液通过0.45μm尼龙滤膜以14,000rpm转速离心，所得的固体在50℃下真空干燥2h后得到式I-1化合物的甲磺酸盐晶型A样品。About 20 mg of the compound of formula I-1 and 1.0 equivalent of methanesulfonic acid were weighed and placed in a 2 mL glass bottle, and 0.15 mL of tetrahydrofuran was added to perform a screening experiment by suspension method. The obtained sample was suspended at 50° C. for 2 hours, then naturally cooled to 25° C., and suspended at 25° C. for at least 48 hours. The obtained suspension was centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane, and the obtained solid was vacuum dried at 50° C. for 2 hours to obtain a sample of the mesylate crystal form A of the compound of formula I-1.

实施例18：式I-1化合物盐酸盐晶型C1制备Example 18: Preparation of Hydrochloride Form C1 of Compound of Formula I-1

式I-1化合物(16.5g)加入乙酸乙酯(165)mL中，冷却至0℃左右，滴加1.0当量4M氯化氢二氧六环溶液，加完恢复至室温搅拌过夜，过滤，干燥得到式I-1化合物盐酸盐晶型C1样品(18.3g)，白色固体。The compound of formula I-1 (16.5 g) was added to ethyl acetate (165) mL, cooled to about 0°C, and 1.0 equivalent of 4M hydrogen chloride dioxane solution was added dropwise. After addition, the mixture was returned to room temperature and stirred overnight. The mixture was filtered and dried to obtain a hydrochloride crystal form C1 sample of the compound of formula I-1 (18.3 g) as a white solid.

实施例19：式I-1化合物盐酸盐晶型C2制备Example 19: Preparation of Hydrochloride Form C2 of Compound of Formula I-1

称取约40mg式I-1化合物盐酸盐晶型E1，加入0.2-0.5mL2-甲基四氢呋喃，在25℃以300-400rpm速率在磁力搅拌下混悬。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm下离心过滤，所得固体部分即是式I-1化合物盐酸盐晶型C2样品。Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.2-0.5 mL of 2-methyltetrahydrofuran, and suspend under magnetic stirring at 300-400 rpm at 25° C. The resulting suspension is centrifuged at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube, and the resulting solid portion is the hydrochloride crystal form C2 sample of the compound of formula I-1.

实施例20：式I-1化合物盐酸盐晶型D制备Example 20: Preparation of Hydrochloride Form D of Compound of Formula I-1

称取约40mg式I-1化合物与1.05当量的盐酸(丁酮稀释10倍后的稀盐酸)置于2mL玻璃瓶中，加入筛选溶剂以混悬法进行筛选实验。所得样品在50℃(35℃,二氯甲烷)下混悬2h，之后自然降温至25℃，并在25℃下混悬至少48h。将所得混悬液通过0.45μm尼龙滤膜以14,000rpm转速离心，所得的固体在50℃下真空干燥2h后式I-1化合物盐酸盐晶型D样品。Weigh about 40 mg of the compound of formula I-1 and 1.05 equivalents of hydrochloric acid (diluted hydrochloric acid after diluting butanone 10 times) into a 2 mL glass bottle, add the screening solvent and perform the screening experiment by suspension method. The obtained sample is suspended at 50°C (35°C, dichloromethane) for 2 hours, then naturally cooled to 25°C, and suspended at 25°C for at least 48 hours. The obtained suspension is centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane, and the obtained solid is vacuum dried at 50°C for 2 hours to obtain the hydrochloride crystal form D sample of the compound of formula I-1.

实施例21：式I-1化合物盐酸盐晶型E1制备Example 21: Preparation of Hydrochloride Form E1 of Compound of Formula I-1

称取3.0g式I-1化合物置于40mL玻璃瓶中。加入4.6mL乙醇和～1.2当量的HCl(12NHCl水溶液用乙醇稀释至1.2N)，在50℃下搅拌10min。向上述体系中加入约5mg式I-1化合物盐酸盐晶型E2晶种，在50℃下搅拌2h后，将溶液体系自然冷却至25℃并在25℃下搅拌3天。向上述体系中加入～0.1当量的HCl(12N HCl水溶液用乙醇稀释至1.2N)，继续在25℃下搅拌1天。通过抽滤收集固体部分，并将所得固体置于25℃真空条件下干燥约17h，将获得的固体置于50℃真空条件下继续干燥2h得到式I-1化合物盐酸盐晶型E1样品(2.8g)，类白色固体。Weigh 3.0 g of the compound of formula I-1 and place it in a 40 mL glass bottle. Add 4.6 mL of ethanol and ~1.2 equivalents of HCl (12N HCl aqueous solution is diluted to 1.2 N with ethanol) and stir at 50°C for 10 min. Add about 5 mg of the hydrochloride crystal form E2 seed of the compound of formula I-1 to the above system, stir at 50°C for 2 hours, and then naturally cool the solution system to 25°C and stir at 25°C for 3 days. Add ~0.1 equivalents of HCl (12N HCl aqueous solution is diluted to 1.2 N with ethanol) to the above system and continue stirring at 25°C for 1 day. Collect the solid part by suction filtration, and dry the obtained solid under vacuum conditions at 25°C for about 17 hours. The obtained solid is placed under vacuum conditions at 50°C and continues to dry for 2 hours to obtain the hydrochloride crystal form E1 sample of the compound of formula I-1 (2.8 g), an off-white solid.

实施例22：式I-1化合物盐酸盐晶型E2制备Example 22: Preparation of Hydrochloride Form E2 of Compound of Formula I-1

称取约40mg式I-1化合物与1.05当量的盐酸(乙醇稀释10倍后的稀盐酸)置于2mL玻璃瓶中，加入筛选溶剂以混悬法进行筛选实验。所得样品在50℃(35℃,二氯甲烷)下混悬2h，之后自然降温至25℃，并在25℃下混悬至少48h。将所得混悬液通过0.45μm尼龙滤膜以14,000rpm转速离心，所得的固体为式I-1化合物盐酸盐晶型F样品，将其在50℃下真空干燥2h后制得式I-1化合物盐酸盐晶型E2样品。Weigh about 40 mg of the compound of formula I-1 and 1.05 equivalents of hydrochloric acid (diluted hydrochloric acid after ethanol was diluted 10 times) into a 2 mL glass bottle, add the screening solvent and perform the screening experiment by suspension method. The obtained sample was suspended at 50°C (35°C, dichloromethane) for 2 hours, then naturally cooled to 25°C, and suspended at 25°C for at least 48 hours. The obtained suspension was centrifuged at 14,000 rpm through a 0.45 μm nylon filter membrane, and the obtained solid was the hydrochloride crystal form F sample of the compound of formula I-1, which was vacuum dried at 50°C for 2 hours to obtain the hydrochloride crystal form E2 sample of the compound of formula I-1.

实施例23：式I-1化合物盐酸盐晶型F制备Example 23: Preparation of Hydrochloride Form F of Compound of Formula I-1

23.1：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.2-0.5mL乙醇，在25℃以300-400rpm速率在磁力搅拌下混悬。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm下离心过滤，所得固体为式I-1化合物盐酸盐晶型F样品。23.1: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.2-0.5 mL of ethanol, and suspend under magnetic stirring at 300-400 rpm at 25°C. The resulting suspension is centrifuged at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube to obtain a solid sample of the hydrochloride crystal form F of the compound of formula I-1.

23.2：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.2-0.5mL丙酮，在25℃以300-400rpm速率在磁力搅拌下混悬。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm下离心过滤，所得固体为式I-1化合物盐酸盐晶型F样品。23.2: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.2-0.5 mL of acetone, and suspend under magnetic stirring at 25°C at a speed of 300-400 rpm. The resulting suspension is centrifuged at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube to obtain a solid sample of the hydrochloride crystal form F of the compound of formula I-1.

23.3：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.2-0.5mL乙腈，在25℃以300-400rpm速率在磁力搅拌下混悬。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm下离心过滤，所得固体为式I-1化合物盐酸盐晶型F样品。23.3: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.2-0.5 mL of acetonitrile, and suspend under magnetic stirring at 300-400 rpm at 25°C. The resulting suspension is centrifuged at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube to obtain a solid sample of the hydrochloride crystal form F of the compound of formula I-1.

23.4：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.2-0.5mL四氢呋喃，在25℃以300-400rpm速率在磁力搅拌下混悬。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm下离心过滤，所得固体为式I-1化合物盐酸盐晶型F样品。23.4: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.2-0.5 mL of tetrahydrofuran, and suspend under magnetic stirring at 300-400 rpm at 25°C. The resulting suspension is centrifuged at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube to obtain a solid sample of the hydrochloride crystal form F of the compound of formula I-1.

23.5：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.2-0.5mL甲基异丁基酮/三氟乙醇(9/1,v/v)，在25℃以300-400rpm速率在磁力搅拌下混悬。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm下离心过滤，所得固体为式I-1化合物盐酸盐晶型F样品。23.5: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.2-0.5 mL of methyl isobutyl ketone/trifluoroethanol (9/1, v/v), and suspend under magnetic stirring at 25° C. at a rate of 300-400 rpm. The resulting suspension is centrifuged at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube to obtain a solid sample of the hydrochloride crystal form F of the compound of formula I-1.

23.6：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.1-0.5mL乙醇，在50℃以300-400rpm速率在磁力搅拌下混悬。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm离心过滤，所得固体为式I-1化合物盐酸盐晶型F样品。23.6: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of ethanol, and suspend under magnetic stirring at 50°C at a speed of 300-400 rpm. The resulting suspension is centrifuged and filtered at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube to obtain a solid sample of the hydrochloride crystal form F of the compound of formula I-1.

23.7：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.1-0.5mL丙酮，在50℃以300-400rpm速率在磁力搅拌下混悬。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm离心过滤，所得固体为式I-1化合物盐酸盐晶型F样品。23.7: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of acetone, and suspend under magnetic stirring at 50°C at a speed of 300-400 rpm. The resulting suspension is centrifuged and filtered at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube to obtain a solid sample of the hydrochloride crystal form F of the compound of formula I-1.

23.8：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.1-0.5mL乙酸乙酯，在50℃以300-400rpm速率在磁力搅拌下混悬。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm离心过滤，所得固体为式I-1化合物盐酸盐晶型F样品。23.8: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of ethyl acetate, and suspend under magnetic stirring at 50°C at a speed of 300-400 rpm. The resulting suspension is centrifuged and filtered at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube to obtain a solid sample of the hydrochloride crystal form F of the compound of formula I-1.

23.9：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.1-0.5mL乙腈，在50℃以300-400rpm速率在磁力搅拌下混悬。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm离心过滤，所得固体为式I-1化合物盐酸盐晶型F样品。23.9: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of acetonitrile, and suspend under magnetic stirring at 50°C at a speed of 300-400 rpm. The resulting suspension is centrifuged and filtered at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube to obtain a solid sample of the hydrochloride crystal form F of the compound of formula I-1.

23.10：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.1-0.5mL四氢呋喃，在50℃以300-400rpm速率在磁力搅拌下混悬。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm离心过滤，所得固体为式I-1化合物盐酸盐晶型F样品。23.10: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of tetrahydrofuran, and suspend under magnetic stirring at 50°C at a speed of 300-400 rpm. The resulting suspension is centrifuged at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube to obtain a solid sample of the hydrochloride crystal form F of the compound of formula I-1.

23.11：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.1-0.5mL甲基异丁基酮/三氟乙醇(9/1,v/v)，在50℃以300-400rpm速率在磁力搅拌下混悬。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm离心过滤，所得固体为式I-1化合物盐酸盐晶型F样品。23.11: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of methyl isobutyl ketone/trifluoroethanol (9/1, v/v), and suspend at 50°C at 300-400 rpm under magnetic stirring. The resulting suspension is centrifuged at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube to obtain a solid sample of the hydrochloride crystal form F of the compound of formula I-1.

23.12：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.1-0.5mL乙醇，在5℃至50℃之间以0.1℃/min的速率进行10个升降温循环，同时用300-400rpm速率在磁力搅拌下进行混悬，取样时温度为10℃。将所得混悬液用0.45μm尼龙滤膜离心管在10℃以14,000rpm离心过滤，所得固体为式I-1化合物盐酸盐晶型F样品。23.12: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of ethanol, and perform 10 heating and cooling cycles between 5°C and 50°C at a rate of 0.1°C/min, while suspending under magnetic stirring at a rate of 300-400 rpm, and the temperature during sampling is 10°C. The resulting suspension is centrifuged and filtered at 14,000 rpm at 10°C using a 0.45 μm nylon filter centrifuge tube, and the resulting solid is the hydrochloride crystal form F sample of the compound of formula I-1.

23.13：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.1-0.5mL丙酮，在5℃至50℃之间以0.1℃/min的速率进行10个升降温循环，同时用300-400rpm速率在磁力搅拌下进行混悬，取样时温度为10℃。将所得混悬液用0.45μm尼龙滤膜离心管在10℃以14,000rpm离心过滤，所得固体为式I-1化合物盐酸盐晶型F样品。23.13: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of acetone, and perform 10 heating and cooling cycles at a rate of 0.1°C/min between 5°C and 50°C, while suspending under magnetic stirring at a rate of 300-400 rpm, and the temperature during sampling is 10°C. The resulting suspension is centrifuged and filtered at 14,000 rpm at 10°C using a 0.45 μm nylon filter centrifuge tube, and the resulting solid is the hydrochloride crystal form F sample of the compound of formula I-1.

23.14：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.1-0.5mL乙酸乙酯，在5℃至50℃之间以0.1℃/min的速率进行10个升降温循环，同时用300-400rpm速率在磁力搅拌下进行混悬，取样时温度为10℃。将所得混悬液用0.45μm尼龙滤膜离心管在10℃以14,000rpm离心过滤，所得固体为式I-1化合物盐酸盐晶型F样品。23.14: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of ethyl acetate, perform 10 heating and cooling cycles between 5°C and 50°C at a rate of 0.1°C/min, and suspend under magnetic stirring at a rate of 300-400 rpm. The temperature during sampling is 10°C. The obtained suspension is centrifuged and filtered at 14,000 rpm at 10°C using a 0.45 μm nylon filter centrifuge tube, and the obtained solid is the hydrochloride crystal form F sample of the compound of formula I-1.

23.15：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.1-0.5mL乙腈，在5℃至50℃之间以0.1℃/min的速率进行10个升降温循环，同时用300-400rpm速率在磁力搅拌下进行混悬，取样时温度为10℃。将所得混悬液用0.45μm尼龙滤膜离心管在10℃以14,000rpm离心过滤，所得固体为式I-1化合物盐酸盐晶型F样品。23.15: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of acetonitrile, and perform 10 heating and cooling cycles between 5°C and 50°C at a rate of 0.1°C/min, while suspending under magnetic stirring at a rate of 300-400 rpm, and the temperature during sampling is 10°C. The resulting suspension is centrifuged and filtered at 14,000 rpm at 10°C using a 0.45 μm nylon filter centrifuge tube, and the resulting solid is the hydrochloride crystal form F sample of the compound of formula I-1.

23.16：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.1-0.5mL四氢呋喃，在5℃至50℃之间以0.1℃/min的速率进行10个升降温循环，同时用300-400rpm速率在磁力搅拌下进行混悬，取样时温度为10℃。将所得混悬液用0.45μm尼龙滤膜离心管在10℃以14,000rpm离心过滤，所得固体为式I-1化合物盐酸盐晶型F样品。23.16: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of tetrahydrofuran, and perform 10 heating and cooling cycles between 5°C and 50°C at a rate of 0.1°C/min, while suspending under magnetic stirring at a rate of 300-400 rpm, and the temperature during sampling is 10°C. The resulting suspension is centrifuged and filtered at 14,000 rpm at 10°C using a 0.45 μm nylon filter centrifuge tube, and the resulting solid is the hydrochloride crystal form F sample of the compound of formula I-1.

23.17：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.1-0.5mL甲基异丁基酮/三氟乙醇(9/1,v/v)，在5℃至50℃之间以0.1℃/min的速率进行10个升降温循环，同时用300-400rpm速率在磁力搅拌下进行混悬，取样时温度为10℃。将所得混悬液用0.45μm尼龙滤膜离心管在10℃以14,000rpm离心过滤，所得固体为式I-1化合物盐酸盐晶型F样品。23.17: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of methyl isobutyl ketone/trifluoroethanol (9/1, v/v), perform 10 heating and cooling cycles between 5°C and 50°C at a rate of 0.1°C/min, and suspend under magnetic stirring at a rate of 300-400 rpm. The temperature during sampling is 10°C. The obtained suspension is centrifuged and filtered at 14,000 rpm at 10°C using a 0.45 μm nylon filter centrifuge tube, and the obtained solid is the hydrochloride crystal form F sample of the compound of formula I-1.

实施例24：式I-1化合物盐酸盐晶型G制备Example 24: Preparation of Hydrochloride Form G of Compound of Formula I-1

24.1：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.2-0.5mL水，在25℃以300-400rpm速率在磁力搅拌下混悬。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm下离心过滤，所得固体为式I-1化合物盐酸盐晶型G样品。24.1: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.2-0.5 mL of water, and suspend under magnetic stirring at 25°C at a speed of 300-400 rpm. The resulting suspension is centrifuged at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube to obtain a solid sample of the hydrochloride crystal form G of the compound of formula I-1.

24.2：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.1-0.5mL甲醇，在50℃以300-400rpm速率在磁力搅拌下混悬。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm离心过滤，所得固体为式I-1化合物盐酸盐晶型G样品。24.2: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of methanol, and suspend under magnetic stirring at 50°C at a speed of 300-400 rpm. The resulting suspension is centrifuged and filtered at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube to obtain a solid sample of the hydrochloride crystal form G of the compound of formula I-1.

24.3：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.1-0.5mL甲基异丁基酮/三氟乙醇(9/1,v/v)，在5℃至50℃之间以0.1℃/min的速率进行10个升降温循环，同时用300-400rpm速率在磁力搅拌下进行混悬，取样时温度为10℃。将所得混悬液用0.45μm尼龙滤膜离心管在10℃以14,000rpm离心过滤，所得固体为式I-1化合物盐酸盐晶型G样品。24.3: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of methyl isobutyl ketone/trifluoroethanol (9/1, v/v), perform 10 heating and cooling cycles between 5°C and 50°C at a rate of 0.1°C/min, and suspend under magnetic stirring at a rate of 300-400 rpm. The temperature during sampling is 10°C. The obtained suspension is centrifuged and filtered at 14,000 rpm at 10°C using a 0.45 μm nylon filter centrifuge tube, and the obtained solid is the hydrochloride crystal form G sample of the compound of formula I-1.

实施例25：式I-1化合物盐酸盐晶型H制备Example 25: Preparation of Hydrochloride Form H of Compound of Formula I-1

25.1：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.2-0.5mL甲醇/水(1/1,v/v)，在25℃以300-400rpm速率在磁力搅拌下混悬。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm下离心过滤，所得固体为式I-1化合物盐酸盐晶型H样品。25.1: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.2-0.5 mL of methanol/water (1/1, v/v), and suspend under magnetic stirring at 25° C. at a rate of 300-400 rpm. The resulting suspension is centrifuged at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube to obtain a solid sample of the hydrochloride crystal form H of the compound of formula I-1.

25.2：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.1-0.5mL甲醇/水(1/1,v/v)，在50℃以300-400rpm速率在磁力搅拌下混悬。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm离心过滤，所得固体为式I-1化合物盐酸盐晶型H样品。25.2: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of methanol/water (1/1, v/v), and suspend at 50°C at 300-400 rpm under magnetic stirring. The resulting suspension is centrifuged at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube to obtain a solid sample of the hydrochloride crystal form H of the compound of formula I-1.

实施例26：式I-1化合物盐酸盐晶型I制备Example 26: Preparation of Hydrochloride Form I of Compound of Formula I-1

26.1：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.1-0.5mL甲醇，在50℃以300-400rpm速率在磁力搅拌下混悬。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm离心过滤，所得固体为式I-1化合物盐酸盐晶型I样品。26.1: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of methanol, and suspend under magnetic stirring at 50°C at a speed of 300-400 rpm. The resulting suspension is centrifuged at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube to obtain a solid sample of the hydrochloride crystal form I of the compound of formula I-1.

26.2：称取约40mg式I-1化合物盐酸盐晶型E1，加入最少体积的甲醇在25℃下充分溶解，所得稀薄的混悬液经0.45μm尼龙滤膜针头式过滤器得到澄清溶液。取每份澄清溶液0.8mL，分别向上述澄清溶液缓慢加入8mL甲基叔丁基醚。将所得混悬液用0.45μm尼龙滤膜离心管以14,000rpm离心过滤，所得固体为式I-1化合物盐酸盐晶型I样品。26.2: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add a minimum volume of methanol to fully dissolve at 25°C, and the resulting thin suspension is filtered through a 0.45 μm nylon filter syringe filter to obtain a clear solution. Take 0.8 mL of each clear solution and slowly add 8 mL of methyl tert-butyl ether to the above clear solution. The resulting suspension is centrifuged and filtered at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube, and the resulting solid is the hydrochloride crystal form I sample of the compound of formula I-1.

