WO2023231996A1 - Crystal forms of hydroxamic acid ester compound and salt thereof, and preparation method - Google Patents

Crystal forms of hydroxamic acid ester compound and salt thereof, and preparation method Download PDF

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WO2023231996A1
WO2023231996A1 PCT/CN2023/096974 CN2023096974W WO2023231996A1 WO 2023231996 A1 WO2023231996 A1 WO 2023231996A1 CN 2023096974 W CN2023096974 W CN 2023096974W WO 2023231996 A1 WO2023231996 A1 WO 2023231996A1
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crystal
crystals
formula
ray powder
type
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PCT/CN2023/096974
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French (fr)
Chinese (zh)
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袁渭
王伟
宗太丽
李志斌
潘德思
鲁先平
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深圳微芯生物科技股份有限公司
成都微芯药业有限公司
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Publication of WO2023231996A1 publication Critical patent/WO2023231996A1/en

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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the invention belongs to the field of medicinal chemistry, and specifically relates to the crystallization form and preparation method of hydroxamate compounds and salts thereof.
  • Nicotinamide is a tyrosine kinase 2 (Tyk2) inhibitor, and its chemical structure is shown in structural formula (I).
  • the pharmacological activity data of the compound represented by formula (I) is recorded in the PCT patent application number PCT/CN2021/134929.
  • the compound has excellent Tyk2 selective inhibitory activity and can be used to treat diseases related to abnormal Tyk2 activity. diseases, clinically it is expected to obtain drugs with better efficacy and fewer side effects.
  • the object of the present invention is to provide the crystal form, salt form and eutectic form of the compound represented by formula (I).
  • the present invention provides the following technical solutions.
  • the unsolvated crystal of the compound represented by formula (I) is selected from the group consisting of its unsolvated crystal AH and its unsolvated crystal E.
  • the X-ray powder diffraction pattern of the unsolvated crystal AH of the compound represented by formula (I) has characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 7.65°, 11.26°, 11.43 °, 15.07°, 15.32°, 19.07°, 20.12° and 20.78°.
  • the X-ray powder diffraction pattern of the unsolvated crystal AH of the compound represented by formula (I) has characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 7.65°, 11.26°, 11.43 °, 15.07°, 15.32°, 16.60°, 19.07°, 20.12°, 20.78° and 23.02°.
  • the X-ray powder diffraction pattern of the unsolvated crystal AH of the compound represented by formula (I) has characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 7.65°, 9.47°, 11.26 °, 11.43°, 15.07°, 15.32°, 16.31°, 16.60°, 19.07°, 20.12°, 20.78°, 23.02° and 25.77°.
  • the unsolvated crystalline AH of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 7.65°, 8.36°, 9.47°, 9.80° ⁇ 11.26° ⁇ 11.43° ⁇ 11.55° ⁇ 11.80° ⁇ 12.95° ⁇ 13.64° ⁇ 14.34° ⁇ 14.74° ⁇ 15.07° ⁇ 15.32° ⁇ 15.91° ⁇ 16.31° ⁇ 16.60° ⁇ 16.87° ⁇ 18.72° ⁇ 19.07° , 19.73°, 20.12°, 20.78°, 21.30°, 21.45°, 21.95°, 22.31°, 23.02°, 23.30°, 23.67°, 23.84°, 24.65°, 25.77°, 26.57°, 26.90°, 28.29°, 28.85 °, 29.54°.
  • the X-ray powder diffraction pattern of the unsolvated crystal AH of the compound represented by formula (I) is shown in Figure 7.
  • the differential scanning calorimetry analysis curve of the unsolvated crystal AH of the compound represented by formula (I) shows an endothermic peak near 188°C and an exothermic peak near 216.7°C.
  • thermogravimetric analysis curve of the unsolvated crystal AH of the compound represented by formula (I) shows that the crystal form has a weight loss of 2.1% during heating to 150°C. After continuing to be heated to 190°C, it may Decomposition occurs.
  • thermogravimetric analysis curve of the unsolvated crystal AH of the compound represented by formula (I) is shown in Figure 10.
  • the X-ray powder diffraction pattern of the unsolvated crystal E of the compound represented by formula (I) has characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 7.19°, 9.59°, 14.46° , 18.15°, 20.41°, 23.44°, 23.67°, 24.01°, 24.34° and 24.60°.
  • the X-ray powder diffraction pattern of the unsolvated crystal E of the compound represented by formula (I) has characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 7.19°, 9.59°, 13.64° , 14.46°, 18.15°, 19.19°, 20.41°, 23.44°, 23.67°, 24.01°, 24.34° and 24.60°.
  • the X-ray powder diffraction pattern of the unsolvated crystal E of the compound represented by formula (I) has characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 7.19°, 8.93°, 9.59° , 12.72°, 13.64°, 14.46°, 18.15°, 19.19°, 19.96°, 20.41°, 23.44°, 23.67°, 24.01°, 24.34°, 24.60° and 28.60°.
  • the unsolvated crystal E of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 7.19°, 8.93°, 9.59°, 10.14° ⁇ 10.52° ⁇ 11.74° ⁇ 12.31° ⁇ 12.72° ⁇ 13.64° ⁇ 14.46° ⁇ 15.33° ⁇ 15.85° ⁇ 16.62° ⁇ 17.02° ⁇ 18.03° ⁇ 18.15° ⁇ 18.72° ⁇ 19.19° ⁇ 19.36° ⁇ 19.96° , 20.41°, 20.90°, 23.44°, 23.67°, 24.01°, 24.34°, 24.60°, 25.69°, 26.66°, 28.60°, 29.19°, 32.08°.
  • the X-ray powder diffraction pattern of the unsolvated crystal E of the compound represented by formula (I) is as shown in Figure 11.
  • the differential scanning calorimetry analysis curve of the unsolvated crystal E of the compound represented by formula (I) shows an endothermic peak near 194.2°C and an exothermic peak near 217.1°C.
  • the differential scanning calorimetry analysis curve of the unsolvated crystal E of the compound represented by formula (I) is as shown in Figure 13.
  • thermogravimetric analysis curve of the unsolvated crystal E of the compound represented by formula (I) shows that the crystal form has a weight loss of 0.0% during heating to 150°C, which may occur after continued heating to 190°C. break down.
  • thermogravimetric analysis curve of the unsolvated crystal E of the compound represented by formula (I) is shown in Figure 14.
  • the hydrate crystal of the compound represented by formula (I) is selected from the group consisting of its hydrate crystal AA, its hydrate crystal T, its hydrate crystal V and its hydrate crystal L.
  • the X-ray powder diffraction pattern of the hydrate crystal AA of the compound represented by formula (I) has characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 7.85°, 8.92°, 10.35° , 11.18°, 12.74°, 14.95°, 17.94°, 18.05°, 19.01°, 20.90°, 24.39° and 27.26°.
  • the X-ray powder diffraction pattern of the hydrate crystal AA of the compound represented by formula (I) has characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 7.85°, 8.62°, 8.92° , 10.35°, 11.18°, 12.74°, 14.95°, 16.71°, 17.94°, 18.05°, 19.01°, 19.99°, 20.90°, 21.57°, 24.39° and 27.26°.
  • the hydrate crystal AA of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 7.85°, 8.62°, 8.92°, 10.35 °, 10.80°, 11.18°, 12.74°, 14.95°, 15.64°, 16.14°, 16.71°, 17.18°, 17.63°, 17.94°, 18.05°, 18.73°, 19.01°, 19.53°, 19.99°, 20.63°, 20.90° ⁇ 21.57° ⁇ 22.25° ⁇ 22.54° ⁇ 22.81° ⁇ 23.18° ⁇ 23.79° ⁇ 24.39° ⁇ 24.90° ⁇ 25.16° ⁇ 25.86° ⁇ 26.08° ⁇ 27.26° ⁇ 27.50° ⁇ 27.93° ⁇ 28.16° ⁇ 28.32° , 29.73°, 31.97°, 34.26°.
  • the X-ray powder diffraction pattern of the hydrate crystal AA of the compound represented by formula (I) is as shown in Figure 3.
  • the hydrate crystal T of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 4.31°, 6.09°, 6.82° , 11.05°, 13.03°, 16.41°, 18.49°, 19.74°, 22.26°, 24.32° and 26.78°.
  • the hydrate crystal T of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 4.31°, 6.09°, 6.82° , 8.65, 11.05°, 13.03°, 13.56°, 16.41°, 17.94°, 18.49°, 19.74°, 22.26°, 24.32° and 26.78°.
  • the hydrate crystal T of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 4.31°, 6.09°, 6.53°, 6.82° , 8.65°, 11.05°, 12.27°, 13.03°, 13.56°, 13.74°, 15.46°, 15.64°, 16.41°, 17.52°, 17.94°, 18.49°, 19.60°, 19.74°, 21.86°, 22.26°, 23.01 °, 24.32°, 24.49°, 24.73°, 26.78°, 27.09°, 27.83°, 31.20°, 33.11°.
  • the hydrate crystal V of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 6.34°, 7.48°, 7.95°, 10.27 °, 12.97°, 17.90°, 20.71° and 23.98°.
  • the hydrate crystal V of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 6.34°, 7.48°, 7.95°, 9.72 °, 10.27°, 12.97°, 17.90°, 20.71° and 23.98°.
  • the hydrate crystal V of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 6.34°, 7.48°, 7.95°, 9.72 °, 10.27°, 12.97°, 14.34°, 15.72°, 16.94°, 17.90°, 18.19°, 19.39°, 20.28°, 20.71°, 21.09°, 22.50°, 23.04°, 23.98°.
  • the X-ray powder diffraction pattern of hydrate crystal V of the compound of formula (I) is shown in Figure 22.
  • the hydrate crystal L of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 6.69°, 8.02°, 9.93°, 14.23 °, 16.13°, 16.29°, 18.13°, 19.18° and 24.32°.
  • the hydrate crystal L of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 6.69°, 8.02°, 9.93°, 12.87 °, 14.23°, 16.13°, 16.29°, 18.13°, 19.18°, 21.07°, 23.38° and 24.32°.
  • the hydrate crystal L of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 6.69°, 7.07°, 8.02°, 9.93 °, 12.87°, 14.23°, 16.13°, 16.29°, 17.47°, 18.13°, 19.18°, 21.07°, 23.38°, 24.32° and 28.21°.
  • the hydrate crystal L of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 6.32°, 6.69°, 7.07°, 8.02 °, 9.93°, 12.87°, 14.23°, 15.16°, 15.57°, 16.13°, 16.29°, 16.50°, 16.87°, 17.47°, 18.13°, 19.18°, 19.43°, 20.02°, 21.07°, 21.55°, 21.93°, 22.26°, 23.38°, 23.96°, 24.32°, 24.99°, 25.43°, 25.75°, 26.98°, 27.86°, 28.21°, 29.51°, 29.94°, 31.27°, 33.20°.
  • the X-ray powder diffraction pattern of hydrate crystal L of the compound of formula (I) is shown in Figure 26.
  • solvated crystals of the compound represented by formula (I) are provided, and the solvent is selected from methanol, formic acid, ethanol,
  • the ratio of the compound represented by formula (I) to the solvent is 1:0.3-1.
  • the solvated crystals of the compound represented by formula (I) are methanol solvated crystals, and the ratio of the compound represented by formula (I) to methanol is 1:0.4-1.
  • the methanol solvated crystal of the compound represented by formula (I) is methanol solvated crystal A.
  • the methanol solvate crystal A of the compound represented by formula (I), the ratio of the compound represented by formula (I) to methanol is 1:1.
  • the methanol solvate crystal A of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 4.56°, 9.16°, 9.34 °, 12.91°, 13.78°, 14.66°, 15.25°, 18.52° and 23.12°.
  • the methanol solvate crystal A of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 4.56°, 9.16°, 9.34 °, 12.91°, 13.78°, 14.66°, 15.25°, 16.52°, 18.52°, 20.58°, 23.12°, 24.02° and 27.83°.
  • the methanol solvated crystal A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 4.56°, 9.16°, 9.34°, 11.36° ⁇ 12.91° ⁇ 13.78° ⁇ 14.66° ⁇ 15.25° ⁇ 16.52° ⁇ 17.82° ⁇ 18.52° ⁇ 19.48° ⁇ 19.62° ⁇ 20.58° ⁇ 22.47° ⁇ 22.93° ⁇ 23.12° ⁇ 24.02° ⁇ 24.90° ⁇ 27.09° , 27.83°, 32.61°, 37.44°.
  • the X-ray powder diffraction pattern of methanol solvate crystal A of the compound represented by formula (I) is as shown in Figure 1.
  • the methanol-solvated crystals of the compound represented by formula (I) are methanol-solvated crystals AE.
  • the methanol solvate crystal AE of the compound represented by formula (I), the ratio of the compound represented by formula (I) to methanol is 1:0.4.
  • the methanol solvate crystal AE of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 9.08°, 9.63°, 13.11° , 13.70°, 14.80°, 15.29°, 17.88°, 18.78°, 22.94° and 23.46°.
  • the methanol solvate crystal AE of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 9.08°, 9.63°, 13.11° , 13.70°, 14.80°, 15.29°, 16.68°, 17.88°, 18.78°, 20.16°, 22.94°, 23.46° and 25.32°.
  • the methanol-solvated crystal AE of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 4.51°, 9.08°, 9.63°, 11.60°, 13.11°, 13.70°, 14.80°, 15.29°, 15.99°, 16.68°, 17.88°, 18.78°, 20.16°, 22.94°, 23.46°, 25.32°.
  • the X-ray powder diffraction pattern of the methanol solvate crystal AE of the compound represented by formula (I) is shown in Figure 5.
  • the solvated crystals of the compound represented by formula (I) are formic acid solvated crystals, wherein the ratio of the compound represented by formula (I) to formic acid is 1:1.
  • the formic acid solvated crystal of the compound represented by formula (I) is selected from the group consisting of formic acid solvated crystal F, formic acid solvated crystal O, and formic acid solvated crystal AF.
  • the formic acid solvated crystal F of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 4.96°, 5.30°, 7.25 °, 8.44°, 12.14°, 15.04°, 15.83°, 19.47° and 20.11°.
  • the formic acid solvated crystal F of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 4.96°, 5.30°, 7.25 °, 8.44°, 9.93°, 12.14°, 12.91°, 14.62°, 15.04°, 15.83°, 19.47° and 20.11°.
  • the formic acid solvated crystal F of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): about 4.96°, 5.30°, 7.25°, 8.44°, 9.93°, 10.71°, 12.14°, 12.91°, 14.62°, 15.04°, 15.83°, 17.08°, 18.52°, 19.47°, 20.11°, 22.07°, 23.14°, 24.48°, 25.64° .
  • the formic acid solvated crystal F of the compound represented by formula (I) has an X-ray powder diffraction pattern as shown in Figure 16.
  • the formic acid solvated crystal O has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 5.30°, 10.68°, 11.72°, 15.25°, 16.09 °, 17.99°, 20.50°, 22.30°, 25.78° and 26.57°.
  • the formic acid solvated crystal O of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 5.30°, 10.54°, 10.68 °, 11.72°, 13.73°, 15.25°, 16.09°, 16.96°, 17.99°, 20.50°, 21.00°, 22.30°, 25.78°, 26.57° and 28.89°.
  • the formic acid solvated crystal O of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 5.30°, 10.54°, 10.68 °, 10.93°, 11.72°, 11.93°, 12.39°, 13.31°, 13.73°, 14.04°, 15.25°, 16.09°, 16.96°, 17.99°, 18.26°, 19.37°, 19.57°, 20.08°, 20.35°, 20.50°, 21.00°, 21.51°, 22.04°, 22.30°, 23.02°, 24.84°, 24.99°, 25.26°, 25.78°, 26.57°, 26.99°, 28.89°, 30.68°, 33.16°.
  • the formic acid solvated crystal O of the compound represented by formula (I) has an X-ray powder diffraction pattern as shown in Figure 18.
  • the formic acid solvated crystal AF of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 6.19°, 7.48°, 8.32 °, 12.49°, 13.46° and 14.76 °.
  • the formic acid solvated crystal AF of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 6.19°, 7.48°, 8.32 °, 12.49°, 12.97°, 13.46°, 14.76°, 17.56°, 23.59° and 25.35°.
  • the formic acid solvated crystal AF of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 5.93°, 6.19°, 7.48 °, 8.32°, 11.30°, 11.65°, 12.49°, 12.97°, 13.46°, 14.76°, 17.56°, 17.81°, 18.48°, 19.37°, 20.48°, 21.57°, 22.75°, 23.59°, 24.93°, 25.35°.
  • the formic acid solvated crystal AF of the compound represented by formula (I) has an X-ray powder diffraction pattern as shown in Figure 24.
  • the ethanol solvated crystal of the compound represented by formula (I) is ethanol solvated crystal R, and the ratio of the compound represented by formula (I) to ethanol is 1:0.3.
  • the ethanol solvate crystal R of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 8.37°, 12.51°, 16.14 °, 17.56°, 17.69°, 18.36°, 18.68°, 19.45°, 21.71°, 23.01° and 24.14°.
  • the ethanol solvate crystal R of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 8.37°, 12.51°, 15.04 °, 16.14°, 16.59°, 17.56°, 17.69°, 18.36°, 18.68°, 19.45°, 21.71°, 23.01°, 24.14°, 24.98° and 26.58°.
  • the ethanol solvate crystal R of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 8.37°, 12.51°, 13.20 °, 13.48°, 14.37°, 15.04°, 15.71°, 16.14°, 16.59°, 16.96°, 17.56°, 17.69°, 18.36°, 18.68°, 19.45°, 19.99°, 20.44°, 21.08°, 21.71°, 22.29°, 23.01°, 23.52°, 23.71°, 24.14°, 24.98°, 25.48°, 26.23°, 26.58°, 27.59°, 28.74°, 29.25°, 30.32°.
  • the X-ray powder diffraction pattern of the ethanol solvate crystal R of the compound represented by formula (I) is as shown in Figure 28.
  • the eutectic crystal of the compound represented by formula (I) is selected from: oxalic acid eutectic crystal of the compound of formula (I), fumaric acid eutectic crystal of the compound of formula (I), compound of formula (I) citric acid eutectic crystals, malic acid eutectic crystals of the compound of formula (I), and glycolic acid eutectic crystals of the compound of formula (I).
  • the oxalic acid co-crystal crystal of the compound of formula (I) is selected from: the oxalic acid co-crystal crystal Type A of the compound of formula (I), the oxalic acid co-crystal crystal Type B of the compound of formula (I), wherein, the formula ( I) The ratio of compound to oxalic acid is 1:1.
  • the oxalic acid eutectic crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 6.07°, 11.01°, 12.23° , 12.80°, 14.28°, 16.93° and 21.76°.
  • the oxalic acid eutectic crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 6.07°, 7.07°, 9.41° , 11.01°, 11.46°, 12.23°, 12.80°, 14.28°, 14.63°, 16.93°, 18.49°, 18.95° and 21.76°.
  • the oxalic acid eutectic crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 3.58°, 6.07°, 7.07° , 9.41°, 11.01°, 11.46°, 12.23°, 12.80°, 14.28°, 14.63°, 15.55°, 16.93°, 17.97°, 18.49°, 18.95°, 21.76°, 24.91°, 25.72°.
  • the X-ray powder diffraction pattern of the oxalic acid eutectic crystal Type A of the compound of formula (I) is shown in Figure 30.
  • the oxalic acid eutectic crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 6.01°, 8.19°, 11.55° , 12.34°, 13.79°, 17.36°, 18.14°, 20.56°, 23.27°, 23.94° and 25.24°.
  • the oxalic acid eutectic crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 3.60°, 6.01°, 8.19° , 11.55°, 12.34°, 13.79°, 14.52°, 17.36°, 18.14°, 18.98°, 20.56°, 22.30°, 23.27°, 23.94° and 25.24°.
  • the oxalic acid eutectic crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 3.60°, 6.01°, 8.19° , 9.41°, 11.55°, 12.05°, 12.34°, 12.77°, 13.79°, 14.25°, 14.52°, 15.64°, 16.43°, 17.36°, 18.14°, 18.98°, 19.69°, 20.56°, 21.40°, 21.93 °, 22.30°, 23.27°, 23.94°, 25.24°, 25.77°, 27.76°.
  • the X-ray powder diffraction pattern of the oxalic acid eutectic crystal Type B of the compound of formula (I) is shown in Figure 32.
  • the fumaric acid eutectic crystal of the compound of formula (I) is selected from: fumaric acid eutectic crystal Type B, fumaric acid eutectic crystal Type C, the compound of formula (I) and fumaric acid.
  • the ratio is 1:1.
  • the fumaric acid eutectic crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 5.18°, 6.43°, 10.93°, 11.46°, 12.39°, 15.96°, 16.22°, 19.28° and 22.09°.
  • the fumaric acid eutectic crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 3.81°, 5.18°, 6.43°, 8.15°, 9.34°, 10.93°, 11.46°, 12.39°, 15.96°, 16.22°, 19.28° and 22.09°.
  • the fumaric acid eutectic crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 3.81°, 5.18°, 6.43°, 7.62°, 8.15°, 9.07°, 9.34°, 10.93°, 11.46°, 12.39°, 15.96°, 16.22°, 19.28°, 22.09°.
  • the fumaric acid cocrystal crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern as shown in Figure 40.
  • the fumaric acid eutectic crystal Type C has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 7.14°, 7.49°, 10.87°, 12.17° , 17.38°, 19.81°, 20.63°, 21.58°, 23.27°, 24.38° and 25.39°.
  • the fumaric acid eutectic crystal Type C has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 7.14°, 7.49°, 8.23°, 10.87° , 12.17°, 16.43°, 17.38°, 17.69°, 19.81°, 20.63°, 21.11°, 21.58°, 23.27°, 24.38°, 25.39°, 28.27°, 29.37° and 31.28°.
  • the fumaric acid eutectic crystal Type C has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 7.14°, 7.49°, 8.23°, 10.87° , 12.17°, 13.24°, 13.96°, 16.43°, 17.38°, 17.69°, 18.74°, 19.81°, 19.97°, 20.63°, 21.11°, 21.58°, 23.27°, 23.54°, 24.38°, 25.39°, 26.48 °, 28.27°, 29.37°, 30.89°, 31.28°, 32.60°.
  • the X-ray powder diffraction pattern of the fumaric acid eutectic crystal Type C is shown in Figure 42.
  • the citric acid co-crystal crystal of the compound of formula (I) is the citric acid co-crystal crystal of the compound of formula (I) Type A, and the ratio of the compound of formula (I) to citric acid is 1:1.
  • the citric acid eutectic crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 5.56°, 6.52°, 9.85 °, 14.27°, 14.62°, 16.60°, 17.73°, 19.71°, 19.86°, 24.36° and 26.42°.
  • the citric acid eutectic crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 5.56°, 6.52°, 9.85 °, 13.20°, 13.46°, 14.27°, 14.62°, 15.78°, 16.60°, 17.73°, 19.71°, 19.86°, 24.36°, 25.16° and 26.42°.
  • the citric acid eutectic crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 5.56°, 6.52°, 7.10 °, 9.85°, 13.20°, 13.46°, 14.27°, 14.62°, 15.41°, 15.78°, 16.29°, 16.60°, 17.73°, 19.31°, 19.71°, 19.86°, 23.15°, 24.36°, 25.16° and 26.42°.
  • the citric acid eutectic crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 5.56°, 6.52°, 7.10 °, 9.85°, 11.00°, 12.76°, 13.20°, 13.46°, 14.27°, 14.62°, 15.41°, 15.78°, 16.29°, 16.60°, 17.73°, 19.31°, 19.71°, 19.86°, 23.15°, 23.51°, 24.36°, 25.16°, 25.56°, 25.70°, 26.42°, 27.08°, 27.53°, 27.74°, 28.08°, 32.03°.
  • the X-ray powder diffraction pattern of the citric acid eutectic crystal Type A of the compound of formula (I) is shown in Figure 58.
  • the malic acid eutectic crystal of the compound of formula (I) is the malic acid eutectic crystal of the compound of formula (I) Type A, and the ratio of the compound of formula (I) to malic acid is 1:1.
  • the malic acid eutectic crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 7.14°, 8.77°, 8.99 °, 9.90°, 11.59°, 11.84°, 17.27°, 19.91°, 20.22°, 21.09°, 23.74° and 25.22°.
  • the malic acid eutectic crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 7.14°, 8.77°, 8.99 °, 9.90°, 11.59°, 11.84°, 17.27°, 18.02°, 19.21°, 19.91°, 20.22°, 21.09°, 22.98°, 23.74°, 24.42° and 25.22°.
  • the malic acid eutectic crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 7.14°, 8.77°, 8.99 °, 9.90°, 11.59°, 11.84°, 13.90°, 14.72°, 15.83°, 17.27°, 18.02°, 19.21°, 19.91°, 20.22°, 21.09°, 22.98°, 23.74°, 24.42° and 25.22°.
  • the malic acid eutectic crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 7.14°, 8.77°, 8.99 °, 9.90°, 11.59°, 11.84°, 13.90°, 14.72°, 15.83°, 17.27°, 18.02°, 18.49°, 19.21°, 19.91°, 20.22°, 20.49°, 21.09°, 22.32°, 22.98°, 23.74°, 24.42°, 25.22°, 25.58°, 26.30°, 27.04°, 27.86°, 28.46°, 29.20°, 29.84°, 31.18°, 31.42°, 34.27°, 34.82°.
  • the X-ray powder diffraction pattern of the malic acid eutectic crystal Type A of the compound of formula (I) is shown in Figure 60.
  • the glycolic acid eutectic crystal of the compound of formula (I) is selected from: the glycolic acid eutectic crystal of the compound of formula (I) Type A, the glycolic acid eutectic crystal of the compound of formula (I) Type B, wherein , the ratio of the compound of formula (I) to glycolic acid is 1:1.
  • the glycolic acid eutectic crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 5.61°, 6.83°, 8.27 °, 11.25°, 13.73°, 14.63°, 16.94°, 19.79° and 23.23°.
  • the glycolic acid eutectic crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 5.61°, 6.83°, 8.27 °, 11.25°, 11.50°, 13.73°, 14.63°, 16.63°, 16.94°, 19.79°, 20.37°, 21.33°, 23.23° and 24.68.
  • the glycolic acid eutectic crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 5.61°, 6.83°, 7.77 °, 8.27°, 9.32°, 9.64°, 11.25°, 11.50°, 12.02°, 13.73°, 14.63°, 15.33°, 16.63°, 16.94°, 17.80°, 19.79°, 20.37°, 21.33°, 21.58°, 22.10°, 22.64°, 23.23°, 24.21°, 24.68°, 25.33°, 26.16°, 27.99°, 32.77°.
  • the X-ray powder diffraction pattern of the glycolic acid eutectic crystal Type A of the compound of formula (I) is shown in Figure 66.
  • the glycolic acid eutectic crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 5.44°, 6.70°, 8.29 °, 10.96°, 13.50°, 14.25°, 16.48°, 20.83° and 25.06°.
  • the glycolic acid eutectic crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 5.44°, 6.70°, 8.29 °, 10.96°, 11.36, 13.50°, 14.25°, 16.48°, 19.66°, 19.92°, 20.48°, 20.83° and 25.06°.
  • the glycolic acid eutectic crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 5.44°, 6.70°, 8.29 °, 10.96°, 11.36°, 12.07°, 13.50°, 14.25°, 16.48°, 19.66°, 19.92°, 20.48°, 20.83°, 22.87, 23.43, 25.06°.
  • the X-ray powder diffraction pattern of the glycolic acid eutectic crystal Type B of the compound of formula (I) is shown in Figure 68.
  • the salt form of the compound represented by formula (I) is selected from: its tosylate, its methanesulfonate, its potassium salt, its maleate, its sodium salt and its hydrochloride .
  • the potassium salt of the compound represented by formula (I) has the structure
  • the maleate salt of the compound represented by formula (I), wherein the ratio of the compound represented by formula (I) to maleic acid is 1:1.
  • the sodium salt of the compound represented by formula (I) has the structure
  • salt form crystals of the compound represented by formula (I) are provided.
  • the salt form crystal of the compound represented by formula (I) is selected from:
  • hydrochloride crystal wherein the ratio of the compound represented by formula (I) to hydrochloric acid is 1:1.