实施例27：式I-1化合物盐酸盐晶型J1制备Example 27: Preparation of Hydrochloride Form J1 of Compound of Formula I-1

27.1：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.1-0.5mL 2-甲基四氢呋喃，在50℃以300-400rpm速率在磁力搅拌下混悬。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm离心过滤，所得固体为式I-1化合物盐酸盐晶型J1样品。27.1: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL 2-methyltetrahydrofuran, and suspend under magnetic stirring at 50°C at a rate of 300-400 rpm. The resulting suspension is centrifuged at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube to obtain a solid sample of the hydrochloride crystal form J1 of the compound of formula I-1.

27.2：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.1-0.5mL2-甲基四氢呋喃，在5℃至50℃之间以0.1℃/min的速率进行10个升降温循环，同时用300-400rpm速率在磁力搅拌下进行混悬，取样时温度为10℃。将所得混悬液用0.45μm尼龙滤膜离心管在10℃以14,000rpm离心过滤，所得固体为式I-1化合物盐酸盐晶型J1样品。27.2: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of 2-methyltetrahydrofuran, and perform 10 heating and cooling cycles between 5°C and 50°C at a rate of 0.1°C/min, while suspending under magnetic stirring at a rate of 300-400 rpm, and the temperature during sampling is 10°C. The resulting suspension is centrifuged and filtered at 14,000 rpm at 10°C using a 0.45 μm nylon filter centrifuge tube, and the resulting solid is the hydrochloride crystal form J1 sample of the compound of formula I-1.

实施例28：式I-1化合物盐酸盐晶型J2制备Example 28: Preparation of Hydrochloride Form J2 of Compound of Formula I-1

将上述式I-1化合物盐酸盐晶型J1样品加热至110℃，得到固体为式I-1化合物盐酸盐晶型J2样品。The above-mentioned hydrochloride crystal form J1 sample of the compound of formula I-1 is heated to 110° C. to obtain a solid which is the hydrochloride crystal form J2 sample of the compound of formula I-1.

实施例29：式I-1化合物盐酸盐晶型K制备Example 29: Preparation of Hydrochloride Form K of Compound of Formula I-1

29.1：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.1-0.5mL甲基叔丁基醚，在50℃以300-400rpm速率在磁力搅拌下混悬。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm离心过滤，所得固体为式I-1化合物盐酸盐晶型K样品。29.1: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of methyl tert-butyl ether, and suspend under magnetic stirring at 50° C. at a speed of 300-400 rpm. The resulting suspension is centrifuged and filtered at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube to obtain a solid sample of the hydrochloride crystal form K of the compound of formula I-1.

29.2：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.1-0.5mL甲基叔丁基醚，在5℃至50℃之间以0.1℃/min的速率进行10个升降温循环，同时用300-400rpm速率在磁力搅拌下进行混悬，取样时温度为10℃。将所得混悬液用0.45μm尼龙滤膜离心管在10℃以14,000rpm离心过滤，所得固体为式I-1化合物盐酸盐晶型K样品。29.2: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of methyl tert-butyl ether, and perform 10 heating and cooling cycles between 5°C and 50°C at a rate of 0.1°C/min, while suspending under magnetic stirring at a rate of 300-400 rpm, and the temperature during sampling is 10°C. The obtained suspension is centrifuged and filtered at 14,000 rpm at 10°C using a 0.45 μm nylon filter centrifuge tube, and the obtained solid is the hydrochloride crystal form K sample of the compound of formula I-1.

29.3：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.1-0.5mL甲苯，在5℃至50℃之间以0.1℃/min的速率进行10个升降温循环，同时用300-400rpm速率在磁力搅拌下进行混悬，取样时温度为10℃。将所得混悬液用0.45μm尼龙滤膜离心管在10℃以14,000rpm离心过滤，所得固体为式I-1化合物盐酸盐晶型K样品。29.3: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of toluene, and perform 10 heating and cooling cycles between 5°C and 50°C at a rate of 0.1°C/min, while suspending under magnetic stirring at a rate of 300-400 rpm, and the temperature during sampling is 10°C. The resulting suspension is centrifuged and filtered at 14,000 rpm at 10°C using a 0.45 μm nylon filter centrifuge tube, and the resulting solid is the hydrochloride crystal form K sample of the compound of formula I-1.

实施例30：式I-1化合物盐酸盐晶型L制备Example 30: Preparation of Hydrochloride Form L of Compound of Formula I-1

30.1：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.1-0.5mL甲苯，在25℃以300-400rpm速率在磁力搅拌下混悬。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm离心过滤，所得固体为式I-1化合物盐酸盐晶型L样品。30.1: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of toluene, and suspend under magnetic stirring at 25°C at a speed of 300-400 rpm. The resulting suspension is centrifuged and filtered at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube to obtain a solid sample of the hydrochloride crystal form L of the compound of formula I-1.

30.2：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.1-0.5mL甲苯，在50℃以300-400rpm速率在磁力搅拌下混悬。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm离心过滤，所得固体为式I-1化合物盐酸盐晶型L样品。30.2: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of toluene, and suspend under magnetic stirring at 50°C at a speed of 300-400 rpm. The resulting suspension is centrifuged and filtered at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube to obtain a solid sample of the hydrochloride crystal form L of the compound of formula I-1.

实施例31：式I-1化合物盐酸盐晶型M制备Example 31: Preparation of Hydrochloride Form M of Compound of Formula I-1

31.1：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.1-0.5mL异丙醇/二甲基亚砜(9/1,v/v)，在25℃以300-400rpm速率在磁力搅拌下混悬。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm离心过滤，所得固体为式I-1化合物盐酸盐晶型M样品。31.1: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of isopropanol/dimethyl sulfoxide (9/1, v/v), and suspend under magnetic stirring at 25° C. at a rate of 300-400 rpm. The resulting suspension is centrifuged and filtered at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube, and the resulting solid is the hydrochloride crystal form M sample of the compound of formula I-1.

31.2：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.1-0.5mL乙酸异丙酯/二甲基亚砜(9/1,v/v)，在25℃以300-400rpm速率在磁力搅拌下混悬。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm离心过滤，所得固体为式I-1化合物盐酸盐晶型M样品。31.2: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of isopropyl acetate/dimethyl sulfoxide (9/1, v/v), and suspend under magnetic stirring at 300-400 rpm at 25° C. The resulting suspension is centrifuged at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube to obtain a solid sample of the hydrochloride crystal form M of the compound of formula I-1.

31.3：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.1-0.5mL二甲基亚砜/水(1/1,v/v)，在25℃以300-400rpm速率在磁力搅拌下混悬。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm离心过滤，所得固体为式I-1化合物盐酸盐晶型M样品。31.3: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of dimethyl sulfoxide/water (1/1, v/v), and suspend under magnetic stirring at 25° C. at a rate of 300-400 rpm. The resulting suspension is centrifuged and filtered at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube, and the resulting solid is the hydrochloride crystal form M sample of the compound of formula I-1.

31.4：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.1-0.5mL异丙醇/二甲基亚砜(9/1,v/v)，在50℃以300-400rpm速率在磁力搅拌下混悬。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm离心过滤，所得固体为式I-1化合物盐酸盐晶型M样品。31.4: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of isopropanol/dimethyl sulfoxide (9/1, v/v), and suspend under magnetic stirring at 50° C. at a rate of 300-400 rpm. The resulting suspension is centrifuged and filtered at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube, and the resulting solid is the hydrochloride crystal form M sample of the compound of formula I-1.

31.5：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.1-0.5mL乙酸异丙酯/二甲基亚砜(9/1,v/v)，在50℃以300-400rpm速率在磁力搅拌下混悬。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm离心过滤，所得固体为式I-1化合物盐酸盐晶型M样品。31.5: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of isopropyl acetate/dimethyl sulfoxide (9/1, v/v), and suspend under magnetic stirring at 50° C. at a rate of 300-400 rpm. The resulting suspension is centrifuged and filtered at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube, and the resulting solid is the hydrochloride crystal form M sample of the compound of formula I-1.

31.6：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.1-0.5mL二甲基亚砜/水(1/1,v/v)，在50℃以300-400rpm速率在磁力搅拌下混悬。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm离心过滤，所得固体为式I-1化合物盐酸盐晶型M样品。31.6: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of dimethyl sulfoxide/water (1/1, v/v), and suspend at 50° C. at 300-400 rpm under magnetic stirring. The resulting suspension is centrifuged at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube to obtain a solid sample of the hydrochloride crystal form M of the compound of formula I-1.

31.7：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.1-0.5mL异丙醇/二甲基亚砜(9/1,v/v)，在5℃至50℃之间以0.1℃/min的速率进行10个升降温循环，同时用300-400rpm速率在磁力搅拌下进行混悬，取样时温度为10℃。将所得混悬液用0.45μm尼龙滤膜离心管在10℃以14,000rpm离心过滤，所得固体为式I-1化合物盐酸盐晶型M样品。31.7: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of isopropanol/dimethyl sulfoxide (9/1, v/v), perform 10 heating and cooling cycles between 5°C and 50°C at a rate of 0.1°C/min, and suspend under magnetic stirring at a rate of 300-400 rpm. The temperature during sampling is 10°C. The obtained suspension is centrifuged and filtered at 14,000 rpm at 10°C using a 0.45 μm nylon filter centrifuge tube, and the obtained solid is the hydrochloride crystal form M sample of the compound of formula I-1.

31.8：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.1-0.5mL乙酸异丙酯/二甲基亚砜(9/1,v/v)，在5℃至50℃之间以0.1℃/min的速率进行10个升降温循环，同时用300-400rpm速率在磁力搅拌下进行混悬，取样时温度为10℃。将所得混悬液用0.45μm尼龙滤膜离心管在10℃以14,000rpm离心过滤，所得固体为式I-1化合物盐酸盐晶型M样品。31.8: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of isopropyl acetate/dimethyl sulfoxide (9/1, v/v), perform 10 heating and cooling cycles between 5°C and 50°C at a rate of 0.1°C/min, and suspend under magnetic stirring at a rate of 300-400 rpm. The temperature during sampling is 10°C. The obtained suspension is centrifuged and filtered at 14,000 rpm at 10°C using a 0.45 μm nylon filter centrifuge tube, and the obtained solid is the hydrochloride crystal form M sample of the compound of formula I-1.

31.9：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.1-0.5mL二甲基亚砜/水(1/1,v/v)，在5℃至50℃之间以0.1℃/min的速率进行10个升降温循环，同时用300-400rpm速率在磁力搅拌下进行混悬，取样时温度为10℃。将所得混悬液用0.45μm尼龙滤膜离心管在10℃以14,000rpm离心过滤，所得固体为式I-1化合物盐酸盐晶型M样品。31.9: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of dimethyl sulfoxide/water (1/1, v/v), perform 10 heating and cooling cycles between 5°C and 50°C at a rate of 0.1°C/min, and suspend under magnetic stirring at a rate of 300-400 rpm. The temperature during sampling is 10°C. The obtained suspension is centrifuged and filtered at 14,000 rpm at 10°C using a 0.45 μm nylon filter centrifuge tube, and the obtained solid is the hydrochloride crystal form M sample of the compound of formula I-1.

实施例32：式I-1化合物盐酸盐晶型N制备Example 32: Preparation of Hydrochloride Form N of Compound of Formula I-1

32.1：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.2-0.5mL甲醇，在25℃以300-400rpm速率在磁力搅拌下混悬。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm下离心过滤，所得固体为式I-1化合物盐酸盐晶型N样品。32.1: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.2-0.5 mL of methanol, and suspend under magnetic stirring at 25°C at a speed of 300-400 rpm. The resulting suspension is centrifuged at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube to obtain a solid sample of the hydrochloride crystal form N of the compound of formula I-1.

32.2：称取约40mg式I-1化合物盐酸盐晶型E1，加入0.1-0.5mL甲醇，在5℃至50℃之间以0.1℃/min的速率进行10个升降温循环，同时用300-400rpm速率在磁力搅拌下进行混悬，取样时温度为10℃。将所得混悬液用0.45μm尼龙滤膜离心管在10℃以14,000rpm离心过滤，所得固体为式I-1化合物盐酸盐晶型N样品。32.2: Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.1-0.5 mL of methanol, and perform 10 heating and cooling cycles at a rate of 0.1°C/min between 5°C and 50°C, while suspending under magnetic stirring at a rate of 300-400 rpm, and the temperature during sampling is 10°C. The resulting suspension is centrifuged and filtered at 14,000 rpm at 10°C using a 0.45 μm nylon filter centrifuge tube, and the resulting solid is the hydrochloride crystal form N sample of the compound of formula I-1.

实施例33：式I-1化合物盐酸盐晶型O制备Example 33: Preparation of Hydrochloride Form O of Compound I-1

称取约40mg式I-1化合物盐酸盐晶型E1，加入0.2-0.5mL二氯甲烷，在25℃以300-400rpm速率在磁力搅拌下混悬。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm下离心过滤，所得固体为式I-1化合物盐酸盐晶型O样品。Weigh about 40 mg of the hydrochloride crystal form E1 of the compound of formula I-1, add 0.2-0.5 mL of dichloromethane, and suspend under magnetic stirring at 300-400 rpm at 25° C. The resulting suspension is centrifuged at 14,000 rpm using a 0.45 μm nylon filter centrifuge tube to obtain a solid sample of the hydrochloride crystal form O of the compound of formula I-1.

实验例1：式I-1化合物盐酸盐晶型I的固体稳定性和溶解度Experimental Example 1: Solid Stability and Solubility of Hydrochloride Form I of Compound I-1

1.1式I-1化合物盐酸盐晶型I的固体稳定性1.1 Solid Stability of Hydrochloride Form I of Compound I-1

将盛有式I-1化合物盐酸盐晶型I的敞口容器放置于25℃/60％RH中1周。将盛有式I-1化合物盐酸盐晶型I的密闭容器放置于60℃中1周。对这些条件下的稳定性样品进行XRPD、HPLC和化学计量比测试，并观察样品是否发生颜色变化。The open container containing the hydrochloride crystal form I of the compound of formula I-1 was placed at 25°C/60% RH for 1 week. The sealed container containing the hydrochloride crystal form I of the compound of formula I-1 was placed at 60°C for 1 week. The stability samples under these conditions were subjected to XRPD, HPLC and stoichiometric ratio tests, and the samples were observed for color changes.

表33式I-1化合物盐酸盐晶型I的固体稳定性
Table 33 Solid stability of hydrochloride salt of compound of formula I-1 Form I

1.2式I-1化合物自由态晶型A的溶解度1.2 Solubility of Free Form A of Compound I-1

称取10mg式I-1化合物的自由态晶型A或10.8mg(相当于10mg自由态无水物)式I-1化合物盐酸盐晶型I样品置于8mL玻璃瓶中。加入5mL溶出介质。所得混悬液/澄清溶液在37℃下以400rpm转速搅拌2h、8h和24h，随后将所得混悬液/澄清溶液在37℃下以14,000rpm转速离心5min。通过HPLC检测上清液的溶解度，通过pH计测定上清液pH，并用XRPD检测残余固体。Weigh 10 mg of the free form A of the compound of formula I-1 or 10.8 mg (equivalent to 10 mg of the free anhydrous substance) of the hydrochloride form I of the compound of formula I-1 into an 8 mL glass bottle. Add 5 mL of the dissolution medium. The resulting suspension/clear solution is stirred at 400 rpm for 2 h, 8 h and 24 h at 37 ° C, and then the resulting suspension/clear solution is centrifuged at 14,000 rpm for 5 min at 37 ° C. The solubility of the supernatant is detected by HPLC, the pH of the supernatant is measured by a pH meter, and the residual solid is detected by XRPD.

表34式I-1化合物自由态晶型A的溶解度测试

Table 34 Solubility test of free crystal form A of compound of formula I-1

表35式I-1化合物盐酸盐晶型I的溶解度测试
Table 35 Solubility test of hydrochloride crystal form I of compound of formula I-1

结论：式I-1化合物盐酸盐晶型I总杂质量和晶型没有变化，表现出良好的物理稳定性。而且式I-1化合物盐酸盐晶型I对比式I-1化合物的自由态晶型在四种介质中都有较大的溶解度提升。Conclusion: The total impurity content and crystal form of the hydrochloride crystal form I of the compound of formula I-1 did not change, showing good physical stability. Moreover, the hydrochloride crystal form I of the compound of formula I-1 has a greater solubility improvement in the four media compared to the free crystal form of the compound of formula I-1.

实验例2：盐酸盐晶型I的FGFR2受体活性抑制测试实验Experimental Example 2: FGFR2 receptor activity inhibition test experiment of hydrochloride crystal form I

2.3式I-1化合物盐酸盐晶型I对FGFR2背景细胞活性的测试2.3 Test of the activity of the hydrochloride form I of the compound of formula I-1 on FGFR2 background cells

本实验通过检测受试化合物在7株肿瘤细胞系(KATO III、NCI-H716、SNU-16、AN3CA、MFE-296、SUM52PE、MFM223)中对体外细胞活性的影响而研究化合物抑制细胞增殖的作用。This experiment studied the inhibitory effect of the compounds on cell proliferation by detecting the effects of the test compounds on in vitro cell activity in 7 tumor cell lines (KATO III, NCI-H716, SNU-16, AN3CA, MFE-296, SUM52PE, and MFM223).

将细胞系在培养条件37℃，5％ CO2的培养箱中进行培养，定期传代，取处于对数生长期的细胞用于铺板。用DMSO将待测化合物配置成10mM溶液。The cell line was cultured in an incubator at 37°C and 5% CO 2 , passaged regularly, and cells in the logarithmic growth phase were used for plating. The test compound was prepared into a 10 mM solution with DMSO.

制备化合物存储板(管)：用DMSO从最高浓度4倍梯度稀释至最低浓度,共9个浓度，内控化合物4倍稀释，共9个浓度。然后，化合物工作液的配制:在平底的96孔透明药板中加入98μL细胞培养液，从化合物存储板中吸取2μL化合物加入96孔透明药板的细胞培养液中。在溶媒对照中加入2μL DMSO。加入化合物或DMSO后用排枪吹打混匀。Prepare compound storage plate (tube): dilute the compound 4-fold from the highest concentration to the lowest concentration with DMSO, for a total of 9 concentrations, and dilute the internal control compound 4-fold, for a total of 9 concentrations. Then, prepare the compound working solution: add 98μL of cell culture medium to a flat-bottomed 96-well transparent medicine plate, draw 2μL of compound from the compound storage plate and add it to the cell culture medium of the 96-well transparent medicine plate. Add 2μL DMSO to the solvent control. After adding the compound or DMSO, mix it with a spray gun.

细胞铺板和给药：1)用台盼兰进行细胞染色并计数活细胞，要求细胞活率90％以上；2)将细胞浓度调整至合适浓度；3)在化合物检测细胞板中每孔加入95μL细胞悬液(6000～10000cells/well)，在Min对照孔中加入不含细胞(含0.1％)的培养液；4)化合物检测细胞板加药：取5μL的20×化合物工作液按表1所示加入到细胞培养板中。在Max对照中加入5μLDMSO-细胞培养液混合液。DMSO终浓度为0.1％；5)将培养板在37℃,5％CO2培养箱中培养72～96小时。Cell plating and drug administration: 1) Use trypan blue to stain cells and count live cells, requiring cell viability to be above 90%; 2) Adjust cell concentration to an appropriate concentration; 3) Add 95 μL of cell suspension (6000-10000 cells/well) to each well of the compound detection cell plate, and add culture medium without cells (containing 0.1%) to the Min control well; 4) Add drugs to the compound detection cell plate: Take 5 μL of 20× compound working solution and add it to the cell culture plate as shown in Table 1. Add 5 μL of DMSO-cell culture medium mixture to the Max control. The final concentration of DMSO is 0.1%; 5) Incubate the culture plate in a 37°C, 5% CO 2 incubator for 72-96 hours.

按照PromegaCellTiter-Glo发光法细胞活性检测试剂盒(Promega-G7573)的说明书来进行：1)将CellTiter-Glo缓冲液融化并放置至室温；2)将CellTiter-Glo底物放置至室温；3)在一瓶CellTiter-Glo底物中加入CellTiter-Glo缓冲液以溶解底物，从而配制CellTiter-Glo工作液；4)缓慢涡旋震荡使充分溶解；5)取出细胞培养板放置10分钟使其平衡至室温；6)在每孔中加入50μL(等于每孔中细胞培养液一半体积)的CellTiter-Glo工作液；7)将培养板在轨道摇床上振摇2分钟以诱导细胞裂解；8)培养板在室温放置10分钟以稳定发光信号；9)在SpectraMaxParadigm读板器上检测发光信号。Follow the instructions of the Promega CellTiter-Glo Luminescent Cell Activity Assay Kit (Promega-G7573): 1) Melt the CellTiter-Glo buffer and bring to room temperature; 2) Bring the CellTiter-Glo substrate to room temperature; 3) Add the CellTiter-Glo buffer to a bottle of CellTiter-Glo substrate to dissolve the substrate, thereby preparing the CellTiter-Glo working solution; 4) Slowly vortex to fully dissolve; 5) Remove the cell culture plate and let it stand for 10 minutes to equilibrate to room temperature; 6) Add 50 μL (equal to half the volume of the cell culture solution in each well) of the CellTiter-Glo working solution to each well; 7) Shake the culture plate on an orbital shaker for 2 minutes to induce cell lysis; 8) Let the culture plate stand at room temperature for 10 minutes to stabilize the luminescent signal; 9) Detect the luminescent signal on a SpectraMax Paradigm plate reader.