  • the p-toluenesulfonate crystals of the compound of formula (I) are selected from the group consisting of p-toluenesulfonate crystals Type A, p-toluenesulfonate crystals Type B, and p-toluenesulfonate crystals Type C , wherein the ratio of the compound represented by formula (I) to p-toluenesulfonic acid is 1:1.
  • the p-toluenesulfonate crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 7.41°, 9.57°, 9.92°, 16.06°, 16.94°, 19.70 °, 20.44°, 22.07° and 26.24°.
  • the p-toluenesulfonate crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 7.41°, 9.14°, 9.57°, 9.92°, 11.25°, 12.95°, 14.45°, 16.06°, 16.94°, 19.70°, 20.44°, 21.30°, 22.07°, 24.82°, 25.52° and 26.24°.
  • the p-toluenesulfonate crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern as shown in Figure 34.
  • the p-toluenesulfonate crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 6.35°, 6.93°, 7.63°, 14.59°, 16.79° and 20.79°.
  • the p-toluenesulfonate crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 6.35°, 6.93°, 7.63°, 11.29°, 14.59°, 16.79°, 17.72°, 20.79°, 22.25° and 26.56°.
  • the p-toluenesulfonate crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 6.35°, 6.93°, 7.63°, 8.29°, 11.29°, 12.72°, 14.59°, 16.79°, 17.72°, 19.33°, 20.79°, 22.25°, 23.05°, 25.19°, 26.56°, 27.84°.
  • the p-toluenesulfonate crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern as shown in Figure 36.
  • the p-toluenesulfonate crystal Type C of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 5.19°, 6.87°, 10.06°, 13.79°, 16.62°, 16.93°, 20.44°, 24.53° and 26.12°.
  • the p-toluenesulfonate crystal Type C of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 5.19°, 6.87°, 10.06°, 13.79°, 14.79°, 16.62°, 16.93°, 17.23°, 20.44°, 21.03°, 24.53°, 24.93° and 26.12°.
  • the p-toluenesulfonate crystal Type C of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 5.19°, 6.87°, 10.06° ⁇ 12.06° ⁇ 12.72° ⁇ 12.95° ⁇ 13.58° ⁇ 13.79° ⁇ 14.17° ⁇ 14.46° ⁇ 14.79° ⁇ 16.62° ⁇ 16.93° ⁇ 17.23° ⁇ 18.76° ⁇ 19.36° ⁇ 20.44° ⁇ 21.03° ⁇ 21.55° , 21.83°, 22.10°, 23.31°, 23.51°, 23.73°, 24.13°, 24.53°, 24.93°, 25.60°, 26.12°, 27.26°, 27.76°, 29.50°, 29.84°, 30.52°.
  • the p-toluenesulfonate crystal Type C of the compound of formula (I) has an X-ray powder diffraction pattern as shown in Figure 38.
  • the mesylate crystal of the compound of formula (I) is selected from its mesylate crystal Type A, its mesylate crystal Type B, its mesylate crystal Type C, wherein, the formula The ratio of the compound shown in (I) to methanesulfonic acid is 1:1 to 1.2.
  • the mesylate crystal of the compound of formula (I) is its mesylate crystal Type A, and the ratio of the compound of formula (I) to methanesulfonic acid is 1:1.
  • the mesylate crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 8.09°, 9.60°, 11.06 °, 12.57°, 14.33°, 14.55°, 16.93°, 19.32°, 19.64°, 20.19°, 20.31°, 21.05° and 26.42°.
  • the mesylate crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 8.09°, 9.60°, 10.75 °, 11.06°, 12.57°, 14.33°, 14.55°, 16.52°, 16.93°, 19.32°, 19.64°, 20.19°, 20.31°, 21.05°, 21.59°, 22.98°, 24.72°, 26.42°, 27.00° and 28.30°.
  • the mesylate crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 8.09°, 8.69°, 9.60 °, 10.75°, 11.06°, 12.02°, 12.57°, 13.85°, 14.33°, 14.55°, 15.33°, 15.89°, 16.52°, 16.93°, 17.39°, 17.67°, 17.93°, 19.32°, 19.64°, 19.96° ⁇ 20.19° ⁇ 20.31° ⁇ 20.65° ⁇ 21.05° ⁇ 21.59° ⁇ 21.78° ⁇ 22.25° ⁇ 22.51° ⁇ 22.70° ⁇ 22.98° ⁇ 24.52° ⁇ 24.72° ⁇ 25.26° ⁇ 25.89° ⁇ 26.42° ⁇ 27.00° , 27.41°, 28.30°, 28.55°, 29.47°, 31.47°, 33.70°.
  • the mesylate crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern as shown in Figure 44.
  • the mesylate crystal of the compound of formula (I) is its mesylate crystal Type B, and the ratio of the compound of formula (I) to p-methanesulfonic acid is 1:1.2.
  • the mesylate crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 5.74°, 5.89°, 11.53 °, 11.93°, 12.47°, 12.90°, 14.06°, 15.01°, 17.14° and 25.52°.
  • the mesylate crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 5.74°, 5.89°, 7.66 °, 11.53°, 11.93°, 12.47°, 12.90°, 14.06°, 15.01°, 17.14°, 22.60° and 25.52°.
  • the mesylate crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 5.74°, 5.89°, 7.66 °, 7.95°, 8.95°, 10.21°, 11.53°, 11.93°, 12.47°, 12.90°, 14.06°, 15.01°, 17.14°, 17.99°, 20.49°, 22.60°, 23.90°, 25.52°, 26.39°.
  • the mesylate crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern as shown in Figure 46.
  • the mesylate crystal of the compound of formula (I) is its methanesulfonate crystal Type C, and the ratio of the compound of formula (I) to p-methanesulfonic acid is 1:1.
  • the mesylate crystal Type C of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 5.32°, 8.45°, 11.84 °, 17.01°, 18.49°, 21.30° and 22.98°.
  • the mesylate crystal Type C of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 5.32°, 8.45°, 10.30 °, 11.84°, 16.06°, 17.01°, 18.49°, 21.30°, 22.98° and 24.30°.
  • the mesylate crystal Type C of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 5.32°, 8.45°, 10.30 °, 11.84°, 14.48°, 14.78°, 15.28°, 16.06°, 17.01°, 18.49°, 20.46°, 20.91°, 21.30°, 22.98°, 23.51°, 24.30°, 24.85°, 25.44°, 25.83°, 28.47°, 30.85°.
  • the mesylate crystal Type C of the compound of formula (I) has an X-ray powder diffraction pattern as shown in Figure 48.
  • the potassium salt crystal of the compound of formula (I) is its potassium salt crystal Type A.
  • the potassium salt crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 5.74°, 6.68°, 7.96°, 11.78°, 13.54°, 14.04°, 15.33°, 17.78°, 19.45°, 20.14°, 23.29°, 24.72°, 26.92° and 28.29°.
  • the potassium salt crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 5.74°, 6.68°, 7.96°, 11.52° ⁇ 11.78° ⁇ 13.54° ⁇ 14.04° ⁇ 14.44° ⁇ 15.33° ⁇ 16.22° ⁇ 16.71° ⁇ 17.43° ⁇ 17.78° ⁇ 18.20° ⁇ 18.40° ⁇ 18.86° ⁇ 19.45° ⁇ 20.14° ⁇ 20.70° ⁇ 22.75° , 23.29°, 24.15°, 24.72°, 26.39°, 26.92°, 27.37°, 27.62°, 28.29°, 31.39°, 36.10°.
  • the maleate crystal of the compound of formula (I) is selected from: its maleate crystal Type A, its maleate crystal Type B, wherein the compound of formula (I) and maleic acid The ratio is 1:1.
  • the maleate crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 4.26°, 4.76°, 7.08 °, 7.96°, 8.54°, 9.53°, 10.18 °, 10.93°, 14.34°, 15.03°, 15.99° and 20.50°.
  • the maleate crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 4.26°, 4.76°, 7.08 °, 7.96°, 8.54°, 9.53°, 10.18°, 10.93°, 13.89°, 14.34°, 15.03°, 15.99°, 20.50°, 21.49° and 24.03°.
  • the maleate crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 4.26°, 4.76°, 7.08 °, 7.96°, 8.54°, 9.53°, 10.18°, 10.93°, 12.41°, 13.89°, 14.34°, 15.03°, 15.99°, 17.93°, 20.50°, 21.49°, 23.55° and 24.03°.
  • the maleate crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 4.26°, 4.76°, 7.08 °, 7.96°, 8.54°, 9.53°, 10.18°, 10.93°, 12.41°, 13.89°, 14.34°, 15.03°, 15.99°, 17.93°, 20.50°, 21.49°, 21.97°, 23.55°, 24.03°, 25.19°, 25.57°, 26.00°.
  • the maleate salt crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern as shown in Figure 52.
  • the maleate crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 4.34°, 4.79°, 5.27 °, 7.20°, 7.86°, 10.22°, 10.56°, 11.08°, 14.73°, 15.20°, 16.14° and 20.50°.
  • the maleate crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 4.34°, 4.79°, 5.27 °, 7.20°, 7.86°, 10.22°, 10.56°, 11.08°, 11.81°, 14.44°, 14.73°, 15.20°, 16.14° and 20.50°.
  • the maleate crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 4.34°, 4.79°, 5.27 °, 7.20°, 7.86°, 8.63°, 9.60°, 10.22°, 10.56°, 11.08°, 11.81°, 13.94°, 14.44°, 14.73°, 15.20°, 16.14°, 20.50°, 21.25°, 21.83°, 26.32°.
  • the X-ray powder diffraction pattern of the maleate salt crystal Type B of the compound of formula (I) is shown in Figure 54.
  • the sodium salt crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 6.01°, 6.61°, 7.94°, 11.88°, 12.48°, 13.10°, 13.70°, 18.31°, 19.98°, 21.19°, 22.35°, 25.36° and 26.27°.
  • the sodium salt crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 6.01°, 6.61°, 7.94°, 11.88°, 12.48°, 13.10°, 13.31°, 13.70°, 16.52°, 17.48°, 18.31°, 19.98°, 21.19°, 22.35°, 24.81°, 25.36° and 26.27°.
  • the sodium salt crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern as follows There are characteristic diffraction peaks at the 2 ⁇ angle ( ⁇ 0.2°): 6.01°, 6.61°, 7.94°, 11.88°, 12.48°, 13.10°, 13.31°, 13.70°, 14.96°, 15.25°, 16.52°, 17.48°, 18.31°, 19.07°, 19.98°, 20.59°, 21.19°, 22.35°, 23.86°, 24.81°, 25.36°, 26.27°, 27.78°, 28.28°, 31.15°, 31.79°.
  • the X-ray powder diffraction pattern of the sodium salt crystal Type B of the compound of formula (I) is as shown in Figure 56.
  • the hydrochloride crystal of the compound of formula (I) is selected from its hydrochloride crystal Type A, its hydrochloride crystal Type B, wherein the ratio of the compound of formula (I) to hydrochloric acid is 1:1 .
  • the hydrochloride crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 5.90°, 7.42°, 7.74° , 10.96°, 14.07°, 14.96°, 18.01°, 25.14° and 26.42°.
  • the hydrochloride crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 5.90°, 7.42°, 7.74° , 10.96°, 11.56°, 12.15°, 13.39°, 14.07°, 14.96°, 17.60°, 18.01°, 19.26°, 19.70°, 21.55°, 21.93°, 23.42°, 25.14°, 25.56°, 26.42°, 27.71 °, 28.84°, 29.26°.
  • the hydrochloride crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 5.42°, 6.48°, 7.20° , 7.90°, 12.85°, 13.01°, 14.16°, 14.48°, 15.68°, 17.31°, 19.36°, 21.76°, 22.91° and 26.53°.
  • the hydrochloride crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 4.80°, 5.42°, 6.48° , 7.20°, 7.90°, 10.00°, 13.50°, 10.39°, 12.85°, 13.01°, 14.16°, 14.48°, 15.68°, 17.31°, 19.36°, 19.64°, 21.76°, 22.91°, 23.86°, 24.40 °, 25.72°, 25.95°, 26.14°, 26.53°, 28.53°, 31.86°,.
  • the X-ray powder diffraction pattern of the hydrochloride crystal Type B of the compound of formula (I) is as shown in Figure 64.
  • ratios of solvate crystals, eutectic crystals or salt-type crystals mentioned in the present invention are molar ratios unless otherwise specified.
  • crystal and “crystal form” have the same meaning and can be interchanged.
  • the present invention provides a variety of new crystal forms, salt forms and eutectic crystal forms of the compound represented by formula (I) to meet different clinical needs.
  • Figure 1 is the XPRD spectrum of compound methanol solvated crystal A represented by formula (I).
  • Figure 2 is a proton nuclear magnetic resonance spectrum of compound methanol solvated crystal A represented by formula (I).
  • Figure 4 is a proton nuclear magnetic resonance spectrum of the hydrate crystal AA of the compound represented by formula (I).
  • Figure 5 is the XPRD spectrum of the methanol solvated crystal AE of the compound represented by formula (I).
  • Figure 6 is a proton nuclear magnetic resonance spectrum of the methanol solvated crystal AE of the compound represented by formula (I).
  • Figure 8 is a proton nuclear magnetic resonance spectrum of the unsolvated crystal AH of the compound represented by formula (I).
  • Figure 9 is a differential scanning calorimetry analysis curve chart of the unsolvate crystal AH of the compound represented by formula (I).
  • Figure 10 is a thermogravimetric analysis curve chart of the unsolvated crystal AH of the compound represented by formula (I).
  • Figure 11 is the XPRD spectrum of the unsolvate crystal E (form E) of the compound represented by formula (I).
  • Figure 12 is a proton nuclear magnetic resonance spectrum of the unsolvate crystal E (form E) of the compound represented by formula (I).
  • Figure 13 is a differential scanning calorimetry analysis curve chart of the unsolvated crystal E (form E) of the compound represented by formula (I).
  • Figure 14 is a thermogravimetric analysis curve chart of the unsolvate crystal E (form E) of the compound represented by formula (I).
  • Figure 15 is the X-ray single crystal diffraction pattern of the nonsolvate crystal E (E crystal form) of the compound represented by formula (I).
  • Figure 16 is the XPRD spectrum of formic acid solvated crystal F of the compound represented by formula (I).
  • Figure 17 is a proton nuclear magnetic resonance spectrum of the formic acid solvated crystal F of the compound represented by formula (I).
  • Figure 18 is the XPRD spectrum of formic acid solvate crystal O of the compound represented by formula (I).
  • Figure 19 is a proton nuclear magnetic resonance spectrum of the formic acid solvate crystal O of the compound represented by formula (I).
  • Figure 20 is the XPRD spectrum of hydrate crystal T of the compound represented by formula (I).
  • Figure 22 is the XPRD spectrum of hydrate crystal V of the compound represented by formula (I).
  • Figure 23 is a proton nuclear magnetic resonance spectrum of hydrate crystal V of the compound represented by formula (I).
  • Figure 24 is the XPRD spectrum of formic acid solvate crystal AF of the compound represented by formula (I).
  • Figure 25 is a proton nuclear magnetic resonance spectrum of the formic acid solvate crystal AF of the compound represented by formula (I).
  • Figure 26 is an XPRD spectrum of hydrate crystal L of the compound represented by formula (I).
  • Figure 27 is a proton nuclear magnetic resonance spectrum of hydrate crystal L of the compound represented by formula (I).
  • Figure 28 is the XPRD spectrum of the ethanol solvate crystal R of the compound represented by formula (I).
  • Figure 29 is a proton nuclear magnetic resonance spectrum of the ethanol solvate crystal R of the compound represented by formula (I).
  • Figure 30 is the XPRD spectrum of the oxalic acid eutectic crystal Type A of the compound represented by formula (I).
  • Figure 31 is the proton nuclear magnetic resonance spectrum of the oxalic acid eutectic crystal Type A of the compound represented by formula (I).
  • Figure 32 is the XPRD spectrum of the oxalic acid eutectic crystal Type B of the compound represented by formula (I).
  • Figure 33 is the proton nuclear magnetic resonance spectrum of the oxalic acid eutectic crystal Type B of the compound represented by formula (I).
  • Figure 34 is the XPRD spectrum of the p-toluenesulfonate crystal Type A of the compound represented by formula (I).
  • Figure 35 is the proton nuclear magnetic resonance spectrum of the compound p-toluenesulfonate crystal Type A represented by formula (I).
  • Figure 36 is the XPRD spectrum of the p-toluenesulfonate crystal Type B of the compound represented by formula (I).
  • Figure 37 is a proton nuclear magnetic resonance spectrum of the compound p-toluenesulfonate crystal Type B represented by formula (I).
  • Figure 38 is the XPRD spectrum of the compound p-toluenesulfonate crystal Type C represented by formula (I).
  • Figure 40 is the XPRD spectrum of fumaric acid eutectic crystal Type B of the compound represented by formula (I).
  • Figure 41 is the proton nuclear magnetic resonance spectrum of the fumaric acid eutectic crystal Type B of the compound represented by formula (I).
  • Figure 42 is the XPRD spectrum of the fumaric acid eutectic crystal Type C of the compound represented by formula (I).
  • Figure 43 is the proton nuclear magnetic resonance spectrum of the fumaric acid eutectic crystal Type C of the compound represented by formula (I).
  • Figure 44 is the XPRD spectrum of the mesylate crystal Type A of the compound represented by formula (I).
  • Figure 45 is the proton nuclear magnetic resonance spectrum of the mesylate crystal Type A of the compound represented by formula (I).
  • Figure 46 is the XPRD spectrum of the mesylate crystal Type B of the compound represented by formula (I).
  • Figure 47 is the proton nuclear magnetic resonance spectrum of the mesylate crystal Type B of the compound represented by formula (I).
  • Figure 49 is the proton nuclear magnetic resonance spectrum of the mesylate crystal Type C of the compound represented by formula (I).
  • Figure 50 is the XPRD spectrum of the potassium salt crystal Type A of the compound represented by formula (I).
  • Figure 51 is the proton nuclear magnetic resonance spectrum of the potassium salt crystal Type A of the compound represented by formula (I).
  • Figure 52 is the XPRD spectrum of the maleate crystal Type A of the compound represented by formula (I).
  • Figure 53 is the proton nuclear magnetic resonance spectrum of the maleate crystal Type A of the compound represented by formula (I).
  • Figure 54 is the XPRD spectrum of maleate crystal Type B of the compound represented by formula (I).
  • Figure 56 is the XPRD spectrum of sodium salt crystal Type B of the compound represented by formula (I).
  • Figure 59 is a proton nuclear magnetic resonance spectrum of the citrate cocrystal Type A of the compound represented by formula (I).
  • Figure 63 is a proton nuclear magnetic resonance spectrum of the hydrochloride Type A of the compound represented by formula (I).
  • Figure 66 is the XPRD spectrum of the glycolic acid eutectic crystal Type A of the compound represented by formula (I).
  • Figure 67 is the proton nuclear magnetic resonance spectrum of the glycolic acid eutectic crystal Type A of the compound represented by formula (I).
  • Figure 68 is the XPRD spectrum of the glycolic acid eutectic crystal Type B of the compound represented by formula (I).
  • Figure 70 is the XRPD pattern of the solid obtained in Example 34.
  • Figure 73 shows the mass changes of the sample under different humidity conditions in the DVS experiment of the unsolvated crystalline form AH of the compound of formula (I) in Example 36.
  • Figure 74 is the XRPD pattern of the sample after DVS experiment of the unsolvated crystalline form AH of the compound of formula (I) in Example 36.
  • Figure 76 is the XRPD pattern of the sample of the maleate salt form Type A of the compound of formula (I) in Example 37 after the DVS experiment.
  • Figure 78 is the XRPD pattern of the sample after the DVS experiment of the citric acid eutectic crystal form Type A of the compound of formula (I) in Example 38.
  • Figure 79 shows the mass changes of the sample under different humidity conditions in the DVS experiment of the malic acid eutectic crystal form Type A of the compound of formula (I) in Example 39.
  • Figure 80 is the XRPD pattern of the sample after the DVS experiment of the malic acid eutectic crystal form Type A of the compound of formula (I) in Example 39.
  • Figure 81 is the XRPD pattern of the sample after the stability test under different conditions of the unsolvated crystalline form E of the compound of formula (I) in Example 40.
  • the percentages mentioned in the present invention are all weight percentages.
  • the ratios of solvate crystals, eutectic crystals or salt-type crystals mentioned in the present invention are molar ratios unless otherwise specified.
  • X-ray powder diffraction test conditions Instrument: Panalytical EMPYREAN (PANalytical, Netherlands); Radiation source: Cu-K ⁇ (40kV, 40mA).
  • X-ray single crystal diffraction test conditions Instrument: SXtaLAB Synergy R (Rigaku, Japan); Radiation source: Cu target light source, Test temperature: 150.0K; Data processing: Use CrysAlisPro software package for analysis and processing.
  • Thermogravimetric analysis test conditions Instrument: TA Discovery 55 (TA, USA); heating rate: 10°C/min; nitrogen flow rate: nitrogen purge rate at the sample is 60mL/min, and nitrogen purge rate at the balance is 40mL/min.
  • Dynamic moisture adsorption and desorption analysis test conditions Instrument: DVS Intrinsic (SMS, UK); Humidity change gradient: The test adopts gradient mode, the humidity change is 50%-95%-0%-50%, in the range of 0% to 90% The humidity change amount of each gradient is 10%. The end point of the gradient is judged by the dm/dt method. The end point of the gradient is when dm/dt is less than 0.002% and maintained for 10 minutes. After the test is completed, XRPD analysis is performed on the sample to confirm whether the solid form has changed.
  • the weight gain by attracting moisture is not less than 15.0%;
  • the moisture-attracting weight gain is less than 15.0% but not less than 2.0%;
  • weight gain due to moisture attraction is less than 2.0% but not less than 0.2%;
  • weight gain due to moisture absorption is less than 0.2%.
  • the structure of a compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR was measured using a Bruker ASCENA-400 nuclear magnetic instrument. The measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD). The internal standard was tetrahydrofuran. For methylsilane (TMS), chemical shifts are given in units of 10 -6 (ppm).
  • Reaction monitoring and MS measurement used a Thermofisher ESQ (ESI) mass spectrometer.
  • ESI Thermofisher ESQ
  • HPLC was measured using a Thermo Fisher U3000DAD high-pressure liquid chromatograph (GL Sciences ODS-HL HP 3 ⁇ m 3.0*100mm column).
  • the thin layer chromatography silica gel plate uses Qingdao Ocean GF254 silica gel plate.
  • the silica gel plate used in thin layer chromatography (TLC) has a specification of 0.15 ⁇ 0.2mm.
  • the specification of the thin layer chromatography separation and purification product is 0.9 ⁇ 1.0mm.
  • Column chromatography uses Qingdao Ocean 200-300 mesh silica gel as the carrier.
  • the systems used as developing agents are A: methylene chloride and methanol system; B: petroleum ether and ethyl acetate system.
  • the volume ratio of the solvent is different according to the polarity of the compound. And make adjustments.
  • biotage isera one type preparative liquid phase is used.
  • All reaction raw materials can be purchased from manufacturers such as Sarn Chemical Technology (Shanghai) Co., Ltd., Shanghai Shaoyuan Reagent Co., Ltd., Nanjing Yaoshi Technology Co., Ltd., Jiangsu Aikang Biopharmaceutical Research and Development Co., Ltd., and Shanghai Bide Pharmaceutical Technology Co., Ltd.
  • Step 1 Combine 3-bromo-2-methoxyaniline (212-a, 2.8g, 13.86mmol), pinacol diborate (5.3g, 20.79mmol), Pd(dppf)Cl 2 (1.03g, 1.39mmol) and potassium acetate (4.08g, 41.58mmol) were added to the dioxane solution in sequence, vacuumed and replaced with nitrogen three times, and continued stirring at 110°C for 20 hours. TLC monitored the reaction to completion, and the reaction solution was completely concentrated. Add water (40mL) to the reaction solution, extract with ethyl acetate (30mL x 2), and wash with saturated brine (30mL x 2).
  • Step 3 (2-Methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tert-butyl- 1-Azakanecarboxylate (212-c, 370mg, 1.06mmol), 2-bromopyrimidine (200mg, 1.27mmol), potassium phosphate (521mg, 2.46mmol) and Pd(dppf)Cl 2 (59mg, 0.082mmol) ) was added to a mixed solution of 7 mL water and dioxane (6:1), evacuated, replaced with nitrogen three times, and stirred at 105°C for 10 hours. TLC monitored the completion of the reaction, and the reaction solution was completely concentrated.
  • Step 4 Dissolve (2-methoxy-3-(pyrimidin-2-yl)phenyl)-2-azacarboxylic acid tert-butyl ester (212-d, 150 mg, 0.5 mmol) in dichloromethane solution, Then add trifluoroacetic acid (421 mg, 3.7 mmol) and stir at room temperature for 5 hours. TLC monitors the completion of the reaction. The reaction solution is completely concentrated. A saturated sodium bicarbonate solution is added to the residue. Extract with dichloromethane and wash with saturated brine. Dry over anhydrous sodium sulfate and concentrate under reduced pressure.
  • Step 5 Combine 2-methoxy-3-(pyrimidin-2-yl)aniline (212-e, 70mg, 0.35mmol), 4,6-dichloro-N-ethoxynicotinamide (74mg, 0.32mmol) ), was added to 5 ml of anhydrous N,N-dimethylacetamide, and LiHMDS solution in tetrahydrofuran (1.28 ml, 1.28 mmol) was added at room temperature, stirred at room temperature for 3 hours, and TLC monitored the reaction to completion.
  • Figure 6 shows that the crystal contains methanol, in which, 6-((( 2,6-Dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide and methanol The ratio is 1:0.4.
  • Example 7 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of formic acid solvated crystals F of phenyl) amino) nicotinamide
  • FIG 17 shows that the crystal contains formic acid, wherein, 6-(( (2,6-Dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide with The ratio of formic acid is 1:1.
  • Example 8 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) phenyl)ammonium Preparation of formic acid solvate crystal O of nicotinamide
  • FIG 19 shows that the crystal contains formic acid, wherein, 6-(( (2,6-Dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide with The ratio of formic acid is 1:1.
  • Example 11 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of formic acid solvate crystal AF of phenyl) amino) nicotinamide
  • Figure 25 shows that the crystal contains the organic solvent formic acid, Among them, 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl) )Amino)Nicotinamide and formic acid ratio is 1:1.
  • Example 12 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of hydrate crystal L of phenyl)amino)nicotinamide
  • Example 13 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of ethanol solvate crystal R of phenyl)amino)nicotinamide
  • Figure 29 shows that the crystal contains ethanol, wherein, 6-(((2 ,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide and ethanol The ratio is 1:0.3.
  • Example 14 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of oxalic acid co-crystal type A of phenyl) amino) nicotinamide
  • Figure 31 shows that the crystal contains oxalic acid, and the proton NMR Compared with the proton nuclear magnetic resonance spectrum of the E crystal form, there is no obvious chemical shift shift in the resonance spectrum. It is judged that this crystal form is a eutectic, in which 6-(((2,6-dimethylpyrimidin-4-yl)amino The ratio of )-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide to oxalic acid is 1:1.
  • Example 15 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of oxalic acid co-crystal type B of phenyl) amino) nicotinamide
  • Figure 33 shows that the crystal contains oxalic acid, and proton Compared with the proton NMR spectrum of the E crystal form, there is no obvious chemical shift shift.
  • This crystal form is judged to be a eutectic, in which 6-(((2,6-dimethylpyrimidin-4-yl) The ratio of amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide to oxalic acid is 1:1.
  • Example 16 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of p-toluenesulfonate crystal Type A of phenyl)amino)nicotinamide
  • the crystal form is a salt-forming crystal, in which 6-( ((2,6-Dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide
  • the ratio to p-toluenesulfonic acid is 1:1.
  • Example 17 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of p-toluenesulfonate crystal Type B of phenyl)amino)nicotinamide
  • the crystal form is a salt-forming crystal, in which 6-( ((2,6-Dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide
  • the ratio to p-toluenesulfonic acid is 1:1.