细胞增殖抑制率(Inhibition Rate)数据采用下列公式来处理：
Inhibition Rate(Inh％)＝100-(RLUDrug-RLUMin)/(RLUMax-RLUMin)*100％。The cell proliferation inhibition rate (Inhibition Rate) data was processed using the following formula:
Inhibition Rate (Inh%)=100-(RLU Drug -RLU Min )/(RLU Max -RLU Min )*100%.

在EXCEL中计算不同浓度化合物对应的抑制率，然后用GraphPad Prism软件作抑制率曲线图并计算相关参数，参数包括细胞最大和最小抑制率，IC50值。The inhibition rates corresponding to different concentrations of compounds were calculated in EXCEL, and then the inhibition rate curve was drawn using GraphPad Prism software and related parameters were calculated, including the maximum and minimum inhibition rates of cells and IC 50 values.

表36测试化合物对FGFR2背景细胞系增殖抑制结果
Table 36 Test compound inhibition results of FGFR2 background cell line proliferation

由表36可见，本发明化合物对FGFR2背景的细胞增殖具有良好的抑制效果。As can be seen from Table 36, the compounds of the present invention have a good inhibitory effect on cell proliferation in the FGFR2 background.

在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims (39)

一种式(I)化合物，
A compound of formula (I),
的无定性或晶体形态或其溶剂合物；an amorphous or crystalline form or a solvate thereof; 其中，m为1、2、3、4、5、6、7、8或9；wherein m is 1, 2, 3, 4, 5, 6, 7, 8 or 9; n为0、0.5、1、1.5、2、2.5或3；且X选自下组：盐酸、氢溴酸、氢氟酸、硫酸、硝酸或磷酸，甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘磺酸、马尿酸、乙醇酸或戊二酸。n is 0, 0.5, 1, 1.5, 2, 2.5 or 3; and X is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid or phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, hippuric acid, glycolic acid or glutaric acid. 如权利要求1所述的式(I)化合物的晶型A，其特征在于，所述式(I)化合物为I-1，n＝0，且所述晶型A的X射线粉末衍射图谱具有选自下组的2θ角：14.16±0.2°、16.74±0.2°、23.01±0.2°。The crystalline form A of the compound of formula (I) as claimed in claim 1, characterized in that the compound of formula (I) is I-1, n=0, and the X-ray powder diffraction pattern of the crystalline form A has a 2θ angle selected from the following group: 14.16±0.2°, 16.74±0.2°, 23.01±0.2°. 在另一优选例中，所述晶型A还具有选自下组的一个或多个特征：In another preferred embodiment, the crystalline form A further has one or more characteristics selected from the following group: a.所述晶型A的X射线粉末衍射图谱还具有1个或1个以上(如1、2、3、4、5、6、7、8、9或10个)选自下组的2θ角：8.44±0.2°、11.59±0.2°、12.00±0.2°、12.34±0.2°、15.50±0.2°、16.50±0.2°、18.38±0.2°、18.81±0.2°、19.79±0.2°、20.44±0.2°、21.32±0.2°、21.53±0.2°、21.80±0.2°、22.24±0.2°、24.37±0.2°、25.43±0.2°、26.50±0.2°、27.13±0.2°、27.74±0.2°、28.90±0.2°、29.72±0.2°、29.93±0.2°、30.83±0.2°、31.56±0.2°、32.47±0.2°、33.64±0.2°、34.12±0.2°、35.03±0.2°、36.17±0.2°；a. The X-ray powder diffraction pattern of the crystalline form A also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the group consisting of 8.44±0.2°, 11.59±0.2°, 12.00±0.2°, 12.34±0.2°, 15.50±0.2°, 16.50±0.2°, 18.38±0.2°, 18.81±0.2°, 19.79±0.2°, 20.44±0.2°, 21.32±0.2°, 21.53±0.2 °, 21.80±0.2°, 22.24±0.2°, 24.37±0.2°, 25.43±0.2°, 26.50±0.2°, 27.13±0.2°, 27.74±0.2°, 28.90±0.2°, 29.72±0.2°, 29.93±0.2°, 30.83±0.2°, 31.56±0.2°, 32.47±0.2°, 33.64±0.2°, 34.12±0.2°, 35.03±0.2°, 36.17±0.2°; b.所述晶型A的差示扫描量热曲线在26.10℃±2℃和223.34℃±2℃两处有吸热峰的起始点；b. The differential scanning calorimetry curve of the crystalline form A has two starting points of endothermic peaks at 26.10°C ± 2°C and 223.34°C ± 2°C; c.所述晶型A的热重分析曲线在24.00℃±2℃、110.00℃±2℃和200.00℃±2℃三处有三个较小的失重台阶，在250.00℃±2℃之后开始分解。c. The thermogravimetric analysis curve of the crystalline form A has three smaller weight loss steps at 24.00℃±2℃, 110.00℃±2℃ and 200.00℃±2℃, and begins to decompose after 250.00℃±2℃. 在另一优选例中，所述晶型A具有基本上如图1所示的X射线粉末衍射图。In another preferred embodiment, the crystalline form A has an X-ray powder diffraction pattern substantially as shown in FIG1 . 在另一优选例中，所述晶型A具有基本上如图2所示的差示扫描量热图。In another preferred example, the crystalline form A has a differential scanning calorimetry diagram substantially as shown in FIG. 2 . 在另一优选例中，所述晶型A具有基本上如图3所示的热重分析图。In another preferred example, the crystalline form A has a thermogravimetric analysis diagram substantially as shown in FIG. 3 . 一种制备如权利要求2所述的晶型A的方法，其特征在于，所述方法包括如下步骤：A method for preparing the crystalline form A according to claim 2, characterized in that the method comprises the following steps: a.将化合物I-1溶解或分散到1～5倍体积的乙腈、醇类溶剂、酯类溶剂、醚类溶剂或醇类溶剂与水的混合溶剂中；a. dissolving or dispersing compound I-1 in 1 to 5 times the volume of acetonitrile, an alcohol solvent, an ester solvent, an ether solvent, or a mixed solvent of an alcohol solvent and water; b.重结晶或打浆；b. Recrystallization or beating; 其中，所述醇类溶剂选自下组：甲醇、乙醇、异丙醇、或其组合；Wherein, the alcohol solvent is selected from the group consisting of methanol, ethanol, isopropanol, or a combination thereof; 所述酯类溶剂选自下组：乙酸乙酯、乙酸异丙酯、甲酸甲酸、甲酸乙酯、甲酸异丙酯、或其组合；The ester solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, formic acid, ethyl formate, isopropyl formate, or a combination thereof; 所述醚类溶剂选自下组：甲基叔丁基醚、四氢呋喃、乙二醇二甲醚、或其组合；The ether solvent is selected from the group consisting of methyl tert-butyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, or a combination thereof; 所述醇类溶剂与水的混合溶剂选自下组：甲醇与水的混合溶剂、乙醇与水的混合溶剂、异丙醇与水的混合溶剂；其中，醇类溶剂和水的体积比为1:(0.1～1.5)。The mixed solvent of alcohol solvent and water is selected from the following group: a mixed solvent of methanol and water, a mixed solvent of ethanol and water, and a mixed solvent of isopropanol and water; wherein the volume ratio of the alcohol solvent to water is 1:(0.1-1.5). 如权利要求1所述的式(I)化合物的晶型，其特征在于，所述式(I)化合物为化合物I-1与酸形成的盐；其中，所述酸为无机酸或有机酸；The crystalline form of the compound of formula (I) according to claim 1, characterized in that the compound of formula (I) is a salt formed by compound I-1 and an acid; wherein the acid is an inorganic acid or an organic acid; 优选地，所述无机酸选自下组：盐酸、氢溴酸、氢氟酸、硫酸、硝酸或磷酸；Preferably, the inorganic acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid or phosphoric acid; 优选地，所述有机酸选自下组：甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘磺酸、马尿酸、乙醇酸或戊二酸；Preferably, the organic acid is selected from the group consisting of formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, hippuric acid, glycolic acid or glutaric acid; 优选地，所述化合物I-1与所述酸的摩尔比为1:(0.8～3)；更优选地，1:(0.8～2)。Preferably, the molar ratio of the compound I-1 to the acid is 1:(0.8-3); more preferably, 1:(0.8-2). 如权利要求4所述的晶型，其特征在于，所述晶型为式I-1化合物的马来酸盐晶型A，所述马来酸盐晶型A的X射线粉末衍射图谱具有选自下组的2θ角：15.17±0.2°、23.02±0.2°、24.42±0.2°。The crystalline form according to claim 4, characterized in that the crystalline form is a maleate crystalline form A of the compound of formula I-1, and the X-ray powder diffraction pattern of the maleate crystalline form A has a 2θ angle selected from the following group: 15.17±0.2°, 23.02±0.2°, 24.42±0.2°. 在另一优选例中，所述马来酸盐晶型A的X射线粉末衍射图谱还具有1个或1个以上(如1、2、3、4、5、6、7、8、9或10个)选自下组的2θ角：5.82±0.2°、9.86±0.2°、11.06±0.2°、11.29±0.2°、11.64±0.2°、11.90±0.2°、12.72±0.2°、13.04±0.2°、15.66±0.2°、16.36±0.2°、17.70±0.2°、17.88±0.2°、18.11±0.2°、18.35±0.2°、18.61±0.2°、19.41±0.2°、20.16±0.2°、20.38±0.2°、20.69±0.2°、21.32±0.2°、21.62±0.2°、22.28±0.2°、22.71±0.2°、25.00±0.2°、25.34±0.2°、26.24±0.2°、26.77±0.2°、29.85±0.2°、34.09±0.2°。In another preferred embodiment, the X-ray powder diffraction pattern of the maleate salt form A further has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 5.82±0.2°, 9.86±0.2°, 11.06±0.2°, 11.29±0.2°, 11.64±0.2°, 11.90±0.2°, 12.72±0.2°, 13.04±0.2°, 15.66±0.2°, 16.36±0.2°, 17.70±0.2°, 17.8 8±0.2°, 18.11±0.2°, 18.35±0.2°, 18.61±0.2°, 19.41±0.2°, 20.16±0.2°, 20.38±0.2°, 20.69±0.2°, 21.32±0.2°, 21.62±0.2°, 22.28±0.2°, 22.71±0.2°, 25.00±0.2°, 25.34±0.2°, 26.24±0.2°, 26.77±0.2°, 29.85±0.2°, and 34.09±0.2°. 在另一优选例中，所述马来酸盐晶型A具有基本上如图4所示的X射线粉末衍射图。In another preferred embodiment, the maleate salt form A has an X-ray powder diffraction pattern substantially as shown in FIG. 4 . 如权利要求4所述的晶型，其特征在于，所述晶型为式I-1化合物的单马来酸盐晶型B，所述单马来酸盐晶型B的X射线粉末衍射图谱具有选自下组的2θ角：16.57±0.2°、17.38±0.2°、20.39±0.2°。The crystalline form according to claim 4, characterized in that the crystalline form is a monomaleate crystalline form B of the compound of formula I-1, and the X-ray powder diffraction pattern of the monomaleate crystalline form B has a 2θ angle selected from the following group: 16.57±0.2°, 17.38±0.2°, 20.39±0.2°. 在另一优选例中，所述单马来酸盐晶型B还具有选自下组的一个或多个特征：In another preferred embodiment, the monomaleate salt form B further has one or more characteristics selected from the following group: a.所述单马来酸盐晶型B的X射线粉末衍射图谱还具有1个或1个以上(如1、2、3、4、5、6、7、8、9或10个)选自下组的2θ角：7.98±0.2°、8.29±0.2°、10.27±0.2°、11.61±0.2°、13.21±0.2°、13.99±0.2°、14.52±0.2°、15.25±0.2°、15.95±0.2°、16.89±0.2°、18.06±0.2°、20.61±0.2°、21.25±0.2°、21.61±0.2°、22.17±0.2°、23.31±0.2°、23.54±0.2°、23.98±0.2°、24.70±0.2°、24.93±0.2°、25.32±0.2°、25.91±0.2°、26.55±0.2°、27.24±0.2°、28.23±0.2°、28.54±0.2°、29.00±0.2°、29.47±0.2°、29.71±0.2°、32.64±0.2°、35.12±0.2°；a. The X-ray powder diffraction pattern of the monomaleate salt form B also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the group consisting of: 7.98±0.2°, 8.29±0.2°, 10.27±0.2°, 11.61±0.2°, 13.21±0.2°, 13.99±0.2°, 14.52±0.2°, 15.25±0.2°, 15.95±0.2°, 16.89±0.2°, 18.06±0.2°, 20.61±0.2°, 21.25±0.2°, .2°, 21.61±0.2°, 22.17±0.2°, 23.31±0.2°, 23.54±0.2°, 23.98±0.2°, 24.70±0.2°, 24.93±0.2°, 25.32±0.2°, 25.91±0.2°, 26.55±0.2°, 27.24±0.2°, 28.23±0.2°, 28.54±0.2°, 29.00±0.2°, 29.47±0.2°, 29.71±0.2°, 32.64±0.2°, 35.12±0.2°; b.所述单马来酸盐晶型B的差示扫描量热曲线在213.92℃±2℃处具有吸热峰的起始点；b. The differential scanning calorimetry curve of the monomaleate salt form B has a starting point of an endothermic peak at 213.92°C ± 2°C; c.所述单马来酸盐晶型B的热重分析曲线在24.00℃±2℃和180.00℃±2℃两处有两个失重台阶，在250.00℃±2℃之后开始分解。c. The thermogravimetric analysis curve of the monomaleate salt form B has two weight loss steps at 24.00°C±2°C and 180.00°C±2°C, and begins to decompose after 250.00°C±2°C. 在另一优选例中，所述马来酸盐晶型B具有基本上如图5所示的X射线粉末衍射图。In another preferred embodiment, the maleate salt form B has an X-ray powder diffraction pattern substantially as shown in FIG. 5 . 在另一优选例中，所述马来酸盐晶型B具有基本上如图6所示的差示扫描量热图。In another preferred embodiment, the maleate salt form B has a differential scanning calorimetry diagram substantially as shown in FIG. 6 . 在另一优选例中，所述马来酸盐晶型B具有基本上如图7所示的热重分析图。In another preferred embodiment, the maleate salt form B has a thermogravimetric analysis diagram substantially as shown in FIG. 7 . 如权利要求4所述的晶型，其特征在于，所述晶型为式I-1化合物的富马酸盐晶型A，所述富马酸盐晶型A的X射线粉末衍射图谱具有选自下组的2θ角：5.11±0.2°、14.23±0.2°、28.85±0.2°。The crystalline form according to claim 4, characterized in that the crystalline form is a fumarate crystalline form A of the compound of formula I-1, and the X-ray powder diffraction pattern of the fumarate crystalline form A has a 2θ angle selected from the following group: 5.11±0.2°, 14.23±0.2°, 28.85±0.2°. 在另一优选例中，所述富马酸盐晶型A的X射线粉末衍射图谱还具有1个或1个以上(如1、2、3、4、5、6、7、8、9或10个)选自下组的2θ角：7.26±0.2°、10.20±0.2°、10.51±0.2°、14.47±0.2°、14.93±0.2°、16.17±0.2°、17.03±0.2°、17.90±0.2°、18.79±0.2°、19.44±0.2°、20.19±0.2°、20.80±0.2°、22.48±0.2°、23.07±0.2°、23.74±0.2°、24.07±0.2°、27.06±0.2°、27.85±0.2°、28.30±0.2°、29.46±0.2°、38.24±0.2°。In another preferred embodiment, the X-ray powder diffraction pattern of the fumarate salt form A further has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 7.26 ± 0.2°, 10.20 ± 0.2°, 10.51 ± 0.2°, 14.47 ± 0.2°, 14.93 ± 0.2°, 16.17 ± 0.2°, 17.03 ± 0.2°, 17.9 0±0.2°, 18.79±0.2°, 19.44±0.2°, 20.19±0.2°, 20.80±0.2°, 22.48±0.2°, 23.07±0.2°, 23.74±0.2°, 24.07±0.2°, 27.06±0.2°, 27.85±0.2°, 28.30±0.2°, 29.46±0.2°, 38.24±0.2°. 在另一优选例中，所述富马酸盐晶型A具有基本上如图8所示的X射线粉末衍射图。In another preferred embodiment, the fumarate salt form A has an X-ray powder diffraction pattern substantially as shown in FIG8 . 如权利要求4所述的晶型，其特征在于，所述晶型为式I-1化合物的半富马酸盐晶型B，所述半富马酸盐晶型B的X射线粉末衍射图谱具有选自下组的2θ角：5.12±0.2°、14.24±0.2°、10.20±0.2°。The crystal form according to claim 4, characterized in that the crystal form is a hemi-fumarate crystal form B of the compound of formula I-1, and the X-ray powder diffraction pattern of the hemi-fumarate crystal form B has a 2θ angle selected from the following group: 5.12±0.2°, 14.24±0.2°, 10.20±0.2°. 在另一优选例中，所述半富马酸盐晶型B还具有选自下组的一个或多个特征：In another preferred embodiment, the hemi-fumarate salt form B further has one or more characteristics selected from the following group: a.所述半富马酸盐晶型B的X射线粉末衍射图谱还具有1个或1个以上(如1、2、3、4、5、6、7、8、9或10个)选自下组的2θ角：7.27±0.2°、7.48±0.2°、8.77±0.2°、9.18±0.2°、9.74±0.2°、10.53±0.2°、14.96±0.2°、16.09±0.2°、16.99±0.2°、17.61±0.2°、17.95±0.2°、18.81±0.2°、19.45±0.2°、20.22±0.2°、20.43±0.2°、20.84±0.2°、22.51±0.2°、23.11±0.2°、23.76±0.2°、24.19±0.2°、25.24±0.2°、27.04±0.2°、27.90±0.2°、28.25±0.2°、28.75±0.2°、29.73±0.2°、30.14±0.2°、30.77±0.2°、31.28±0.2°、33.95±0.2°、34.52±0.2°、37.07±0.2°、38.26±0.2°；a. The X-ray powder diffraction pattern of the hemi-fumarate salt form B also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the group consisting of 7.27±0.2°, 7.48±0.2°, 8.77±0.2°, 9.18±0.2°, 9.74±0.2°, 10.53±0.2°, 14.96±0.2°, 16.09±0.2°, 16.99±0.2°, 17.61±0.2°, 17.95±0.2°, 18.81±0.2°, 19.45±0.2°, 20.22±0.2°, 21.80±0.2°, 23.37±0.2°, 24.70±0.2°, 25.91±0.2°, 26.33±0.2°, 27.70±0.2°, 28.61±0.2°, 29.81±0.2°, 30. 2°, 20.43±0.2°, 20.84±0.2°, 22.51±0.2°, 23.11±0.2°, 23.76±0.2°, 24.19±0.2°, 25.24±0.2°, 27.04±0.2°, 27.90±0.2°, 28.25±0.2°, 28.75±0.2°, 29.73±0.2°, 30.14±0.2°, 30.77±0.2°, 31.28±0.2°, 33.95±0.2°, 34.52±0.2°, 37.07±0.2°, 38.26±0.2°; b.所述半富马酸盐晶型B的差示扫描量热曲线在21.34℃±2℃、172.21℃±2℃、234.34℃±2℃三处具有吸热峰的起始点；b. The differential scanning calorimetry curve of the hemi-fumarate salt form B has three starting points of endothermic peaks at 21.34°C ± 2°C, 172.21°C ± 2°C, and 234.34°C ± 2°C; c.所述半富马酸盐晶型B的其热重分析曲线在31.90℃±2℃、90.00℃±2℃和190.00℃±2℃三个温度处有三个失重台阶，在270.00℃±2℃之后开始分解。c. The thermogravimetric analysis curve of the hemi-fumarate salt form B has three weight loss steps at three temperatures of 31.90°C±2°C, 90.00°C±2°C and 190.00°C±2°C, and begins to decompose after 270.00°C±2°C. 在另一优选例中，所述半富马酸盐晶型B具有基本上如图9所示的X射线粉末衍射图。In another preferred embodiment, the hemi-fumarate salt form B has an X-ray powder diffraction pattern substantially as shown in FIG. 9 . 在另一优选例中，所述半富马酸盐晶型B具有基本上如图10所示的差示扫描量热图。In another preferred example, the hemi-fumarate salt form B has a differential scanning calorimetry diagram substantially as shown in FIG. 10 . 在另一优选例中，所述半富马酸盐晶型B具有基本上如图11所示的热重分析图。In another preferred embodiment, the hemi-fumarate salt form B has a thermogravimetric analysis diagram substantially as shown in FIG. 11 . 如权利要求4所述的晶型，其特征在于，所述晶型为式I-1化合物的单乙醇酸盐晶型A，所述单乙醇酸盐晶型A的X射线粉末衍射图谱具有选自下组的2θ角：18.22±0.2°、22.83±0.2°、26.41±0.2°。The crystalline form according to claim 4, characterized in that the crystalline form is a monoglycolate crystalline form A of the compound of formula I-1, and the X-ray powder diffraction pattern of the monoglycolate crystalline form A has a 2θ angle selected from the following group: 18.22±0.2°, 22.83±0.2°, 26.41±0.2°. 在另一优选例中，所述单乙醇酸盐晶型A还具有选自下组的一个或多个特征：In another preferred embodiment, the monoglycolate crystalline form A further has one or more characteristics selected from the following group: a.所述单乙醇酸盐晶型A的X射线粉末衍射图谱还具有1个或1个以上(如1、2、3、4、5、6、7、8、9或10个)选自下组的2θ角：6.37±0.2°、10.37±0.2°、11.09±0.2°、11.70±0.2°、12.69±0.2°、13.55±0.2°、14.06±0.2°、15.97±0.2°、17.34±0.2°、18.47±0.2°、19.09±0.2°、20.41±0.2°、20.71±0.2°、21.25±0.2°、22.06±0.2°、22.43±0.2°、23.49±0.2°、24.09±0.2°、24.79±0.2°、25.21±0.2°、27.23±0.2°、28.00±0.2°、29.59±0.2°、30.44±0.2°、30.96±0.2°、38.67±0.2°；a. The X-ray powder diffraction pattern of the monoglycolic acid salt form A also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the group consisting of 6.37±0.2°, 10.37±0.2°, 11.09±0.2°, 11.70±0.2°, 12.69±0.2°, 13.55±0.2°, 14.06±0.2°, 15.97±0.2°, 17.34±0.2°, 18.47±0.2°, 1 9.09±0.2°, 20.41±0.2°, 20.71±0.2°, 21.25±0.2°, 22.06±0.2°, 22.43±0.2°, 23.49±0.2°, 24.09±0.2°, 24.79±0.2°, 25.21±0.2°, 27.23±0.2°, 28.00±0.2°, 29.59±0.2°, 30.44±0.2°, 30.96±0.2°, 38.67±0.2°; b.所述单乙醇酸盐晶型A的差示扫描量热曲线在109.66℃±2℃和198.83℃±2℃两处具有吸热峰的起始点；b. The differential scanning calorimetry curve of the monoglycolate salt form A has two starting points of endothermic peaks at 109.66°C ± 2°C and 198.83°C ± 2°C; c.所述单乙醇酸盐晶型A的热重分析曲线在33.00℃±2℃、100.00℃±2℃和165.00℃±2℃三处有三个失重台阶，在200.00℃±2℃之后开始分解。c. The thermogravimetric analysis curve of the monoglycolate crystal form A has three weight loss steps at 33.00℃±2℃, 100.00℃±2℃ and 165.00℃±2℃, and begins to decompose after 200.00℃±2℃. 在另一优选例中，所述单乙醇酸盐晶型A具有基本上如图12所示的X射线粉末衍射图。In another preferred example, the monoglycolic acid salt form A has an X-ray powder diffraction pattern substantially as shown in FIG. 12 . 在另一优选例中，所述单乙醇酸盐晶型A具有基本上如图13所示的差示扫描量热图。In another preferred example, the monoglycolic acid salt form A has a differential scanning calorimetry diagram substantially as shown in FIG. 13 . 在另一优选例中，所述单乙醇酸盐晶型A具有基本上如图14所示的热重分析图。In another preferred example, the monoglycolic acid salt form A has a thermogravimetric analysis diagram substantially as shown in FIG. 14 . 如权利要求4所述的晶型，其特征在于，所述晶型为式I-1化合物的乙醇酸盐晶型B，所述乙醇酸盐晶型B的X射线粉末衍射图谱具有选自下组的2θ角：13.87±0.2°、17.30±0.2°、19.49±0.2°、23.50±0.2°。The crystalline form according to claim 4, characterized in that the crystalline form is the glycolate crystalline form B of the compound of formula I-1, and the X-ray powder diffraction pattern of the glycolate crystalline form B has a 2θ angle selected from the following group: 13.87±0.2°, 17.30±0.2°, 19.49±0.2°, 23.50±0.2°. 在另一优选例中，所述乙醇酸盐晶型B的X射线粉末衍射图谱还具有1个或1个以上(如1、2、3、4、5、6、7、8、9或10个)选自下组的2θ角：5.95±0.2°、11.06±0.2°、12.20±0.2°、15.01±0.2°、15.79±0.2°、15.97±0.2°、16.44±0.2°、16.63±0.2°、16.79±0.2°、17.90±0.2°、18.33±0.2°、18.91±0.2°、21.59±0.2°、22.18±0.2°、22.80±0.2°、23.16±0.2°、23.93±0.2°、24.49±0.2°、25.13±0.2°、26.68±0.2°、27.95±0.2°、30.49±0.2°、31.62±0.2°、32.27±0.2°。In another preferred embodiment, the X-ray powder diffraction pattern of the glycolate crystalline form B further has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 5.95±0.2°, 11.06±0.2°, 12.20±0.2°, 15.01±0.2°, 15.79±0.2°, 15.97±0.2°, 16.44±0.2°, 16.63±0.2°, 16.79±0.2 °, 17.90±0.2°, 18.33±0.2°, 18.91±0.2°, 21.59±0.2°, 22.18±0.2°, 22.80±0.2°, 23.16±0.2°, 23.93±0.2°, 24.49±0.2°, 25.13±0.2°, 26.68±0.2°, 27.95±0.2°, 30.49±0.2°, 31.62±0.2°, and 32.27±0.2°. 在另一优选例中，所述乙醇酸盐晶型B具有基本上如图15所示的X射线粉末衍射图。In another preferred embodiment, the glycolate salt form B has an X-ray powder diffraction pattern substantially as shown in FIG. 15 . 如权利要求4所述的晶型，其特征在于，所述晶型为式I-1化合物的，所述单L-苹果酸盐晶型A的X射线粉末衍射图谱具有选自下组的2θ角：17.99±0.2°、22.58±0.2°、24.00±0.2°。The crystalline form according to claim 4, characterized in that the crystalline form is of the compound of formula I-1, and the X-ray powder diffraction pattern of the mono L-malate crystalline form A has a 2θ angle selected from the following group: 17.99±0.2°, 22.58±0.2°, 24.00±0.2°. 在另一优选例中，所述单L-苹果酸盐晶型A还具有选自下组的一个或多个特征：In another preferred embodiment, the mono L-malate crystalline form A further has one or more characteristics selected from the following group: a.所述单L-苹果酸盐晶型A的X射线粉末衍射图谱还具有1个或1个以上(如1、2、3、4、5、6、7、8、9或10个)选自下组的2θ角：6.01±0.2°、10.06±0.2°、11.04±0.2°、11.98±0.2°、12.66±0.2°、12.86±0.2°、13.39±0.2°、15.15±0.2°、15.62±0.2°、16.46±0.2°、17.27±0.2°、18.58±0.2°、19.53±0.2°、19.77±0.2°、20.25±0.2°、21.01±0.2°、21.57±0.2°、22.04±0.2°、23.67±0.2°、24.50±0.2°、25.00±0.2°、27.34±0.2°、28.54±0.2°、28.91±0.2°、29.40±0.2°、29.89±0.2°、30.53±0.2°、31.33±0.2°、33.67±0.2°、36.16±0.2°；a. The X-ray powder diffraction pattern of the mono L-malate crystalline form A further comprises one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the group consisting of 6.01 ± 0.2°, 10.06 ± 0.2°, 11.04 ± 0.2°, 11.98 ± 0.2°, 12.66 ± 0.2°, 12.86 ± 0.2°, 13.39 ± 0.2°, 15.15 ± 0.2°, 15.62 ± 0.2°, 16.46 ± 0.2°, 17.27 ± 0.2°, 18.58 ± 0.2°, 19.53±0.2°, 19.77±0.2°, 20.25±0.2°, 21.01±0.2°, 21.57±0.2°, 22.04±0.2°, 23.67±0.2°, 24.50±0.2°, 25.00±0.2°, 27.34±0.2°, 28.54±0.2°, 28.91±0.2°, 29.40±0.2°, 29.89±0.2°, 30.53±0.2°, 31.33±0.2°, 33.67±0.2°, 36.16±0.2°; b.所述单L-苹果酸盐晶型A的差示扫描量热曲线在204.74℃±2℃处具有吸热峰的起始点；b. The differential scanning calorimetry curve of the mono L-malate salt form A has a starting point of an endothermic peak at 204.74°C ± 2°C; c.所述单L-苹果酸盐晶型A的热重分析曲线在33.00℃±2℃和185.00℃±2℃两处有两个失重台阶，在250.00℃±2℃之后开始分解。c. The thermogravimetric analysis curve of the mono L-malate salt form A has two weight loss steps at 33.00°C±2°C and 185.00°C±2°C, and begins to decompose after 250.00°C±2°C. 在另一优选例中，所述单L-苹果酸盐晶型A具有基本上如图16所示的X射线粉末衍射图。In another preferred example, the mono L-malate crystalline form A has an X-ray powder diffraction pattern substantially as shown in FIG. 16 . 在另一优选例中，所述单L-苹果酸盐晶型A具有基本上如图17所示的差示扫描量热图。In another preferred example, the mono L-malate crystalline form A has a differential scanning calorimetry diagram substantially as shown in FIG. 17 . 在另一优选例中，所述单L-苹果酸盐晶型A具有基本上如图18所示的热重分析图。In another preferred example, the mono L-malate crystal form A has a thermogravimetric analysis diagram substantially as shown in FIG. 18 . 如权利要求4所述的晶型，其特征在于，所述晶型为式I-1化合物的单琥珀酸盐晶型A，其特征在于，所述单琥珀酸盐晶型A的X射线粉末衍射图谱具有选自下组的2θ角：18.40±0.2°、24.09±0.2°、24.62±0.2°。The crystalline form according to claim 4, characterized in that the crystalline form is a monosuccinate crystalline form A of the compound of formula I-1, characterized in that the X-ray powder diffraction pattern of the monosuccinate crystalline form A has a 2θ angle selected from the following group: 18.40±0.2°, 24.09±0.2°, 24.62±0.2°. 在另一优选例中，所述单琥珀酸盐晶型A还具有选自下组的一个或多个特征：In another preferred embodiment, the monosuccinate crystalline form A further has one or more characteristics selected from the following group: a.所述单琥珀酸盐晶型A的X射线粉末衍射图谱还具有1个或1个以上(如1、2、3、4、5、6、7、8、9或10个)选自下组的2θ角：6.15±0.2°、9.64±0.2°、9.95±0.2°、11.19±0.2°、12.26±0.2°、12.70±0.2°、13.30±0.2°、14.95±0.2°、15.25±0.2°、16.18±0.2°、17.59±0.2°、18.89±0.2°、19.11±0.2°、19.73±0.2°、20.28±0.2°、20.90±0.2°、21.27±0.2°、21.64±0.2°、22.12±0.2°、23.12±0.2°、23.83±0.2°、24.35±0.2°、24.93±0.2°、25.17±0.2°、26.05±0.2°、27.00±0.2°、28.27±0.2°、28.72±0.2°、30.12±0.2°、31.20±0.2°、33.57±0.2°、34.13±0.2°、34.58±0.2°、35.60±0.2°、38.23±0.2°；a. The X-ray powder diffraction pattern of the monosuccinate crystalline form A also has one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the group consisting of 6.15±0.2°, 9.64±0.2°, 9.95±0.2°, 11.19±0.2°, 12.26±0.2°, 12.70±0.2°, 13.30±0.2°, 14.95±0.2°, 15.25±0.2°, 16.18±0.2°, 17.59±0.2°, 18.89±0.2°, 19.11±0.2°, 19.73±0.2°, 20.28±0.2°, .2°, 20.90±0.2°, 21.27±0.2°, 21.64±0.2°, 22.12±0.2°, 23.12±0.2°, 23.83±0.2°, 24.35±0.2°, 24.93±0.2°, 25.17±0.2°, 26.05±0.2°, 27.00±0.2°, 28.27±0.2°, 28.72±0.2°, 30.12±0.2°, 31.20±0.2°, 33.57±0.2°, 34.13±0.2°, 34.58±0.2°, 35.60±0.2°, 38.23±0.2°; b.所述单琥珀酸盐晶型A的差示扫描量热曲线在72.75℃±2℃、146.41℃±2℃和175.72℃±2℃三处具有吸热峰的起始点；b. The differential scanning calorimetry curve of the monosuccinate salt form A has three starting points of endothermic peaks at 72.75°C ± 2°C, 146.41°C ± 2°C and 175.72°C ± 2°C; c.所述单琥珀酸盐晶型A的热重分析曲线在33.00℃±2℃、90.00℃±2℃和160.00℃±2℃三处有三个失重台阶，在260.00℃±2℃之后开始分解。c. The thermogravimetric analysis curve of the monosuccinate crystal form A has three weight loss steps at 33.00℃±2℃, 90.00℃±2℃ and 160.00℃±2℃, and begins to decompose after 260.00℃±2℃. 在另一优选例中，所述单琥珀酸盐晶型A具有基本上如图19所示的X射线粉末衍射图。In another preferred example, the monosuccinate salt form A has an X-ray powder diffraction pattern substantially as shown in Figure 19. 在另一优选例中，所述单琥珀酸盐晶型A具有基本上如图20所示的差示扫描量热图。In another preferred example, the monosuccinate salt form A has a differential scanning calorimetry diagram substantially as shown in Figure 20. 在另一优选例中，所述单琥珀酸盐晶型A具有基本上如图21所示的热重分析图。In another preferred example, the monosuccinate salt form A has a thermogravimetric analysis diagram substantially as shown in Figure 21. 如权利要求4所述的晶型，其特征在于，所述晶型为式I-1化合物的硫酸盐晶型A，所述硫酸盐晶型A的X射线粉末衍射图谱具有选自下组的2θ角：14.97±0.2°、20.21±0.2°、22.58±0.2°。The crystalline form according to claim 4, characterized in that the crystalline form is sulfate crystalline form A of the compound of formula I-1, and the X-ray powder diffraction pattern of the sulfate crystalline form A has a 2θ angle selected from the following group: 14.97±0.2°, 20.21±0.2°, 22.58±0.2°. 在另一优选例中，所述硫酸盐晶型A的X射线粉末衍射图谱还具有1个或1个以上(如1、2、3、4、5、6、7、8、9或10个)选自下组的2θ角：6.74±0.2°、9.56±0.2°、12.89±0.2°、13.78±0.2°、14.68±0.2°、15.49±0.2°、15.70±0.2°、16.41±0.2°、16.90±0.2°、18.47±0.2°、18.68±0.2°、18.86±0.2°、19.33±0.2°、19.87±0.2°、20.70±0.2°、21.54±0.2°、21.76±0.2°、22.25±0.2°、23.75±0.2°、24.11±0.2°、24.50±0.2°、25.25±0.2°、25.86±0.2°、26.10±0.2°、26.71±0.2°、26.96±0.2°、27.73±0.2°、28.41±0.2°、28.90±0.2°、29.70±0.2°、30.21±0.2°、30.99±0.2°。In another preferred embodiment, the X-ray powder diffraction pattern of the sulfate crystalline form A also has 1 or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 6.74±0.2°, 9.56±0.2°, 12.89±0.2°, 13.78±0.2°, 14.68±0.2°, 15.49±0.2°, 15.70±0.2°, 16.41±0.2°, 16.90±0.2°, 18.47±0.2°, 18.68±0.2°, 18.86±0.2°, 19.33±0.2° , 19.87±0.2°, 20.70±0.2°, 21.54±0.2°, 21.76±0.2°, 22.25±0.2°, 23.75±0.2°, 24.11±0.2°, 24.50±0.2°, 25.25±0.2°, 25.86±0.2°, 26.10±0.2°, 26.71±0.2°, 26.96±0.2°, 27.73±0.2°, 28.41±0.2°, 28.90±0.2°, 29.70±0.2°, 30.21±0.2°, 30.99±0.2°. 在另一优选例中，所述硫酸盐晶型A具有基本上如图22所示的X射线粉末衍射图。In another preferred example, the sulfate crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 22. 如权利要求4所述的晶型，其特征在于，所述晶型为式I-1化合物的L-酒石酸盐晶型A，所述L-酒石酸盐晶型A的X射线粉末衍射图谱具有选自下组的2θ角：5.53±0.2°、16.95±0.2°、20.79±0.2°。The crystalline form according to claim 4, characterized in that the crystalline form is L-tartrate crystalline form A of the compound of formula I-1, and the X-ray powder diffraction pattern of the L-tartrate crystalline form A has a 2θ angle selected from the following group: 5.53±0.2°, 16.95±0.2°, 20.79±0.2°. 在另一优选例中，所述L-酒石酸盐晶型A的X射线粉末衍射图谱还具有1个或1个以上(如1、2、3、4、5、6、7、8、9或10个)选自下组的2θ角：8.90±0.2°、9.35±0.2°、11.05±0.2°、12.54±0.2°、12.90±0.2°、14.35±0.2°、14.64±0.2°、18.70±0.2°、19.45±0.2°、19.74±0.2°、20.38±0.2°、21.45±0.2°、21.94±0.2°、22.88±0.2°、23.80±0.2°、25.01±0.2°、25.77±0.2°、27.33±0.2°、27.80±0.2°、28.65±0.2°、29.41±0.2°、30.00±0.2°、31.09±0.2°。In another preferred embodiment, the X-ray powder diffraction pattern of the L-tartrate salt form A also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 8.90±0.2°, 9.35±0.2°, 11.05±0.2°, 12.54±0.2°, 12.90±0.2°, 14.35±0.2°, 14.64±0.2°, 18.70±0.2°, 19. 45±0.2°, 19.74±0.2°, 20.38±0.2°, 21.45±0.2°, 21.94±0.2°, 22.88±0.2°, 23.80±0.2°, 25.01±0.2°, 25.77±0.2°, 27.33±0.2°, 27.80±0.2°, 28.65±0.2°, 29.41±0.2°, 30.00±0.2°, 31.09±0.2°. 在另一优选例中，所述L-酒石酸盐晶型A具有基本上如图23所示的X射线粉末衍射图。In another preferred example, the L-tartrate salt form A has an X-ray powder diffraction pattern substantially as shown in Figure 23. 如权利要求4所述的晶型，其特征在于，所述晶型为式I-1化合物的马尿酸盐晶型A，所述马尿酸盐晶型A的X射线粉末衍射图谱具有选自下组的2θ角：6.17±0.2°、12.30±0.2°、18.78±0.2°。The crystal form as described in claim 4 is characterized in that the crystal form is hippurate crystal form A of the compound of formula I-1, and the X-ray powder diffraction pattern of the hippurate crystal form A has a 2θ angle selected from the following group: 6.17±0.2°, 12.30±0.2°, 18.78±0.2°. 在另一优选例中，所述马尿酸盐晶型A的X射线粉末衍射图谱还具有1个或1个以上(如1、2、3、4、5、6、7、8、9或10个)选自下组的2θ角：6.52±0.2°、8.77±0.2°、10.74±0.2°、11.16±0.2°、14.18±0.2°、14.70±0.2°、15.62±0.2°、16.06±0.2°、16.78±0.2°、17.64±0.2°、20.42±0.2°、21.15±0.2°、21.29±0.2°、21.79±0.2°、23.03±0.2°、24.05±0.2°、24.42±0.2°、25.32±0.2°、26.45±0.2°、26.87±0.2°、28.85±0.2°。In another preferred embodiment, the X-ray powder diffraction pattern of the hippurate crystalline form A also has 1 or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 6.52±0.2°, 8.77±0.2°, 10.74±0.2°, 11.16±0.2°, 14.18±0.2°, 14.70±0.2°, 15.62±0.2°, 16.0 6±0.2°, 16.78±0.2°, 17.64±0.2°, 20.42±0.2°, 21.15±0.2°, 21.29±0.2°, 21.79±0.2°, 23.03±0.2°, 24.05±0.2°, 24.42±0.2°, 25.32±0.2°, 26.45±0.2°, 26.87±0.2°, 28.85±0.2°. 在另一优选例中，所述马尿酸盐晶型A具有基本上如图24所示的X射线粉末衍射图。In another preferred embodiment, the hippurate salt form A has an X-ray powder diffraction pattern substantially as shown in Figure 24. 如权利要求4所述的晶型，其特征在于，所述晶型为式I-1化合物的戊二酸盐晶型A，所述戊二酸盐晶型A的X射线粉末衍射图谱具有选自下组的2θ角：17.82±0.2°、23.20±0.2°、24.47±0.2°。The crystalline form according to claim 4, characterized in that the crystalline form is a glutaric acid salt form A of the compound of formula I-1, and the X-ray powder diffraction pattern of the glutaric acid salt form A has a 2θ angle selected from the following group: 17.82±0.2°, 23.20±0.2°, 24.47±0.2°. 在另一优选例中，所述戊二酸盐晶型A的X射线粉末衍射图谱还具有1个或1个以上(如1、2、3、4、5、6、7、8、9或10个)选自下组的2θ角：9.86±0.2°、10.97±0.2°、11.82±0.2°、12.29±0.2°、12.75±0.2°、13.19±0.2°、14.87±0.2°、15.10±0.2°、15.37±0.2°、16.33±0.2°、17.10±0.2°、18.35±0.2°、19.17±0.2°、19.75±0.2°、20.14±0.2°、20.70±0.2°、21.14±0.2°、22.23±0.2°、24.26±0.2°、24.86±0.2°、25.28±0.2°、29.92±0.2°。In another preferred embodiment, the X-ray powder diffraction pattern of the glutaric acid salt form A further has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 9.86±0.2°, 10.97±0.2°, 11.82±0.2°, 12.29±0.2°, 12.75±0.2°, 13.19±0.2°, 14.87±0.2°, 15.10±0.2 °, 15.37±0.2°, 16.33±0.2°, 17.10±0.2°, 18.35±0.2°, 19.17±0.2°, 19.75±0.2°, 20.14±0.2°, 20.70±0.2°, 21.14±0.2°, 22.23±0.2°, 24.26±0.2°, 24.86±0.2°, 25.28±0.2°, 29.92±0.2°. 在另一优选例中，所述戊二酸盐晶型A具有基本上如图25所示的X射线粉末衍射图。In another preferred example, the glutaric acid salt form A has an X-ray powder diffraction pattern substantially as shown in Figure 25. 如权利要求4所述的晶型，其特征在于，所述晶型为式I-1化合物的对甲苯磺酸盐晶型A，所述对甲苯磺酸盐晶型A的X射线粉末衍射图谱具有选自下组的2θ角：19.12±0.2°、20.11±0.2°、20.53±0.2°。