  • Example 18 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of p-toluenesulfonate crystal Type C of phenyl)amino)nicotinamide
  • Figure 39 shows that the crystal contains p-toluenesulfonic acid, and compared with the proton NMR spectrum of the E crystal form, there is an obvious chemical shift shift, and the crystal form is judged to be a salt-forming crystal, among which, 6-(((2,6- Dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide and p-toluenesulfonic acid The ratio is 1:1.
  • Example 19 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of fumaric acid eutectic crystal Type B of phenyl) amino) nicotinamide
  • Example 20 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of fumaric acid eutectic crystal Type C of phenyl)amino)nicotinamide
  • Example 21 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of mesylate crystal Type A of phenyl)amino)nicotinamide
  • the obtained sample was subjected to XRPD testing and proton nuclear magnetic resonance analysis, and its X-ray powder diffraction pattern was obtained as shown in Figure 44, and its proton nuclear magnetic resonance pattern was shown in Figure 45.
  • Figure 45 shows the The crystal contains methanesulfonic acid, and the proton NMR spectrum has an obvious chemical shift shift compared with the proton NMR spectrum of the E crystal form. It is judged that the crystal form is a salt-forming crystal, in which 6-(((2,6 -Dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide and methanesulfonic acid The ratio is 1:1.
  • Example 22 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of mesylate crystal Type B of phenyl)amino)nicotinamide
  • Figure 55 shows that its proton NMR Compared with the proton nuclear magnetic resonance spectrum of the E crystal form, there is an obvious chemical shift shift in the resonance spectrum. It is judged that the crystal form is a salt-forming crystal. Among them, 6-(((2,6-dimethylpyrimidine-4-yl )Amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide and maleic acid ratio is 1:1.
  • Example 28 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of citrate cocrystal Type A of phenyl)amino)nicotinamide
  • Example 29 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of malic acid eutectic crystal Type A of phenyl) amino) nicotinamide
  • the crystal form is a hydrochloride crystal, in which 6-(((2,6-dimethylpyrimidin-4-yl The ratio of )amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide to hydrochloric acid is 1:1.
  • Example 33 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of glycolic acid eutectic crystal Type B of phenyl) amino) nicotinamide
  • Example 39 Hygroscopicity of the malic acid eutectic crystal form Type A of the compound of formula (I)
  • the unsolvated crystalline form E remains stable under high temperature, high humidity, acceleration and room temperature conditions, and has high stability.
  • the unsolvated crystalline form AH remains stable under high temperature, high humidity, light, acceleration and room temperature conditions, and has high stability.
  • Example 42 Stability of the maleate crystal form Type A of the compound of formula (I)
  • Example 44 Stability of the malic acid eutectic crystal form Type A of the compound of formula (I)
  • the malate eutectic crystal form Type A remains stable under high temperature, high humidity, acceleration and room temperature conditions, and has high stability.

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Abstract

The present invention relates to a non-solvated crystal, hydrate crystal, solvated crystal, eutectic crystal or salt-type crystal of a compound as represented by formula (I),

Description

羟肟酸酯化合物及其盐的结晶形式与制备方法Crystalline forms and preparation methods of hydroxamate compounds and salts thereof 技术领域Technical field
本发明属于药物化学领域，具体涉及羟肟酸酯化合物及其盐的结晶形式与制备方法。The invention belongs to the field of medicinal chemistry, and specifically relates to the crystallization form and preparation method of hydroxamate compounds and salts thereof.
背景技术Background technique
6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺是一种酪氨酸激酶2(Tyk2)抑制剂，其化学结构如结构式(I)所示。
6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino ) Nicotinamide is a tyrosine kinase 2 (Tyk2) inhibitor, and its chemical structure is shown in structural formula (I).
在PCT专利申请号为PCT/CN2021/134929的专利申请文本中记载了式(I)所示化合物的药理活性数据，该化合物具有优异的Tyk2选择抑制活性，可以用于治疗与Tyk2活性异常相关的疾病，在临床上有望获得具有更好疗效且更小的药物副作用。The pharmacological activity data of the compound represented by formula (I) is recorded in the PCT patent application number PCT/CN2021/134929. The compound has excellent Tyk2 selective inhibitory activity and can be used to treat diseases related to abnormal Tyk2 activity. diseases, clinically it is expected to obtain drugs with better efficacy and fewer side effects.
目前尚无式(I)所示化合物的相关信息公开，也未发现有其晶型、盐型以及共晶晶体结构，更未发现有制备其溶剂化晶体、无溶剂化晶体、盐型和共晶晶体的方法。At present, there is no relevant information disclosed about the compound represented by formula (I), and its crystal form, salt form and co-crystal crystal structure have not been found, nor has its solvated crystal, unsolvated crystal, salt form and co-crystal structure been prepared. Crystal crystal method.
本领域技术人员知晓，药物不同晶型对于药物的稳定性、溶解性、生物利用度及疗效具有重大影响。因此，研究获得式(I)化合物的相关晶体，对于药物后续开发具有重要影响，并且意义重大，提供多种不同的晶型、盐型或其共晶结构，能够满足更多不同临床需求。因此，基于式(I)所示化合物的优秀临床应用前景，有必要对式(I)所示化合物的晶体、盐型及共晶体等微观结构进行进一步研究，以期获得更多有利于临床药物开发的式(I)所示化合物的微观结构体。Those skilled in the art know that different crystal forms of drugs have a significant impact on the stability, solubility, bioavailability and efficacy of drugs. Therefore, research to obtain related crystals of compounds of formula (I) has an important impact on the subsequent development of drugs and is of great significance. It provides a variety of different crystal forms, salt forms or their co-crystal structures, which can meet more different clinical needs. Therefore, based on the excellent clinical application prospects of the compound represented by formula (I), it is necessary to further study the microstructure such as crystals, salt forms and co-crystals of the compound represented by formula (I), in order to obtain more information that is beneficial to clinical drug development. The microstructure of the compound represented by formula (I).
发明内容Contents of the invention
发明要解决的问题：本发明的目的在于提供式(I)所示化合物的晶型、盐型及共晶晶型。Problems to be solved by the invention: The object of the present invention is to provide the crystal form, salt form and eutectic form of the compound represented by formula (I).
用于解决问题的方案：Solutions used to solve the problem:
为了解决上述问题，本发明提供了下述技术方案。In order to solve the above problems, the present invention provides the following technical solutions.
在本发明的第一个方面，提供了式(I)所示化合物的非溶剂化晶体，
In a first aspect of the invention, unsolvated crystals of the compound represented by formula (I) are provided,
在一些具体实施方案中，式(I)所示化合物的非溶剂化晶体选自其非溶剂化晶体AH和其非溶剂化晶体E。In some specific embodiments, the unsolvated crystal of the compound represented by formula (I) is selected from the group consisting of its unsolvated crystal AH and its unsolvated crystal E.
在一些具体实施方案中，式(I)所示化合物的非溶剂化晶体AH，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：7.65°、11.26°、11.43°、15.07°、15.32°、19.07°、20.12°和20.78°。In some specific embodiments, the X-ray powder diffraction pattern of the unsolvated crystal AH of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles (±0.2°): 7.65°, 11.26°, 11.43 °, 15.07°, 15.32°, 19.07°, 20.12° and 20.78°.
在一些具体实施方案中，式(I)所示化合物的非溶剂化晶体AH，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：7.65°、11.26°、11.43°、15.07°、15.32°、16.60°、19.07°、20.12°、20.78°和23.02°。In some specific embodiments, the X-ray powder diffraction pattern of the unsolvated crystal AH of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles (±0.2°): 7.65°, 11.26°, 11.43 °, 15.07°, 15.32°, 16.60°, 19.07°, 20.12°, 20.78° and 23.02°.
在一些具体实施方案中，式(I)所示化合物的非溶剂化晶体AH，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：7.65°、9.47°、11.26°、11.43°、15.07°、15.32°、16.31°、16.60°、19.07°、20.12°、20.78°、23.02°和25.77°。In some specific embodiments, the X-ray powder diffraction pattern of the unsolvated crystal AH of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles (±0.2°): 7.65°, 9.47°, 11.26 °, 11.43°, 15.07°, 15.32°, 16.31°, 16.60°, 19.07°, 20.12°, 20.78°, 23.02° and 25.77°.
在一些具体实施方案中，式(I)化合物的非溶剂化晶体AH，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：7.65°、8.36°、9.47°、9.80°、11.26°、11.43°、11.55°、11.80°、12.95°、13.64°、14.34°、14.74°、15.07°、15.32°、15.91°、16.31°、16.60°、16.87°、18.72°、19.07°、19.73°、20.12°、20.78°、21.30°、21.45°、21.95°、22.31°、23.02°、23.30°、23.67°、23.84°、24.65°、25.77°、26.57°、26.90°、28.29°、28.85°、29.54°。In some embodiments, the unsolvated crystalline AH of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 7.65°, 8.36°, 9.47°, 9.80°、11.26°、11.43°、11.55°、11.80°、12.95°、13.64°、14.34°、14.74°、15.07°、15.32°、15.91°、16.31°、16.60°、16.87°、18.72°、19.07° , 19.73°, 20.12°, 20.78°, 21.30°, 21.45°, 21.95°, 22.31°, 23.02°, 23.30°, 23.67°, 23.84°, 24.65°, 25.77°, 26.57°, 26.90°, 28.29°, 28.85 °, 29.54°.
在一些具体实施方案中，式(I)所示化合物的非溶剂化晶体AH，其X-射线粉末衍射图如图7所示。In some specific embodiments, the X-ray powder diffraction pattern of the unsolvated crystal AH of the compound represented by formula (I) is shown in Figure 7.
在一些具体实施方案中，式(I)所示化合物的非溶剂化晶体AH，其差示扫描量热分析曲线显示在188℃附近有吸热峰，在216.7℃附近有放热峰。In some specific embodiments, the differential scanning calorimetry analysis curve of the unsolvated crystal AH of the compound represented by formula (I) shows an endothermic peak near 188°C and an exothermic peak near 216.7°C.
在一些具体实施方案中，式(I)所示化合物的非溶剂化晶体AH，其差示扫描量热分析曲线如图9所示。In some specific embodiments, the differential scanning calorimetry analysis curve of the unsolvated crystal AH of the compound represented by formula (I) is as shown in Figure 9.
在一些具体实施方案中，式(I)所示化合物的非溶剂化晶体AH，其热重分析曲线显示该晶型在加热至150℃过程中有2.1％的失重，继续加热至190℃后可能发生分解。In some specific embodiments, the thermogravimetric analysis curve of the unsolvated crystal AH of the compound represented by formula (I) shows that the crystal form has a weight loss of 2.1% during heating to 150°C. After continuing to be heated to 190°C, it may Decomposition occurs.
在一些具体实施方案中，式(I)所示化合物的非溶剂化晶体AH，其热重分析曲线如图10。In some specific embodiments, the thermogravimetric analysis curve of the unsolvated crystal AH of the compound represented by formula (I) is shown in Figure 10.
在一个实施方案中，式(I)所示化合物的非溶剂化晶体E，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：7.19°、9.59°、14.46°、18.15°、20.41°、23.44°、23.67°、24.01°、24.34°和24.60°。 In one embodiment, the X-ray powder diffraction pattern of the unsolvated crystal E of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles (±0.2°): 7.19°, 9.59°, 14.46° , 18.15°, 20.41°, 23.44°, 23.67°, 24.01°, 24.34° and 24.60°.
在一个实施方案中，式(I)所示化合物的非溶剂化晶体E，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：7.19°、9.59°、13.64°、14.46°、18.15°、19.19°、20.41°、23.44°、23.67°、24.01°、24.34°和24.60°。In one embodiment, the X-ray powder diffraction pattern of the unsolvated crystal E of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles (±0.2°): 7.19°, 9.59°, 13.64° , 14.46°, 18.15°, 19.19°, 20.41°, 23.44°, 23.67°, 24.01°, 24.34° and 24.60°.
在一个实施方案中，式(I)所示化合物的非溶剂化晶体E，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：7.19°、8.93°、9.59°、12.72°、13.64°、14.46°、18.15°、19.19°、19.96°、20.41°、23.44°、23.67°、24.01°、24.34°、24.60°和28.60°。In one embodiment, the X-ray powder diffraction pattern of the unsolvated crystal E of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles (±0.2°): 7.19°, 8.93°, 9.59° , 12.72°, 13.64°, 14.46°, 18.15°, 19.19°, 19.96°, 20.41°, 23.44°, 23.67°, 24.01°, 24.34°, 24.60° and 28.60°.
在一些具体实施方案中，式(I)化合物的非溶剂化晶体E，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：7.19°、8.93°、9.59°、10.14°、10.52°、11.74°、12.31°、12.72°、13.64°、14.46°、15.33°、15.85°、16.62°、17.02°、18.03°、18.15°、18.72°、19.19°、19.36°、19.96°、20.41°、20.90°、23.44°、23.67°、24.01°、24.34°、24.60°、25.69°、26.66°、28.60°、29.19°、32.08°。In some specific embodiments, the unsolvated crystal E of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 7.19°, 8.93°, 9.59°, 10.14°、10.52°、11.74°、12.31°、12.72°、13.64°、14.46°、15.33°、15.85°、16.62°、17.02°、18.03°、18.15°、18.72°、19.19°、19.36°、19.96° , 20.41°, 20.90°, 23.44°, 23.67°, 24.01°, 24.34°, 24.60°, 25.69°, 26.66°, 28.60°, 29.19°, 32.08°.
在一个实施方案中，式(I)所示化合物的非溶剂化晶体E，其X-射线粉末衍射图如图11所示。In one embodiment, the X-ray powder diffraction pattern of the unsolvated crystal E of the compound represented by formula (I) is as shown in Figure 11.
在一个实施方案中，式(I)所示化合物的非溶剂化晶体E，其差示扫描量热分析曲线显示在194.2℃附近有吸热峰，在217.1℃附近有放热峰。In one embodiment, the differential scanning calorimetry analysis curve of the unsolvated crystal E of the compound represented by formula (I) shows an endothermic peak near 194.2°C and an exothermic peak near 217.1°C.
在一个实施方案中，式(I)所示化合物的非溶剂化晶体E，其差示扫描量热分析曲线如图13所示。In one embodiment, the differential scanning calorimetry analysis curve of the unsolvated crystal E of the compound represented by formula (I) is as shown in Figure 13.
在一个实施方案中，式(I)所示化合物的非溶剂化晶体E，其热重分析曲线显示该晶型在加热至150℃过程中有0.0％的失重，继续加热至190℃后可能发生分解。In one embodiment, the thermogravimetric analysis curve of the unsolvated crystal E of the compound represented by formula (I) shows that the crystal form has a weight loss of 0.0% during heating to 150°C, which may occur after continued heating to 190°C. break down.
在一个实施方案中，式(I)所示化合物的非溶剂化晶体E，其热重分析曲线如图14。In one embodiment, the thermogravimetric analysis curve of the unsolvated crystal E of the compound represented by formula (I) is shown in Figure 14.
在一个实施方案中，式(I)所示化合物的非溶剂化晶体E，其晶型为三斜晶系，晶胞参数值为：α＝76.404(2)°；β＝86.6962(16)°；γ＝70.126(2)°；空间群：P-1；每个晶胞中的分子(Z)：2；晶胞体积：计算密度：1.376g/cm3。In one embodiment, the crystal form of the unsolvated crystal E of the compound represented by formula (I) is a triclinic system, and the unit cell parameter values are: α=76.404(2)°; β=86.6962(16)°; γ=70.126(2)°; Space group: P-1; Molecules (Z) in each unit cell: 2; Unit cell volume: Calculated density: 1.376g/cm 3 .
在本发明的第二个方面，提供了式(I)所示化合物的水合物晶体，
In a second aspect of the present invention, hydrate crystals of the compound represented by formula (I) are provided,
在一些具体实施方案中，式(I)所示化合物的水合物晶体选自其水合物晶体AA、其水合物晶体T、其水合物晶体V和其水合物晶体L。In some specific embodiments, the hydrate crystal of the compound represented by formula (I) is selected from the group consisting of its hydrate crystal AA, its hydrate crystal T, its hydrate crystal V and its hydrate crystal L.
在一些具体实施方案中，式(I)所示化合物的水合物晶体AA，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：7.85°、10.35°、12.74°、14.95°、17.94°、18.05 °、19.01°、20.90°和27.26°。In some specific embodiments, the X-ray powder diffraction pattern of the hydrate crystal AA of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles (±0.2°): 7.85°, 10.35°, 12.74° ,14.95°,17.94°,18.05 °, 19.01°, 20.90° and 27.26°.
在一些具体实施方案中，式(I)所示化合物的水合物晶体AA，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：7.85°、8.92°、10.35°、11.18°、12.74°、14.95°、17.94°、18.05°、19.01°、20.90°、24.39°和27.26°。In some specific embodiments, the X-ray powder diffraction pattern of the hydrate crystal AA of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles (±0.2°): 7.85°, 8.92°, 10.35° , 11.18°, 12.74°, 14.95°, 17.94°, 18.05°, 19.01°, 20.90°, 24.39° and 27.26°.
在一些具体实施方案中，式(I)所示化合物的水合物晶体AA，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：7.85°、8.62°、8.92°、10.35°、11.18°、12.74°、14.95°、16.71°、17.94°、18.05°、19.01°、19.99°、20.90°、21.57°、24.39°和27.26°。In some specific embodiments, the X-ray powder diffraction pattern of the hydrate crystal AA of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles (±0.2°): 7.85°, 8.62°, 8.92° , 10.35°, 11.18°, 12.74°, 14.95°, 16.71°, 17.94°, 18.05°, 19.01°, 19.99°, 20.90°, 21.57°, 24.39° and 27.26°.
在一些具体实施方案中，式(I)化合物的水合物晶体AA，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：7.85°、8.62°、8.92°、10.35°、10.80°、11.18°、12.74°、14.95°、15.64°、16.14°、16.71°、17.18°、17.63°、17.94°、18.05°、18.73°、19.01°、19.53°、19.99°、20.63°、20.90°、21.57°、22.25°、22.54°、22.81°、23.18°、23.79°、24.39°、24.90°、25.16°、25.86°、26.08°、27.26°、27.50°、27.93°、28.16°、28.32°、29.73°、31.97°、34.26°。In some specific embodiments, the hydrate crystal AA of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 7.85°, 8.62°, 8.92°, 10.35 °, 10.80°, 11.18°, 12.74°, 14.95°, 15.64°, 16.14°, 16.71°, 17.18°, 17.63°, 17.94°, 18.05°, 18.73°, 19.01°, 19.53°, 19.99°, 20.63°, 20.90°、21.57°、22.25°、22.54°、22.81°、23.18°、23.79°、24.39°、24.90°、25.16°、25.86°、26.08°、27.26°、27.50°、27.93°、28.16°、28.32° , 29.73°, 31.97°, 34.26°.
在一些具体实施方案中，式(I)所示化合物的水合物晶体AA，其X-射线粉末衍射图如图3所示。In some specific embodiments, the X-ray powder diffraction pattern of the hydrate crystal AA of the compound represented by formula (I) is as shown in Figure 3.
在一些具体实施方案中，式(I)所示化合物的水合物晶体T，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：4.31°、6.09°、6.82°、11.05°、18.49°、19.74°、24.32°和26.78°。In some specific embodiments, the hydrate crystal T of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 4.31°, 6.09°, 6.82° , 11.05°, 18.49°, 19.74°, 24.32° and 26.78°.
在一些具体实施方案中，式(I)所示化合物的水合物晶体T，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：4.31°、6.09°、6.82°、11.05°、13.03°、16.41°、18.49°、19.74°、22.26°、24.32°和26.78°。In some specific embodiments, the hydrate crystal T of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 4.31°, 6.09°, 6.82° , 11.05°, 13.03°, 16.41°, 18.49°, 19.74°, 22.26°, 24.32° and 26.78°.
在一些具体实施方案中，式(I)所示化合物的水合物晶体T，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：4.31°、6.09°、6.82°、8.65、11.05°、13.03°、13.56°、16.41°、17.94°、18.49°、19.74°、22.26°、24.32°和26.78°。In some specific embodiments, the hydrate crystal T of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 4.31°, 6.09°, 6.82° , 8.65, 11.05°, 13.03°, 13.56°, 16.41°, 17.94°, 18.49°, 19.74°, 22.26°, 24.32° and 26.78°.
在一个实施方案中，式(I)化合物的水合物晶体T，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：4.31°、6.09°、6.53°、6.82°、8.65°、11.05°、12.27°、13.03°、13.56°、13.74°、15.46°、15.64°、16.41°、17.52°、17.94°、18.49°、19.60°、19.74°、21.86°、22.26°、23.01°、24.32°、24.49°、24.73°、26.78°、27.09°、27.83°、31.20°、33.11°。In one embodiment, the hydrate crystal T of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 4.31°, 6.09°, 6.53°, 6.82° , 8.65°, 11.05°, 12.27°, 13.03°, 13.56°, 13.74°, 15.46°, 15.64°, 16.41°, 17.52°, 17.94°, 18.49°, 19.60°, 19.74°, 21.86°, 22.26°, 23.01 °, 24.32°, 24.49°, 24.73°, 26.78°, 27.09°, 27.83°, 31.20°, 33.11°.
在一些具体实施方案中，式(I)所示化合物的水合物晶体T，其X-射线粉末衍射图如图20所示。In some specific embodiments, the X-ray powder diffraction pattern of the hydrate crystal T of the compound represented by formula (I) is as shown in Figure 20.
在一些具体实施方案中，式(I)化合物的水合物晶体V，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：6.34°、7.48°、7.95°、10.27°、12.97°、17.90°、20.71°和23.98°。 In some specific embodiments, the hydrate crystal V of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 6.34°, 7.48°, 7.95°, 10.27 °, 12.97°, 17.90°, 20.71° and 23.98°.
在一些具体实施方案中，式(I)化合物的水合物晶体V，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：6.34°、7.48°、7.95°、9.72°、10.27°、12.97°、17.90°、20.71°和23.98°。In some specific embodiments, the hydrate crystal V of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 6.34°, 7.48°, 7.95°, 9.72 °, 10.27°, 12.97°, 17.90°, 20.71° and 23.98°.
在一些具体实施方案中，式(I)化合物的水合物晶体V，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：6.34°、7.48°、7.95°、9.72°、10.27°、12.97°、14.34°、17.90°、18.19°、20.71°和23.98°。In some specific embodiments, the hydrate crystal V of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 6.34°, 7.48°, 7.95°, 9.72 °, 10.27°, 12.97°, 14.34°, 17.90°, 18.19°, 20.71° and 23.98°.
在一些具体实施方案中，式(I)化合物的水合物晶体V，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：6.34°、7.48°、7.95°、9.72°、10.27°、12.97°、14.34°、15.72°、16.94°、17.90°、18.19°、19.39°、20.28°、20.71°、21.09°、22.50°、23.04°、23.98°。In some specific embodiments, the hydrate crystal V of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 6.34°, 7.48°, 7.95°, 9.72 °, 10.27°, 12.97°, 14.34°, 15.72°, 16.94°, 17.90°, 18.19°, 19.39°, 20.28°, 20.71°, 21.09°, 22.50°, 23.04°, 23.98°.
在一些具体实施方案中，式(I)化合物的水合物晶体V，其X-射线粉末衍射图如图22所示。In some embodiments, the X-ray powder diffraction pattern of hydrate crystal V of the compound of formula (I) is shown in Figure 22.
在一些具体实施方案中，式(I)化合物的水合物晶体L，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：6.69°、8.02°、9.93°、14.23°、16.13°、16.29°、18.13°、19.18°和24.32°。In some specific embodiments, the hydrate crystal L of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 6.69°, 8.02°, 9.93°, 14.23 °, 16.13°, 16.29°, 18.13°, 19.18° and 24.32°.
在一些具体实施方案中，式(I)化合物的水合物晶体L，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：6.69°、8.02°、9.93°、12.87°、14.23°、16.13°、16.29°、18.13°、19.18°、21.07°、23.38°和24.32°。In some specific embodiments, the hydrate crystal L of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 6.69°, 8.02°, 9.93°, 12.87 °, 14.23°, 16.13°, 16.29°, 18.13°, 19.18°, 21.07°, 23.38° and 24.32°.
在一些具体实施方案中，式(I)化合物的水合物晶体L，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：6.69°、7.07°、8.02°、9.93°、12.87°、14.23°、16.13°、16.29°、17.47°、18.13°、19.18°、21.07°、23.38°、24.32°和28.21°。In some specific embodiments, the hydrate crystal L of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 6.69°, 7.07°, 8.02°, 9.93 °, 12.87°, 14.23°, 16.13°, 16.29°, 17.47°, 18.13°, 19.18°, 21.07°, 23.38°, 24.32° and 28.21°.
在一些具体实施方案中，式(I)化合物的水合物晶体L，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：6.32°、6.69°、7.07°、8.02°、9.93°、12.87°、14.23°、15.16°、15.57°、16.13°、16.29°、16.50°、16.87°、17.47°、18.13°、19.18°、19.43°、20.02°、21.07°、21.55°、21.93°、22.26°、23.38°、23.96°、24.32°、24.99°、25.43°、25.75°、26.98°、27.86°、28.21°、29.51°、29.94°、31.27°、33.20°。In some specific embodiments, the hydrate crystal L of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 6.32°, 6.69°, 7.07°, 8.02 °, 9.93°, 12.87°, 14.23°, 15.16°, 15.57°, 16.13°, 16.29°, 16.50°, 16.87°, 17.47°, 18.13°, 19.18°, 19.43°, 20.02°, 21.07°, 21.55°, 21.93°, 22.26°, 23.38°, 23.96°, 24.32°, 24.99°, 25.43°, 25.75°, 26.98°, 27.86°, 28.21°, 29.51°, 29.94°, 31.27°, 33.20°.
在一些具体实施方案中，式(I)化合物的水合物晶体L，其X-射线粉末衍射图如图26所示。In some specific embodiments, the X-ray powder diffraction pattern of hydrate crystal L of the compound of formula (I) is shown in Figure 26.
在本发明的第三个方面，提供了式(I)所示化合物的溶剂化晶体，所述溶剂选自甲醇，甲酸，乙醇，
In the third aspect of the present invention, solvated crystals of the compound represented by formula (I) are provided, and the solvent is selected from methanol, formic acid, ethanol,
其中，式(I)所示化合物与所述溶剂比例为1:0.3～1。Wherein, the ratio of the compound represented by formula (I) to the solvent is 1:0.3-1.
在一些具体实施方案中，式(I)所示化合物的溶剂化晶体为甲醇溶剂化晶体，式(I)所示化合物与甲醇的比例为1:0.4～1。In some specific embodiments, the solvated crystals of the compound represented by formula (I) are methanol solvated crystals, and the ratio of the compound represented by formula (I) to methanol is 1:0.4-1.
在一些具体实施方案中，式(I)所示化合物的甲醇溶剂化晶体为甲醇溶剂化晶体A。In some specific embodiments, the methanol solvated crystal of the compound represented by formula (I) is methanol solvated crystal A.
在一些具体实施方案中，式(I)所示化合物的甲醇溶剂化物晶体A，式(I)所示化合物与甲醇的比例为1:1。In some specific embodiments, the methanol solvate crystal A of the compound represented by formula (I), the ratio of the compound represented by formula (I) to methanol is 1:1.
在一些具体实施方案中，式(I)所示化合物的甲醇溶剂化物晶体A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：4.56°、9.16°、9.34°、12.91°、13.78°、14.66°、15.25°、18.52°和23.12°。In some specific embodiments, the methanol solvate crystal A of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 4.56°, 9.16°, 9.34 °, 12.91°, 13.78°, 14.66°, 15.25°, 18.52° and 23.12°.
在一些具体实施方案中，式(I)所示化合物的甲醇溶剂化物晶体A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：4.56°、9.16°、9.34°、12.91°、13.78°、14.66°、15.25°、16.52°、18.52°、20.58°、23.12°、24.02°和27.83°。In some specific embodiments, the methanol solvate crystal A of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 4.56°, 9.16°, 9.34 °, 12.91°, 13.78°, 14.66°, 15.25°, 16.52°, 18.52°, 20.58°, 23.12°, 24.02° and 27.83°.