The crystalline form according to claim 4, characterized in that the crystalline form is a p-toluenesulfonate crystalline form A of the compound of formula I-1, and the X-ray powder diffraction pattern of the p-toluenesulfonate crystalline form A has a 2θ angle selected from the following group: 19.12±0.2°, 20.11±0.2°, 20.53±0.2°. 在另一优选例中，所述对甲苯磺酸盐晶型A的X射线粉末衍射图谱还具有1个或1个以上(如1、2、3、4、5、6、7、8、9或10个)选自下组的2θ角：7.08±0.2°、8.00±0.2°、9.39±0.2°、10.23±0.2°、13.36±0.2°、14.16±0.2°、14.81±0.2°、15.77±0.2°、16.21±0.2°、17.77±0.2°、18.10±0.2°、18.90±0.2°、20.91±0.2°、21.29±0.2°、22.49±0.2°、23.11±0.2°、24.41±0.2°、25.51±0.2°、26.77±0.2°、28.28±0.2°、28.81±0.2°、29.22±0.2°、29.95±0.2°、30.98±0.2°、35.22±0.2°。In another preferred embodiment, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form A further has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 7.08±0.2°, 8.00±0.2°, 9.39±0.2°, 10.23±0.2°, 13.36±0.2°, 14.16±0.2°, 14.81±0.2°, 15.77±0.2°, 16.21±0.2°, 17.7 7±0.2°, 18.10±0.2°, 18.90±0.2°, 20.91±0.2°, 21.29±0.2°, 22.49±0.2°, 23.11±0.2°, 24.41±0.2°, 25.51±0.2°, 26.77±0.2°, 28.28±0.2°, 28.81±0.2°, 29.22±0.2°, 29.95±0.2°, 30.98±0.2°, 35.22±0.2°. 在另一优选例中，所述对甲苯磺酸盐晶型A具有基本上如图26所示的X射线粉末衍射图。In another preferred example, the p-toluenesulfonate salt form A has an X-ray powder diffraction pattern substantially as shown in Figure 26. 如权利要求4所述的晶型，其特征在于，所述晶型为式I-1化合物的对甲苯磺酸盐晶型B，所述对甲苯磺酸盐晶型B的X射线粉末衍射图谱具有选自下组的2θ角：13.95±0.2°、19.52±0.2°、25.40±0.2°。The crystalline form according to claim 4, characterized in that the crystalline form is a p-toluenesulfonate crystalline form B of the compound of formula I-1, and the X-ray powder diffraction pattern of the p-toluenesulfonate crystalline form B has a 2θ angle selected from the following group: 13.95±0.2°, 19.52±0.2°, 25.40±0.2°. 在另一优选例中，所述对甲苯磺酸盐晶型B的X射线粉末衍射图谱还具有1个或1个以上(如1、2、3、4、5、6、7、8、9或10个)选自下组的2θ角：8.27±0.2°、12.59±0.2°、13.69±0.2°、14.63±0.2°、16.15±0.2°、17.72±0.2°、18.68±0.2°、20.75±0.2°、21.05±0.2°、21.92±0.2°、22.45±0.2°、23.23±0.2°、23.91±0.2°、27.33±0.2°、29.25±0.2°。In another preferred embodiment, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form B also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 8.27±0.2°, 12.59±0.2°, 13.69±0.2°, 14.63±0.2°, 16.15±0.2°, 17.72±0.2°, 18.68±0.2°, 20.75±0.2°, 21.05±0.2°, 21.92±0.2°, 22.45±0.2°, 23.23±0.2°, 23.91±0.2°, 27.33±0.2°, 29.25±0.2°. 在另一优选例中，所述对甲苯磺酸盐晶型B具有基本上如图27所示的X射线粉末衍射图。In another preferred example, the p-toluenesulfonate salt form B has an X-ray powder diffraction pattern substantially as shown in FIG. 27 . 如权利要求4所述的晶型，其特征在于，所述晶型为式I-1化合物的甲磺酸盐晶型A，所述甲磺酸盐晶型A的X射线粉末衍射图谱具有选自下组的2θ角：19.57±0.2°、14.27±0.2°、24.99±0.2°。The crystalline form according to claim 4, characterized in that the crystalline form is a mesylate crystalline form A of the compound of formula I-1, and the X-ray powder diffraction pattern of the mesylate crystalline form A has a 2θ angle selected from the following group: 19.57±0.2°, 14.27±0.2°, 24.99±0.2°. 在另一优选例中，所述甲磺酸盐晶型A的X射线粉末衍射图谱还具有1个或1个以上(如1、2、3、4、5、6、7、8、9或10个)选自下组的2θ角：6.70±0.2°、9.10±0.2°、9.81±0.2°、10.16±0.2°、13.34±0.2°、13.87±0.2°、15.37±0.2°、15.79±0.2°、17.21±0.2°、18.75±0.2°、21.16±0.2°、22.09±0.2°、23.31±0.2°、23.86±0.2°、24.30±0.2°、27.18±0.2°、28.04±0.2°、28.83±0.2°。In another preferred embodiment, the X-ray powder diffraction pattern of the mesylate salt form A also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 6.70±0.2°, 9.10±0.2°, 9.81±0.2°, 10.16±0.2°, 13.34±0.2°, 13.87±0.2° , 15.37±0.2°, 15.79±0.2°, 17.21±0.2°, 18.75±0.2°, 21.16±0.2°, 22.09±0.2°, 23.31±0.2°, 23.86±0.2°, 24.30±0.2°, 27.18±0.2°, 28.04±0.2°, 28.83±0.2°. 在另一优选例中，所述甲磺酸盐晶型A具有基本上如图28所示的X射线粉末衍射图。In another preferred example, the mesylate salt form A has an X-ray powder diffraction pattern substantially as shown in Figure 28. 如权利要求4所述的晶型，其特征在于，所述晶型为式I-1化合物的盐酸盐晶型C1，所述盐酸盐晶型C1的X射线粉末衍射图谱具有选自下组的2θ角：7.73±0.2°、19.57±0.2°、19.78±0.2°。The crystalline form according to claim 4, characterized in that the crystalline form is the hydrochloride crystalline form C1 of the compound of formula I-1, and the X-ray powder diffraction pattern of the hydrochloride crystalline form C1 has a 2θ angle selected from the following group: 7.73±0.2°, 19.57±0.2°, 19.78±0.2°. 在另一优选例中，所述盐酸盐晶型C1还具有选自下组的一个或多个特征：In another preferred embodiment, the hydrochloride salt form C1 further has one or more characteristics selected from the following group: a.所述盐酸盐晶型C1的X射线粉末衍射图谱还具有1个或1个以上(如1、2、3、4、5、6、7、8、9或10个)选自下组的2θ角：7.47±0.2°、9.63±0.2°、11.46±0.2°、12.25±0.2°、13.18±0.2°、13.51±0.2°、14.96±0.2°、15.46±0.2°、16.79±0.2°、17.04±0.2°、17.31±0.2°、17.72±0.2°、18.56±0.2°、19.34±0.2°、20.01±0.2°、20.41±0.2°、20.76±0.2°、22.60±0.2°、23.09±0.2°、23.80±0.2°、24.36±0.2°、25.63±0.2°、26.47±0.2°、27.51±0.2°、29.09±0.2°、30.76±0.2°、31.99±0.2°、36.24±0.2°；a. The X-ray powder diffraction pattern of the hydrochloride salt form C1 also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 7.47±0.2°, 9.63±0.2°, 11.46±0.2°, 12.25±0.2°, 13.18±0.2°, 13.51±0.2°, 14.96±0.2°, 15.46±0.2°, 16.79±0.2°, 17.04±0.2°, 17.31±0.2°, 17. .72±0.2°, 18.56±0.2°, 19.34±0.2°, 20.01±0.2°, 20.41±0.2°, 20.76±0.2°, 22.60±0.2°, 23.09±0.2°, 23.80±0.2°, 24.36±0.2°, 25.63±0.2°, 26.47±0.2°, 27.51±0.2°, 29.09±0.2°, 30.76±0.2°, 31.99±0.2°, 36.24±0.2°; b.所述盐酸盐晶型C1的差示扫描量热曲线在39.76℃±2℃和153.80℃±2℃两处具有吸热峰的起始点；b. The differential scanning calorimetry curve of the hydrochloride salt form C1 has two starting points of endothermic peaks at 39.76°C ± 2°C and 153.80°C ± 2°C; c.所述盐酸盐晶型C1的热重分析曲线在26.03℃±2℃、100.00℃±2℃和150.00℃±2℃三处有三个失重台阶，在214.75℃±2℃处分解。c. The thermogravimetric analysis curve of the hydrochloride salt form C1 has three weight loss steps at 26.03°C±2°C, 100.00°C±2°C and 150.00°C±2°C, and decomposes at 214.75°C±2°C. 在另一优选例中，所述盐酸盐晶型C1具有基本上如图29所示的X射线粉末衍射图。In another preferred embodiment, the hydrochloride salt form C1 has an X-ray powder diffraction pattern substantially as shown in Figure 29. 在另一优选例中，所述盐酸盐晶型C1具有基本上如图30所示的差示扫描量热图。In another preferred embodiment, the hydrochloride salt form C1 has a differential scanning calorimetry diagram substantially as shown in FIG. 30 . 在另一优选例中，所述盐酸盐晶型C1具有基本上如图31所示的热重分析图。In another preferred embodiment, the hydrochloride salt form C1 has a thermogravimetric analysis diagram substantially as shown in FIG. 31 . 在另一优选例中，所述盐酸盐晶型C1为乙酸乙酯溶剂和水合物晶型，其中，乙酸乙酯含量为0.1～1当量，水含量为1～5当量。In another preferred embodiment, the hydrochloride salt crystal form C1 is an ethyl acetate solvent and a hydrate crystal form, wherein the ethyl acetate content is 0.1 to 1 equivalents, and the water content is 1 to 5 equivalents. 如权利要求4所述的晶型，其特征在于，所述晶型为式I-1化合物的盐酸盐晶型C2，所述盐酸盐晶型C2的X射线粉末衍射图谱具有选自下组的2θ角：7.79±0.2°、19.66±0.2°、19.82±0.2°。The crystalline form according to claim 4, characterized in that the crystalline form is the hydrochloride crystalline form C2 of the compound of formula I-1, and the X-ray powder diffraction pattern of the hydrochloride crystalline form C2 has a 2θ angle selected from the following group: 7.79±0.2°, 19.66±0.2°, 19.82±0.2°. 在另一优选例中，所述盐酸盐晶型C2还具有选自下组的一个或多个特征：In another preferred embodiment, the hydrochloride salt form C2 further has one or more characteristics selected from the following group: a.所述盐酸盐晶型C2的X射线粉末衍射图谱还具有1个或1个以上(如1、2、3、4、5、6、7、8、9或10个)选自下组的2θ角：7.56±0.2°、9.65±0.2°、11.48±0.2°、12.32±0.2°、13.21±0.2°、13.63±0.2°、15.10±0.2°、15.56±0.2°、16.86±0.2°、17.16±0.2°、17.41±0.2°、17.77±0.2°、18.58±0.2°、19.36±0.2°、20.32±0.2°、20.91±0.2°、22.71±0.2°、23.21±0.2°、23.80±0.2°、24.35±0.2°、25.71±0.2°、26.56±0.2°、27.53±0.2°、27.80±0.2°、28.20±0.2°、29.15±0.2°、30.74±0.2°、32.06±0.2°、36.30±0.2°、38.22±0.2°；a. The X-ray powder diffraction pattern of the hydrochloride salt form C2 also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 7.56±0.2°, 9.65±0.2°, 11.48±0.2°, 12.32±0.2°, 13.21±0.2°, 13.63±0.2°, 15.10±0.2°, 15.56±0.2°, 16.86±0.2°, 17.16±0.2°, 17.41±0.2°, 17.77±0.2°, 18 .58±0.2°, 19.36±0.2°, 20.32±0.2°, 20.91±0.2°, 22.71±0.2°, 23.21±0.2°, 23.80±0.2°, 24.35±0.2°, 25.71±0.2°, 26.56±0.2°, 27.53±0.2°, 27.80±0.2°, 28.20±0.2°, 29.15±0.2°, 30.74±0.2°, 32.06±0.2°, 36.30±0.2°, 38.22±0.2°; b.所述盐酸盐晶型C2的差示扫描量热曲线在33.27℃±2℃和155.72℃±2℃两处具有吸热峰的起始点；b. The differential scanning calorimetry curve of the hydrochloride salt form C2 has two starting points of endothermic peaks at 33.27°C ± 2°C and 155.72°C ± 2°C; c.所述盐酸盐晶型C2的热重分析曲线在28.19℃±2℃、115.00℃±2℃和150.00℃±2℃三处有三个失重台阶，在212.45℃±2℃处开始分解。c. The thermogravimetric analysis curve of the hydrochloride salt form C2 has three weight loss steps at 28.19°C±2°C, 115.00°C±2°C and 150.00°C±2°C, and begins to decompose at 212.45°C±2°C. 在另一优选例中，所述盐酸盐晶型C2具有基本上如图32所示的X射线粉末衍射图。In another preferred embodiment, the hydrochloride salt form C2 has an X-ray powder diffraction pattern substantially as shown in Figure 32. 在另一优选例中，所述盐酸盐晶型C2具有基本上如图33所示的差示扫描量热图。In another preferred embodiment, the hydrochloride salt form C2 has a differential scanning calorimetry diagram substantially as shown in Figure 33. 在另一优选例中，所述盐酸盐晶型C2具有基本上如图34所示的热重分析图。In another preferred embodiment, the hydrochloride salt form C2 has a thermogravimetric analysis diagram substantially as shown in Figure 34. 在另一优选例中，所述盐酸盐晶型C2为2-甲基四氢呋喃溶剂和水合物晶型，其中，2-甲基四氢呋喃含量为0.05～0.5当量，水含量为1～5当量。In another preferred embodiment, the hydrochloride salt crystal form C2 is a 2-methyltetrahydrofuran solvent and a hydrate crystal form, wherein the 2-methyltetrahydrofuran content is 0.05 to 0.5 equivalents, and the water content is 1 to 5 equivalents. 如权利要求4所述的晶型，其特征在于，所述晶型为式I-1化合物的盐酸盐晶型D，所述盐酸盐晶型D的X射线粉末衍射图谱具有选自下组的2θ角：15.93±0.2°、20.09±0.2°、20.41±0.2°。The crystalline form according to claim 4, characterized in that the crystalline form is the hydrochloride crystalline form D of the compound of formula I-1, and the X-ray powder diffraction pattern of the hydrochloride crystalline form D has a 2θ angle selected from the following group: 15.93±0.2°, 20.09±0.2°, 20.41±0.2°. 在另一优选例中，所述盐酸盐晶型D还具有选自下组的一个或多个特征：In another preferred embodiment, the hydrochloride salt form D further has one or more characteristics selected from the following group: a.所述盐酸盐晶型D的X射线粉末衍射图谱还具有1个或1个以上(如1、2、3、4、5、6、7、8、9或10个)选自下组的2θ角：6.60±0.2°、7.26±0.2°、7.79±0.2°、8.48±0.2°、9.84±0.2°、11.18±0.2°、13.31±0.2°、13.89±0.2°、14.64±0.2°、14.98±0.2°、15.23±0.2°、16.27±0.2°、17.04±0.2°、18.21±0.2°、19.33±0.2°、21.23±0.2°、21.80±0.2°、23.49±0.2°、24.79±0.2°、28.43±0.2°；a. The X-ray powder diffraction pattern of the hydrochloride salt form D also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 6.60±0.2°, 7.26±0.2°, 7.79±0.2°, 8.48±0.2°, 9.84±0.2°, 11.18±0.2°, 13.31±0.2°, 13.8 9±0.2°, 14.64±0.2°, 14.98±0.2°, 15.23±0.2°, 16.27±0.2°, 17.04±0.2°, 18.21±0.2°, 19.33±0.2°, 21.23±0.2°, 21.80±0.2°, 23.49±0.2°, 24.79±0.2°, 28.43±0.2°; b.所述盐酸盐晶型D的差示扫描量热曲线在55.20℃±2℃和164.37℃±2℃两处具有吸热峰的起始点，b. The differential scanning calorimetry curve of the hydrochloride salt form D has two starting points of endothermic peaks at 55.20°C ± 2°C and 164.37°C ± 2°C, c.所述盐酸盐晶型D的热重分析曲线在36.24℃±2℃和110.00℃±2℃两处有两个失重台阶，在211.35℃±2℃处开始分解。c. The thermogravimetric analysis curve of the hydrochloride salt form D has two weight loss steps at 36.24°C±2°C and 110.00°C±2°C, and starts to decompose at 211.35°C±2°C. 在另一优选例中，所述盐酸盐晶型D具有基本上如图35所示的X射线粉末衍射图。In another preferred example, the hydrochloride salt form D has an X-ray powder diffraction pattern substantially as shown in Figure 35. 在另一优选例中，所述盐酸盐晶型D具有基本上如图36所示的差示扫描量热图。In another preferred example, the hydrochloride salt form D has a differential scanning calorimetry diagram substantially as shown in Figure 36. 在另一优选例中，所述盐酸盐晶型D具有基本上如图37所示的热重分析图。In another preferred example, the hydrochloride salt form D has a thermogravimetric analysis diagram substantially as shown in Figure 37. 如权利要求4所述的晶型，其特征在于，所述晶型为式I-1化合物的盐酸盐晶型E1，所述盐酸盐晶型E1的X射线粉末衍射图谱具有选自下组的2θ角：7.90±0.2°、14.06±0.2°、20.19±0.2°。The crystalline form according to claim 4, characterized in that the crystalline form is the hydrochloride crystalline form E1 of the compound of formula I-1, and the X-ray powder diffraction pattern of the hydrochloride crystalline form E1 has a 2θ angle selected from the following group: 7.90±0.2°, 14.06±0.2°, 20.19±0.2°. 在另一优选例中，所述盐酸盐晶型E1还具有选自下组的一个或多个特征：In another preferred embodiment, the hydrochloride salt form E1 further has one or more characteristics selected from the following group: a.所述盐酸盐晶型E1的X射线粉末衍射图谱还具有1个或1个以上(如1、2、3、4、5、6、7、8、9或10个)选自下组的2θ角：6.15±0.2°、7.66±0.2°、8.41±0.2°、9.49±0.2°、9.91±0.2°、10.88±0.2°、11.42±0.2°、13.06±0.2°、13.66±0.2°、14.69±0.2°、15.32±0.2°、15.52±0.2°、15.88±0.2°、16.25±0.2°、16.81±0.2°、17.35±0.2°、18.37±0.2°、19.01±0.2°、19.75±0.2°、21.15±0.2°、21.51±0.2°、21.81±0.2°、22.50±0.2°、22.87±0.2°、23.56±0.2°、24.95±0.2°、25.18±0.2°、25.63±0.2°、26.71±0.2°、27.10±0.2°、27.91±0.2°、28.47±0.2°、29.30±0.2°、29.81±0.2°、30.12±0.2°、32.93±0.2°、34.96±0.2°；a. The X-ray powder diffraction pattern of the hydrochloride salt form E1 also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 6.15±0.2°, 7.66±0.2°, 8.41±0.2°, 9.49±0.2°, 9.91±0.2°, 10.88±0.2°, 11.42±0.2°, 13.06±0.2°, 13.66±0.2°, 14.69±0.2°, 15.32±0.2°, 15.52±0.2°, 15.88±0.2°, 16.25±0.2°, 16.81±0.2°, 17.35±0.2 °, 18.37±0.2°, 19.01±0.2°, 19.75±0.2°, 21.15±0.2°, 21.51±0.2°, 21.81±0.2°, 22.50±0.2°, 22.87±0.2°, 23.56±0.2°, 24.95±0.2°, 25.18±0.2°, 25.63±0.2°, 26.71±0.2°, 27.10±0.2°, 27.91±0.2°, 28.47±0.2°, 29.30±0.2°, 29.81±0.2°, 30.12±0.2°, 32.93±0.2°, 34.96±0.2°; b.所述盐酸盐晶型E1的差示扫描量热曲线在13.36℃±2℃和174.06℃±2℃两处具有吸热峰的起始点；b. The differential scanning calorimetry curve of the hydrochloride salt form E1 has two starting points of endothermic peaks at 13.36°C ± 2°C and 174.06°C ± 2°C; c.所述盐酸盐晶型E1的热重分析曲线在25.81℃±2℃、120.00℃±2℃和160.00℃±2℃三处有三个失重台阶，在211.29℃±2℃处开始分解。c. The thermogravimetric analysis curve of the hydrochloride salt form E1 has three weight loss steps at 25.81°C±2°C, 120.00°C±2°C and 160.00°C±2°C, and begins to decompose at 211.29°C±2°C. 在另一优选例中，所述盐酸盐晶型E1具有基本上如图38所示的X射线粉末衍射图。In another preferred embodiment, the hydrochloride salt form E1 has an X-ray powder diffraction pattern substantially as shown in Figure 38. 在另一优选例中，所述盐酸盐晶型E1具有基本上如图39所示的差示扫描量热图。In another preferred example, the hydrochloride salt form E1 has a differential scanning calorimetry diagram substantially as shown in Figure 39. 在另一优选例中，所述盐酸盐晶型E1具有基本上如图40所示的热重分析图。In another preferred example, the hydrochloride salt form E1 has a thermogravimetric analysis diagram substantially as shown in FIG. 40 . 在另一优选例中，所述式(I)化合物的盐酸盐晶型E1为水合物晶型，其中，水含量为0.5～4当量。In another preferred embodiment, the hydrochloride crystal form E1 of the compound of formula (I) is a hydrate crystal form, wherein the water content is 0.5 to 4 equivalents. 如权利要求4所述的晶型，其特征在于，所述晶型为式I-1化合物的盐酸盐晶型E2，所述盐酸盐晶型E2的X射线粉末衍射图谱具有选自下组的2θ角：7.88±0.2°、14.14±0.2°、19.75±0.2°。The crystalline form according to claim 4, characterized in that the crystalline form is the hydrochloride crystalline form E2 of the compound of formula I-1, and the X-ray powder diffraction pattern of the hydrochloride crystalline form E2 has a 2θ angle selected from the following group: 7.88±0.2°, 14.14±0.2°, 19.75±0.2°. 在另一优选例中，所述盐酸盐晶型E2还具有选自下组的一个或多个特征：In another preferred embodiment, the hydrochloride salt form E2 further has one or more characteristics selected from the following group: a.所述盐酸盐晶型E2的X射线粉末衍射图谱还具有1个或1个以上(如1、2、3、4、5、6、7、8、9或10个)选自下组的2θ角：9.51±0.2°、10.90±0.2°、11.49±0.2°、13.10±0.2°、13.64±0.2°、14.76±0.2°、15.39±0.2°、15.75±0.2°、16.30±0.2°、16.93±0.2°、19.01±0.2°、20.69±0.2°、21.54±0.2°、21.84±0.2°、22.19±0.2°、22.57±0.2°、23.01±0.2°、23.63±0.2°、24.96±0.2°、25.90±0.2°、26.32±0.2°、26.78±0.2°、27.19±0.2°、27.48±0.2°、27.94±0.2°、28.68±0.2°、29.07±0.2°、29.50±0.2°、29.91±0.2°、31.74±0.2°、32.96±0.2°、33.66±0.2°；a. The X-ray powder diffraction pattern of the hydrochloride salt form E2 also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 9.51±0.2°, 10.90±0.2°, 11.49±0.2°, 13.10±0.2°, 13.64±0.2°, 14.76±0.2°, 15.39±0.2°, 15.75±0.2°, 16.30±0.2°, 16.93±0.2°, 19.01±0.2°, 20.69±0.2°, 21.54±0.2°, 2 1.84±0.2°, 22.19±0.2°, 22.57±0.2°, 23.01±0.2°, 23.63±0.2°, 24.96±0.2°, 25.90±0.2°, 26.32±0.2°, 26.78±0.2°, 27.19±0.2°, 27.48±0.2°, 27.94±0.2°, 28.68±0.2°, 29.07±0.2°, 29.50±0.2°, 29.91±0.2°, 31.74±0.2°, 32.96±0.2°, 33.66±0.2°; b.所述盐酸盐晶型E2的差示扫描量热曲线在14.99℃±2℃和174.19℃±2℃两处具有吸热峰的起始点；b. The differential scanning calorimetry curve of the hydrochloride salt form E2 has two starting points of endothermic peaks at 14.99°C ± 2°C and 174.19°C ± 2°C; c.所述盐酸盐晶型E2的热重分析曲线在33.18℃±2℃、90.00℃±2℃和140.00℃±2℃三处有三个失重台阶，在213.17℃±2℃处开始分解。c. The thermogravimetric analysis curve of the hydrochloride salt form E2 has three weight loss steps at 33.18°C±2°C, 90.00°C±2°C and 140.00°C±2°C, and begins to decompose at 213.17°C±2°C. 在另一优选例中，所述盐酸盐晶型E2具有基本上如图41所示的X射线粉末衍射图。In another preferred embodiment, the hydrochloride salt form E2 has an X-ray powder diffraction pattern substantially as shown in Figure 41. 在另一优选例中，所述盐酸盐晶型E2具有基本上如图42所示的差示扫描量热图。In another preferred example, the hydrochloride salt form E2 has a differential scanning calorimetry diagram substantially as shown in Figure 42. 在另一优选例中，所述盐酸盐晶型E2具有基本上如图43所示的热重分析图。In another preferred example, the hydrochloride salt form E2 has a thermogravimetric analysis diagram substantially as shown in Figure 43. 在另一优选例中，所述式(I)化合物的盐酸盐晶型E2由式(I)化合物的盐酸盐晶型F在10℃～70℃真空制得。In another preferred embodiment, the hydrochloride crystal form E2 of the compound of formula (I) is prepared from the hydrochloride crystal form F of the compound of formula (I) at 10°C to 70°C in vacuum. 在另一优选例中，所述式(I)化合物的盐酸盐晶型E2由式(I)化合物的盐酸盐晶型F在80℃～120℃干燥制得。In another preferred embodiment, the hydrochloride crystal form E2 of the compound of formula (I) is prepared by drying the hydrochloride crystal form F of the compound of formula (I) at 80°C to 120°C. 在另一优选例中，所述式(I)化合物的盐酸盐晶型E2为水合物晶型，其中，水含量为0.5～4当量。In another preferred embodiment, the hydrochloride crystal form E2 of the compound of formula (I) is a hydrate crystal form, wherein the water content is 0.5 to 4 equivalents. 如权利要求4所述的晶型，其特征在于，所述晶型为式I-1化合物的盐酸盐晶型F，所述盐酸盐晶型F的X射线粉末衍射图谱具有选自下组的2θ角：7.65±0.2°、11.47±0.2°、13.93±0.2°。The crystalline form according to claim 4, characterized in that the crystalline form is the hydrochloride crystalline form F of the compound of formula I-1, and the X-ray powder diffraction pattern of the hydrochloride crystalline form F has a 2θ angle selected from the following group: 7.65±0.2°, 11.47±0.2°, 13.93±0.2°. 在另一优选例中，所述盐酸盐晶型F还具有选自下组的一个或多个特征：In another preferred embodiment, the hydrochloride salt form F further has one or more characteristics selected from the following group: a.所述盐酸盐晶型F的X射线粉末衍射图谱还具有1个或1个以上(如1、2、3、4、5、6、7、8、9或10个)选自下组的2θ角：6.85±0.2°、10.21±0.2°、10.70±0.2°、14.80±0.2°、15.25±0.2°、16.60±0.2°、16.88±0.2°、17.84±0.2°、19.00±0.2°、19.16±0.2°、19.84±0.2°、20.09±0.2°、20.34±0.2°、21.51±0.2°、22.35±0.2°、23.22±0.2°、23.86±0.2°、25.06±0.2°、25.31±0.2°、25.63±0.2°、26.68±0.2°、28.10±0.2°、28.87±0.2°、30.53±0.2°、32.45±0.2°、33.59±0.2°；a. The X-ray powder diffraction pattern of the hydrochloride salt form F also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the group consisting of 6.85±0.2°, 10.21±0.2°, 10.70±0.2°, 14.80±0.2°, 15.25±0.2°, 16.60±0.2°, 16.88±0.2°, 17.84±0.2°, 19.00±0.2°, 19.16±0.2°, 19. .84±0.2°, 20.09±0.2°, 20.34±0.2°, 21.51±0.2°, 22.35±0.2°, 23.22±0.2°, 23.86±0.2°, 25.06±0.2°, 25.31±0.2°, 25.63±0.2°, 26.68±0.2°, 28.10±0.2°, 28.87±0.2°, 30.53±0.2°, 32.45±0.2°, 33.59±0.2°; b.所述盐酸盐晶型F的差示扫描量热曲线在36.03℃±2℃和172.45℃±2℃两处具有吸热峰的起始点；b. The differential scanning calorimetry curve of the hydrochloride salt form F has two starting points of endothermic peaks at 36.03°C ± 2°C and 172.45°C ± 2°C; c.所述盐酸盐晶型F的热重分析曲线在33.35℃±2℃、100.00℃±2℃和150.00℃±2℃三处有三个失重台阶，在212.66℃±2℃处开始分解。c. The thermogravimetric analysis curve of the hydrochloride salt form F has three weight loss steps at 33.35°C±2°C, 100.00°C±2°C and 150.00°C±2°C, and begins to decompose at 212.66°C±2°C. 在另一优选例中，所述盐酸盐晶型F具有基本上如图44所示的X射线粉末衍射图。In another preferred example, the hydrochloride salt form F has an X-ray powder diffraction pattern substantially as shown in Figure 44. 在另一优选例中，所述盐酸盐晶型F具有基本上如图45所示的差示扫描量热图。In another preferred example, the hydrochloride salt form F has a differential scanning calorimetry diagram substantially as shown in Figure 45. 在另一优选例中，所述盐酸盐晶型F具有基本上如图46所示的热重分析图。In another preferred example, the hydrochloride salt form F has a thermogravimetric analysis diagram substantially as shown in Figure 46. 在另一优选例中，所述式(I)化合物的盐酸盐晶型F为水合物晶型，其中，水含量为1～4当量。In another preferred embodiment, the hydrochloride crystal form F of the compound of formula (I) is a hydrate crystal form, wherein the water content is 1 to 4 equivalents. 如权利要求4所述的晶型，其特征在于，所述晶型为式I-1化合物的盐酸盐晶型G，所述盐酸盐晶型G的X射线粉末衍射图谱具有选自下组的2θ角：15.52±0.2°、16.77±0.2°、23.04±0.2°。The crystalline form according to claim 4, characterized in that the crystalline form is the hydrochloride crystalline form G of the compound of formula I-1, and the X-ray powder diffraction pattern of the hydrochloride crystalline form G has a 2θ angle selected from the following group: 15.52±0.2°, 16.77±0.2°, 23.04±0.2°. 在另一优选例中，所述盐酸盐晶型G还具有选自下组的一个或多个特征：In another preferred embodiment, the hydrochloride salt form G further has one or more characteristics selected from the following group: a.所述盐酸盐晶型G的X射线粉末衍射图谱还具有1个或1个以上(如1、2、3、4、5、6、7、8、9或10个)选自下组的2θ角：5.83±0.2°、7.18±0.2°、9.97±0.2°、11.63±0.2°、12.00±0.2°、12.35±0.2°、13.26±0.2°、13.58±0.2°、14.17±0.2°、14.60±0.2°、17.64±0.2°、18.37±0.2°、18.81±0.2°、19.14±0.2°、19.80±0.2°、20.27±0.2°、20.48±0.2°、21.35±0.2°、21.82±0.2°、22.65±0.2°、23.35±0.2°、24.43±0.2°、25.47±0.2°、26.24±0.2°、26.54±0.2°、26.84±0.2°、27.92±0.2°、28.94±0.2°、29.31±0.2°、30.18±0.2°；a. The X-ray powder diffraction pattern of the hydrochloride crystalline form G also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the group consisting of 5.83±0.2°, 7.18±0.2°, 9.97±0.2°, 11.63±0.2°, 12.00±0.2°, 12.35±0.2°, 13.26±0.2°, 13.58±0.2°, 14.17±0.2°, 14.60±0.2°, 17.64±0.2°, 18.37±0.2°, 18. 81±0.2°, 19.14±0.2°, 19.80±0.2°, 20.27±0.2°, 20.48±0.2°, 21.35±0.2°, 21.82±0.2°, 22.65±0.2°, 23.35±0.2°, 24.43±0.2°, 25.47±0.2°, 26.24±0.2°, 26.54±0.2°, 26.84±0.2°, 27.92±0.2°, 28.94±0.2°, 29.31±0.2°, 30.18±0.2°; b.所述盐酸盐晶型G的差示扫描量热曲线在59.42℃±2℃、151.02℃±2℃和166.01℃±2℃三处具有吸热峰的起始点；b. The differential scanning calorimetry curve of the hydrochloride form G has three starting points of endothermic peaks at 59.42°C ± 2°C, 151.02°C ± 2°C and 166.01°C ± 2°C; c.所述盐酸盐晶型G的热重分析曲线在26.28℃±2℃、120.00℃±2℃和150.00℃±2℃三处有三个失重台阶。c. The thermogravimetric analysis curve of the hydrochloride salt form G has three weight loss steps at 26.28°C±2°C, 120.00°C±2°C and 150.00°C±2°C. 在另一优选例中，所述盐酸盐晶型G具有基本上如图47所示的X射线粉末衍射图。In another preferred example, the hydrochloride salt form G has an X-ray powder diffraction pattern substantially as shown in Figure 47. 在另一优选例中，所述盐酸盐晶型G具有基本上如图48所示的差示扫描量热图。In another preferred example, the hydrochloride salt form G has a differential scanning calorimetry diagram substantially as shown in Figure 48. 在另一优选例中，所述盐酸盐晶型G具有基本上如图49所示的热重分析图。In another preferred example, the hydrochloride salt form G has a thermogravimetric analysis diagram substantially as shown in Figure 49. 在另一优选例中，所述式(I)化合物的盐酸盐晶型G为水合物晶型，其中，水含量为1.0～6当量。In another preferred embodiment, the hydrochloride crystal form G of the compound of formula (I) is a hydrate crystal form, wherein the water content is 1.0 to 6 equivalents. 如权利要求4所述的晶型，其特征在于，所述晶型为式I-1化合物的盐酸盐晶型H，所述盐酸盐晶型H的X射线粉末衍射图谱具有选自下组的2θ角：5.83±0.2°、16.67±0.2°、18.40±0.2°。The crystalline form according to claim 4, characterized in that the crystalline form is the hydrochloride crystalline form H of the compound of formula I-1, and the X-ray powder diffraction pattern of the hydrochloride crystalline form H has a 2θ angle selected from the following group: 5.83±0.2°, 16.67±0.2°, 18.40±0.2°. 在另一优选例中，所述盐酸盐晶型H还具有选自下组的一个或多个特征：In another preferred embodiment, the hydrochloride salt form H further has one or more characteristics selected from the following group: a.所述盐酸盐晶型H的X射线粉末衍射图谱还具有1个或1个以上(如1、2、3、4、5、6、7、8、9或10个)选自下组的2θ角：7.16±0.2°、10.02±0.2°、11.64±0.2°、12.35±0.2°、13.23±0.2°、13.59±0.2°、14.58±0.2°、15.51±0.2°、15.97±0.2°、17.63±0.2°、18.62±0.2°、19.11±0.2°、20.23±0.2°、20.54±0.2°、21.40±0.2°、22.07±0.2°、22.62±0.2°、22.78±0.2°、23.36±0.2°、24.73±0.2°、24.98±0.2°、26.23±0.2°、26.57±0.2°、26.91±0.2°、27.88±0.2°、29.01±0.2°、29.30±0.2°、29.61±0.2°、30.21±0.2°、31.21±0.2°、32.12±0.2°、34.66±0.2°；a. The X-ray powder diffraction pattern of the hydrochloride salt form H also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the group consisting of: 7.16±0.2°, 10.02±0.2°, 11.64±0.2°, 12.35±0.2°, 13.23±0.2°, 13.59±0.2°, 14.58±0.2°, 15.51±0.2°, 15.97±0.2°, 17.63±0.2°, 18.62±0.2°, 19.11±0.2°, 20.23±0.2°, 20. .54±0.2°, 21.40±0.2°, 22.07±0.2°, 22.62±0.2°, 22.78±0.2°, 23.36±0.2°, 24.73±0.2°, 24.98±0.2°, 26.23±0.2°, 26.57±0.2°, 26.91±0.2°, 27.88±0.2°, 29.01±0.2°, 29.30±0.2°, 29.61±0.2°, 30.21±0.2°, 31.21±0.2°, 32.12±0.2°, 34.66±0.2°; b.所述盐酸盐晶型H的差示扫描量热曲线在51.49℃±2℃和153.61℃±2℃两处具有吸热峰的起始点；b. The differential scanning calorimetry curve of the hydrochloride salt form H has two starting points of endothermic peaks at 51.49°C ± 2°C and 153.61°C ± 2°C; c.所述盐酸盐晶型H的热重分析曲线在26.12℃±2℃、110.00℃±2℃和150.00℃±2℃三处有三个失重台阶，在211.73℃±2℃处开始分解。c. The thermogravimetric analysis curve of the hydrochloride salt form H has three weight loss steps at 26.12°C±2°C, 110.00°C±2°C and 150.00°C±2°C, and begins to decompose at 211.73°C±2°C. 在另一优选例中，所述盐酸盐晶型H具有基本上如图50所示的X射线粉末衍射图。In another preferred example, the hydrochloride salt form H has an X-ray powder diffraction pattern substantially as shown in Figure 50. 在另一优选例中，所述盐酸盐晶型H具有基本上如图51所示的差示扫描量热图。In another preferred example, the hydrochloride salt form H has a differential scanning calorimetry diagram substantially as shown in Figure 51. 在另一优选例中，所述盐酸盐晶型H具有基本上如图52所示的热重分析图。In another preferred example, the hydrochloride salt form H has a thermogravimetric analysis diagram substantially as shown in Figure 52. 在另一优选例中，所述式(I)化合物的盐酸盐晶型H为水合物晶型，其中，水含量为2～8当量。In another preferred embodiment, the hydrochloride crystal form H of the compound of formula (I) is a hydrate crystal form, wherein the water content is 2 to 8 equivalents. 如权利要求4所述的晶型，其特征在于，所述晶型为盐酸盐晶型I，所述盐酸盐晶型I的X射线粉末衍射图谱具有选自下组的2θ角：6.68±0.2°、13.34±0.2°、21.42±0.2°。The crystalline form according to claim 4, characterized in that the crystalline form is hydrochloride crystalline form I, and the X-ray powder diffraction pattern of the hydrochloride crystalline form I has a 2θ angle selected from the following group: 6.68±0.2°, 13.34±0.2°, 21.42±0.2°. 在另一优选例中，所述盐酸盐晶型I还具有选自下组的一个或多个特征：In another preferred embodiment, the hydrochloride salt form I further has one or more characteristics selected from the following group: a.所述盐酸盐晶型I的X射线粉末衍射图谱还具有1个或1个以上(如1、2、3、4、5、6、7、8、9或10个)选自下组的2θ角：9.50±0.2°、12.31±0.2°、12.54±0.2°、14.05±0.2°、14.96±0.2°、15.38±0.2°、17.18±0.2°、17.92±0.2°、19.03±0.2°、19.74±0.2°、19.99±0.2°、20.96±0.2°、21.62±0.2°、21.99±0.2°、22.98±0.2°、23.52±0.2°、23.80±0.2°、24.38±0.2°、25.92±0.2°、26.81±0.2°、27.21±0.2°、27.60±0.2°、27.78±0.2°、28.26±0.2°、28.74±0.2°、30.07±0.2°、31.00±0.2°、32.69±0.2°、34.02±0.2°、34.83±0.2°；a. The X-ray powder diffraction pattern of the hydrochloride salt form I also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 9.50±0.2°, 12.31±0.2°, 12.54±0.2°, 14.05±0.2°, 14.96±0.2°, 15.38±0.2°, 17.18±0.2°, 17.92±0.2°, 19.03±0.2°, 19.74±0.2°, 19.99±0.2°, 20.96±0.2°, 21. .62±0.2°, 21.99±0.2°, 22.98±0.2°, 23.52±0.2°, 23.80±0.2°, 24.38±0.2°, 25.92±0.2°, 26.81±0.2°, 27.21±0.2°, 27.60±0.2°, 27.78±0.2°, 28.26±0.2°, 28.74±0.2°, 30.07±0.2°, 31.00±0.2°, 32.69±0.2°, 34.02±0.2°, 34.83±0.2°; b.所述盐酸盐晶型I的差示扫描量热曲线在18.15℃±2℃和194.49℃±2℃两处具有吸热峰的起始点；b. The differential scanning calorimetry curve of the hydrochloride salt form I has two starting points of endothermic peaks at 18.15°C ± 2°C and 194.49°C ± 2°C; c.所述盐酸盐晶型I的热重分析曲线在28.31℃±2℃、70.00℃±2℃和173.00℃±2℃三处有三个失重台阶，在215.51℃±2℃处开始分解。c. The thermogravimetric analysis curve of the hydrochloride salt form I has three weight loss steps at 28.31°C±2°C, 70.00°C±2°C and 173.00°C±2°C, and begins to decompose at 215.51°C±2°C. 在另一优选例中，所述盐酸盐晶型I具有基本上如图53所示的X射线粉末衍射图。In another preferred embodiment, the hydrochloride salt form I has an X-ray powder diffraction pattern substantially as shown in Figure 53. 在另一优选例中，所述盐酸盐晶型I具有基本上如图54所示的差示扫描量热图。In another preferred embodiment, the hydrochloride salt form I has a differential scanning calorimetry diagram substantially as shown in Figure 54. 在另一优选例中，所述盐酸盐晶型I具有基本上如图55所示的热重分析图。In another preferred embodiment, the hydrochloride salt form I has a thermogravimetric analysis diagram substantially as shown in Figure 55. 在另一优选例中，所述式(I)化合物的盐酸盐晶型I为无水晶型。In another preferred embodiment, the hydrochloride crystalline form I of the compound of formula (I) is an anhydrous crystalline form. 如权利要求4所述的晶型，其特征在于，所述晶型为盐酸盐晶型J1，所述盐酸盐晶型J1的X射线粉末衍射图谱具有选自下组的2θ角：6.80±0.2°、14.87±0.2°、20.41±0.2°。The crystal form according to claim 4, characterized in that the crystal form is hydrochloride crystal form J1, and the X-ray powder diffraction pattern of the hydrochloride crystal form J1 has a 2θ angle selected from the following group: 6.80±0.2°, 14.87±0.2°, 20.41±0.2°. 