在一些具体实施方案中，式(I)化合物的甲醇溶剂化晶体A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：4.56°、9.16°、9.34°、11.36°、12.91°、13.78°、14.66°、15.25°、16.52°、17.82°、18.52°、19.48°、19.62°、20.58°、22.47°、22.93°、23.12°、24.02°、24.90°、27.09°、27.83°、32.61°、37.44°。In some embodiments, the methanol solvated crystal A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 4.56°, 9.16°, 9.34°, 11.36°、12.91°、13.78°、14.66°、15.25°、16.52°、17.82°、18.52°、19.48°、19.62°、20.58°、22.47°、22.93°、23.12°、24.02°、24.90°、27.09° , 27.83°, 32.61°, 37.44°.
在一些具体实施方案中，式(I)所示化合物的甲醇溶剂化物晶体A，其X-射线粉末衍射图如图1所示。In some specific embodiments, the X-ray powder diffraction pattern of methanol solvate crystal A of the compound represented by formula (I) is as shown in Figure 1.
在一些具体实施方案中，式(I)所示化合物的甲醇溶剂化晶体为甲醇溶剂化晶体AE。In some specific embodiments, the methanol-solvated crystals of the compound represented by formula (I) are methanol-solvated crystals AE.
在一些具体实施方案中，式(I)所示化合物的甲醇溶剂化物晶体AE，式(I)所示化合物与甲醇的比例为1:0.4。In some specific embodiments, the methanol solvate crystal AE of the compound represented by formula (I), the ratio of the compound represented by formula (I) to methanol is 1:0.4.
在一个实施方案中，式(I)所示化合物的甲醇溶剂化物晶体AE，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：9.08°、9.63°、13.11°、13.70°、14.80°、15.29°、17.88°、18.78°、22.94°和23.46°。In one embodiment, the methanol solvate crystal AE of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 9.08°, 9.63°, 13.11° , 13.70°, 14.80°, 15.29°, 17.88°, 18.78°, 22.94° and 23.46°.
在一个实施方案中，式(I)所示化合物的甲醇溶剂化物晶体AE，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：9.08°、9.63°、13.11°、13.70°、14.80°、15.29°、16.68°、17.88°、18.78°、20.16°、22.94°、23.46°和25.32°。In one embodiment, the methanol solvate crystal AE of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 9.08°, 9.63°, 13.11° , 13.70°, 14.80°, 15.29°, 16.68°, 17.88°, 18.78°, 20.16°, 22.94°, 23.46° and 25.32°.
在一些具体实施方案中，式(I)化合物的甲醇溶剂化晶体AE，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：4.51°、9.08°、9.63°、11.60°、13.11°、13.70°、 14.80°、15.29°、15.99°、16.68°、17.88°、18.78°、20.16°、22.94°、23.46°、25.32°。In some embodiments, the methanol-solvated crystal AE of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 4.51°, 9.08°, 9.63°, 11.60°, 13.11°, 13.70°, 14.80°, 15.29°, 15.99°, 16.68°, 17.88°, 18.78°, 20.16°, 22.94°, 23.46°, 25.32°.
在一个实施方案中，式(I)所示化合物的甲醇溶剂化物晶体AE，其X-射线粉末衍射图如图5所示。In one embodiment, the X-ray powder diffraction pattern of the methanol solvate crystal AE of the compound represented by formula (I) is shown in Figure 5.
在一些具体实施方案中，式(I)所示化合物的溶剂化晶体为甲酸溶剂化晶体，其中，式(I)所示化合物与甲酸的比例为1:1。In some specific embodiments, the solvated crystals of the compound represented by formula (I) are formic acid solvated crystals, wherein the ratio of the compound represented by formula (I) to formic acid is 1:1.
在一些具体实施方案中，式(I)所示化合物的甲酸溶剂化晶体选自甲酸溶剂化晶体F、甲酸溶剂化晶体O、甲酸溶剂化晶体AF。In some specific embodiments, the formic acid solvated crystal of the compound represented by formula (I) is selected from the group consisting of formic acid solvated crystal F, formic acid solvated crystal O, and formic acid solvated crystal AF.
在一些具体实施方案中，式(I)所示化合物的甲酸溶剂化晶体F，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：4.96°、5.30°、7.25°、8.44°、12.14°、15.04°、15.83°、19.47°和20.11°。In some specific embodiments, the formic acid solvated crystal F of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 4.96°, 5.30°, 7.25 °, 8.44°, 12.14°, 15.04°, 15.83°, 19.47° and 20.11°.
在一些具体实施方案中，式(I)所示化合物的甲酸溶剂化晶体F，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：4.96°、5.30°、7.25°、8.44°、9.93°、12.14°、12.91°、14.62°、15.04°、15.83°、19.47°和20.11°。In some specific embodiments, the formic acid solvated crystal F of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 4.96°, 5.30°, 7.25 °, 8.44°, 9.93°, 12.14°, 12.91°, 14.62°, 15.04°, 15.83°, 19.47° and 20.11°.
在一些具体实施方案中，式(I)所示化合物的甲酸溶剂化晶体F，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：约4.96°、5.30°、7.25°、8.44°、9.93°、10.71°、12.14°、12.91°、14.62°、15.04°、15.83°、17.08°、18.52°、19.47°、20.11°、22.07°、23.14°、24.48°、25.64°。In some specific embodiments, the formic acid solvated crystal F of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): about 4.96°, 5.30°, 7.25°, 8.44°, 9.93°, 10.71°, 12.14°, 12.91°, 14.62°, 15.04°, 15.83°, 17.08°, 18.52°, 19.47°, 20.11°, 22.07°, 23.14°, 24.48°, 25.64° .
在一些具体实施方案中，式(I)所示化合物的甲酸溶剂化晶体F，其X-射线粉末衍射图如图16所示。In some specific embodiments, the formic acid solvated crystal F of the compound represented by formula (I) has an X-ray powder diffraction pattern as shown in Figure 16.
在一些具体实施方案中，所述甲酸溶剂化晶体O，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.30°、10.68°、11.72°、15.25°、16.09°、17.99°、20.50°、22.30°、25.78°和26.57°。In some specific embodiments, the formic acid solvated crystal O has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.30°, 10.68°, 11.72°, 15.25°, 16.09 °, 17.99°, 20.50°, 22.30°, 25.78° and 26.57°.
在一些具体实施方案中，式(I)所示化合物的甲酸溶剂化晶体O，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.30°、10.54°、10.68°、11.72°、13.73°、15.25°、16.09°、16.96°、17.99°、20.50°、21.00°、22.30°、25.78°、26.57°和28.89°。In some specific embodiments, the formic acid solvated crystal O of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.30°, 10.54°, 10.68 °, 11.72°, 13.73°, 15.25°, 16.09°, 16.96°, 17.99°, 20.50°, 21.00°, 22.30°, 25.78°, 26.57° and 28.89°.
在一些具体实施方案中，式(I)所示化合物的甲酸溶剂化晶体O，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.30°、10.54°、10.68°、10.93°、11.72°、11.93°、12.39°、13.31°、13.73°、14.04°、15.25°、16.09°、16.96°、17.99°、18.26°、19.37°、19.57°、20.08°、20.35°、20.50°、21.00°、21.51°、22.04°、22.30°、23.02°、24.84°、24.99°、25.26°、25.78°、26.57°、26.99°、28.89°、30.68°、33.16°。In some specific embodiments, the formic acid solvated crystal O of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.30°, 10.54°, 10.68 °, 10.93°, 11.72°, 11.93°, 12.39°, 13.31°, 13.73°, 14.04°, 15.25°, 16.09°, 16.96°, 17.99°, 18.26°, 19.37°, 19.57°, 20.08°, 20.35°, 20.50°, 21.00°, 21.51°, 22.04°, 22.30°, 23.02°, 24.84°, 24.99°, 25.26°, 25.78°, 26.57°, 26.99°, 28.89°, 30.68°, 33.16°.
在一些具体实施方案中，式(I)所示化合物的甲酸溶剂化晶体O，其X-射线粉末衍射图如图18所示。In some specific embodiments, the formic acid solvated crystal O of the compound represented by formula (I) has an X-ray powder diffraction pattern as shown in Figure 18.
在一些具体实施方案中，式(I)所示化合物的甲酸溶剂化晶体AF，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：6.19°、7.48°、8.32°、12.49°、13.46°和14.76 °。In some specific embodiments, the formic acid solvated crystal AF of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 6.19°, 7.48°, 8.32 °, 12.49°, 13.46° and 14.76 °.
在一些具体实施方案中，式(I)所示化合物的甲酸溶剂化晶体AF，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：6.19°、7.48°、8.32°、12.49°、12.97°、13.46°、14.76°、17.56°、23.59°和25.35°。In some specific embodiments, the formic acid solvated crystal AF of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 6.19°, 7.48°, 8.32 °, 12.49°, 12.97°, 13.46°, 14.76°, 17.56°, 23.59° and 25.35°.
在一些具体实施方案中，式(I)所示化合物的甲酸溶剂化晶体AF，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.93°、6.19°、7.48°、8.32°、11.30°、11.65°、12.49°、12.97°、13.46°、14.76°、17.56°、17.81°、18.48°、19.37°、20.48°、21.57°、22.75°、23.59°、24.93°、25.35°。In some specific embodiments, the formic acid solvated crystal AF of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.93°, 6.19°, 7.48 °, 8.32°, 11.30°, 11.65°, 12.49°, 12.97°, 13.46°, 14.76°, 17.56°, 17.81°, 18.48°, 19.37°, 20.48°, 21.57°, 22.75°, 23.59°, 24.93°, 25.35°.
在一些具体实施方案中，式(I)所示化合物的甲酸溶剂化晶体AF，其X-射线粉末衍射图如图24所示。In some specific embodiments, the formic acid solvated crystal AF of the compound represented by formula (I) has an X-ray powder diffraction pattern as shown in Figure 24.
在一些具体实施方案中，式(I)所示化合物的乙醇溶剂化晶体为乙醇溶剂化晶体R，式(I)所示化合物与乙醇的比例为1:0.3。In some specific embodiments, the ethanol solvated crystal of the compound represented by formula (I) is ethanol solvated crystal R, and the ratio of the compound represented by formula (I) to ethanol is 1:0.3.
在一些具体实施方案中，式(I)所示化合物的乙醇溶剂化物晶体R，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：8.37°、12.51°、16.14°、17.56°、17.69°、18.36°、18.68°、19.45°、21.71°、23.01°和24.14°。In some specific embodiments, the ethanol solvate crystal R of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 8.37°, 12.51°, 16.14 °, 17.56°, 17.69°, 18.36°, 18.68°, 19.45°, 21.71°, 23.01° and 24.14°.
在一些具体实施方案中，式(I)所示化合物的乙醇溶剂化物晶体R，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：8.37°、12.51°、15.04°、16.14°、16.59°、17.56°、17.69°、18.36°、18.68°、19.45°、21.71°、23.01°、24.14°、24.98°和26.58°。In some specific embodiments, the ethanol solvate crystal R of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 8.37°, 12.51°, 15.04 °, 16.14°, 16.59°, 17.56°, 17.69°, 18.36°, 18.68°, 19.45°, 21.71°, 23.01°, 24.14°, 24.98° and 26.58°.
在一些具体实施方案中，式(I)所示化合物的乙醇溶剂化物晶体R，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：8.37°、12.51°、13.20°、13.48°、14.37°、15.04°、15.71°、16.14°、16.59°、16.96°、17.56°、17.69°、18.36°、18.68°、19.45°、19.99°、20.44°、21.08°、21.71°、22.29°、23.01°、23.52°、23.71°、24.14°、24.98°、25.48°、26.23°、26.58°、27.59°、28.74°、29.25°、30.32°。In some specific embodiments, the ethanol solvate crystal R of the compound represented by formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 8.37°, 12.51°, 13.20 °, 13.48°, 14.37°, 15.04°, 15.71°, 16.14°, 16.59°, 16.96°, 17.56°, 17.69°, 18.36°, 18.68°, 19.45°, 19.99°, 20.44°, 21.08°, 21.71°, 22.29°, 23.01°, 23.52°, 23.71°, 24.14°, 24.98°, 25.48°, 26.23°, 26.58°, 27.59°, 28.74°, 29.25°, 30.32°.
在一些具体实施方案中，式(I)所示化合物的乙醇溶剂化物晶体R，其X-射线粉末衍射图如图28所示。In some specific embodiments, the X-ray powder diffraction pattern of the ethanol solvate crystal R of the compound represented by formula (I) is as shown in Figure 28.
在本发明的第四个方面，提供了式(I)所示化合物的共晶晶体，
In a fourth aspect of the present invention, a eutectic crystal of the compound represented by formula (I) is provided,
在一些具体实施方案中，式(I)所示化合物的共晶晶体选自：式(I)化合物的草酸共晶晶体、式(I)化合物的富马酸共晶晶体、式(I)化合物的柠檬酸共晶晶体、式(I)化合物的苹果酸共晶晶体、式(I)化合物的乙醇酸共晶晶体。 In some specific embodiments, the eutectic crystal of the compound represented by formula (I) is selected from: oxalic acid eutectic crystal of the compound of formula (I), fumaric acid eutectic crystal of the compound of formula (I), compound of formula (I) citric acid eutectic crystals, malic acid eutectic crystals of the compound of formula (I), and glycolic acid eutectic crystals of the compound of formula (I).
在一些具体实施方案中，式(I)化合物的草酸共晶晶体选自：式(I)化合物的草酸共晶晶体Type A、式(I)化合物的草酸共晶晶体Type B，其中，式(I)化合物与草酸的比例为1:1。In some specific embodiments, the oxalic acid co-crystal crystal of the compound of formula (I) is selected from: the oxalic acid co-crystal crystal Type A of the compound of formula (I), the oxalic acid co-crystal crystal Type B of the compound of formula (I), wherein, the formula ( I) The ratio of compound to oxalic acid is 1:1.
在一些具体实施方案中，式(I)化合物的草酸共晶晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：6.07°、11.01°、12.23°、12.80°、14.28°、16.93°和21.76°。In some specific embodiments, the oxalic acid eutectic crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 6.07°, 11.01°, 12.23° , 12.80°, 14.28°, 16.93° and 21.76°.
在一些具体实施方案中，式(I)化合物的草酸共晶晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：6.07°、7.07°、9.41°、11.01°、11.46°、12.23°、12.80°、14.28°、14.63°、16.93°、18.49°、18.95°和21.76°。In some embodiments, the oxalic acid eutectic crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 6.07°, 7.07°, 9.41° , 11.01°, 11.46°, 12.23°, 12.80°, 14.28°, 14.63°, 16.93°, 18.49°, 18.95° and 21.76°.
在一些具体实施方案中，式(I)化合物的草酸共晶晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：3.58°、6.07°、7.07°、9.41°、11.01°、11.46°、12.23°、12.80°、14.28°、14.63°、15.55°、16.93°、17.97°、18.49°、18.95°、21.76°、24.91°、25.72°。In some specific embodiments, the oxalic acid eutectic crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 3.58°, 6.07°, 7.07° , 9.41°, 11.01°, 11.46°, 12.23°, 12.80°, 14.28°, 14.63°, 15.55°, 16.93°, 17.97°, 18.49°, 18.95°, 21.76°, 24.91°, 25.72°.
在一些具体实施方案中，式(I)化合物的草酸共晶晶体Type A，其X-射线粉末衍射图如图30所示。In some embodiments, the X-ray powder diffraction pattern of the oxalic acid eutectic crystal Type A of the compound of formula (I) is shown in Figure 30.
在一些具体实施方案中，式(I)化合物的草酸共晶晶体Type B，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：6.01°、8.19°、11.55°、12.34°、13.79°、17.36°、18.14°、20.56°、23.27°、23.94°和25.24°。In some specific embodiments, the oxalic acid eutectic crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 6.01°, 8.19°, 11.55° , 12.34°, 13.79°, 17.36°, 18.14°, 20.56°, 23.27°, 23.94° and 25.24°.
在一些具体实施方案中，式(I)化合物的草酸共晶晶体Type B，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：3.60°、6.01°、8.19°、11.55°、12.34°、13.79°、14.52°、17.36°、18.14°、18.98°、20.56°、22.30°、23.27°、23.94°和25.24°。In some specific embodiments, the oxalic acid eutectic crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 3.60°, 6.01°, 8.19° , 11.55°, 12.34°, 13.79°, 14.52°, 17.36°, 18.14°, 18.98°, 20.56°, 22.30°, 23.27°, 23.94° and 25.24°.
在一些具体实施方案中，式(I)化合物的草酸共晶晶体Type B，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：3.60°、6.01°、8.19°、9.41°、11.55°、12.05°、12.34°、12.77°、13.79°、14.25°、14.52°、15.64°、16.43°、17.36°、18.14°、18.98°、19.69°、20.56°、21.40°、21.93°、22.30°、23.27°、23.94°、25.24°、25.77°、27.76°。In some specific embodiments, the oxalic acid eutectic crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 3.60°, 6.01°, 8.19° , 9.41°, 11.55°, 12.05°, 12.34°, 12.77°, 13.79°, 14.25°, 14.52°, 15.64°, 16.43°, 17.36°, 18.14°, 18.98°, 19.69°, 20.56°, 21.40°, 21.93 °, 22.30°, 23.27°, 23.94°, 25.24°, 25.77°, 27.76°.
在一些具体实施方案中，式(I)化合物的草酸共晶晶体Type B，其X-射线粉末衍射图如图32所示。In some embodiments, the X-ray powder diffraction pattern of the oxalic acid eutectic crystal Type B of the compound of formula (I) is shown in Figure 32.
在一些具体实施方案中，式(I)化合物的富马酸共晶晶体选自：富马酸共晶晶体Type B、富马酸共晶晶体Type C，式(I)化合物与富马酸的比例为1：1。In some specific embodiments, the fumaric acid eutectic crystal of the compound of formula (I) is selected from: fumaric acid eutectic crystal Type B, fumaric acid eutectic crystal Type C, the compound of formula (I) and fumaric acid. The ratio is 1:1.
在一些具体实施方案中，式(I)化合物的富马酸共晶晶体Type B，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.18°、6.43°、10.93°、11.46°、12.39°、15.96°、16.22°、19.28°和22.09°。In some specific embodiments, the fumaric acid eutectic crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.18°, 6.43°, 10.93°, 11.46°, 12.39°, 15.96°, 16.22°, 19.28° and 22.09°.
在一些具体实施方案中，式(I)化合物的富马酸共晶晶体Type B，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：3.81°、5.18°、6.43°、8.15°、9.34°、10.93°、 11.46°、12.39°、15.96°、16.22°、19.28°和22.09°。In some specific embodiments, the fumaric acid eutectic crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 3.81°, 5.18°, 6.43°, 8.15°, 9.34°, 10.93°, 11.46°, 12.39°, 15.96°, 16.22°, 19.28° and 22.09°.
在一些具体实施方案中，式(I)化合物的富马酸共晶晶体Type B，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：3.81°、5.18°、6.43°、7.62°、8.15°、9.07°、9.34°、10.93°、11.46°、12.39°、15.96°、16.22°、19.28°、22.09°。In some embodiments, the fumaric acid eutectic crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 3.81°, 5.18°, 6.43°, 7.62°, 8.15°, 9.07°, 9.34°, 10.93°, 11.46°, 12.39°, 15.96°, 16.22°, 19.28°, 22.09°.
在一些具体实施方案中，式(I)化合物的富马酸共晶晶体Type B，其X-射线粉末衍射图如图40所示。In some specific embodiments, the fumaric acid cocrystal crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern as shown in Figure 40.
在一个实施方案中，所述富马酸共晶晶体Type C，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：7.14°、7.49°、10.87°、12.17°、17.38°、19.81°、20.63°、21.58°、23.27°、24.38°和25.39°。In one embodiment, the fumaric acid eutectic crystal Type C has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 7.14°, 7.49°, 10.87°, 12.17° , 17.38°, 19.81°, 20.63°, 21.58°, 23.27°, 24.38° and 25.39°.
在一个实施方案中，所述富马酸共晶晶体Type C，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：7.14°、7.49°、8.23°、10.87°、12.17°、16.43°、17.38°、17.69°、19.81°、20.63°、21.11°、21.58°、23.27°、24.38°、25.39°、28.27°、29.37°和31.28°。In one embodiment, the fumaric acid eutectic crystal Type C has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 7.14°, 7.49°, 8.23°, 10.87° , 12.17°, 16.43°, 17.38°, 17.69°, 19.81°, 20.63°, 21.11°, 21.58°, 23.27°, 24.38°, 25.39°, 28.27°, 29.37° and 31.28°.
在一个实施方案中，所述富马酸共晶晶体Type C，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：7.14°、7.49°、8.23°、10.87°、12.17°、13.24°、13.96°、16.43°、17.38°、17.69°、18.74°、19.81°、19.97°、20.63°、21.11°、21.58°、23.27°、23.54°、24.38°、25.39°、26.48°、28.27°、29.37°、30.89°、31.28°、32.60°。In one embodiment, the fumaric acid eutectic crystal Type C has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 7.14°, 7.49°, 8.23°, 10.87° , 12.17°, 13.24°, 13.96°, 16.43°, 17.38°, 17.69°, 18.74°, 19.81°, 19.97°, 20.63°, 21.11°, 21.58°, 23.27°, 23.54°, 24.38°, 25.39°, 26.48 °, 28.27°, 29.37°, 30.89°, 31.28°, 32.60°.
在一个实施方案中，所述富马酸共晶晶体Type C，其X-射线粉末衍射图如图42所示。In one embodiment, the X-ray powder diffraction pattern of the fumaric acid eutectic crystal Type C is shown in Figure 42.
在一些具体实施方案中，式(I)化合物的柠檬酸共晶晶体为式(I)化合物的柠檬酸共晶晶体Type A，式(I)化合物与柠檬酸的比例为1:1。In some specific embodiments, the citric acid co-crystal crystal of the compound of formula (I) is the citric acid co-crystal crystal of the compound of formula (I) Type A, and the ratio of the compound of formula (I) to citric acid is 1:1.
在一些具体实施方案中，式(I)化合物的柠檬酸共晶晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.56°、6.52°、9.85°、14.27°、14.62°、16.60°、17.73°、19.71°、19.86°、24.36°和26.42°。In some embodiments, the citric acid eutectic crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.56°, 6.52°, 9.85 °, 14.27°, 14.62°, 16.60°, 17.73°, 19.71°, 19.86°, 24.36° and 26.42°.
在一些具体实施方案中，式(I)化合物的柠檬酸共晶晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.56°、6.52°、9.85°、13.20°、13.46°、14.27°、14.62°、15.78°、16.60°、17.73°、19.71°、19.86°、24.36°、25.16°和26.42°。In some embodiments, the citric acid eutectic crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.56°, 6.52°, 9.85 °, 13.20°, 13.46°, 14.27°, 14.62°, 15.78°, 16.60°, 17.73°, 19.71°, 19.86°, 24.36°, 25.16° and 26.42°.
在一些具体实施方案中，式(I)化合物的柠檬酸共晶晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.56°、6.52°、7.10°、9.85°、13.20°、13.46°、14.27°、14.62°、15.41°、15.78°、16.29°、16.60°、17.73°、19.31°、19.71°、19.86°、23.15°、24.36°、25.16°和26.42°。In some specific embodiments, the citric acid eutectic crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.56°, 6.52°, 7.10 °, 9.85°, 13.20°, 13.46°, 14.27°, 14.62°, 15.41°, 15.78°, 16.29°, 16.60°, 17.73°, 19.31°, 19.71°, 19.86°, 23.15°, 24.36°, 25.16° and 26.42°.
在一些具体实施方案中，式(I)化合物的柠檬酸共晶晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.56°、6.52°、7.10°、9.85°、11.00°、12.76°、13.20°、13.46°、14.27°、14.62°、15.41°、15.78°、16.29°、16.60°、17.73°、19.31°、19.71°、19.86°、23.15°、23.51°、24.36°、25.16°、25.56°、25.70°、26.42°、27.08°、27.53°、27.74°、28.08°、32.03°。 In some specific embodiments, the citric acid eutectic crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.56°, 6.52°, 7.10 °, 9.85°, 11.00°, 12.76°, 13.20°, 13.46°, 14.27°, 14.62°, 15.41°, 15.78°, 16.29°, 16.60°, 17.73°, 19.31°, 19.71°, 19.86°, 23.15°, 23.51°, 24.36°, 25.16°, 25.56°, 25.70°, 26.42°, 27.08°, 27.53°, 27.74°, 28.08°, 32.03°.
在一些具体实施方案中，式(I)化合物的柠檬酸共晶晶体Type A，其X-射线粉末衍射图如图58所示。In some embodiments, the X-ray powder diffraction pattern of the citric acid eutectic crystal Type A of the compound of formula (I) is shown in Figure 58.
在一些具体实施方案中，式(I)化合物的苹果酸共晶晶体为式(I)化合物的苹果酸共晶晶体Type A，式(I)化合物与苹果酸的比例为1:1。In some specific embodiments, the malic acid eutectic crystal of the compound of formula (I) is the malic acid eutectic crystal of the compound of formula (I) Type A, and the ratio of the compound of formula (I) to malic acid is 1:1.
在一些具体实施方案中，式(I)化合物的苹果酸共晶晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：7.14°、8.77°、8.99°、9.90°、11.59°、11.84°、17.27°、19.91°、20.22°、21.09°、23.74°和25.22°。In some specific embodiments, the malic acid eutectic crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 7.14°, 8.77°, 8.99 °, 9.90°, 11.59°, 11.84°, 17.27°, 19.91°, 20.22°, 21.09°, 23.74° and 25.22°.
在一些具体实施方案中，式(I)化合物的苹果酸共晶晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：7.14°、8.77°、8.99°、9.90°、11.59°、11.84°、17.27°、18.02°、19.21°、19.91°、20.22°、21.09°、22.98°、23.74°、24.42°和25.22°。In some specific embodiments, the malic acid eutectic crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 7.14°, 8.77°, 8.99 °, 9.90°, 11.59°, 11.84°, 17.27°, 18.02°, 19.21°, 19.91°, 20.22°, 21.09°, 22.98°, 23.74°, 24.42° and 25.22°.
在一些具体实施方案中，式(I)化合物的苹果酸共晶晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：7.14°、8.77°、8.99°、9.90°、11.59°、11.84°、13.90°、14.72°、15.83°、17.27°、18.02°、19.21°、19.91°、20.22°、21.09°、22.98°、23.74°、24.42°和25.22°。In some specific embodiments, the malic acid eutectic crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 7.14°, 8.77°, 8.99 °, 9.90°, 11.59°, 11.84°, 13.90°, 14.72°, 15.83°, 17.27°, 18.02°, 19.21°, 19.91°, 20.22°, 21.09°, 22.98°, 23.74°, 24.42° and 25.22°.
在一些具体实施方案中，式(I)化合物的苹果酸共晶晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：7.14°、8.77°、8.99°、9.90°、11.59°、11.84°、13.90°、14.72°、15.83°、17.27°、18.02°、18.49°、19.21°、19.91°、20.22°、20.49°、21.09°、22.32°、22.98°、23.74°、24.42°、25.22°、25.58°、26.30°、27.04°、27.86°、28.46°、29.20°、29.84°、31.18°、31.42°、34.27°、34.82°。In some specific embodiments, the malic acid eutectic crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 7.14°, 8.77°, 8.99 °, 9.90°, 11.59°, 11.84°, 13.90°, 14.72°, 15.83°, 17.27°, 18.02°, 18.49°, 19.21°, 19.91°, 20.22°, 20.49°, 21.09°, 22.32°, 22.98°, 23.74°, 24.42°, 25.22°, 25.58°, 26.30°, 27.04°, 27.86°, 28.46°, 29.20°, 29.84°, 31.18°, 31.42°, 34.27°, 34.82°.
在一些具体实施方案中，式(I)化合物的苹果酸共晶晶体Type A，其X-射线粉末衍射图如图60所示。In some embodiments, the X-ray powder diffraction pattern of the malic acid eutectic crystal Type A of the compound of formula (I) is shown in Figure 60.