在另一优选例中，所述盐酸盐晶型J1还具有选自下组的一个或多个特征：In another preferred embodiment, the hydrochloride salt form J1 further has one or more characteristics selected from the following group: a.所述盐酸盐晶型J1的X射线粉末衍射图谱还具有1个或1个以上(如1、2、3、4、5、6、7、8、9或10个)选自下组的2θ角：7.82±0.2°、7.95±0.2°、10.08±0.2°、11.69±0.2°、12.30±0.2°、12.60±0.2°、13.60±0.2°、15.98±0.2°、16.25±0.2°、18.05±0.2°、18.60±0.2°、18.79±0.2°、19.49±0.2°、20.82±0.2°、21.55±0.2°、21.70±0.2°、22.06±0.2°、22.88±0.2°、23.69±0.2°、24.92±0.2°、25.13±0.2°、26.19±0.2°、26.57±0.2°、29.07±0.2°、30.16±0.2°、31.85±0.2°、32.80±0.2°；a. The X-ray powder diffraction pattern of the hydrochloride salt form J1 also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 7.82±0.2°, 7.95±0.2°, 10.08±0.2°, 11.69±0.2°, 12.30±0.2°, 12.60±0.2°, 13.60±0.2°, 15.98±0.2°, 16.25±0.2°, 18.05±0.2°, 18.60±0.2° .2°, 18.79±0.2°, 19.49±0.2°, 20.82±0.2°, 21.55±0.2°, 21.70±0.2°, 22.06±0.2°, 22.88±0.2°, 23.69±0.2°, 24.92±0.2°, 25.13±0.2°, 26.19±0.2°, 26.57±0.2°, 29.07±0.2°, 30.16±0.2°, 31.85±0.2°, 32.80±0.2°; b.所述盐酸盐晶型J1的差示扫描量热曲线在70.82℃±2℃和165.48℃±2℃两处具有吸热峰的起始点；b. The differential scanning calorimetry curve of the hydrochloride salt form J1 has two starting points of endothermic peaks at 70.82°C ± 2°C and 165.48°C ± 2°C; c.所述盐酸盐晶型J1的热重分析曲线在33.94℃±2℃和110.00℃±2℃两处有两个失重台阶，在212.96℃±2℃处开始分解。c. The thermogravimetric analysis curve of the hydrochloride salt form J1 has two weight loss steps at 33.94°C±2°C and 110.00°C±2°C, and starts to decompose at 212.96°C±2°C. 在另一优选例中，所述盐酸盐晶型J1具有基本上如图56所示的X射线粉末衍射图。In another preferred example, the hydrochloride salt form J1 has an X-ray powder diffraction pattern substantially as shown in Figure 56. 在另一优选例中，所述盐酸盐晶型J1具有基本上如图57所示的差示扫描量热图。In another preferred example, the hydrochloride salt form J1 has a differential scanning calorimetry diagram substantially as shown in Figure 57. 在另一优选例中，所述盐酸盐晶型J1具有基本上如图58所示的热重分析图。In another preferred example, the hydrochloride salt form J1 has a thermogravimetric analysis diagram substantially as shown in Figure 58. 在另一优选例中，所述式(I)化合物的盐酸盐晶型J1为2-甲基四氢呋喃和水的溶剂合物，其中，2-甲基四氢呋喃含量为0.1～2当量，水含量为0.1～2当量。In another preferred embodiment, the hydrochloride salt form J1 of the compound of formula (I) is a solvate of 2-methyltetrahydrofuran and water, wherein the content of 2-methyltetrahydrofuran is 0.1 to 2 equivalents, and the content of water is 0.1 to 2 equivalents. 如权利要求4所述的晶型，其特征在于，所述晶型为盐酸盐晶型J2，所述盐酸盐晶型J2的X射线粉末衍射图谱具有选自下组的2θ角：14.69±0.2°、18.89±0.2°、22.23±0.2°。The crystal form according to claim 4, characterized in that the crystal form is hydrochloride crystal form J2, and the X-ray powder diffraction pattern of the hydrochloride crystal form J2 has a 2θ angle selected from the following group: 14.69±0.2°, 18.89±0.2°, 22.23±0.2°. 在另一优选例中，所述盐酸盐晶型J2还具有选自下组的一个或多个特征：In another preferred embodiment, the hydrochloride salt form J2 further has one or more characteristics selected from the following group: a.所述盐酸盐晶型J2的X射线粉末衍射图谱还具有1个或1个以上(如1、2、3、4、5、6、7、8、9或10个)选自下组的2θ角：6.78±0.2°、7.96±0.2°、8.31±0.2°、11.59±0.2°、12.24±0.2°、13.56±0.2°、16.44±0.2°、16.63±0.2°、17.45±0.2°、18.12±0.2°、19.51±0.2°、20.12±0.2°、20.35±0.2°、20.49±0.2°、21.28±0.2°、21.46±0.2°、22.75±0.2°、23.27±0.2°、24.09±0.2°、24.86±0.2°、24.99±0.2°、25.37±0.2°、25.65±0.2°、26.54±0.2°、27.62±0.2°、28.61±0.2°、29.00±0.2°、30.43±0.2°、32.10±0.2°、33.01±0.2°、36.96±0.2°；a. The X-ray powder diffraction pattern of the hydrochloride salt form J2 also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 6.78±0.2°, 7.96±0.2°, 8.31±0.2°, 11.59±0.2°, 12.24±0.2°, 13.56±0.2°, 16.44±0.2°, 16.63±0.2°, 17.45±0.2°, 18.12±0.2°, 19.51±0.2°, 20.12±0.2°, 20.35±0. 2°, 20.49±0.2°, 21.28±0.2°, 21.46±0.2°, 22.75±0.2°, 23.27±0.2°, 24.09±0.2°, 24.86±0.2°, 24.99±0.2°, 25.37±0.2°, 25.65±0.2°, 26.54±0.2°, 27.62±0.2°, 28.61±0.2°, 29.00±0.2°, 30.43±0.2°, 32.10±0.2°, 33.01±0.2°, 36.96±0.2°; b.所述盐酸盐晶型J2的差示扫描量热曲线在77.60℃±2℃和163.47℃±2℃两处具有吸热峰的起始点；b. The differential scanning calorimetry curve of the hydrochloride salt form J2 has two starting points of endothermic peaks at 77.60°C ± 2°C and 163.47°C ± 2°C; c.所述盐酸盐晶型J2的其热重分析曲线在28.73℃±2℃和120.00℃±2℃两处有两个失重台阶，在211.78℃±2℃处开始分解。c. The thermogravimetric analysis curve of the hydrochloride salt form J2 has two weight loss steps at 28.73°C±2°C and 120.00°C±2°C, and starts to decompose at 211.78°C±2°C. 在另一优选例中，所述盐酸盐晶型J2具有基本上如图59所示的X射线粉末衍射图。In another preferred example, the hydrochloride salt form J2 has an X-ray powder diffraction pattern substantially as shown in Figure 59. 在另一优选例中，所述盐酸盐晶型J2具有基本上如图60所示的差示扫描量热图。In another preferred example, the hydrochloride salt form J2 has a differential scanning calorimetry diagram substantially as shown in Figure 60. 在另一优选例中，所述盐酸盐晶型J2具有基本上如图61所示的热重分析图。In another preferred example, the hydrochloride salt form J2 has a thermogravimetric analysis diagram substantially as shown in Figure 61. 在另一优选例中，所述式(I)化合物的盐酸盐晶型J2由式(I)化合物的盐酸盐晶型J1加热至90℃～130℃制得.In another preferred embodiment, the hydrochloride crystalline form J2 of the compound of formula (I) is prepared by heating the hydrochloride crystalline form J1 of the compound of formula (I) to 90°C to 130°C. 在另一优选例中，所述式(I)化合物的盐酸盐晶型J2为2-甲基四氢呋喃和水的溶剂合物，其中，2-甲基四氢呋喃含量为0.2～0.8当量，水含量为0.5～2当量。In another preferred embodiment, the hydrochloride salt form J2 of the compound of formula (I) is a solvate of 2-methyltetrahydrofuran and water, wherein the content of 2-methyltetrahydrofuran is 0.2 to 0.8 equivalents, and the content of water is 0.5 to 2 equivalents. 如权利要求4所述的晶型，其特征在于，所述晶型为盐酸盐晶型K，所述盐酸盐晶型K的X射线粉末衍射图谱具有选自下组的2θ角：14.93±0.2°、16.08±0.2°、23.68±0.2°。The crystal form according to claim 4, characterized in that the crystal form is hydrochloride crystal form K, and the X-ray powder diffraction pattern of the hydrochloride crystal form K has a 2θ angle selected from the following group: 14.93±0.2°, 16.08±0.2°, 23.68±0.2°. 在另一优选例中，所述盐酸盐晶型K还具有选自下组的一个或多个特征：In another preferred embodiment, the hydrochloride salt form K further has one or more characteristics selected from the following group: a.所述盐酸盐晶型K的X射线粉末衍射图谱还具有1个或1个以上(如1、2、3、4、5、6、7、8、9或10个)选自下组的2θ角：6.79±0.2°、7.83±0.2°、8.04±0.2°、10.00±0.2°、10.74±0.2°、11.61±0.2°、12.25±0.2°、12.64±0.2°、13.57±0.2°、18.05±0.2°、18.63±0.2°、19.43±0.2°、20.15±0.2°、20.49±0.2°、20.64±0.2°、21.52±0.2°、21.72±0.2°、21.93±0.2°、23.27±0.2°、24.73±0.2°、25.19±0.2°、26.25±0.2°、26.57±0.2°、27.42±0.2°、28.02±0.2°、28.67±0.2°、29.13±0.2°、29.91±0.2°、32.56±0.2°；a. The X-ray powder diffraction pattern of the hydrochloride salt form K also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the group consisting of 6.79±0.2°, 7.83±0.2°, 8.04±0.2°, 10.00±0.2°, 10.74±0.2°, 11.61±0.2°, 12.25±0.2°, 12.64±0.2°, 13.57±0.2°, 18.05±0.2°, 18.63±0.2°, 19.43±0. 2°, 20.15±0.2°, 20.49±0.2°, 20.64±0.2°, 21.52±0.2°, 21.72±0.2°, 21.93±0.2°, 23.27±0.2°, 24.73±0.2°, 25.19±0.2°, 26.25±0.2°, 26.57±0.2°, 27.42±0.2°, 28.02±0.2°, 28.67±0.2°, 29.13±0.2°, 29.91±0.2°, 32.56±0.2°; b.所述盐酸盐晶型K的差示扫描量热曲线在80.73℃±2℃和171.74℃±2℃两处具有吸热峰的起始点；b. The differential scanning calorimetry curve of the hydrochloride salt form K has two starting points of endothermic peaks at 80.73°C ± 2°C and 171.74°C ± 2°C; c.所述盐酸盐晶型K的热重分析曲线在33.39℃±2℃、125.00℃±2℃和155.00℃±2℃三处有三个失重台阶，211.42℃±2℃处开始分解。c. The thermogravimetric analysis curve of the hydrochloride salt form K has three weight loss steps at 33.39°C±2°C, 125.00°C±2°C and 155.00°C±2°C, and starts to decompose at 211.42°C±2°C. 在另一优选例中，所述盐酸盐晶型K具有基本上如图62所示的X射线粉末衍射图。In another preferred example, the hydrochloride salt form K has an X-ray powder diffraction pattern substantially as shown in Figure 62. 在另一优选例中，所述盐酸盐晶型K具有基本上如图63所示的差示扫描量热图。In another preferred example, the hydrochloride salt form K has a differential scanning calorimetry diagram substantially as shown in Figure 63. 在另一优选例中，所述盐酸盐晶型K具有基本上如图64所示的热重分析图。In another preferred example, the hydrochloride salt form K has a thermogravimetric analysis diagram substantially as shown in Figure 64. 在另一优选例中，所述式(I)化合物的盐酸盐晶型K为甲基叔丁基醚和水的溶剂合物，其中，甲基叔丁基醚含量为0.1～1当量，水含量为0.5～2当量。In another preferred embodiment, the hydrochloride crystal form K of the compound of formula (I) is a solvate of methyl tert-butyl ether and water, wherein the content of methyl tert-butyl ether is 0.1 to 1 equivalents, and the content of water is 0.5 to 2 equivalents. 如权利要求4所述的晶型，其特征在于，所述晶型为盐酸盐晶型L，所述盐酸盐晶型L的X射线粉末衍射图谱具有选自下组的2θ角：16.89±0.2°、21.69±0.2°、22.60±0.2°。The crystal form according to claim 4, characterized in that the crystal form is hydrochloride crystal form L, and the X-ray powder diffraction pattern of the hydrochloride crystal form L has a 2θ angle selected from the following group: 16.89±0.2°, 21.69±0.2°, 22.60±0.2°. 在另一优选例中，所述盐酸盐晶型L还具有选自下组的一个或多个特征：In another preferred embodiment, the hydrochloride salt form L further has one or more characteristics selected from the following group: a.所述盐酸盐晶型L的X射线粉末衍射图谱还具有1个或1个以上(如1、2、3、4、5、6、7、8、9或10个)选自下组的2θ角：7.70±0.2°、8.15±0.2°、8.82±0.2°、9.85±0.2°、11.25±0.2°、12.72±0.2°、13.59±0.2°、14.68±0.2°、15.07±0.2°、15.56±0.2°、16.60±0.2°、17.56±0.2°、18.53±0.2°、18.98±0.2°、19.74±0.2°、20.29±0.2°、20.52±0.2°、21.30±0.2°、22.79±0.2°、24.38±0.2°、25.57±0.2°、26.21±0.2°、26.50±0.2°、26.97±0.2°、27.48±0.2°、28.17±0.2°、28.60±0.2°、29.54±0.2°、29.80±0.2°、31.17±0.2°、33.28±0.2°；a. The X-ray powder diffraction pattern of the hydrochloride salt form L also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 7.70±0.2°, 8.15±0.2°, 8.82±0.2°, 9.85±0.2°, 11.25±0.2°, 12.72±0.2°, 13.59±0.2°, 14.68±0.2°, 15.07±0.2°, 15.56±0.2°, 16.60±0.2°, 17.56±0.2°, 18.53±0.2 °, 18.98±0.2°, 19.74±0.2°, 20.29±0.2°, 20.52±0.2°, 21.30±0.2°, 22.79±0.2°, 24.38±0.2°, 25.57±0.2°, 26.21±0.2°, 26.50±0.2°, 26.97±0.2°, 27.48±0.2°, 28.17±0.2°, 28.60±0.2°, 29.54±0.2°, 29.80±0.2°, 31.17±0.2°, 33.28±0.2°; b.所述盐酸盐晶型L的差示扫描量热曲线在180.17℃±2℃处具有吸热峰的起始点；b. The differential scanning calorimetry curve of the hydrochloride salt form L has a starting point of an endothermic peak at 180.17°C ± 2°C; c.所述盐酸盐晶型L的热重分析曲线在33.53℃±2℃和140.00℃±2℃两处有两个失重台阶，在212.43℃±2℃处开始分解。c. The thermogravimetric analysis curve of the hydrochloride crystal form L has two weight loss steps at 33.53°C±2°C and 140.00°C±2°C, and starts to decompose at 212.43°C±2°C. 在另一优选例中，所述盐酸盐晶型L具有基本上如图65所示的X射线粉末衍射图。In another preferred example, the hydrochloride salt form L has an X-ray powder diffraction pattern substantially as shown in Figure 65. 在另一优选例中，所述盐酸盐晶型L具有基本上如图66所示的差示扫描量热图。In another preferred example, the hydrochloride salt form L has a differential scanning calorimetry diagram substantially as shown in Figure 66. 在另一优选例中，所述盐酸盐晶型L具有基本上如图67所示的热重分析图。In another preferred example, the hydrochloride salt form L has a thermogravimetric analysis diagram substantially as shown in Figure 67. 在另一优选例中，所述式(I)化合物的盐酸盐晶型L为甲苯的溶剂合物，其中，甲苯含量为0.2～1当量。In another preferred embodiment, the hydrochloride crystal form L of the compound of formula (I) is a toluene solvate, wherein the toluene content is 0.2 to 1 equivalent. 如权利要求4所述的晶型，其特征在于，所述晶型为盐酸盐晶型M，所述盐酸盐晶型M的X射线粉末衍射图谱具有选自下组的2θ角：14.17±0.2°、20.82±0.2°、22.60±0.2°。The crystal form according to claim 4, characterized in that the crystal form is a hydrochloride crystal form M, and the X-ray powder diffraction pattern of the hydrochloride crystal form M has a 2θ angle selected from the following group: 14.17±0.2°, 20.82±0.2°, 22.60±0.2°. 在另一优选例中，所述盐酸盐晶型M还具有选自下组的一个或多个特征：In another preferred embodiment, the hydrochloride salt form M further has one or more characteristics selected from the following group: a.所述盐酸盐晶型M的X射线粉末衍射图谱还具有1个或1个以上(如1、2、3、4、5、6、7、8、9或10个)选自下组的2θ角：6.84±0.2°、7.21±0.2°、8.92±0.2°、10.07±0.2°、10.69±0.2°、10.89±0.2°、11.24±0.2°、13.23±0.2°、14.90±0.2°、15.59±0.2°、16.74±0.2°、17.67±0.2°、18.29±0.2°、18.94±0.2°、19.46±0.2°、19.71±0.2°、19.96±0.2°、21.49±0.2°、21.83±0.2°、23.14±0.2°、23.54±0.2°、24.17±0.2°、25.17±0.2°、25.45±0.2°、26.10±0.2°、27.17±0.2°、27.61±0.2°、28.09±0.2°、28.88±0.2°、29.42±0.2°、30.12±0.2°、32.48±0.2°、35.22±0.2°；a. The X-ray powder diffraction pattern of the hydrochloride salt form M also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the group consisting of 6.84±0.2°, 7.21±0.2°, 8.92±0.2°, 10.07±0.2°, 10.69±0.2°, 10.89±0.2°, 11.24±0.2°, 13.23±0.2°, 14.90±0.2°, 15.59±0.2°, 16.74±0.2°, 17.67±0.2°, 18.29±0.2°, 18.94±0. 2°, 19.46±0.2°, 19.71±0.2°, 19.96±0.2°, 21.49±0.2°, 21.83±0.2°, 23.14±0.2°, 23.54±0.2°, 24.17±0.2°, 25.17±0.2°, 25.45±0.2°, 26.10±0.2°, 27.17±0.2°, 27.61±0.2°, 28.09±0.2°, 28.88±0.2°, 29.42±0.2°, 30.12±0.2°, 32.48±0.2°, 35.22±0.2°; b.所述盐酸盐晶型M的差示扫描量热曲线在31.74℃±2℃和150.05℃±2℃处具有吸热峰的起始点；b. The differential scanning calorimetry curve of the hydrochloride salt form M has the starting points of the endothermic peaks at 31.74°C ± 2°C and 150.05°C ± 2°C; c.所述盐酸盐晶型M的热重分析曲线在32.98℃±2℃和115.00℃±2℃两处有两个失重台阶，在215.09℃±2℃处开始分解。c. The thermogravimetric analysis curve of the hydrochloride salt form M has two weight loss steps at 32.98°C±2°C and 115.00°C±2°C, and starts to decompose at 215.09°C±2°C. 在另一优选例中，所述盐酸盐晶型M具有基本上如图68所示的X射线粉末衍射图。In another preferred example, the hydrochloride salt form M has an X-ray powder diffraction pattern substantially as shown in Figure 68. 在另一优选例中，所述盐酸盐晶型M具有基本上如图69所示的差示扫描量热图。In another preferred example, the hydrochloride salt form M has a differential scanning calorimetry diagram substantially as shown in Figure 69. 在另一优选例中，所述盐酸盐晶型M具有基本上如图70所示的热重分析图。In another preferred example, the hydrochloride salt form M has a thermogravimetric analysis diagram substantially as shown in Figure 70. 在另一优选例中，所述式(I)化合物的盐酸盐晶型M为二甲基亚砜和水的溶剂合物，其中，二甲基亚砜含量为1～7当量，水的含量为5～25当量。In another preferred embodiment, the hydrochloride crystal form M of the compound of formula (I) is a solvate of dimethyl sulfoxide and water, wherein the content of dimethyl sulfoxide is 1 to 7 equivalents, and the content of water is 5 to 25 equivalents. 如权利要求4所述的晶型，其特征在于，所述晶型为盐酸盐晶型N，所述盐酸盐晶型N的X射线粉末衍射图谱具有选自下组的2θ角：16.19±0.2°、20.10±0.2°、28.42±0.2°。The crystal form according to claim 4, characterized in that the crystal form is hydrochloride crystal form N, and the X-ray powder diffraction pattern of the hydrochloride crystal form N has a 2θ angle selected from the following group: 16.19±0.2°, 20.10±0.2°, 28.42±0.2°. 在另一优选例中，所述盐酸盐晶型N还具有选自下组的一个或多个特征：In another preferred embodiment, the hydrochloride salt form N further has one or more characteristics selected from the following group: a.所述盐酸盐晶型N的X射线粉末衍射图谱还具有1个或1个以上(如1、2、3、4、5、6、7、8、9或10个)选自下组的2θ角：6.61±0.2°、7.80±0.2°、9.75±0.2°、11.19±0.2°、12.53±0.2°、13.17±0.2°、14.61±0.2°、15.24±0.2°、16.02±0.2°、18.51±0.2°、19.36±0.2°、21.57±0.2°、21.95±0.2°、23.47±0.2°、25.60±0.2°、27.32±0.2°、29.12±0.2°；a. The X-ray powder diffraction pattern of the hydrochloride salt form N also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the group consisting of 6.61±0.2°, 7.80±0.2°, 9.75±0.2°, 11.19±0.2°, 12.53±0.2°, 13.17±0.2°, 14.61±0.2°, 15.24±0.2°, 16.02±0.2°, 18.51±0.2°, 19.36±0.2°, 21.57±0.2°, 21.95±0.2°, 23.47±0.2°, 25.60±0.2°, 27.32±0.2°, 29.12±0.2°; b.所述盐酸盐晶型N的差示扫描量热曲线在47.38℃±2℃和167.91℃±2℃处具有吸热峰的起始点；b. The differential scanning calorimetry curve of the hydrochloride salt form N has the starting points of the endothermic peaks at 47.38°C ± 2°C and 167.91°C ± 2°C; c.所述盐酸盐晶型N的热重分析曲线在33.22℃±2℃、75.00℃±2℃和150.00℃±2℃三处有三个失重台阶，在212.57℃±2℃处开始分解。c. The thermogravimetric analysis curve of the hydrochloride salt form N has three weight loss steps at 33.22°C±2°C, 75.00°C±2°C and 150.00°C±2°C, and begins to decompose at 212.57°C±2°C. 在另一优选例中，所述盐酸盐晶型N具有基本上如图71所示的X射线粉末衍射图。In another preferred example, the hydrochloride salt form N has an X-ray powder diffraction pattern substantially as shown in Figure 71. 在另一优选例中，所述盐酸盐晶型N具有基本上如图72所示的差示扫描量热图。In another preferred example, the hydrochloride salt form N has a differential scanning calorimetry diagram substantially as shown in Figure 72. 在另一优选例中，所述盐酸盐晶型N具有基本上如图73所示的热重分析图。In another preferred example, the hydrochloride salt form N has a thermogravimetric analysis diagram substantially as shown in Figure 73. 在另一优选例中，所述式(I)化合物的盐酸盐晶型N为水合物晶型，其中，水的含量为1～6当量。In another preferred embodiment, the hydrochloride crystal form N of the compound of formula (I) is a hydrate crystal form, wherein the water content is 1 to 6 equivalents. 如权利要求4所述的晶型，其特征在于，所述晶型为盐酸盐晶型O，所述盐酸盐晶型O的X射线粉末衍射图谱具有选自下组的2θ角：15.51±0.2°、18.36±0.2°、20.17±0.2°。The crystal form according to claim 4, characterized in that the crystal form is hydrochloride crystal form O, and the X-ray powder diffraction pattern of the hydrochloride crystal form O has a 2θ angle selected from the following group: 15.51±0.2°, 18.36±0.2°, 20.17±0.2°. 在另一优选例中，所述盐酸盐晶型O还具有选自下组的一个或多个特征：In another preferred embodiment, the hydrochloride salt form O further has one or more characteristics selected from the following group: a.所述盐酸盐晶型O的X射线粉末衍射图谱还具有1个或1个以上(如1、2、3、4、5、6、7、8、9或10个)选自下组的2θ角：6.14±0.2°、8.39±0.2°、9.90±0.2°、11.28±0.2°、13.19±0.2°、13.54±0.2°、14.40±0.2°、15.33±0.2°、15.87±0.2°、16.79±0.2°、17.32±0.2°、19.03±0.2°、19.38±0.2°、19.84±0.2°、20.39±0.2°、21.14±0.2°、21.82±0.2°、22.51±0.2°、22.84±0.2°、23.77±0.2°、24.59±0.2°、25.28±0.2°、26.21±0.2°、26.82±0.2°、27.07±0.2°、27.93±0.2°、28.45±0.2°、29.24±0.2°、29.70±0.2°、30.12±0.2°、30.91±0.2°、31.32±0.2°、32.02±0.2°、32.81±0.2°、33.99±0.2°、35.51±0.2°、37.27±0.2°；a. The X-ray powder diffraction pattern of the hydrochloride crystal form O also has one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 2θ angles selected from the following group: 6.14±0.2°, 8.39±0.2°, 9.90±0.2°, 11.28±0.2°, 13.19±0.2°, 13.54±0.2°, 14.40±0.2°, 15.33±0.2°, 15.87±0.2°, 16.79±0.2°, 17.32±0.2°, 19.03±0.2°, 19.38±0.2°, 19.84±0.2°, 20.39±0.2°, 21.14±0.2° 2°, 21.82±0.2°, 22.51±0.2°, 22.84±0.2°, 23.77±0.2°, 24.59±0.2°, 25.28±0.2°, 26.21±0.2°, 26.82±0.2°, 27.07±0.2°, 27.93±0.2°, 28.45±0.2°, 29.24±0.2°, 29.70±0.2°, 30.12±0.2°, 30.91±0.2°, 31.32±0.2°, 32.02±0.2°, 32.81±0.2°, 33.99±0.2°, 35.51±0.2°, 37.27±0.2°; b.所述盐酸盐晶型O的差示扫描量热曲线在12.36℃±2℃和174.87℃±2℃处具有吸热峰的起始点；b. The differential scanning calorimetry curve of the hydrochloride salt form O has the starting points of the endothermic peaks at 12.36°C ± 2°C and 174.87°C ± 2°C; c.所述盐酸盐晶型O的热重分析曲线在27.70℃±2℃、115.00℃±2℃和160.00℃±2℃三处有三个失重台阶，在212.00℃±2℃处开始分解。c. The thermogravimetric analysis curve of the hydrochloride salt form O has three weight loss steps at 27.70°C±2°C, 115.00°C±2°C and 160.00°C±2°C, and begins to decompose at 212.00°C±2°C. 在另一优选例中，所述盐酸盐晶型O具有基本上如图74所示的X射线粉末衍射图。In another preferred example, the hydrochloride salt form O has an X-ray powder diffraction pattern substantially as shown in Figure 74. 在另一优选例中，所述盐酸盐晶型O具有基本上如图75所示的差示扫描量热图。In another preferred example, the hydrochloride salt form O has a differential scanning calorimetry diagram substantially as shown in Figure 75. 在另一优选例中，所述盐酸盐晶型O具有基本上如图76所示的热重分析图。In another preferred example, the hydrochloride salt form O has a thermogravimetric analysis diagram substantially as shown in Figure 76. 在另一优选例中，所述式(I)化合物的盐酸盐晶型O为水合物晶型，其中，水的含量为0.4～2当量。In another preferred embodiment, the hydrochloride crystal form O of the compound of formula (I) is a hydrate crystal form, wherein the water content is 0.4 to 2 equivalents. 一种制备权利要求5-35中任一项所述的式(I)化合物的药学上可接受的盐的晶型的方法，其特征在于，包括如下步骤：A method for preparing a crystalline form of a pharmaceutically acceptable salt of a compound of formula (I) according to any one of claims 5 to 35, characterized in that it comprises the following steps: a.将式(I)化合物和酸按1:(0.8-3)的摩尔比溶解到或分散到1～20倍体积的溶剂A中；a. dissolving or dispersing the compound of formula (I) and the acid in a molar ratio of 1:(0.8-3) into 1 to 20 times the volume of solvent A; b.混悬、重结晶或打浆；b. Suspension, recrystallization or slurrying; 其中，所述酸不选自盐酸(优选地，所述酸选自下组：马来酸、富马酸、乙醇酸、L-苹果酸、琥珀酸、硫酸、L-酒石酸、马尿酸、戊二酸、对甲苯磺酸或甲磺酸)；wherein the acid is not selected from hydrochloric acid (preferably, the acid is selected from the group consisting of maleic acid, fumaric acid, glycolic acid, L-malic acid, succinic acid, sulfuric acid, L-tartaric acid, hippuric acid, glutaric acid, p-toluenesulfonic acid or methanesulfonic acid); 所述溶剂A选自下组：乙腈、二氯甲烷、四氢呋喃、或其组合；The solvent A is selected from the group consisting of acetonitrile, dichloromethane, tetrahydrofuran, or a combination thereof; 或所述酸为盐酸或氯化氢二氧六环；且所述溶剂A选自下组：乙酸乙酯、2-甲基四氢呋喃、丁酮、乙醇、丙酮、乙酸乙酯、乙腈、四氢呋喃、甲基异丁基酮、三氟乙醇、水、甲醇、甲基叔丁基醚、甲苯、异丙醇、二甲基亚砜、乙酸异丙酯、二氯甲烷、或其组合。Or the acid is hydrochloric acid or hydrochloric acid dioxane; and the solvent A is selected from the following group: ethyl acetate, 2-methyltetrahydrofuran, butanone, ethanol, acetone, ethyl acetate, acetonitrile, tetrahydrofuran, methyl isobutyl ketone, trifluoroethanol, water, methanol, methyl tert-butyl ether, toluene, isopropanol, dimethyl sulfoxide, isopropyl acetate, dichloromethane, or a combination thereof. 在另一优选例中，所述溶剂A选自下组：甲基异丁基酮/三氟乙醇、甲醇/水、甲醇/甲基叔丁基醚、异丙醇/二甲基亚砜、乙酸异丙酯/二甲基亚砜、水/二甲基亚砜。In another preferred embodiment, the solvent A is selected from the following group: methyl isobutyl ketone/trifluoroethanol, methanol/water, methanol/methyl tert-butyl ether, isopropanol/dimethyl sulfoxide, isopropyl acetate/dimethyl sulfoxide, water/dimethyl sulfoxide. 在另一优选例中，所述混悬包括如下步骤：In another preferred embodiment, the suspending comprises the following steps: a.将式(I)化合物、酸和溶剂在45～65℃下混悬1～3h；a. suspending the compound of formula (I), the acid and the solvent at 45 to 65 ° C for 1 to 3 hours; b.自然降温至20～30℃，并继续混悬至少48h；b. Cool naturally to 20-30°C and continue to suspend for at least 48 hours; c.将所得混悬液通过0.4～0.5μm滤膜以12000～16000rpm转速离心；c. The resulting suspension was centrifuged at 12000-16000 rpm through a 0.4-0.5 μm filter membrane; d.将所得固体在45～65℃下真空干燥。d. The obtained solid was dried under vacuum at 45-65°C. 一种制备权利要求5-36中任一项所述的式(I)化合物的药学上可接受的盐的晶型的方法，其特征在于，所述方法为通过晶型转化的方法，将式(I)化合物的药学上可接受的盐的一种晶型转化为该盐的另外一种晶型；A method for preparing a crystalline form of a pharmaceutically acceptable salt of a compound of formula (I) according to any one of claims 5 to 36, characterized in that the method is a method of converting a crystalline form of a pharmaceutically acceptable salt of a compound of formula (I) into another crystalline form of the salt by a crystalline form conversion method; 其中，晶型转化的方法包括以下步骤：Wherein, the method for crystal form transformation comprises the following steps: a.将式(I)化合物的药学上可接受的盐的一种晶型溶解到或分散到1～20倍体积的溶剂A中；a. dissolving or dispersing a crystalline form of a pharmaceutically acceptable salt of a compound of formula (I) into 1 to 20 times the volume of solvent A; b.混悬；b. Suspension; c.将所得混悬液通过0.4～0.5μm滤膜以12000～16000rpm转速离心过滤；c. The resulting suspension was centrifuged through a 0.4-0.5 μm filter membrane at a speed of 12000-16000 rpm; 其中，溶剂A选自下组：乙醇、丙酮、乙酸乙酯、乙腈、四氢呋喃、甲基异丁基酮、三氟乙醇、甲醇、2-甲基四氢呋喃、甲基叔丁基醚、甲苯、异丙醇、二甲基亚砜、乙酸异丙酯、二甲基亚砜、甲醇、二氯甲烷、水或其组合。Wherein, solvent A is selected from the following group: ethanol, acetone, ethyl acetate, acetonitrile, tetrahydrofuran, methyl isobutyl ketone, trifluoroethanol, methanol, 2-methyltetrahydrofuran, methyl tert-butyl ether, toluene, isopropanol, dimethyl sulfoxide, isopropyl acetate, dimethyl sulfoxide, methanol, dichloromethane, water or a combination thereof. 在另一优选例中，所述溶剂A选自下组：甲基异丁基酮/三氟乙醇、甲醇/水、异丙醇/二甲基亚砜、乙酸异丙酯/二甲基亚砜、二甲基亚砜/水。In another preferred embodiment, the solvent A is selected from the following group: methyl isobutyl ketone/trifluoroethanol, methanol/water, isopropanol/dimethyl sulfoxide, isopropyl acetate/dimethyl sulfoxide, and dimethyl sulfoxide/water. 在另一优选例中，所述混悬包括步骤：在20～30℃下，以300-400rpm速率搅拌。In another preferred embodiment, the suspending comprises the steps of: stirring at a rate of 300-400 rpm at 20-30°C. 在另一优选例中，所述混悬包括步骤：在40～60℃下，以300-400rpm速率搅拌。In another preferred embodiment, the suspending comprises the steps of: stirring at 40-60°C and at a rate of 300-400 rpm. 在另一优选例中，所述混悬包括步骤：在5～50℃之间以0.05～0.2℃/min的速率进行8～12个升降温循环，同时以300-400rpm速率搅拌，混悬液的终温度为10～15℃。In another preferred embodiment, the suspension comprises the steps of: performing 8 to 12 temperature rise and fall cycles at a rate of 0.05 to 0.2°C/min between 5 and 50°C, while stirring at a rate of 300-400 rpm, and the final temperature of the suspension is 10 to 15°C. 在另一优选例中，所述混悬包括步骤：利用0.4～0.5μm滤膜过滤得到澄清溶液，以1:(8～12)的比例添加甲基叔丁基醚后混悬。In another preferred embodiment, the suspending comprises the steps of: filtering with a 0.4-0.5 μm filter membrane to obtain a clear solution, adding methyl tert-butyl ether in a ratio of 1:(8-12) and then suspending. 一种药物组合物，包括权利要求1-2中任一所述的式(I)化合物，权利要求3-4中任一所述的晶型A，或权利要求5-36中任一项所述的式(I)化合物的晶型；A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1 to 2, the crystalline form A according to any one of claims 3 to 4, or the crystalline form of the compound of formula (I) according to any one of claims 5 to 36; 和and 一种或多种可药用的载体、赋形剂、佐剂、辅料和/或稀释剂。One or more pharmaceutically acceptable carriers, excipients, adjuvants, auxiliary materials and/or diluents. 在另一优选例中，所述药物组合物还包括其他治疗剂。In another preferred embodiment, the pharmaceutical composition further comprises other therapeutic agents. 在另一优选例中，所述其他治疗剂选自下组：化疗药物、激酶抑制剂、靶向表观遗传调节剂、抗体药物、免疫检查点抑制剂，或其组合。在另一优选例中，所述化疗药物选自下组：顺铂、多柔比星、紫杉醇、依托泊苷、伊立替康、环磷酰胺、吉西他滨、异环磷酰胺、他莫昔芬、托瑞米芬、氟维司群、阿那曲唑、依西美坦、戈舍瑞林、亮丙瑞林、美法仑、苯丁酸氮芥、白消安、氟尿苷、阿糖胞苷、奥沙利铂、亚叶酸、喷司他丁、己烯雌酚。In another preferred embodiment, the other therapeutic agent is selected from the group consisting of chemotherapeutic drugs, kinase inhibitors, targeted epigenetic regulators, antibody drugs, immune checkpoint inhibitors, or combinations thereof. In another preferred embodiment, the chemotherapeutic drug is selected from the group consisting of cisplatin, doxorubicin, paclitaxel, etoposide, irinotecan, cyclophosphamide, gemcitabine, ifosfamide, tamoxifen, toremifene, fulvestrant, anastrozole, exemestane, goserelin, leuprorelin, melphalan, chlorambucil, busulfan, floxuridine, cytarabine, oxaliplatin, folinic acid, pentostatin, diethylstilbestrol. 在另一优选例中，所述激酶抑制剂选自下组：Akt、TGF-βR、Pim、PKA、PKG、PKC、CaM激酶、CDK2、CDK4、CDK4/6、MEK、ERK、MAPK、mTOR、EGFR、HER2、HER3、HER4、PDGFαR、PDGFβR、CSFIR、KIT、c-Met、TRKA、TRKB、TRKC、FLT3、VEGFR、BTK、FAK、SYK、FRK、JAK、HPK1、AXL、ALK、B-Raf抑制剂。在另一优选例中，所述靶向表观遗传调节剂选自下组：溴结构域抑制剂、组蛋白赖氨酸甲基转移酶、组蛋白精氨酸甲基转移酶、组蛋白脱甲基酶、组蛋白脱乙酰酶、组蛋白乙酰化酶、DNA甲基转移酶。在另一优选例中，所述抗体药物选自下组：抗HER 2抗体、抗VEGFR抗体、抗EGFR抗体、抗c-MET抗体、抗CD20抗体。In another preferred embodiment, the kinase inhibitor is selected from the group consisting of Akt, TGF-βR, Pim, PKA, PKG, PKC, CaM kinase, CDK2, CDK4, CDK4/6, MEK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, PDGFαR, PDGFβR, CSFIR, KIT, c-Met, TRKA, TRKB, TRKC, FLT3, VEGFR, BTK, FAK, SYK, FRK, JAK, HPK1, AXL, ALK, B-Raf inhibitor. In another preferred embodiment, the targeted epigenetic regulator is selected from the group consisting of bromodomain inhibitors, histone lysine methyltransferases, histone arginine methyltransferases, histone demethylases, histone deacetylases, histone acetylases, and DNA methyltransferases. In another preferred embodiment, the antibody drug is selected from the following group: anti-HER 2 antibody, anti-VEGFR antibody, anti-EGFR antibody, anti-c-MET antibody, and anti-CD20 antibody. 在另一优选例中，所述免疫检查点抑制剂选自下组：CD27、CD28、CD40、CD122、CD96、CD73、CD47、OX40、GITR、A2AR、B7-H3、B7-H4、BTLA、CTLA-4、LAG3、TIM3、VISTA、PD-1、PD-L1、PD-L2。In another preferred embodiment, the immune checkpoint inhibitor is selected from the following group: CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1, PD-L1, and PD-L2. 一种权利要求1-2中任一所述的式(I)化合物，权利要求3-4中任一所述的晶型A，权利要求5-36中任一项所述的式(I)化合物的晶型，和权利要求38中所述的药物组合物在制备预防和/或治疗FGFR2的活性或表达量增加相关的疾病的药物中的用途。Use of a compound of formula (I) as described in any one of claims 1 to 2, the crystalline form A as described in any one of claims 3 to 4, the crystalline form of the compound of formula (I) as described in any one of claims 5 to 36, and the pharmaceutical composition as described in claim 38 in the preparation of a medicament for preventing and/or treating diseases related to increased activity or expression of FGFR2. 在另一优选例中，所述FGFR2的活性或表达量增加选自下组：FGFR2扩增、FGFR2基因突变、FGFR2基因融合/重排、FGFR2基因易位、FGFR2基因激活。In another preferred embodiment, the increased activity or expression of FGFR2 is selected from the group consisting of: FGFR2 amplification, FGFR2 gene mutation, FGFR2 gene fusion/rearrangement, FGFR2 gene translocation, and FGFR2 gene activation. 在另一优选例中，所述FGFR2的活性或表达量增加相关的疾病选自下组：胆管癌、肝癌、乳腺癌、前列腺癌、肺癌、甲状腺癌、胃癌、卵巢癌、食管癌、胰腺癌、宫颈癌、结直肠癌、唾液腺癌、子宫内膜癌和尿道上皮癌等。In another preferred embodiment, the disease associated with increased activity or expression of FGFR2 is selected from the following group: bile duct cancer, liver cancer, breast cancer, prostate cancer, lung cancer, thyroid cancer, gastric cancer, ovarian cancer, esophageal cancer, pancreatic cancer, cervical cancer, colorectal cancer, salivary gland cancer, endometrial cancer and urothelial cancer, etc. 在另一优选例中，所述胆管癌为肝内胆管癌。In another preferred embodiment, the bile duct cancer is intrahepatic bile duct cancer. 在另一优选例中，所述肝癌为肝细胞癌。In another preferred embodiment, the liver cancer is hepatocellular carcinoma. 在另一优选例中，所述肺癌是肺鳞状细胞癌或非小细胞肺癌。In another preferred embodiment, the lung cancer is squamous cell lung carcinoma or non-small cell lung cancer.
PCT/CN2024/143407 2023-12-29 2024-12-27 Crystal form of acid salt of sulfoximine compound, preparation method therefor, and use thereof Pending WO2025140636A1 (en)

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