在一些具体实施方案中，式(I)化合物的乙醇酸共晶晶体选自：式(I)化合物的乙醇酸共晶晶体Type A、式(I)化合物的乙醇酸共晶晶体Type B，其中，式(I)化合物与乙醇酸的比例为1:1。In some specific embodiments, the glycolic acid eutectic crystal of the compound of formula (I) is selected from: the glycolic acid eutectic crystal of the compound of formula (I) Type A, the glycolic acid eutectic crystal of the compound of formula (I) Type B, wherein , the ratio of the compound of formula (I) to glycolic acid is 1:1.
在一些具体实施方案中，式(I)化合物的乙醇酸共晶晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.61°、6.83°、8.27°、11.25°、13.73°、14.63°、16.94°、19.79°和23.23°。In some specific embodiments, the glycolic acid eutectic crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.61°, 6.83°, 8.27 °, 11.25°, 13.73°, 14.63°, 16.94°, 19.79° and 23.23°.
在一些具体实施方案中，式(I)化合物的乙醇酸共晶晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.61°、6.83°、8.27°、11.25°、11.50°、13.73°、14.63°、16.63°、16.94°、19.79°、20.37°、21.33°、23.23°和24.68。In some specific embodiments, the glycolic acid eutectic crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.61°, 6.83°, 8.27 °, 11.25°, 11.50°, 13.73°, 14.63°, 16.63°, 16.94°, 19.79°, 20.37°, 21.33°, 23.23° and 24.68.
在一些具体实施方案中，式(I)化合物的乙醇酸共晶晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.61°、6.83°、7.77°、8.27°、9.32°、9.64°、11.25°、11.50°、12.02°、13.73°、14.63°、15.33°、16.63°、16.94°、17.80°、19.79°、20.37°、21.33°、21.58°、22.10°、22.64°、23.23°、24.21°、24.68°、25.33°、26.16°、27.99°、 32.77°。In some specific embodiments, the glycolic acid eutectic crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.61°, 6.83°, 7.77 °, 8.27°, 9.32°, 9.64°, 11.25°, 11.50°, 12.02°, 13.73°, 14.63°, 15.33°, 16.63°, 16.94°, 17.80°, 19.79°, 20.37°, 21.33°, 21.58°, 22.10°, 22.64°, 23.23°, 24.21°, 24.68°, 25.33°, 26.16°, 27.99°, 32.77°.
在一些具体实施方案中，式(I)化合物的乙醇酸共晶晶体Type A，其X-射线粉末衍射图如图66所示。In some embodiments, the X-ray powder diffraction pattern of the glycolic acid eutectic crystal Type A of the compound of formula (I) is shown in Figure 66.
在一些具体实施方案中，式(I)化合物的乙醇酸共晶晶体Type B，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.44°、6.70°、8.29°、10.96°、13.50°、14.25°、16.48°、20.83°和25.06°。In some embodiments, the glycolic acid eutectic crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.44°, 6.70°, 8.29 °, 10.96°, 13.50°, 14.25°, 16.48°, 20.83° and 25.06°.
在一些具体实施方案中，式(I)化合物的乙醇酸共晶晶体Type B，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.44°、6.70°、8.29°、10.96°、11.36、13.50°、14.25°、16.48°、19.66°、19.92°、20.48°、20.83°和25.06°。In some embodiments, the glycolic acid eutectic crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.44°, 6.70°, 8.29 °, 10.96°, 11.36, 13.50°, 14.25°, 16.48°, 19.66°, 19.92°, 20.48°, 20.83° and 25.06°.
在一些具体实施方案中，式(I)化合物的乙醇酸共晶晶体Type B，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.44°、6.70°、8.29°、10.96°、11.36°、12.07°、13.50°、14.25°、16.48°、19.66°、19.92°、20.48°、20.83°、22.87、23.43、25.06°。In some embodiments, the glycolic acid eutectic crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.44°, 6.70°, 8.29 °, 10.96°, 11.36°, 12.07°, 13.50°, 14.25°, 16.48°, 19.66°, 19.92°, 20.48°, 20.83°, 22.87, 23.43, 25.06°.
在一些具体实施方案中，式(I)化合物的乙醇酸共晶晶体Type B，其X-射线粉末衍射图如图68所示。In some embodiments, the X-ray powder diffraction pattern of the glycolic acid eutectic crystal Type B of the compound of formula (I) is shown in Figure 68.
在本发明的第四个方面，提供了式(I)所示化合物的盐型，
In a fourth aspect of the present invention, a salt form of the compound represented by formula (I) is provided,
在一些具体实施方案中，式(I)所示化合物的盐型选自：其甲苯磺酸盐、其甲磺酸盐、其钾盐、其马来酸盐、其钠盐和其盐酸盐。In some specific embodiments, the salt form of the compound represented by formula (I) is selected from: its tosylate, its methanesulfonate, its potassium salt, its maleate, its sodium salt and its hydrochloride .
在一些具体实施方案中，式(I)所示化合物的对甲苯磺酸盐，其中，式(I)所示化合物与对甲苯磺酸的比例为1:1。In some specific embodiments, the p-toluenesulfonate salt of the compound represented by formula (I), wherein the ratio of the compound represented by formula (I) to p-toluenesulfonic acid is 1:1.
在一些具体实施方案中，式(I)所示化合物的甲磺酸盐，其中，式(I)所示化合物与甲磺酸的比例为1:1～1.2。In some specific embodiments, the methanesulfonate salt of the compound represented by formula (I), wherein the ratio of the compound represented by formula (I) to methanesulfonic acid is 1:1 to 1.2.
在一些具体实施方案中，式(I)所示化合物的钾盐，其具有结构 In some specific embodiments, the potassium salt of the compound represented by formula (I) has the structure
在一些具体实施方案中，式(I)所示化合物的其马来酸盐，其中，式(I)所示化合物与马来酸的比例为1:1。 In some specific embodiments, the maleate salt of the compound represented by formula (I), wherein the ratio of the compound represented by formula (I) to maleic acid is 1:1.
在一些具体实施方案中，式(I)所示化合物的钠盐，其具有结构 In some specific embodiments, the sodium salt of the compound represented by formula (I) has the structure
在一些具体实施方案中，式(I)所示化合物的盐酸盐，其中，式(I)所示化合物与盐酸的比例为1:1。In some specific embodiments, the hydrochloride salt of the compound represented by formula (I), wherein the ratio of the compound represented by formula (I) to hydrochloric acid is 1:1.
在本发明的第五个方面，提供了式(I)所示化合物的盐型晶体，
In the fifth aspect of the present invention, salt form crystals of the compound represented by formula (I) are provided,
在一些具体实施方案中，式(I)所示化合物的盐型晶体选自：In some specific embodiments, the salt form crystal of the compound represented by formula (I) is selected from:
其对甲苯磺酸盐晶体，其中，式(I)所示化合物与对甲苯磺酸的比例为1:1；Its p-toluenesulfonate crystal, wherein the ratio of the compound represented by formula (I) to p-toluenesulfonic acid is 1:1;
其甲磺酸盐晶体，其中，式(I)所示化合物与甲磺酸的比例为1:1～1.2；Its methanesulfonate crystal, wherein the ratio of the compound represented by formula (I) to methanesulfonic acid is 1:1 to 1.2;
其钾盐晶体，其具有结构 Its potassium salt crystals, which have the structure
其马来酸盐晶体，其中，式(I)所示化合物与马来酸的比例为1:1；Its maleate crystal, wherein the ratio of the compound represented by formula (I) to maleic acid is 1:1;
其钠盐晶体，其具有结构 Its sodium salt crystals, which have the structure
其盐酸盐晶体，其中，式(I)所示化合物与盐酸的比例为1:1。Its hydrochloride crystal, wherein the ratio of the compound represented by formula (I) to hydrochloric acid is 1:1.
在一些具体实施方案中，式(I)化合物的对甲苯磺酸盐晶体选自其对甲苯磺酸盐晶体Type A、其对甲苯磺酸盐晶体Type B、其对甲苯磺酸盐晶体Type C，其中，式(I)所示化合物与对甲苯磺酸的比例为1:1。In some specific embodiments, the p-toluenesulfonate crystals of the compound of formula (I) are selected from the group consisting of p-toluenesulfonate crystals Type A, p-toluenesulfonate crystals Type B, and p-toluenesulfonate crystals Type C , wherein the ratio of the compound represented by formula (I) to p-toluenesulfonic acid is 1:1.
在一些具体实施方案中，式(I)化合物的对甲苯磺酸盐晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：7.41°、9.57°、9.92°、16.06°、16.94°、19.70 °、20.44°、22.07°和26.24°。In some specific embodiments, the p-toluenesulfonate crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 7.41°, 9.57°, 9.92°, 16.06°, 16.94°, 19.70 °, 20.44°, 22.07° and 26.24°.
在一些具体实施方案中，式(I)化合物的对甲苯磺酸盐晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：7.41°、9.14°、9.57°、9.92°、11.25°、12.95°、14.45°、16.06°、16.94°、19.70°、20.44°、21.30°、22.07°、24.82°、25.52°和26.24°。In some specific embodiments, the p-toluenesulfonate crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 7.41°, 9.14°, 9.57°, 9.92°, 11.25°, 12.95°, 14.45°, 16.06°, 16.94°, 19.70°, 20.44°, 21.30°, 22.07°, 24.82°, 25.52° and 26.24°.
在一些具体实施方案中，式(I)化合物的对甲苯磺酸盐晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：7.41°、9.14°、9.57°、9.92°、10.98°、11.25°、12.95°、14.33°、14.45°、15.05°、15.21°、15.82°、16.06°、16.94°、17.56°、17.77°、18.07°、18.38°、19.23°、19.41°、19.70°、20.44°、21.08°、21.30°、22.07°、22.41°、22.67°、23.19°、23.46°、24.82°、25.52°、26.02°、26.24°、28.12°、28.72°、30.18°、30.74°、32.03°。In some specific embodiments, the p-toluenesulfonate crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 7.41°, 9.14°, 9.57°、9.92°、10.98°、11.25°、12.95°、14.33°、14.45°、15.05°、15.21°、15.82°、16.06°、16.94°、17.56°、17.77°、18.07°、18.38°、19.23° , 19.41°, 19.70°, 20.44°, 21.08°, 21.30°, 22.07°, 22.41°, 22.67°, 23.19°, 23.46°, 24.82°, 25.52°, 26.02°, 26.24°, 28.12°, 28.72°, 30.18 °, 30.74°, 32.03°.
在一些具体实施方案中，式(I)化合物的对甲苯磺酸盐晶体Type A，其X-射线粉末衍射图如图34所示。In some embodiments, the p-toluenesulfonate crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern as shown in Figure 34.
在一些具体实施方案中，式(I)化合物的对甲苯磺酸盐晶体Type B，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：6.35°、6.93°、7.63°、14.59°、16.79°和20.79°。In some embodiments, the p-toluenesulfonate crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 6.35°, 6.93°, 7.63°, 14.59°, 16.79° and 20.79°.
在一些具体实施方案中，式(I)化合物的对甲苯磺酸盐晶体Type B，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：6.35°、6.93°、7.63°、11.29°、14.59°、16.79°、17.72°、20.79°、22.25°和26.56°。In some embodiments, the p-toluenesulfonate crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 6.35°, 6.93°, 7.63°, 11.29°, 14.59°, 16.79°, 17.72°, 20.79°, 22.25° and 26.56°.
在一些具体实施方案中，式(I)化合物的对甲苯磺酸盐晶体Type B，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：6.35°、6.93°、7.63°、8.29°、11.29°、12.72°、14.59°、16.79°、17.72°、19.33°、20.79°、22.25°、23.05°、25.19°、26.56°、27.84°。In some embodiments, the p-toluenesulfonate crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 6.35°, 6.93°, 7.63°, 8.29°, 11.29°, 12.72°, 14.59°, 16.79°, 17.72°, 19.33°, 20.79°, 22.25°, 23.05°, 25.19°, 26.56°, 27.84°.
在一些具体实施方案中，式(I)化合物的对甲苯磺酸盐晶体Type B，其X-射线粉末衍射图如图36所示。In some embodiments, the p-toluenesulfonate crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern as shown in Figure 36.
在一些具体实施方案中，式(I)化合物的对甲苯磺酸盐晶体Type C，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.19°、6.87°、10.06°、13.79°、16.62°、16.93°、20.44°、24.53°和26.12°。In some specific embodiments, the p-toluenesulfonate crystal Type C of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.19°, 6.87°, 10.06°, 13.79°, 16.62°, 16.93°, 20.44°, 24.53° and 26.12°.
在一些具体实施方案中，式(I)化合物的对甲苯磺酸盐晶体Type C，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.19°、6.87°、10.06°、13.79°、14.79°、16.62°、16.93°、17.23°、20.44°、21.03°、24.53°、24.93°和26.12°。In some specific embodiments, the p-toluenesulfonate crystal Type C of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.19°, 6.87°, 10.06°, 13.79°, 14.79°, 16.62°, 16.93°, 17.23°, 20.44°, 21.03°, 24.53°, 24.93° and 26.12°.
在一些具体实施方案中，式(I)化合物的对甲苯磺酸盐晶体Type C，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.19°、6.87°、10.06°、12.06°、12.72°、12.95°、13.58°、13.79°、14.17°、14.46°、14.79°、16.62°、16.93°、17.23°、18.76°、19.36°、20.44°、21.03°、21.55°、21.83°、22.10°、23.31°、23.51°、23.73°、24.13°、24.53°、24.93°、25.60°、26.12°、27.26°、27.76°、29.50°、29.84°、30.52°。 In some specific embodiments, the p-toluenesulfonate crystal Type C of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.19°, 6.87°, 10.06°、12.06°、12.72°、12.95°、13.58°、13.79°、14.17°、14.46°、14.79°、16.62°、16.93°、17.23°、18.76°、19.36°、20.44°、21.03°、21.55° , 21.83°, 22.10°, 23.31°, 23.51°, 23.73°, 24.13°, 24.53°, 24.93°, 25.60°, 26.12°, 27.26°, 27.76°, 29.50°, 29.84°, 30.52°.
在一些具体实施方案中，式(I)化合物的对甲苯磺酸盐晶体Type C，其X-射线粉末衍射图如图38所示。In some embodiments, the p-toluenesulfonate crystal Type C of the compound of formula (I) has an X-ray powder diffraction pattern as shown in Figure 38.
在一些具体实施方案中，式(I)化合物的甲磺酸盐晶体选自其甲磺酸盐晶体Type A、其甲磺酸盐晶体Type B、其甲磺酸盐晶体Type C，其中，式(I)所示化合物与甲磺酸的比例为1:1～1.2。In some specific embodiments, the mesylate crystal of the compound of formula (I) is selected from its mesylate crystal Type A, its mesylate crystal Type B, its mesylate crystal Type C, wherein, the formula The ratio of the compound shown in (I) to methanesulfonic acid is 1:1 to 1.2.
在一些具体实施方案中，式(I)化合物的甲磺酸盐晶体为其甲磺酸盐晶体Type A，式(I)所示化合物与甲磺酸的比例为1:1。In some specific embodiments, the mesylate crystal of the compound of formula (I) is its mesylate crystal Type A, and the ratio of the compound of formula (I) to methanesulfonic acid is 1:1.
在一些具体实施方案中，式(I)化合物的甲磺酸盐晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：8.09°、9.60°、11.06°、12.57°、14.33°、14.55°、16.93°、19.32°、19.64°、20.19°、20.31°、21.05°和26.42°。In some embodiments, the mesylate crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 8.09°, 9.60°, 11.06 °, 12.57°, 14.33°, 14.55°, 16.93°, 19.32°, 19.64°, 20.19°, 20.31°, 21.05° and 26.42°.
在一些具体实施方案中，式(I)化合物的甲磺酸盐晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：8.09°、9.60°、10.75°、11.06°、12.57°、14.33°、14.55°、16.52°、16.93°、19.32°、19.64°、20.19°、20.31°、21.05°、21.59°、22.98°、24.72°、26.42°、27.00°和28.30°。In some embodiments, the mesylate crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 8.09°, 9.60°, 10.75 °, 11.06°, 12.57°, 14.33°, 14.55°, 16.52°, 16.93°, 19.32°, 19.64°, 20.19°, 20.31°, 21.05°, 21.59°, 22.98°, 24.72°, 26.42°, 27.00° and 28.30°.
在一些具体实施方案中，式(I)化合物的甲磺酸盐晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：8.09°、8.69°、9.60°、10.75°、11.06°、12.02°、12.57°、13.85°、14.33°、14.55°、15.33°、15.89°、16.52°、16.93°、17.39°、17.67°、17.93°、19.32°、19.64°、19.96°、20.19°、20.31°、20.65°、21.05°、21.59°、21.78°、22.25°、22.51°、22.70°、22.98°、24.52°、24.72°、25.26°、25.89°、26.42°、27.00°、27.41°、28.30°、28.55°、29.47°、31.47°、33.70°。In some specific embodiments, the mesylate crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 8.09°, 8.69°, 9.60 °, 10.75°, 11.06°, 12.02°, 12.57°, 13.85°, 14.33°, 14.55°, 15.33°, 15.89°, 16.52°, 16.93°, 17.39°, 17.67°, 17.93°, 19.32°, 19.64°, 19.96°、20.19°、20.31°、20.65°、21.05°、21.59°、21.78°、22.25°、22.51°、22.70°、22.98°、24.52°、24.72°、25.26°、25.89°、26.42°、27.00° , 27.41°, 28.30°, 28.55°, 29.47°, 31.47°, 33.70°.
在一些具体实施方案中，式(I)化合物的甲磺酸盐晶体Type A，其X-射线粉末衍射图如图44所示。In some embodiments, the mesylate crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern as shown in Figure 44.
在一些具体实施方案中，式(I)化合物的甲磺酸盐晶体为其甲磺酸盐晶体Type B，式(I)所示化合物与对甲磺酸的比例为1:1.2。In some specific embodiments, the mesylate crystal of the compound of formula (I) is its mesylate crystal Type B, and the ratio of the compound of formula (I) to p-methanesulfonic acid is 1:1.2.
在一些具体实施方案中，式(I)化合物的甲磺酸盐晶体Type B，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.74°、5.89°、11.53°、11.93°、12.47°、12.90°、14.06°、15.01°、17.14°和25.52°。In some embodiments, the mesylate crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.74°, 5.89°, 11.53 °, 11.93°, 12.47°, 12.90°, 14.06°, 15.01°, 17.14° and 25.52°.
在一些具体实施方案中，式(I)化合物的甲磺酸盐晶体Type B，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.74°、5.89°、7.66°、11.53°、11.93°、12.47°、12.90°、14.06°、15.01°、17.14°、22.60°和25.52°。In some embodiments, the mesylate crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.74°, 5.89°, 7.66 °, 11.53°, 11.93°, 12.47°, 12.90°, 14.06°, 15.01°, 17.14°, 22.60° and 25.52°.
在一些具体实施方案中，式(I)化合物的甲磺酸盐晶体Type B，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.74°、5.89°、7.66°、7.95°、8.95°、10.21°、11.53°、11.93°、12.47°、12.90°、14.06°、15.01°、17.14°、17.99°、20.49°、22.60°、23.90°、25.52°、26.39°。 In some specific embodiments, the mesylate crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.74°, 5.89°, 7.66 °, 7.95°, 8.95°, 10.21°, 11.53°, 11.93°, 12.47°, 12.90°, 14.06°, 15.01°, 17.14°, 17.99°, 20.49°, 22.60°, 23.90°, 25.52°, 26.39°.
在一些具体实施方案中，式(I)化合物的甲磺酸盐晶体Type B，其X-射线粉末衍射图如图46所示。In some embodiments, the mesylate crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern as shown in Figure 46.
在一些具体实施方案中，式(I)化合物的甲磺酸盐晶体为其甲磺酸盐晶体Type C，式(I)所示化合物与对甲磺酸的比例为1:1。In some specific embodiments, the mesylate crystal of the compound of formula (I) is its methanesulfonate crystal Type C, and the ratio of the compound of formula (I) to p-methanesulfonic acid is 1:1.
在一些具体实施方案中，式(I)化合物的甲磺酸盐晶体Type C，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.32°、8.45°、11.84°、17.01°、18.49°、21.30°和22.98°。In some embodiments, the mesylate crystal Type C of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.32°, 8.45°, 11.84 °, 17.01°, 18.49°, 21.30° and 22.98°.
在一些具体实施方案中，式(I)化合物的甲磺酸盐晶体Type C，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.32°、8.45°、10.30°、11.84°、16.06°、17.01°、18.49°、21.30°、22.98°和24.30°。In some specific embodiments, the mesylate crystal Type C of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.32°, 8.45°, 10.30 °, 11.84°, 16.06°, 17.01°, 18.49°, 21.30°, 22.98° and 24.30°.
在一些具体实施方案中，式(I)化合物的甲磺酸盐晶体Type C，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.32°、8.45°、10.30°、11.84°、14.48°、14.78°、15.28°、16.06°、17.01°、18.49°、20.46°、20.91°、21.30°、22.98°、23.51°、24.30°、24.85°、25.44°、25.83°、28.47°、30.85°。In some specific embodiments, the mesylate crystal Type C of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.32°, 8.45°, 10.30 °, 11.84°, 14.48°, 14.78°, 15.28°, 16.06°, 17.01°, 18.49°, 20.46°, 20.91°, 21.30°, 22.98°, 23.51°, 24.30°, 24.85°, 25.44°, 25.83°, 28.47°, 30.85°.
在一些具体实施方案中，式(I)化合物的甲磺酸盐晶体Type C，其X-射线粉末衍射图如图48所示。In some embodiments, the mesylate crystal Type C of the compound of formula (I) has an X-ray powder diffraction pattern as shown in Figure 48.
在一些具体实施方案中，式(I)化合物的钾盐晶体为其钾盐晶体Type A。In some embodiments, the potassium salt crystal of the compound of formula (I) is its potassium salt crystal Type A.
在一些具体实施方案中，式(I)化合物的钾盐晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.74°、6.68°、7.96°、13.54°、14.04°、17.78°、20.14°和23.29°。In some specific embodiments, the potassium salt crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.74°, 6.68°, 7.96°, 13.54°, 14.04°, 17.78°, 20.14° and 23.29°.
在一些具体实施方案中，式(I)化合物的钾盐晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.74°、6.68°、7.96°、11.78°、13.54°、14.04°、15.33°、17.78°、19.45°、20.14°、23.29°、24.72°、26.92°和28.29°。In some specific embodiments, the potassium salt crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.74°, 6.68°, 7.96°, 11.78°, 13.54°, 14.04°, 15.33°, 17.78°, 19.45°, 20.14°, 23.29°, 24.72°, 26.92° and 28.29°.
在一些具体实施方案中，式(I)化合物的钾盐晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.74°、6.68°、7.96°、11.52°、11.78°、13.54°、14.04°、14.44°、15.33°、16.22°、16.71°、17.43°、17.78°、18.20°、18.40°、18.86°、19.45°、20.14°、20.70°、22.75°、23.29°、24.15°、24.72°、26.39°、26.92°、27.37°、27.62°、28.29°、31.39°、36.10°。In some specific embodiments, the potassium salt crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.74°, 6.68°, 7.96°, 11.52°、11.78°、13.54°、14.04°、14.44°、15.33°、16.22°、16.71°、17.43°、17.78°、18.20°、18.40°、18.86°、19.45°、20.14°、20.70°、22.75° , 23.29°, 24.15°, 24.72°, 26.39°, 26.92°, 27.37°, 27.62°, 28.29°, 31.39°, 36.10°.
在一些具体实施方案中，式(I)化合物的钾盐晶体Type A，其X-射线粉末衍射图如图50所示。In some embodiments, the X-ray powder diffraction pattern of the potassium salt crystal Type A of the compound of formula (I) is as shown in Figure 50.
在一些具体实施方案中，式(I)化合物的马来酸盐晶体选自：其马来酸盐晶体Type A、其马来酸盐晶体Type B，其中，式(I)化合物与马来酸的比例为1:1。In some specific embodiments, the maleate crystal of the compound of formula (I) is selected from: its maleate crystal Type A, its maleate crystal Type B, wherein the compound of formula (I) and maleic acid The ratio is 1:1.
在一些具体实施方案中，式(I)化合物的马来酸盐晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：4.26°、4.76°、7.08°、7.96°、8.54°、9.53°、10.18 °、10.93°、14.34°、15.03°、15.99°和20.50°。In some specific embodiments, the maleate crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 4.26°, 4.76°, 7.08 °, 7.96°, 8.54°, 9.53°, 10.18 °, 10.93°, 14.34°, 15.03°, 15.99° and 20.50°.
在一些具体实施方案中，式(I)化合物的马来酸盐晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：4.26°、4.76°、7.08°、7.96°、8.54°、9.53°、10.18°、10.93°、13.89°、14.34°、15.03°、15.99°、20.50°、21.49°和24.03°。In some embodiments, the maleate crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 4.26°, 4.76°, 7.08 °, 7.96°, 8.54°, 9.53°, 10.18°, 10.93°, 13.89°, 14.34°, 15.03°, 15.99°, 20.50°, 21.49° and 24.03°.
在一些具体实施方案中，式(I)化合物的马来酸盐晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：4.26°、4.76°、7.08°、7.96°、8.54°、9.53°、10.18°、10.93°、12.41°、13.89°、14.34°、15.03°、15.99°、17.93°、20.50°、21.49°、23.55°和24.03°。In some embodiments, the maleate crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 4.26°, 4.76°, 7.08 °, 7.96°, 8.54°, 9.53°, 10.18°, 10.93°, 12.41°, 13.89°, 14.34°, 15.03°, 15.99°, 17.93°, 20.50°, 21.49°, 23.55° and 24.03°.
在一些具体实施方案中，式(I)化合物的马来酸盐晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：4.26°、4.76°、7.08°、7.96°、8.54°、9.53°、10.18°、10.93°、12.41°、13.89°、14.34°、15.03°、15.99°、17.93°、20.50°、21.49°、21.97°、23.55°、24.03°、25.19°、25.57°、26.00°。In some embodiments, the maleate crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 4.26°, 4.76°, 7.08 °, 7.96°, 8.54°, 9.53°, 10.18°, 10.93°, 12.41°, 13.89°, 14.34°, 15.03°, 15.99°, 17.93°, 20.50°, 21.49°, 21.97°, 23.55°, 24.03°, 25.19°, 25.57°, 26.00°.
在一些具体实施方案中，式(I)化合物的马来酸盐晶体Type A，其X-射线粉末衍射图如图52所示。In some embodiments, the maleate salt crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern as shown in Figure 52.
在一些具体实施方案中，式(I)化合物的马来酸盐晶体Type B，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：4.34°、4.79°、5.27°、7.20°、7.86°、10.22°、10.56°、11.08°、14.73°、15.20°、16.14°和20.50°。In some embodiments, the maleate crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 4.34°, 4.79°, 5.27 °, 7.20°, 7.86°, 10.22°, 10.56°, 11.08°, 14.73°, 15.20°, 16.14° and 20.50°.
在一些具体实施方案中，式(I)化合物的马来酸盐晶体Type B，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：4.34°、4.79°、5.27°、7.20°、7.86°、10.22°、10.56°、11.08°、11.81°、14.44°、14.73°、15.20°、16.14°和20.50°。In some embodiments, the maleate crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 4.34°, 4.79°, 5.27 °, 7.20°, 7.86°, 10.22°, 10.56°, 11.08°, 11.81°, 14.44°, 14.73°, 15.20°, 16.14° and 20.50°.
在一些具体实施方案中，式(I)化合物的马来酸盐晶体Type B，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：4.34°、4.79°、5.27°、7.20°、7.86°、8.63°、9.60°、10.22°、10.56°、11.08°、11.81°、13.94°、14.44°、14.73°、15.20°、16.14°、20.50°、21.25°、21.83°、26.32°。In some embodiments, the maleate crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 4.34°, 4.79°, 5.27 °, 7.20°, 7.86°, 8.63°, 9.60°, 10.22°, 10.56°, 11.08°, 11.81°, 13.94°, 14.44°, 14.73°, 15.20°, 16.14°, 20.50°, 21.25°, 21.83°, 26.32°.
在一些具体实施方案中，式(I)化合物的马来酸盐晶体Type B，其X-射线粉末衍射图如图54所示。In some embodiments, the X-ray powder diffraction pattern of the maleate salt crystal Type B of the compound of formula (I) is shown in Figure 54.
在一些具体实施方案中，式(I)化合物的钠盐晶体为其钠盐晶体Type B。In some specific embodiments, the sodium salt crystal of the compound of formula (I) is its sodium salt crystal Type B.
在一些具体实施方案中，式(I)化合物的钠盐晶体Type B，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：6.01°、6.61°、7.94°、11.88°、12.48°、13.10°、13.70°、18.31°、19.98°、21.19°、22.35°、25.36°和26.27°。In some specific embodiments, the sodium salt crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 6.01°, 6.61°, 7.94°, 11.88°, 12.48°, 13.10°, 13.70°, 18.31°, 19.98°, 21.19°, 22.35°, 25.36° and 26.27°.
在一些具体实施方案中，式(I)化合物的钠盐晶体Type B，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：6.01°、6.61°、7.94°、11.88°、12.48°、13.10°、13.31°、13.70°、16.52°、17.48°、18.31°、19.98°、21.19°、22.35°、24.81°、25.36°和26.27°。In some specific embodiments, the sodium salt crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 6.01°, 6.61°, 7.94°, 11.88°, 12.48°, 13.10°, 13.31°, 13.70°, 16.52°, 17.48°, 18.31°, 19.98°, 21.19°, 22.35°, 24.81°, 25.36° and 26.27°.
在一些具体实施方案中，式(I)化合物的钠盐晶体Type B，其X-射线粉末衍射图在下 列2θ角处(±0.2°)具有特征衍射峰：6.01°、6.61°、7.94°、11.88°、12.48°、13.10°、13.31°、13.70°、14.96°、15.25°、16.52°、17.48°、18.31°、19.07°、19.98°、20.59°、21.19°、22.35°、23.86°、24.81°、25.36°、26.27°、27.78°、28.28°、31.15°、31.79°。In some specific embodiments, the sodium salt crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern as follows There are characteristic diffraction peaks at the 2θ angle (±0.2°): 6.01°, 6.61°, 7.94°, 11.88°, 12.48°, 13.10°, 13.31°, 13.70°, 14.96°, 15.25°, 16.52°, 17.48°, 18.31°, 19.07°, 19.98°, 20.59°, 21.19°, 22.35°, 23.86°, 24.81°, 25.36°, 26.27°, 27.78°, 28.28°, 31.15°, 31.79°.
在一些具体实施方案中，式(I)化合物的钠盐晶体Type B，其X-射线粉末衍射图如图56所示。In some embodiments, the X-ray powder diffraction pattern of the sodium salt crystal Type B of the compound of formula (I) is as shown in Figure 56.
在一些具体实施方案中，式(I)化合物的盐酸盐晶体选自其盐酸盐晶体Type A、其盐酸盐晶体Type B，其中，式(I)化合物与盐酸的比例为1:1。In some specific embodiments, the hydrochloride crystal of the compound of formula (I) is selected from its hydrochloride crystal Type A, its hydrochloride crystal Type B, wherein the ratio of the compound of formula (I) to hydrochloric acid is 1:1 .
在一些具体实施方案中，式(I)化合物的盐酸盐晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.90°、7.42°、7.74°、10.96°、14.07°、14.96°、18.01°、25.14°和26.42°。In some embodiments, the hydrochloride crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.90°, 7.42°, 7.74° , 10.96°, 14.07°, 14.96°, 18.01°, 25.14° and 26.42°.
在一些具体实施方案中，式(I)化合物的盐酸盐晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.90°、7.42°、7.74°、10.96°、11.56°、12.15°、14.07°、14.96°、18.01°、21.93°、23.42°、25.14°和26.42°。In some embodiments, the hydrochloride crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.90°, 7.42°, 7.74° , 10.96°, 11.56°, 12.15°, 14.07°, 14.96°, 18.01°, 21.93°, 23.42°, 25.14° and 26.42°.
在一些具体实施方案中，式(I)化合物的盐酸盐晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.90°、7.42°、7.74°、10.96°、11.56°、12.15°、13.39°、14.07°、14.96°、17.60°、18.01°、19.26°、19.70°、21.55°、21.93°、23.42°、25.14°、25.56°、26.42°、27.71°、28.84°、29.26°。In some embodiments, the hydrochloride crystal Type A of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.90°, 7.42°, 7.74° , 10.96°, 11.56°, 12.15°, 13.39°, 14.07°, 14.96°, 17.60°, 18.01°, 19.26°, 19.70°, 21.55°, 21.93°, 23.42°, 25.14°, 25.56°, 26.42°, 27.71 °, 28.84°, 29.26°.
在一些具体实施方案中，式(I)化合物的盐酸盐晶体Type A，其X-射线粉末衍射图如图62所示。In some embodiments, the X-ray powder diffraction pattern of the hydrochloride crystal Type A of the compound of formula (I) is as shown in Figure 62.
在一些具体实施方案中，式(I)化合物的盐酸盐晶体Type B，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：6.48°、7.20°、7.90°、14.16°、14.48°、15.68°、17.31°、21.76°和26.53°。In some embodiments, the hydrochloride crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 6.48°, 7.20°, 7.90° , 14.16°, 14.48°, 15.68°, 17.31°, 21.76° and 26.53°.
在一些具体实施方案中，式(I)化合物的盐酸盐晶体Type B，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.42°、6.48°、7.20°、7.90°、12.85°、13.01°、14.16°、14.48°、15.68°、17.31°、19.36°、21.76°、22.91°和26.53°。In some specific embodiments, the hydrochloride crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.42°, 6.48°, 7.20° , 7.90°, 12.85°, 13.01°, 14.16°, 14.48°, 15.68°, 17.31°, 19.36°, 21.76°, 22.91° and 26.53°.
在一些具体实施方案中，式(I)化合物的盐酸盐晶体Type B，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：4.80°、5.42°、6.48°、7.20°、7.90°、10.00°、13.50°、10.39°、12.85°、13.01°、14.16°、14.48°、15.68°、17.31°、19.36°、19.64°、21.76°、22.91°、23.86°、24.40°、25.72°、25.95°、26.14°、26.53°、28.53°、31.86°、。In some embodiments, the hydrochloride crystal Type B of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 4.80°, 5.42°, 6.48° , 7.20°, 7.90°, 10.00°, 13.50°, 10.39°, 12.85°, 13.01°, 14.16°, 14.48°, 15.68°, 17.31°, 19.36°, 19.64°, 21.76°, 22.91°, 23.86°, 24.40 °, 25.72°, 25.95°, 26.14°, 26.53°, 28.53°, 31.86°,.
在一些具体实施方案中，式(I)化合物的盐酸盐晶体Type B，其X-射线粉末衍射图如图64所示。In some embodiments, the X-ray powder diffraction pattern of the hydrochloride crystal Type B of the compound of formula (I) is as shown in Figure 64.
说明：illustrate:
本发明中所述的溶剂化物晶体、共晶晶体或者盐型晶体的比例，除特别注明外，均为摩尔比。 The ratios of solvate crystals, eutectic crystals or salt-type crystals mentioned in the present invention are molar ratios unless otherwise specified.
本发明中“溶剂合物”、“溶剂化物”为表达的同样的意思，可以互换。In the present invention, "solvate" and "solvate" have the same meaning and can be interchanged.
本发明中“晶体”、“晶型”为表达的同样的意思，可以互换。In the present invention, "crystal" and "crystal form" have the same meaning and can be interchanged.
发明效果：Invention effect:
本发明的提供式(I)所示化合物的多种新晶型、盐型及共晶晶型，以满足不同临床需求。The present invention provides a variety of new crystal forms, salt forms and eutectic crystal forms of the compound represented by formula (I) to meet different clinical needs.
附图说明：Picture description:
图1为式(I)所示为化合物甲醇溶剂化晶体A的XPRD谱图。Figure 1 is the XPRD spectrum of compound methanol solvated crystal A represented by formula (I).
图2为式(I)所示为化合物甲醇溶剂化晶体A的质子核磁共振图谱。Figure 2 is a proton nuclear magnetic resonance spectrum of compound methanol solvated crystal A represented by formula (I).
图3为式(I)所示化合物水合物晶体AA的XPRD谱图。Figure 3 is the XPRD spectrum of hydrate crystal AA of the compound represented by formula (I).
图4为式(I)所示化合物水合物晶体AA的质子核磁共振图谱。Figure 4 is a proton nuclear magnetic resonance spectrum of the hydrate crystal AA of the compound represented by formula (I).
图5为式(I)所示化合物甲醇溶剂化晶体AE的XPRD谱图。Figure 5 is the XPRD spectrum of the methanol solvated crystal AE of the compound represented by formula (I).
图6为式(I)所示化合物甲醇溶剂化晶体AE的质子核磁共振图谱。Figure 6 is a proton nuclear magnetic resonance spectrum of the methanol solvated crystal AE of the compound represented by formula (I).
图7为式(I)所示化合物非溶剂化物晶体AH的XPRD谱图。Figure 7 is the XPRD spectrum of the unsolvate crystal AH of the compound represented by formula (I).
图8为式(I)所示化合物非溶剂化物晶体AH的质子核磁共振图谱。Figure 8 is a proton nuclear magnetic resonance spectrum of the unsolvated crystal AH of the compound represented by formula (I).
图9为式(I)所示化合物非溶剂化物晶体AH的差示扫描量热分析曲线图谱。Figure 9 is a differential scanning calorimetry analysis curve chart of the unsolvate crystal AH of the compound represented by formula (I).
图10为式(I)所示化合物非溶剂化物晶体AH的热重分析曲线图谱。Figure 10 is a thermogravimetric analysis curve chart of the unsolvated crystal AH of the compound represented by formula (I).
图11为式(I)所示化合物非溶剂化物晶体E(E晶型)的XPRD谱图。Figure 11 is the XPRD spectrum of the unsolvate crystal E (form E) of the compound represented by formula (I).
图12为式(I)所示化合物非溶剂化物晶体E(E晶型)的质子核磁共振图谱。Figure 12 is a proton nuclear magnetic resonance spectrum of the unsolvate crystal E (form E) of the compound represented by formula (I).
图13为式(I)所示化合物非溶剂化物晶体E(E晶型)的差示扫描量热分析曲线图谱。Figure 13 is a differential scanning calorimetry analysis curve chart of the unsolvated crystal E (form E) of the compound represented by formula (I).
图14为式(I)所示化合物非溶剂化物晶体E(E晶型)的热重分析曲线图谱。Figure 14 is a thermogravimetric analysis curve chart of the unsolvate crystal E (form E) of the compound represented by formula (I).
图15为式(I)所示化合物非溶剂化物晶体E(E晶型)的X-射线单晶衍射图谱。Figure 15 is the X-ray single crystal diffraction pattern of the nonsolvate crystal E (E crystal form) of the compound represented by formula (I).
图16为式(I)所示化合物甲酸溶剂化晶体F的XPRD谱图。Figure 16 is the XPRD spectrum of formic acid solvated crystal F of the compound represented by formula (I).
图17为式(I)所示化合物甲酸溶剂化晶体F的质子核磁共振图谱。Figure 17 is a proton nuclear magnetic resonance spectrum of the formic acid solvated crystal F of the compound represented by formula (I).
图18为式(I)所示化合物甲酸溶剂合物晶体O的XPRD谱图。Figure 18 is the XPRD spectrum of formic acid solvate crystal O of the compound represented by formula (I).
图19为式(I)所示化合物甲酸溶剂合物晶体O的质子核磁共振图谱。Figure 19 is a proton nuclear magnetic resonance spectrum of the formic acid solvate crystal O of the compound represented by formula (I).
图20为式(I)所示化合物水合物晶体T的XPRD谱图。Figure 20 is the XPRD spectrum of hydrate crystal T of the compound represented by formula (I).
图21为式(I)所示化合物水合物晶体T的质子核磁共振图谱。Figure 21 is a proton nuclear magnetic resonance spectrum of hydrate crystal T of the compound represented by formula (I).
图22为式(I)所示化合物水合物晶体V的XPRD谱图。Figure 22 is the XPRD spectrum of hydrate crystal V of the compound represented by formula (I).
图23为式(I)所示化合物水合物晶体V的质子核磁共振图谱。Figure 23 is a proton nuclear magnetic resonance spectrum of hydrate crystal V of the compound represented by formula (I).
图24为式(I)所示化合物甲酸溶剂合物晶体AF的XPRD谱图。Figure 24 is the XPRD spectrum of formic acid solvate crystal AF of the compound represented by formula (I).
图25为式(I)所示化合物甲酸溶剂合物晶体AF的质子核磁共振图谱。Figure 25 is a proton nuclear magnetic resonance spectrum of the formic acid solvate crystal AF of the compound represented by formula (I).
图26为式(I)所示化合物水合物晶体L的XPRD谱图。Figure 26 is an XPRD spectrum of hydrate crystal L of the compound represented by formula (I).
图27为式(I)所示化合物水合物晶体L的质子核磁共振图谱。 Figure 27 is a proton nuclear magnetic resonance spectrum of hydrate crystal L of the compound represented by formula (I).
图28为式(I)所示化合物乙醇溶剂合物晶体R的XPRD谱图。Figure 28 is the XPRD spectrum of the ethanol solvate crystal R of the compound represented by formula (I).
图29为式(I)所示化合物乙醇溶剂合物晶体R的质子核磁共振图谱。Figure 29 is a proton nuclear magnetic resonance spectrum of the ethanol solvate crystal R of the compound represented by formula (I).
图30为式(I)所示化合物草酸共晶晶体Type A的XPRD谱图。Figure 30 is the XPRD spectrum of the oxalic acid eutectic crystal Type A of the compound represented by formula (I).
图31为式(I)所示化合物草酸共晶晶体Type A的质子核磁共振图谱。Figure 31 is the proton nuclear magnetic resonance spectrum of the oxalic acid eutectic crystal Type A of the compound represented by formula (I).
图32为式(I)所示化合物草酸共晶晶体Type B的XPRD谱图。Figure 32 is the XPRD spectrum of the oxalic acid eutectic crystal Type B of the compound represented by formula (I).
图33为式(I)所示化合物草酸共晶晶体Type B的质子核磁共振图谱。Figure 33 is the proton nuclear magnetic resonance spectrum of the oxalic acid eutectic crystal Type B of the compound represented by formula (I).
图34为式(I)所示化合物对甲苯磺酸盐晶体Type A的XPRD谱图。Figure 34 is the XPRD spectrum of the p-toluenesulfonate crystal Type A of the compound represented by formula (I).
图35为式(I)所示化合物对甲苯磺酸盐晶体Type A的质子核磁共振图谱。Figure 35 is the proton nuclear magnetic resonance spectrum of the compound p-toluenesulfonate crystal Type A represented by formula (I).
图36为式(I)所示化合物对甲苯磺酸盐晶体Type B的XPRD谱图。Figure 36 is the XPRD spectrum of the p-toluenesulfonate crystal Type B of the compound represented by formula (I).
图37为式(I)所示化合物对甲苯磺酸盐晶体Type B的质子核磁共振图谱。Figure 37 is a proton nuclear magnetic resonance spectrum of the compound p-toluenesulfonate crystal Type B represented by formula (I).
图38为式(I)所示化合物对甲苯磺酸盐晶体Type C的XPRD谱图。Figure 38 is the XPRD spectrum of the compound p-toluenesulfonate crystal Type C represented by formula (I).
图39为式(I)所示化合物对甲苯磺酸盐晶体Type C的质子核磁共振图谱。Figure 39 is the proton nuclear magnetic resonance spectrum of the compound p-toluenesulfonate crystal Type C represented by formula (I).
图40为式(I)所示化合物富马酸共晶晶体Type B的XPRD谱图。Figure 40 is the XPRD spectrum of fumaric acid eutectic crystal Type B of the compound represented by formula (I).
图41为式(I)所示化合物富马酸共晶晶体Type B的质子核磁共振图谱。Figure 41 is the proton nuclear magnetic resonance spectrum of the fumaric acid eutectic crystal Type B of the compound represented by formula (I).
图42为式(I)所示化合物富马酸共晶晶体Type C的XPRD谱图。Figure 42 is the XPRD spectrum of the fumaric acid eutectic crystal Type C of the compound represented by formula (I).
图43为式(I)所示化合物富马酸共晶晶体Type C的质子核磁共振图谱。Figure 43 is the proton nuclear magnetic resonance spectrum of the fumaric acid eutectic crystal Type C of the compound represented by formula (I).
图44为式(I)所示化合物甲磺酸盐晶体Type A的XPRD谱图。Figure 44 is the XPRD spectrum of the mesylate crystal Type A of the compound represented by formula (I).
图45为式(I)所示化合物甲磺酸盐晶体Type A的质子核磁共振图谱。Figure 45 is the proton nuclear magnetic resonance spectrum of the mesylate crystal Type A of the compound represented by formula (I).
图46为式(I)所示化合物甲磺酸盐晶体Type B的XPRD谱图。Figure 46 is the XPRD spectrum of the mesylate crystal Type B of the compound represented by formula (I).
图47为式(I)所示化合物甲磺酸盐晶体Type B的质子核磁共振图谱。Figure 47 is the proton nuclear magnetic resonance spectrum of the mesylate crystal Type B of the compound represented by formula (I).
图48为式(I)所示化合物甲磺酸盐晶体Type C的XPRD谱图。Figure 48 is the XPRD spectrum of the mesylate crystal Type C of the compound represented by formula (I).
图49为式(I)所示化合物甲磺酸盐晶体Type C的质子核磁共振图谱。Figure 49 is the proton nuclear magnetic resonance spectrum of the mesylate crystal Type C of the compound represented by formula (I).
图50为式(I)所示化合物钾盐晶体Type A的XPRD谱图。Figure 50 is the XPRD spectrum of the potassium salt crystal Type A of the compound represented by formula (I).
图51为式(I)所示化合物钾盐晶体Type A的质子核磁共振图谱。Figure 51 is the proton nuclear magnetic resonance spectrum of the potassium salt crystal Type A of the compound represented by formula (I).
图52为式(I)所示化合物马来酸盐晶体Type A的XPRD谱图。Figure 52 is the XPRD spectrum of the maleate crystal Type A of the compound represented by formula (I).
图53为式(I)所示化合物马来酸盐晶体Type A的质子核磁共振图谱。Figure 53 is the proton nuclear magnetic resonance spectrum of the maleate crystal Type A of the compound represented by formula (I).
图54为式(I)所示化合物马来酸盐晶体Type B的XPRD谱图。Figure 54 is the XPRD spectrum of maleate crystal Type B of the compound represented by formula (I).
图55为式(I)所示化合物马来酸盐晶体Type B的质子核磁共振图谱。Figure 55 is the proton nuclear magnetic resonance spectrum of the maleate crystal Type B of the compound represented by formula (I).
图56为式(I)所示化合物钠盐晶体Type B的XPRD谱图。Figure 56 is the XPRD spectrum of sodium salt crystal Type B of the compound represented by formula (I).
图57为式(I)所示化合物钠盐晶体Type B的质子核磁共振图谱。Figure 57 is the proton nuclear magnetic resonance spectrum of the sodium salt crystal Type B of the compound represented by formula (I).
图58为式(I)所示化合物柠檬酸盐共晶Type A的XPRD谱图。Figure 58 is the XPRD spectrum of the citrate cocrystal Type A of the compound represented by formula (I).
图59为式(I)所示化合物柠檬酸盐共晶Type A的质子核磁共振图谱。Figure 59 is a proton nuclear magnetic resonance spectrum of the citrate cocrystal Type A of the compound represented by formula (I).
图60为式(I)所示化合物苹果酸共晶晶体Type A的XPRD谱图。Figure 60 is the XPRD spectrum of the malic acid eutectic crystal Type A of the compound represented by formula (I).
图61为式(I)所示化合物苹果酸共晶晶体Type A的质子核磁共振图谱。 Figure 61 is a proton nuclear magnetic resonance spectrum of the malic acid eutectic crystal Type A of the compound represented by formula (I).
图62为式(I)所示化合物盐酸盐Type A的XPRD谱图。Figure 62 is the XPRD spectrum of the hydrochloride Type A of the compound represented by formula (I).
图63为式(I)所示化合物盐酸盐Type A的质子核磁共振图谱。Figure 63 is a proton nuclear magnetic resonance spectrum of the hydrochloride Type A of the compound represented by formula (I).
图64为式(I)所示化合物盐酸盐Type B的XPRD谱图。Figure 64 is the XPRD spectrum of the hydrochloride Type B of the compound represented by formula (I).
图65为式(I)所示化合物盐酸盐Type B的质子核磁共振图谱。Figure 65 is a proton nuclear magnetic resonance spectrum of the hydrochloride Type B of the compound represented by formula (I).
图66为式(I)所示化合物乙醇酸共晶晶体Type A的XPRD谱图。Figure 66 is the XPRD spectrum of the glycolic acid eutectic crystal Type A of the compound represented by formula (I).
图67为式(I)所示化合物乙醇酸共晶晶体Type A的质子核磁共振图谱。Figure 67 is the proton nuclear magnetic resonance spectrum of the glycolic acid eutectic crystal Type A of the compound represented by formula (I).
图68为式(I)所示化合物乙醇酸共晶晶体Type B的XPRD谱图。Figure 68 is the XPRD spectrum of the glycolic acid eutectic crystal Type B of the compound represented by formula (I).
图69为式(I)所示化合物乙醇酸共晶晶体Type B的质子核磁共振图谱。Figure 69 is the proton nuclear magnetic resonance spectrum of the glycolic acid eutectic crystal Type B of the compound represented by formula (I).
图70为实施例34所得固体的XRPD图谱。Figure 70 is the XRPD pattern of the solid obtained in Example 34.
图71为实施例35中式(I)化合物非溶剂化晶型E在DVS实验中不同湿度条件下样品的质量变化情况。Figure 71 shows the mass changes of the unsolvated crystalline form E of the compound of formula (I) in Example 35 under different humidity conditions in the DVS experiment.
图72为实施例35中式(I)化合物非溶剂化晶型E经DVS实验后样品的XRPD图谱。Figure 72 is the XRPD pattern of the sample after the DVS experiment of the unsolvated crystalline form E of the compound of formula (I) in Example 35.
图73为实施例36中式(I)化合物非溶剂化晶型AH在DVS实验中不同湿度条件下样品的质量变化情况。Figure 73 shows the mass changes of the sample under different humidity conditions in the DVS experiment of the unsolvated crystalline form AH of the compound of formula (I) in Example 36.
图74为实施例36中式(I)化合物非溶剂化晶型AH经DVS实验后样品的XRPD图谱。Figure 74 is the XRPD pattern of the sample after DVS experiment of the unsolvated crystalline form AH of the compound of formula (I) in Example 36.
图75为实施例37中式(I)化合物马来酸盐晶型Type A在DVS实验中不同湿度条件下样品的质量变化情况。Figure 75 shows the mass changes of the sample of the maleate crystal form Type A of the compound of formula (I) in Example 37 under different humidity conditions in the DVS experiment.
图76为实施例37中式(I)化合物马来酸盐晶型Type A经DVS实验后样品的XRPD图谱。Figure 76 is the XRPD pattern of the sample of the maleate salt form Type A of the compound of formula (I) in Example 37 after the DVS experiment.
图77为实施例38中式(I)化合物柠檬酸共晶晶型Type A在DVS实验中不同湿度条件下样品的质量变化情况。Figure 77 shows the mass changes of the sample under different humidity conditions in the DVS experiment of the citric acid eutectic crystal form Type A of the compound of formula (I) in Example 38.
图78为实施例38中式(I)化合物柠檬酸共晶晶型Type A经DVS实验后样品的XRPD图谱。Figure 78 is the XRPD pattern of the sample after the DVS experiment of the citric acid eutectic crystal form Type A of the compound of formula (I) in Example 38.
图79为实施例39中式(I)化合物苹果酸共晶晶型Type A在DVS实验中不同湿度条件下样品的质量变化情况。Figure 79 shows the mass changes of the sample under different humidity conditions in the DVS experiment of the malic acid eutectic crystal form Type A of the compound of formula (I) in Example 39.
图80为实施例39中式(I)化合物苹果酸共晶晶型Type A经DVS实验后样品的XRPD图谱。Figure 80 is the XRPD pattern of the sample after the DVS experiment of the malic acid eutectic crystal form Type A of the compound of formula (I) in Example 39.
图81为实施例40中式(I)化合物非溶剂化晶型E在不同条件下稳定性试验后样品的XRPD图谱。Figure 81 is the XRPD pattern of the sample after the stability test under different conditions of the unsolvated crystalline form E of the compound of formula (I) in Example 40.
图82为实施例41中式(I)化合物非溶剂化晶型AH在不同条件下稳定性试验后样品的XRPD图谱。Figure 82 is the XRPD pattern of the sample after the stability test under different conditions of the unsolvated crystalline form AH of the compound of formula (I) in Example 41.
图83为实施例42中式(I)化合物马来酸盐晶型Type A在不同条件下稳定性试验后样品的XRPD图谱。 Figure 83 is the XRPD pattern of the sample after the stability test of the maleate salt form Type A of the compound of formula (I) in Example 42 under different conditions.
图84为实施例43中式(I)化合物柠檬酸共晶晶型Type A在不同条件下稳定性试验后样品的XRPD图谱。Figure 84 is the XRPD pattern of the sample after the stability test under different conditions of the citric acid co-crystal type A of the compound of formula (I) in Example 43.
图85为实施例44中式(I)化合物苹果酸共晶晶型Type A在不同条件下稳定性试验后样品的XRPD图谱。Figure 85 is the XRPD pattern of the sample after the stability test under different conditions of the malic acid eutectic crystal form Type A of the compound of formula (I) in Example 44.
具体实施方式Detailed ways
下面结合实例进一步阐明本发明的内容，应该理解，此处采用的术语目的在于描述具体的实施方案，并非意在限制，说明书中所描述的数值范围，如计量单位、反应条件、化合物物理状态或百分比，均是为了提供明白无误的书面参考。本领域熟练技术人员在实践本专利时，使用在此范围之外或有别于单个数值的温度、浓度、数量、碳原子数等，仍然可以得到预期的结果。类似或者等价于此处描述的任何方法、装置和材料用于实施或者测试本发明，均在本申请的保护范畴。The content of the present invention will be further clarified below in conjunction with examples. It should be understood that the terminology used here is intended to describe specific embodiments and is not intended to limit the numerical range described in the specification, such as measurement units, reaction conditions, physical states of compounds, or Percentages are for the purpose of providing unambiguous written reference. When practicing this patent, those skilled in the art can still obtain the expected results by using temperatures, concentrations, quantities, number of carbon atoms, etc. that are outside this range or different from a single value. Any methods, devices, and materials similar or equivalent to those described herein for implementing or testing the present invention fall within the scope of the present application.
说明：本发明所述的百分比除特别注明外，均为重量百分比。本发明中所述的溶剂化物晶体、共晶晶体或者盐型晶体的比例，除特别注明外，均为摩尔比。Note: Unless otherwise noted, the percentages mentioned in the present invention are all weight percentages. The ratios of solvate crystals, eutectic crystals or salt-type crystals mentioned in the present invention are molar ratios unless otherwise specified.
试验条件与检测方法：Test conditions and detection methods:
X-射线粉末衍射测试条件：仪器：Panalytical EMPYREAN(PANalytical，荷兰)；辐射源：Cu-Kα(40kV、40mA)。X-ray powder diffraction test conditions: Instrument: Panalytical EMPYREAN (PANalytical, Netherlands); Radiation source: Cu-Kα (40kV, 40mA).
X-射线单晶衍射测试条件：仪器：SXtaLAB Synergy R(Rigaku，日本)；辐射源：Cu靶光源，测试温度：150.0K；数据处理：使用CrysAlisPro软件包进行分析处理。X-ray single crystal diffraction test conditions: Instrument: SXtaLAB Synergy R (Rigaku, Japan); Radiation source: Cu target light source, Test temperature: 150.0K; Data processing: Use CrysAlisPro software package for analysis and processing.
差示扫描量热分析测试条件：仪器：TA Discovery 2500(TA，美国)；升温速率：10℃/min；氮气流速：50mL/min。Differential scanning calorimetry analysis test conditions: Instrument: TA Discovery 2500 (TA, USA); heating rate: 10°C/min; nitrogen flow rate: 50mL/min.
热重分析测试条件：仪器：TA Discovery 55(TA，美国)；升温速率：10℃/min；氮气流速：样品处氮气吹扫速度为60mL/min，天平处氮气吹扫速度为40mL/min。Thermogravimetric analysis test conditions: Instrument: TA Discovery 55 (TA, USA); heating rate: 10°C/min; nitrogen flow rate: nitrogen purge rate at the sample is 60mL/min, and nitrogen purge rate at the balance is 40mL/min.
动态水分吸脱附分析测试条件：仪器：DVS Intrinsic(SMS，英国)；湿度变化梯度：测试采用梯度模式，湿度变化为50％-95％-0％-50％，在0％至90％范围内每个梯度的湿度变化量为10％，梯度终点采用dm/dt方式进行判断，以dm/dt小于0.002％并维持10分钟为梯度终点。测试完成后，对样品进行XRPD分析确认固体形态是否发生变化。Dynamic moisture adsorption and desorption analysis test conditions: Instrument: DVS Intrinsic (SMS, UK); Humidity change gradient: The test adopts gradient mode, the humidity change is 50%-95%-0%-50%, in the range of 0% to 90% The humidity change amount of each gradient is 10%. The end point of the gradient is judged by the dm/dt method. The end point of the gradient is when dm/dt is less than 0.002% and maintained for 10 minutes. After the test is completed, XRPD analysis is performed on the sample to confirm whether the solid form has changed.
质子核磁共振测试条件：仪器：AV-400(德国BRUKER公司)；溶剂：DMSO-d6。Proton NMR test conditions: Instrument: AV-400 (BRUKER, Germany); Solvent: DMSO-d6.
稳定性试验条件(实施例40-44)：按中国药典2010年版二部附录XIX C进行高温(60℃)、高湿(90％)和强光照射(4500Lx)试验。Stability test conditions (Examples 40-44): Conduct high temperature (60°C), high humidity (90%) and strong light irradiation (4500Lx) tests according to Appendix XIX C of the Chinese Pharmacopoeia 2010 Edition.
离心条件：仪器：大龙D3024；转速：10000rpm；时间：3min。Centrifugal conditions: Instrument: Dalong D3024; rotation speed: 10000 rpm; time: 3 minutes.
术语定义：Definition of Terms:
关于引湿性特征描述与引湿性增重的界定(中国药典2015年版通则9103药物引湿性 试验指导原则，实验条件：25℃±1℃，80％相对湿度)：Regarding the description of hygroscopic characteristics and the definition of hygroscopic weight gain (Chinese Pharmacopoeia 2015 Edition General Chapter 9103 Drugs Hygroscopic Test guidelines, experimental conditions: 25℃±1℃, 80% relative humidity):
潮解：吸收足水分形成液体；Deliquescence: absorbing enough water to form a liquid;
极有引湿性：引湿增重不小于15.0％；Extremely hygroscopic: the weight gain by attracting moisture is not less than 15.0%;
有引湿性：引湿增重小于15.0％但不小于2.0％；It has hygroscopicity: the moisture-attracting weight gain is less than 15.0% but not less than 2.0%;
略有引湿性：引湿增重小于2.0％但不小于0.2％；Slightly hygroscopic: weight gain due to moisture attraction is less than 2.0% but not less than 0.2%;
无或几乎无引湿性：引湿增重小于0.2％。No or almost no hygroscopicity: weight gain due to moisture absorption is less than 0.2%.
实施例A：式(I)化合物的制备：Example A: Preparation of compounds of formula (I):
化合物的结构是通过核磁共振(NMR)或质谱(MS)来确定的。NMR的测定是用Bruker ASCENA-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD)，内标为四甲基甲硅烷(TMS)，化学位移是以10-6(ppm)作为单位给出。The structure of a compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR was measured using a Bruker ASCENA-400 nuclear magnetic instrument. The measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD). The internal standard was tetrahydrofuran. For methylsilane (TMS), chemical shifts are given in units of 10 -6 (ppm).
反应监控及MS的测定使用Thermofisher ESQ(ESI)质谱仪。Reaction monitoring and MS measurement used a Thermofisher ESQ (ESI) mass spectrometer.
HPLC的测定使用赛默飞U3000DAD高压液相色谱仪(GL Sciences ODS-HL HP 3μm 3.0*100mm色谱柱)。HPLC was measured using a Thermo Fisher U3000DAD high-pressure liquid chromatograph (GL Sciences ODS-HL HP 3μm 3.0*100mm column).
薄层层析硅胶板使用青岛海洋GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15～0.2mm，薄层层析分离纯化产品采用的规格是0.9～1.0mm的高效薄层色谱制备板。柱层析使用青岛海洋200～300目硅胶为载体，展开剂所使用的体系有A：二氯甲烷和甲醇体系；B：石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节。中压制备液相纯化时使用的是biotage isera one型制备液相。The thin layer chromatography silica gel plate uses Qingdao Ocean GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) has a specification of 0.15~0.2mm. The specification of the thin layer chromatography separation and purification product is 0.9~1.0mm. Thin layer chromatography preparation plates. Column chromatography uses Qingdao Ocean 200-300 mesh silica gel as the carrier. The systems used as developing agents are A: methylene chloride and methanol system; B: petroleum ether and ethyl acetate system. The volume ratio of the solvent is different according to the polarity of the compound. And make adjustments. For medium-pressure preparative liquid phase purification, biotage isera one type preparative liquid phase is used.
所有反应原料可以从萨恩化学技术(上海)有限公司、上海韶远试剂有限公司、南京药石科技股份有限公司、江苏艾康生物医药研发有限公司、上海毕得医药科技有限公司等厂家购买获得。All reaction raw materials can be purchased from manufacturers such as Sarn Chemical Technology (Shanghai) Co., Ltd., Shanghai Shaoyuan Reagent Co., Ltd., Nanjing Yaoshi Technology Co., Ltd., Jiangsu Aikang Biopharmaceutical Research and Development Co., Ltd., and Shanghai Bide Pharmaceutical Technology Co., Ltd.
6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺
6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino )Nicotinamide
步骤1：将3-溴-2-甲氧基苯胺(212-a,2.8g,13.86mmol)、联硼酸频那醇酯(5.3g,20.79mmol)、Pd(dppf)Cl2(1.03g,1.39mmol)和醋酸钾(4.08g,41.58mmol)依次加入二氧六环溶液中，抽真空氮气置换3次，于110℃继续搅拌20小时，TLC监测反应完成，将反应液完全浓缩。向反应液中加入水(40mL),乙酸乙酯萃取(30mL x 2),饱和食盐水(30mL x 2)洗 涤，无水硫酸钠干燥，减压浓缩，残余物经硅胶柱层析(乙酸乙酯:石油醚＝1:4)分离纯化得2-甲氧基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯胺(212-b,2.3g,9.23mmol,66％yield)。MS Calcd:249.15；MS Found:250.01([M+H]+).Step 1: Combine 3-bromo-2-methoxyaniline (212-a, 2.8g, 13.86mmol), pinacol diborate (5.3g, 20.79mmol), Pd(dppf)Cl 2 (1.03g, 1.39mmol) and potassium acetate (4.08g, 41.58mmol) were added to the dioxane solution in sequence, vacuumed and replaced with nitrogen three times, and continued stirring at 110°C for 20 hours. TLC monitored the reaction to completion, and the reaction solution was completely concentrated. Add water (40mL) to the reaction solution, extract with ethyl acetate (30mL x 2), and wash with saturated brine (30mL x 2). Polyester, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:4) to obtain 2-methoxy-3-(4,4,5,5 -Tetramethyl-1,3,2-dioxaboran-2-yl)aniline (212-b, 2.3g, 9.23mmol, 66% yield). MS Calcd:249.15; MS Found:250.01([M+H] + ).
步骤2：将2-甲氧基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯胺(212-b,2.3g,9.23mmol)和Boc酸酐(2.41g,11.07mmol)10mL乙醇溶剂中，置于室温条件下搅拌过夜。TLC监测反应完成，滤液浓缩，残余物经硅胶柱层析(乙酸乙酯:石油醚＝1:4)分离纯化得(2-甲氧基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼硼烷-2-基)苯基)叔丁基-1-氮杂烷羧酸酯(212-c,2.4g,8mmol,86％yield)。MS Calcd:348.20；MS Found:250.16([M-100]+).Step 2: 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)aniline (212-b, 2.3g, 9.23mmol) and Boc acid anhydride (2.41g, 11.07mmol) in 10 mL of ethanol solvent, and stirred at room temperature overnight. TLC monitored the completion of the reaction, the filtrate was concentrated, and the residue was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:4) to obtain (2-methoxy-3-(4,4,5,5-tetramethyl) (212-c, 2.4 g, 8 mmol, 86% yield). MS Calcd:348.20; MS Found:250.16([M-100] + ).
步骤3：将(2-甲氧基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼硼烷-2-基)苯基)叔丁基-1-氮杂烷羧酸酯(212-c,370mg,1.06mmol)、2-溴嘧啶(200mg，1.27mmol)，磷酸钾(521mg，2.46mmol)和Pd(dppf)Cl2(59mg，0.082mmol)加入到7mL水和二氧六环(6:1)的混合溶液中，抽真空，氮气置换3次，于105℃条件下搅拌10小时。TLC监测反应完成，将反应液完全浓缩，残余物经硅胶柱层析(乙酸乙酯:石油醚＝1:1)分离纯化得(2-甲氧基-3-(嘧啶-2-基)苯基)-2-氮杂甲酸叔丁酯(212-d,150mg,0.5mmol,39％yield)。MS Calcd:300.13；MS Found:301.12([M+H]+).Step 3: (2-Methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tert-butyl- 1-Azakanecarboxylate (212-c, 370mg, 1.06mmol), 2-bromopyrimidine (200mg, 1.27mmol), potassium phosphate (521mg, 2.46mmol) and Pd(dppf)Cl 2 (59mg, 0.082mmol) ) was added to a mixed solution of 7 mL water and dioxane (6:1), evacuated, replaced with nitrogen three times, and stirred at 105°C for 10 hours. TLC monitored the completion of the reaction, and the reaction solution was completely concentrated. The residue was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain (2-methoxy-3-(pyrimidin-2-yl)benzene). (212-d, 150 mg, 0.5 mmol, 39% yield). MS Calcd:300.13; MS Found:301.12([M+H] + ).
步骤4：将(2-甲氧基-3-(嘧啶-2-基)苯基)-2-氮杂甲酸叔丁酯(212-d,150mg,0.5mmol)溶于二氯甲烷溶液中，然后加入三氟乙酸(421mg，3.7mmol)，置于室温搅拌5h，TLC监测反应完成，将反应液完全浓缩，向残余物中加入饱和碳酸氢钠溶液，二氯甲烷萃取，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，残余物经硅胶柱层析分离纯化得产物2-甲氧基-3-(嘧啶-2-基)苯胺(212-e,70mg,0.35mmol,70％yield)。MS Calcd:201.23；MS Found:202.10([M+H]+).Step 4: Dissolve (2-methoxy-3-(pyrimidin-2-yl)phenyl)-2-azacarboxylic acid tert-butyl ester (212-d, 150 mg, 0.5 mmol) in dichloromethane solution, Then add trifluoroacetic acid (421 mg, 3.7 mmol) and stir at room temperature for 5 hours. TLC monitors the completion of the reaction. The reaction solution is completely concentrated. A saturated sodium bicarbonate solution is added to the residue. Extract with dichloromethane and wash with saturated brine. Dry over anhydrous sodium sulfate and concentrate under reduced pressure. The residue is separated and purified by silica gel column chromatography to obtain the product 2-methoxy-3-(pyrimidin-2-yl)aniline (212-e, 70 mg, 0.35 mmol, 70% yield ). MS Calcd:201.23; MS Found:202.10([M+H] + ).
步骤5：将2-甲氧基-3-(嘧啶-2-基)苯胺(212-e,70mg,0.35mmol),4,6-二氯-N-乙氧基烟酰胺(74mg,0.32mmol),加入到5ml无水N,N-二甲基乙酰胺中，并室温下加入LiHMDS的四氢呋喃溶液(1.28ml,1.28mmol)，于室温下搅拌3小时，TLC监测反应完成，用盐酸(4N)调pH到5，并用乙酸乙酯萃取(20ml x 3)，合并有机层，经干燥，浓缩后用硅胶柱层析纯化(PE：EA＝1：2)，得到6-氯-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺(212-f，110mg,0.27mmol,72％yield)。MS Calcd:399.11；MS Found:400.11([M+H]+).Step 5: Combine 2-methoxy-3-(pyrimidin-2-yl)aniline (212-e, 70mg, 0.35mmol), 4,6-dichloro-N-ethoxynicotinamide (74mg, 0.32mmol) ), was added to 5 ml of anhydrous N,N-dimethylacetamide, and LiHMDS solution in tetrahydrofuran (1.28 ml, 1.28 mmol) was added at room temperature, stirred at room temperature for 3 hours, and TLC monitored the reaction to completion. Use hydrochloric acid (4N ), adjust the pH to 5, and extract with ethyl acetate (20ml Oxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide (212-f, 110 mg, 0.27 mmol, 72% yield). MS Calcd:399.11; MS Found:400.11([M+H] + ).
步骤6：将6-氯-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺(212-f，110mg,0.27mmol),4-氨基-2,6-二甲基嘧啶(44mg，0.36mmol)，碳酸铯(195mg，0.6mmol)，XantPhos(25mg，0.04mmol)和Pd2(dba)3(27mg，0.029mmol)加入到无水二氧六环中(2ml)并抽真空，用氮气置换3次，升温到125℃，搅拌10小时，抽滤，滤液经浓缩，制备型TLC纯化(MeOH:DCM＝1:20)得到标题化合物：6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺(212，20mg,0.04mmol,15％yield)。MS Calcd:486.21；MS Found:487.21([M+H]+).1H NMR(400MHz,DMSO-d6)δ11.70(s,1H),10.22(s,1H),10.10(s,1H),8.95(d,J＝4.8Hz,2H),8.39(s,1H),8.17(s,1H),7.73(dd,J＝8.0,1.6Hz,1H),7.51(t,J ＝4.8Hz,1H),7.46(dd,J＝8.0,1.6Hz,1H),7.32(t,J＝8.0Hz,1H),7.09(s,1H),3.96(q,J＝7.2Hz,2H),3.70(s,3H),2.39(s,3H),2.28(s,3H),1.23(t,J＝7.2Hz,3H).Step 6: 6-Chloro-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide (212-f, 110 mg, 0.27 mmol) , 4-amino-2,6-dimethylpyrimidine (44mg, 0.36mmol), cesium carbonate (195mg, 0.6mmol), XantPhos (25mg, 0.04mmol) and Pd 2 (dba) 3 (27mg, 0.029mmol) were added into anhydrous dioxane (2ml) and evacuated, replaced with nitrogen three times, heated to 125°C, stirred for 10 hours, filtered, the filtrate was concentrated, and purified by preparative TLC (MeOH:DCM=1:20) The title compound was obtained: 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Phenyl) amino) nicotinamide (212, 20 mg, 0.04 mmol, 15% yield). MS Calcd: 486.21; MS Found: 487.21 ([M+H] + ). 1 H NMR (400MHz, DMSO-d 6 ) δ11 .70(s,1H),10.22(s,1H),10.10(s,1H),8.95(d,J＝4.8Hz,2H),8.39(s,1H),8.17(s,1H),7.73( dd,J＝8.0,1.6Hz,1H),7.51(t,J ＝4.8Hz,1H),7.46(dd,J＝8.0,1.6Hz,1H),7.32(t,J＝8.0Hz,1H),7.09(s,1H),3.96(q,J＝7.2Hz,2H ),3.70(s,3H),2.39(s,3H),2.28(s,3H),1.23(t,J＝7.2Hz,3H).
实施例1：式(I)化合物的甲醇溶剂化晶体A的制备Example 1: Preparation of methanol solvated crystal A of the compound of formula (I)
将19.3mg 6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺置于4mL EP管中，加入1.2mL甲醇，在50℃下加热至完全溶解，然后将溶液迅速转移至25℃冷却析晶，析晶3小时，离心分离收集固体，于25℃下真空干燥24小时，得到样品。对所得样品进行XRPD测试和质子核磁共振分析，得到其X-射线粉末衍射图如图1所示，其质子核磁共振图谱如图2所示。图2显示该晶体含有甲醇，其中，6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺与甲醇的比例为1:1。19.3 mg of 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)benzene) Place the base) amino) nicotinamide into a 4mL EP tube, add 1.2 mL of methanol, and heat it at 50°C until it is completely dissolved. Then quickly transfer the solution to 25°C and cool it for crystallization. Crystallize for 3 hours. Centrifuge and collect the solid. The sample was obtained by vacuum drying at 25°C for 24 hours. The obtained sample was subjected to XRPD testing and proton NMR analysis, and its X-ray powder diffraction pattern was obtained as shown in Figure 1, and its proton NMR pattern was shown in Figure 2. Figure 2 The crystals were shown to contain methanol, 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidine- The ratio of 2-yl)phenyl)amino)nicotinamide to methanol is 1:1.
实施例2：6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺的水合物晶体AA的制备Example 2: 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of hydrate crystal AA of phenyl)amino)nicotinamide
将20.6mg 6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺置于10mL EP管中，加入10mL水，加热至50℃悬浮搅拌24小时，然后将悬浮液离心分离，所得固体在25℃真空干燥24小时，得到样品。对所得样品进行XRPD测试和质子核磁共振分析，得到其X-射线粉末衍射图如图3所示，其质子核磁共振图谱如图4所示。图4显示该晶体不含有有机溶剂。20.6 mg of 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)benzene) Base) amino) nicotinamide was placed in a 10 mL EP tube, added 10 mL of water, heated to 50°C, suspended and stirred for 24 hours, then the suspension was centrifuged, and the resulting solid was vacuum dried at 25°C for 24 hours to obtain a sample. The obtained sample was subjected to XRPD test and proton nuclear magnetic resonance analysis, the X-ray powder diffraction pattern is shown in Figure 3, and the proton nuclear magnetic resonance pattern is shown in Figure 4. Figure 4 shows that the crystal does not contain organic solvents.
实施例3：6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺的甲醇溶剂化晶体AE的制备Example 3: 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of Methanol Solved Crystals AE of Phenyl)Amino)Nicotinamide
将20.7mg 6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺置于4mL EP管中，加入1.0mL甲醇，在25℃下悬浮搅拌7天后，将悬浮液离心分离，收集固体，于25℃下真空干燥24小时，得到样品。对所得样品进行XRPD测试和质子核磁共振分析，得到其X-射线粉末衍射图如图5所示，其质子核磁共振图谱如图6所示。图6显示该晶体含有甲醇，其中，6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺与甲醇的比例为1:0.4。20.7 mg of 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)benzene) Base) amino) nicotinamide was placed in a 4mL EP tube, 1.0 mL of methanol was added, suspended and stirred at 25°C for 7 days, the suspension was centrifuged, the solids were collected, and vacuum dried at 25°C for 24 hours to obtain a sample. For the obtained The sample was subjected to XRPD testing and proton nuclear magnetic resonance analysis, and its X-ray powder diffraction pattern is shown in Figure 5, and its proton nuclear magnetic resonance pattern is shown in Figure 6. Figure 6 shows that the crystal contains methanol, in which, 6-((( 2,6-Dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide and methanol The ratio is 1:0.4.
实施例4：6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺的非溶剂化物晶体AH的制备Example 4: 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of unsolvate crystal AH of phenyl)amino)nicotinamide
将591.4mg 6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺置于40mL玻璃瓶中，加入3mL四氢呋喃，25℃搅拌使其溶解，溶剂挥发干后将所得固体置于120℃加热约30分钟，之后将所得固体置于80℃真空干燥18小时，得到样品。对所得样品进行XRPD测试、差示扫描量热分析、热重分析和质子核磁共振分析，得到其X-射线粉末衍射图如图7所示，其质子核磁共振图谱如图8所示，其差示扫描量热分析曲线如图9所示，其热重分析曲线如图10所示。图8显示该晶体不含有有机溶剂。 591.4 mg of 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)benzene) Base) amino) nicotinamide was placed in a 40 mL glass bottle, added 3 mL of tetrahydrofuran, and stirred at 25°C to dissolve it. After the solvent evaporated to dryness, the resulting solid was heated at 120°C for about 30 minutes, and then the resulting solid was vacuum dried at 80°C. After 18 hours, the sample was obtained. The obtained sample was subjected to XRPD test, differential scanning calorimetry analysis, thermogravimetric analysis and proton nuclear magnetic resonance analysis, and its X-ray powder diffraction pattern was obtained as shown in Figure 7, and its proton nuclear magnetic resonance pattern was obtained as shown in Figure 7 8, its differential scanning calorimetry analysis curve is shown in Figure 9, and its thermogravimetric analysis curve is shown in Figure 10. Figure 8 shows that the crystal does not contain organic solvents.
实施例5：6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺的非溶剂化物晶体E的制备Example 5: 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of nonsolvate crystal E of phenyl)amino)nicotinamide
将602.2mg 6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺置于40mL玻璃瓶中，加入21mL乙酸乙酯，在50℃悬浮搅拌24小时，然后将悬浮液离心分离，所得固体在40℃真空干燥24小时，得到样品。对所得样品进行XRPD测试、差示扫描量热分析、热重分析和质子核磁共振分析，得到其X-射线粉末衍射图如图11所示，其质子核磁共振图谱如图12所示，其差示扫描量热分析曲线如图13所示，其热重分析曲线如图14所示。图12显示该晶体不含有有机溶剂。602.2mg 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)benzene) Base) amino) nicotinamide was placed in a 40 mL glass bottle, added 21 mL of ethyl acetate, suspended and stirred at 50°C for 24 hours, then the suspension was centrifuged, and the resulting solid was vacuum dried at 40°C for 24 hours to obtain a sample. For the obtained sample Perform XRPD test, differential scanning calorimetry analysis, thermogravimetric analysis and proton nuclear magnetic resonance analysis, and obtain its X-ray powder diffraction pattern as shown in Figure 11, its proton nuclear magnetic resonance spectrum as shown in Figure 12, and its differential scanning volume The thermal analysis curve is shown in Figure 13, and its thermogravimetric analysis curve is shown in Figure 14. Figure 12 shows that the crystal does not contain organic solvent.
实施例6：6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺的非溶剂化物晶体E单晶的制备Example 6: 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of single crystal E of the unsolvate crystal of phenyl) amino) nicotinamide
将20.9mg 6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺置于4mL EP管中，加入2.6mL乙腈，在50℃下加热溶解，然后溶液降温至25℃，所得片状晶体中，挑选单块晶体，在150K测定其X-射线单晶衍射图谱，如图15所示，测得晶胞参数如下：20.9 mg of 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)benzene) Base) amino) nicotinamide is placed in a 4mL EP tube, add 2.6 mL acetonitrile, heat to dissolve at 50°C, and then cool the solution to 25°C. Among the obtained flake crystals, select a single crystal and measure its X-ray at 150K The single crystal diffraction pattern is shown in Figure 15. The measured unit cell parameters are as follows:
晶型：三斜晶系


Crystal form: triclinic system


α＝76.404(2)°；α=76.404(2)°;
β＝86.6962(16)°；β=86.6962(16)°;
γ＝70.126(2)°；γ=70.126(2)°;
空间群：P-1；Space group: P-1;
每个晶胞中的分子(Z)：2；
Molecules per unit cell (Z): 2;
计算密度：1.376g/cm3。Calculated density: 1.376g/cm 3 .
实施例7：6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺的甲酸溶剂化晶体F的制备Example 7: 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of formic acid solvated crystals F of phenyl) amino) nicotinamide
将20.2mg 6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺置于4mL EP管中，加入10mL甲酸丁酯，在25℃下悬浮搅拌7天后，将悬浮液离心分离，收集固体，于25℃下真空干燥24小时，得到样品。对所得样品进行XRPD测试和质子核磁共振分析，得到其X-射线粉末衍射图如图16所示，其质子核磁共振图谱如图17所示。图17显示该晶体含有甲酸，其中，6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺与甲酸的比例为1:1。20.2 mg of 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)benzene) Base) amino) nicotinamide was placed in a 4mL EP tube, and 10 mL of butyl formate was added. After suspension and stirring at 25°C for 7 days, the suspension was centrifuged, the solids were collected, and vacuum dried at 25°C for 24 hours to obtain the sample. For The obtained sample was subjected to XRPD testing and proton nuclear magnetic resonance analysis, and its X-ray powder diffraction pattern was obtained as shown in Figure 16, and its proton nuclear magnetic resonance spectrum was shown in Figure 17. Figure 17 shows that the crystal contains formic acid, wherein, 6-(( (2,6-Dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide with The ratio of formic acid is 1:1.
实施例8：6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨 基)烟酰胺的甲酸溶剂合物晶体O的制备Example 8: 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) phenyl)ammonium Preparation of formic acid solvate crystal O of nicotinamide
将20.0mg 6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺置于4mL EP管中，加入2.0mL甲酸乙酯，加热至50℃悬浮搅拌24小时，然后将悬浮液离心分离，所得固体在25℃真空干燥24小时，得到样品。对所得样品进行XRPD测试和质子核磁共振分析，得到其X-射线粉末衍射图如图18所示，其质子核磁共振图谱如图19所示。图19显示该晶体含有甲酸，其中，6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺与甲酸的比例为1:1。20.0 mg of 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)benzene) Base) amino) nicotinamide was placed in a 4mL EP tube, added 2.0 mL of ethyl formate, heated to 50°C, suspended and stirred for 24 hours, then the suspension was centrifuged, and the resulting solid was vacuum dried at 25°C for 24 hours to obtain a sample. For The obtained sample was subjected to XRPD testing and proton nuclear magnetic resonance analysis, and its X-ray powder diffraction pattern was obtained as shown in Figure 18, and its proton nuclear magnetic resonance spectrum was shown in Figure 19. Figure 19 shows that the crystal contains formic acid, wherein, 6-(( (2,6-Dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide with The ratio of formic acid is 1:1.
实施例9：6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺的水合物晶体T的制备Example 9: 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of hydrate crystal T of phenyl) amino) nicotinamide
将43.6mg 6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺置于4mL EP管中，加入3.0mL水，在25℃悬浮搅拌7天，然后将悬浮液离心分离，所得固体在25℃真空干燥24小时，得到样品。对所得样品进行XRPD测试和质子核磁共振分析，得到其X-射线粉末衍射图如图20所示，其质子核磁共振图谱如图21所示。图21显示该晶体不含有有机溶剂。43.6 mg of 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)benzene) Base) amino) nicotinamide was placed in a 4mL EP tube, added 3.0 mL of water, suspended and stirred at 25°C for 7 days, then the suspension was centrifuged, and the resulting solid was vacuum dried at 25°C for 24 hours to obtain a sample. The obtained sample was subjected to XRPD test and proton nuclear magnetic resonance analysis, the X-ray powder diffraction pattern is shown in Figure 20, and the proton nuclear magnetic resonance pattern is shown in Figure 21. Figure 21 shows that the crystal does not contain organic solvents.
实施例10：6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺的水合物晶体V的制备Example 10: 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of hydrate crystal V of phenyl)amino)nicotinamide
将46.5mg 6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺置于4mL EP管中，加入0.5mL水，加入0.5mL异丙醇，在25℃悬浮搅拌7天，然后将悬浮液离心分离，所得固体在25℃真空干燥24小时，得到样品。对所得样品进行XRPD测试和质子核磁共振分析，得到其X-射线粉末衍射图如图22所示，其质子核磁共振图谱如图23所示。图23显示该晶体不含有有机溶剂。46.5 mg of 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)benzene) Base) amino) nicotinamide was placed in a 4mL EP tube, added 0.5mL water, added 0.5mL isopropyl alcohol, suspended and stirred at 25°C for 7 days, then centrifuged the suspension, and the resulting solid was vacuum dried at 25°C for 24 hours. A sample was obtained. The obtained sample was subjected to XRPD testing and proton nuclear magnetic resonance analysis, and its X-ray powder diffraction pattern was obtained as shown in Figure 22, and its proton nuclear magnetic resonance pattern was shown in Figure 23. Figure 23 shows that the crystal does not contain organic solvents.
实施例11：6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺的甲酸溶剂合物晶体AF的制备Example 11: 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of formic acid solvate crystal AF of phenyl) amino) nicotinamide
将20.1mg 6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺置于10mL EP管中，25℃下加入3.2mL甲醇和6.0mL甲酸乙酯使其完全溶清。然后将该溶液25℃下敞口静置挥发，7天后挥发完全，得到样品。对所得样品进行XRPD测试和质子核磁共振分析，得到其X-射线粉末衍射图如图24所示，其质子核磁共振图谱如图25所示。图25显示该晶体含有有机溶剂甲酸，其中，6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺与甲酸的比例为1:1。20.1 mg of 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)benzene) Base) amino) nicotinamide was placed in a 10mL EP tube, and 3.2mL methanol and 6.0mL ethyl formate were added at 25°C to completely dissolve it. Then the solution was left open at 25°C to evaporate, and it would evaporate completely after 7 days. A sample was obtained. The obtained sample was subjected to XRPD testing and proton NMR analysis, and its X-ray powder diffraction pattern was obtained as shown in Figure 24, and its proton NMR pattern was shown in Figure 25. Figure 25 shows that the crystal contains the organic solvent formic acid, Among them, 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl) )Amino)Nicotinamide and formic acid ratio is 1:1.
实施例12：6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺的水合物晶体L的制备Example 12: 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of hydrate crystal L of phenyl)amino)nicotinamide
将21.7mg 6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺置于10mL EP管中，25℃下加入1.8mL丙酮使其完全溶解，再滴加6.0mL正 庚烷析出固体，保温25℃搅拌析晶24小时。然后将固液混合物离心分离，所得固体在25℃真空干燥24小时，得到样品。对所得样品进行XRPD测试和质子核磁共振分析，得到其X-射线粉末衍射图如图26所示，其质子核磁共振图谱如图27所示。图27显示该晶体为不含有有机溶剂。21.7 mg of 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)benzene) Base) amino) nicotinamide is placed in a 10mL EP tube, add 1.8mL acetone at 25°C to completely dissolve it, and then dropwise add 6.0mL normal Heptane precipitated as a solid, and the mixture was kept at 25°C for 24 hours with stirring and crystallization. The solid-liquid mixture was then centrifuged, and the resulting solid was vacuum dried at 25°C for 24 hours to obtain a sample. The obtained sample was subjected to XRPD testing and proton nuclear magnetic resonance analysis, and its X-ray powder diffraction pattern was obtained as shown in Figure 26, and its proton nuclear magnetic resonance pattern was shown in Figure 27. Figure 27 shows that the crystal does not contain organic solvent.
实施例13：6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺的乙醇溶剂合物晶体R的制备Example 13: 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of ethanol solvate crystal R of phenyl)amino)nicotinamide
将21.1mg 6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺置于10mL EP管中，加入0.6mL乙醇，在25℃下悬浮搅拌7天后，然后将悬浮液离心分离，所得固体在25℃真空干燥24小时，得到样品。对所得样品进行XRPD测试和质子核磁共振分析，得到其X-射线粉末衍射图如图28所示，其质子核磁共振图谱如图29所示。图29显示该晶体含有乙醇，其中，6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺和乙醇的比例为1:0.3。21.1 mg of 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)benzene) Base) amino) nicotinamide was placed in a 10mL EP tube, added 0.6 mL of ethanol, suspended and stirred at 25°C for 7 days, and then the suspension was centrifuged, and the resulting solid was vacuum dried at 25°C for 24 hours to obtain a sample. For the obtained sample Carry out XRPD test and proton nuclear magnetic resonance analysis, and obtain its X-ray powder diffraction pattern as shown in Figure 28, and its proton nuclear magnetic resonance pattern as shown in Figure 29. Figure 29 shows that the crystal contains ethanol, wherein, 6-(((2 ,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide and ethanol The ratio is 1:0.3.
实施例14：6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺的草酸共晶晶体Type A的制备Example 14: 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of oxalic acid co-crystal type A of phenyl) amino) nicotinamide
将29.2mg 6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺置于4mL EP管中，加入0.5mL甲醇和5.6mg草酸，在25℃下悬浮搅拌2天后，将悬浮液离心分离，收集固体，于25℃下真空干燥24小时，得到样品。对所得样品进行XRPD测试和质子核磁共振分析，得到其X-射线粉末衍射图如图30所示，其质子核磁共振图谱如图31所示。图31显示该晶体含有草酸，且质子核磁共振图谱与E晶型质子核磁共振谱图相比，没有明显化学位移偏移，判断该晶型为共晶，其中，6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺与草酸的比例为1:1。29.2 mg of 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)benzene) Base) amino) nicotinamide was placed in a 4mL EP tube, added 0.5 mL methanol and 5.6 mg oxalic acid, suspended and stirred at 25°C for 2 days, centrifuged the suspension, collected the solid, and vacuum dried at 25°C for 24 hours to obtain Sample. The obtained sample was subjected to XRPD testing and proton NMR analysis, and its X-ray powder diffraction pattern is shown in Figure 30, and its proton NMR spectrum is shown in Figure 31. Figure 31 shows that the crystal contains oxalic acid, and the proton NMR Compared with the proton nuclear magnetic resonance spectrum of the E crystal form, there is no obvious chemical shift shift in the resonance spectrum. It is judged that this crystal form is a eutectic, in which 6-(((2,6-dimethylpyrimidin-4-yl)amino The ratio of )-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide to oxalic acid is 1:1.
实施例15：6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺的草酸共晶晶体Type B的制备Example 15: 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of oxalic acid co-crystal type B of phenyl) amino) nicotinamide
将29.3mg 6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺置于4mL EP管中，加入1mL乙酸乙酯和5.6mg草酸，在25℃下悬浮搅拌2天后，将悬浮液离心分离，收集固体，于40℃下真空干燥24小时，得到样品。对所得样品进行XRPD测试和质子核磁共振分析，得到其X-射线粉末衍射图如图32所示，其质子核磁共振图谱如图33所示。图33显示该晶体含有草酸，且质子核磁共振图谱与E晶型质子核磁共振谱图相比，没有明显化学位移偏移，判断该晶型为共晶，其中，6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺与草酸的比例为1:1。29.3 mg of 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)benzene) Base) amino) nicotinamide was placed in a 4mL EP tube, added 1mL ethyl acetate and 5.6mg oxalic acid, suspended and stirred at 25°C for 2 days, centrifuged the suspension, collected the solid, and vacuum dried at 40°C for 24 hours. Obtain a sample. Perform XRPD testing and proton NMR analysis on the obtained sample, and obtain its X-ray powder diffraction pattern as shown in Figure 32, and its proton NMR pattern as shown in Figure 33. Figure 33 shows that the crystal contains oxalic acid, and proton Compared with the proton NMR spectrum of the E crystal form, there is no obvious chemical shift shift. This crystal form is judged to be a eutectic, in which 6-(((2,6-dimethylpyrimidin-4-yl) The ratio of amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide to oxalic acid is 1:1.
实施例16：6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺的对甲苯磺酸盐晶体Type A的制备Example 16: 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of p-toluenesulfonate crystal Type A of phenyl)amino)nicotinamide
将28.6mg 6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺置于4mL EP管中，加入0.5mL甲醇和11.8mg对甲苯磺酸，在25℃下悬浮搅 拌2天后，将悬浮液离心分离，收集固体，于25℃下真空干燥24小时，得到样品。对所得样品进行XRPD测试和质子核磁共振分析，得到其X-射线粉末衍射图如图34所示，其质子核磁共振图谱如图35所示。图35显示该晶体含有对甲苯磺酸，且质子核磁共振图谱与E晶型质子核磁共振谱图相比，有明显的化学位移偏移，判断该晶型为成盐晶体，其中，6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺与对甲苯磺酸的比例为1:1。28.6 mg of 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)benzene) Base) amino) nicotinamide was placed in a 4 mL EP tube, added 0.5 mL methanol and 11.8 mg p-toluenesulfonic acid, suspended and stirred at 25°C After stirring for 2 days, the suspension was centrifuged, the solid was collected, and vacuum dried at 25°C for 24 hours to obtain a sample. The obtained sample was subjected to XRPD testing and proton nuclear magnetic resonance analysis, and its X-ray powder diffraction pattern was obtained as shown in Figure 34, and its proton nuclear magnetic resonance pattern was shown in Figure 35. Figure 35 shows that the crystal contains p-toluenesulfonic acid, and the proton NMR spectrum has an obvious chemical shift shift compared with the proton NMR spectrum of the E crystal form. It is judged that the crystal form is a salt-forming crystal, in which 6-( ((2,6-Dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide The ratio to p-toluenesulfonic acid is 1:1.
实施例17：6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺的对甲苯磺酸盐晶体Type B的制备Example 17: 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of p-toluenesulfonate crystal Type B of phenyl)amino)nicotinamide
将27.8mg 6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺置于4mL EP管中，加入1.0mL 4-甲基-2-戊酮和11.6mg对甲苯磺酸，在25℃下悬浮搅拌2天后，将悬浮液离心分离，收集固体，于25℃下真空干燥24小时，得到样品。对所得样品进行XRPD测试和质子核磁共振分析，得到其X-射线粉末衍射图如图36所示，其质子核磁共振图谱如图37所示。图37显示该晶体含有对甲苯磺酸，且质子核磁共振图谱与E晶型质子核磁共振谱图相比，有明显的化学位移偏移，判断该晶型为成盐晶体，其中，6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺与对甲苯磺酸的比例为1:1。27.8 mg of 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)benzene) Base) amino) nicotinamide is placed in a 4mL EP tube, add 1.0mL 4-methyl-2-pentanone and 11.6mg p-toluenesulfonic acid, suspend and stir at 25°C for 2 days, centrifuge the suspension and collect the solid , vacuum dried at 25°C for 24 hours to obtain a sample. The obtained sample was subjected to XRPD testing and proton nuclear magnetic resonance analysis, and its X-ray powder diffraction pattern was obtained as shown in Figure 36, and its proton nuclear magnetic resonance pattern was shown in Figure 37. Figure 37 shows that the crystal contains p-toluenesulfonic acid, and the proton NMR spectrum has an obvious chemical shift shift compared with the proton NMR spectrum of the E crystal form. It is judged that the crystal form is a salt-forming crystal, in which 6-( ((2,6-Dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide The ratio to p-toluenesulfonic acid is 1:1.
实施例18：6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺的对甲苯磺酸盐晶体Type C的制备Example 18: 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of p-toluenesulfonate crystal Type C of phenyl)amino)nicotinamide
将29.1mg 6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺置于4mL EP管中，加入1.0mL乙酸乙酯和11.3mg对甲苯磺酸，在25℃下悬浮搅拌2天后，将悬浮液离心分离，收集固体，于40℃下真空干燥24小时，得到样品。对所得样品进行XRPD测试和质子核磁共振分析，得到其X-射线粉末衍射图如图38所示，其质子核磁共振图谱如图39所示。图39显示该晶体含有对甲苯磺酸，且质子核磁共振图谱与E晶型质子核磁共振谱图相比，有明显的化学位移偏移，判断该晶型为成盐晶体，其中，6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺与对甲苯磺酸的比例为1:1。29.1 mg of 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)benzene) Base) amino) nicotinamide was placed in a 4mL EP tube, added 1.0 mL ethyl acetate and 11.3 mg p-toluenesulfonic acid, suspended and stirred at 25°C for 2 days, centrifuged the suspension, collected the solid, and vacuumed at 40°C After drying for 24 hours, the sample was obtained. The obtained sample was subjected to XRPD testing and proton nuclear magnetic resonance analysis, and its X-ray powder diffraction pattern was obtained as shown in Figure 38, and its proton nuclear magnetic resonance pattern was shown in Figure 39. Figure 39 shows that the crystal contains p-toluenesulfonic acid, and compared with the proton NMR spectrum of the E crystal form, there is an obvious chemical shift shift, and the crystal form is judged to be a salt-forming crystal, among which, 6-(((2,6- Dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide and p-toluenesulfonic acid The ratio is 1:1.
实施例19：6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺的富马酸共晶晶体Type B的制备Example 19: 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of fumaric acid eutectic crystal Type B of phenyl) amino) nicotinamide
将29.1mg 6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺置于4mL EP管中，加入1.0mL 4-甲基-2-戊酮和7.1mg富马酸，在25℃下悬浮搅拌2天后，将悬浮液离心分离，收集固体，于25℃下真空干燥24小时，得到样品。对所得样品直接进行XRPD测试和质子核磁共振分析，得到其X-射线粉末衍射图如图40所示，其质子核磁共振图谱如图41所示。图41显示该晶体含有富马酸，且质子核磁共振图谱与E晶型质子核磁共振谱图相比，没有明显化学位移偏移，判断该晶型为共晶，其中，6- (((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺与富马酸的比例为1:1。29.1 mg of 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)benzene) Base) amino) nicotinamide was placed in a 4 mL EP tube, added 1.0 mL 4-methyl-2-pentanone and 7.1 mg fumaric acid, suspended and stirred at 25°C for 2 days, centrifuged the suspension, and collected the solids. The sample was obtained by vacuum drying at 25°C for 24 hours. The obtained sample was directly subjected to XRPD testing and proton nuclear magnetic resonance analysis, and its X-ray powder diffraction pattern was obtained as shown in Figure 40, and its proton nuclear magnetic resonance pattern was obtained as shown in Figure 41. Figure 41 shows that this crystal contains fumaric acid, and compared with the proton NMR spectrum of the E crystal form, there is no obvious chemical shift shift. It is judged that this crystal form is a eutectic, among which, 6- (((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotine The ratio of amide to fumaric acid is 1:1.
实施例20：6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺的富马酸共晶晶体Type C的制备Example 20: 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of fumaric acid eutectic crystal Type C of phenyl)amino)nicotinamide
将29.2mg 6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺置于4mL EP管中，加入1.0mL乙酸乙酯和7.2mg富马酸，在25℃下悬浮搅拌2天后，将悬浮液离心分离，收集固体，于40℃下真空干燥24小时，得到样品。对所得样品进行XRPD测试和质子核磁共振分析，得到其X-射线粉末衍射图如图42所示，其质子核磁共振图谱如图43所示。图43显示该晶体含有富马酸，且质子核磁共振图谱与E晶型质子核磁共振谱图相比，没有明显化学位移偏移，判断该晶型为共晶，其中，6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺与富马酸的比例为1:1。29.2 mg of 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)benzene) Base) amino) nicotinamide was placed in a 4 mL EP tube, added 1.0 mL ethyl acetate and 7.2 mg fumaric acid, suspended and stirred at 25°C for 2 days, centrifuged the suspension, collected the solid, and dried under vacuum at 40°C After 24 hours, the sample was obtained. The obtained sample was subjected to XRPD testing and proton nuclear magnetic resonance analysis, and its X-ray powder diffraction pattern was obtained as shown in Figure 42, and its proton nuclear magnetic resonance pattern was shown in Figure 43. Figure 43 shows that the crystal contains rich Maleic acid, and compared with the proton NMR spectrum of the E crystal form, there is no obvious chemical shift shift, so this crystal form is judged to be a eutectic, in which 6-(((2,6-dimethylpyrimidine The ratio of -4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide to fumaric acid is 1:1 .
实施例21：6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺的甲磺酸盐晶体Type A的制备Example 21: 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of mesylate crystal Type A of phenyl)amino)nicotinamide
将28.7mg 6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺置于4mL EP管中，加入0.5mL甲醇和60μL甲磺酸的1mol/L乙醇溶液，在25℃下悬浮搅拌2天后，将悬浮液离心分离，收集固体，于25℃下真空干燥24小时，得到样品。对所得样品进行XRPD测试和质子核磁共振分析，得到其X-射线粉末衍射图如图44所示，其质子核磁共振图谱如图45所示。图45显示该晶体含有甲磺酸，且质子核磁共振图谱与E晶型质子核磁共振谱图相比，有明显的化学位移偏移，判断该晶型为成盐晶体，其中，6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺与甲磺酸的比例为1:1。28.7 mg of 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)benzene) Place amino) nicotinamide into a 4mL EP tube, add 0.5mL methanol and 60μL methanesulfonic acid 1mol/L ethanol solution, suspend and stir at 25℃ for 2 days, centrifuge the suspension, collect the solid, and incubate at 25℃ Dry under vacuum for 24 hours to obtain the sample. The obtained sample was subjected to XRPD testing and proton nuclear magnetic resonance analysis, and its X-ray powder diffraction pattern was obtained as shown in Figure 44, and its proton nuclear magnetic resonance pattern was shown in Figure 45. Figure 45 shows the The crystal contains methanesulfonic acid, and the proton NMR spectrum has an obvious chemical shift shift compared with the proton NMR spectrum of the E crystal form. It is judged that the crystal form is a salt-forming crystal, in which 6-(((2,6 -Dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide and methanesulfonic acid The ratio is 1:1.
实施例22：6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺的甲磺酸盐晶体Type B的制备Example 22: 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of mesylate crystal Type B of phenyl)amino)nicotinamide
将29.5mg 6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺置于4mL EP管中，加入1.0mL 4-甲基-2-戊酮和60μL甲磺酸的1mol/L乙醇溶液，在25℃下悬浮搅拌2天后，将悬浮液离心分离，收集固体，于25℃下真空干燥24小时，得到样品。对所得样品进行XRPD测试和质子核磁共振分析，得到其X-射线粉末衍射图如图46所示，其质子核磁共振图谱如图47所示。图47显示该晶体含有甲磺酸，且质子核磁共振图谱与E晶型质子核磁共振谱图相比，有明显的化学位移偏移，判断该晶型为成盐晶体，其中，6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺与甲磺酸的比例为1:1.2。29.5 mg of 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)benzene) Base) amino) nicotinamide was placed in a 4 mL EP tube, added 1.0 mL of 4-methyl-2-pentanone and 60 μL of 1 mol/L ethanol solution of methanesulfonic acid, suspended and stirred at 25°C for 2 days, and then centrifuged. Separate, collect the solid, and dry it under vacuum at 25°C for 24 hours to obtain a sample. Perform XRPD testing and proton nuclear magnetic resonance analysis on the obtained sample, and obtain its X-ray powder diffraction pattern as shown in Figure 46, and its proton nuclear magnetic resonance pattern as shown in Figure 46 47. Figure 47 shows that the crystal contains methanesulfonic acid, and the proton NMR spectrum has an obvious chemical shift shift compared with the proton NMR spectrum of the E crystal form. It is judged that the crystal form is a salt-forming crystal, where, 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino )The ratio of nicotinamide to methanesulfonic acid is 1:1.2.
实施例23：6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺的甲磺酸盐晶体Type C的制备 Example 23: 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of mesylate crystal Type C of phenyl)amino)nicotinamide
将29.5mg 6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺置于4mL EP管中，加入1.0mL乙酸乙酯和60uL 1mol/L的甲磺酸乙醇溶液，在25℃下悬浮搅拌2天后，将悬浮液离心分离，收集固体，于40℃下真空干燥24小时，得到样品。对所得样品进行XRPD测试和质子核磁共振分析，得到其X-射线粉末衍射图如图48所示，其质子核磁共振图谱如图49所示。图49显示该晶体含有甲磺酸，且质子核磁共振图谱与E晶型质子核磁共振谱图相比，有明显的化学位移偏移，判断该晶型为成盐晶体，其中，6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺与甲磺酸的比例为1:1。29.5 mg of 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)benzene) Place amino) nicotinamide into a 4mL EP tube, add 1.0mL ethyl acetate and 60uL 1mol/L methanesulfonic acid ethanol solution, suspend and stir at 25°C for 2 days, centrifuge the suspension, collect the solid, and The sample was obtained by vacuum drying at 40°C for 24 hours. The obtained sample was subjected to XRPD testing and proton nuclear magnetic resonance analysis, and its X-ray powder diffraction pattern was obtained as shown in Figure 48, and its proton nuclear magnetic resonance pattern was shown in Figure 49. Figure 49 It shows that the crystal contains methanesulfonic acid, and the proton NMR spectrum has an obvious chemical shift shift compared with the proton NMR spectrum of the E crystal form. It is judged that the crystal form is a salt-forming crystal, in which 6-(((2 ,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide and methanesulfonate The ratio of acids is 1:1.
实施例24：6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺的钾盐晶体Type A的制备Example 24: 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of Potassium Salt Crystal Type A of Phenyl)Amino)Nicotinamide
将28.5mg 6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺置于4mL EP管中，加入1.0mL 4-甲基-2-戊酮和3.7mg氢氧化钾，在25℃下悬浮搅拌2天后，将悬浮液离心分离，收集固体，于25℃下真空干燥24小时，得到样品。对所得样品进行XRPD测试和质子核磁共振分析，得到其X-射线粉末衍射图如图50所示，其质子核磁共振图谱如图51所示。图51显示，其质子核磁共振图谱与E晶型质子核磁共振谱图相比，有明显的化学位移偏移，判断该晶型为成盐晶体。28.5 mg of 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)benzene) Base) amino) nicotinamide is placed in a 4mL EP tube, add 1.0mL 4-methyl-2-pentanone and 3.7mg potassium hydroxide, suspend and stir at 25°C for 2 days, centrifuge the suspension and collect the solid. The sample was obtained by vacuum drying at 25°C for 24 hours. The obtained sample was subjected to XRPD testing and proton nuclear magnetic resonance analysis, and its X-ray powder diffraction pattern was obtained as shown in Figure 50, and its proton nuclear magnetic resonance pattern was shown in Figure 51. Figure 51 shows that its proton NMR spectrum has an obvious chemical shift shift compared with the proton NMR spectrum of the E crystal form, indicating that this crystal form is a salt-forming crystal.
实施例25：6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺的马来酸盐晶体Type A的制备Example 25: 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of maleate crystals of phenyl)amino)nicotinamide Type A
将28.8mg 6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺置于4mL EP管中，加入7.0mg马来酸和1.0mL 4-甲基-2-戊酮，在25℃下悬浮搅拌2天后，将悬浮液离心分离，收集固体，于25℃下真空干燥24小时，得到样品。对所得样品进行XRPD测试和质子核磁共振分析，得到其X-射线粉末衍射图如图52所示，其质子核磁共振图谱如图53所示。图53显示，其质子核磁共振图谱与E晶型质子核磁共振谱图相比，有明显的化学位移偏移，判断该晶型为成盐晶体，其中，6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺与马来酸的比例为1:1。28.8 mg of 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)benzene) Base) amino) nicotinamide was placed in a 4mL EP tube, and 7.0 mg maleic acid and 1.0 mL 4-methyl-2-pentanone were added. After suspension and stirring at 25°C for 2 days, the suspension was centrifuged and the solid was collected. The sample was obtained by vacuum drying at 25°C for 24 hours. The obtained sample was subjected to XRPD testing and proton nuclear magnetic resonance analysis, and its X-ray powder diffraction pattern was obtained as shown in Figure 52, and its proton nuclear magnetic resonance pattern was shown in Figure 53. Figure 53 shows that compared with the proton NMR spectrum of the E crystal form, there is an obvious chemical shift shift. It is judged that the crystal form is a salt-forming crystal. Among them, 6-(((2,6-dimethyl The ratio of nicotinamide to maleic acid is 1 :1.
实施例26：6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺的马来酸盐晶体Type B的制备Example 26: 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of maleate crystals of phenyl)amino)nicotinamide Type B
将29.3mg 6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺置于4mL EP管中，加入7.0mg马来酸和2.0mL乙酸乙酯，在25℃下悬浮搅拌2天后，将悬浮液离心分离，收集固体，于25℃下真空干燥24小时，得到样品。对所得样品进行XRPD测试和质子核磁共振分析，得到其X-射线粉末衍射图如图54所示，其质子核磁共振图谱如图55所示。图55显示，其质子核磁共振图谱与E晶型质子核磁共振谱图相比，有明显的化学位移偏移，判断该晶型为成盐晶体，其中，6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺与马来酸的比例为1:1。 29.3 mg of 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)benzene) Base) amino) nicotinamide was placed in a 4mL EP tube, added 7.0 mg maleic acid and 2.0 mL ethyl acetate, suspended and stirred at 25°C for 2 days, centrifuged the suspension, collected the solid, and dried it under vacuum at 25°C After 24 hours, the sample was obtained. The obtained sample was subjected to XRPD testing and proton NMR analysis, and its X-ray powder diffraction pattern was obtained as shown in Figure 54, and its proton NMR spectrum was shown in Figure 55. Figure 55 shows that its proton NMR Compared with the proton nuclear magnetic resonance spectrum of the E crystal form, there is an obvious chemical shift shift in the resonance spectrum. It is judged that the crystal form is a salt-forming crystal. Among them, 6-(((2,6-dimethylpyrimidine-4-yl )Amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide and maleic acid ratio is 1:1.
实施例27：6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺的钠盐晶体Type B的制备Example 27: 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of sodium salt crystal Type B of phenyl) amino) nicotinamide
将29.2mg 6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺置于4mL EP管中，加入2.6mg氢氧化钠和1.0mL乙酸乙酯，在25℃下悬浮搅拌2天后，将悬浮液离心分离，收集固体，于25℃下真空干燥24小时，得到样品。对所得样品进行XRPD测试和质子核磁共振分析，得到其X-射线粉末衍射图如图56所示，其质子核磁共振图谱如图57所示。图57显示，其质子核磁共振图谱与E晶型质子核磁共振谱图相比，有明显的化学位移偏移，判断该晶型为成盐晶体。29.2 mg of 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)benzene) Base) amino) nicotinamide was placed in a 4mL EP tube, added 2.6 mg sodium hydroxide and 1.0 mL ethyl acetate, suspended and stirred at 25°C for 2 days, centrifuged the suspension, collected the solid, and dried under vacuum at 25°C After 24 hours, the sample was obtained. The obtained sample was subjected to XRPD testing and proton NMR analysis, and its X-ray powder diffraction pattern was obtained as shown in Figure 56, and its proton NMR spectrum was shown in Figure 57. Figure 57 shows that its proton NMR Compared with the proton nuclear magnetic resonance spectrum of the E crystal form, the resonance spectrum has an obvious chemical shift shift, indicating that the crystal form is a salt-forming crystal.
实施例28：6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺的柠檬酸盐共晶Type A的制备Example 28: 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of citrate cocrystal Type A of phenyl)amino)nicotinamide
将28.8mg 6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺置于4mL EP管中，加入11.6mg柠檬酸和1.0mL 4-甲基-2-戊酮，在25℃下悬浮搅拌2天后，将悬浮液离心分离，收集固体，于25℃下真空干燥24小时，得到样品。对所得样品进行XRPD测试和质子核磁共振分析，得到其X-射线粉末衍射图如图58所示，其质子核磁共振图谱如图59所示。图59显示，其质子核磁共振图谱与E晶型质子核磁共振谱图相比，无明显的化学位移偏移，判定未成盐，其中，6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺:柠檬酸＝1:1。28.8 mg of 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)benzene) Base) amino) nicotinamide was placed in a 4mL EP tube, added 11.6 mg citric acid and 1.0 mL 4-methyl-2-pentanone, suspended and stirred at 25°C for 2 days, centrifuged the suspension, collected the solid, and The sample was obtained by vacuum drying at 25°C for 24 hours. The obtained sample was subjected to XRPD testing and proton nuclear magnetic resonance analysis, and its X-ray powder diffraction pattern was obtained as shown in Figure 58, and its proton nuclear magnetic resonance pattern was shown in Figure 59. Figure 59 It shows that compared with the proton NMR spectrum of the E crystal form, there is no obvious chemical shift shift, and it is determined that it has not formed a salt. Among them, 6-(((2,6-dimethylpyrimidine-4-yl )amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide:citric acid=1:1.
实施例29：6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺的苹果酸共晶晶体Type A的制备Example 29: 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of malic acid eutectic crystal Type A of phenyl) amino) nicotinamide
将29.0mg 6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺置于4mL EP管中，加入1.0mL 4-甲基-2-戊酮和8.1mg苹果酸，在25℃下悬浮搅拌2天后，将悬浮液离心分离，收集固体，于25℃下真空干燥24小时，得到样品。对所得样品进行XRPD测试和质子核磁共振分析，得到其X-射线粉末衍射图如图60所示，其质子核磁共振图谱如图61所示。图61显示该晶体含有苹果酸，且质子核磁共振图谱与A晶型质子核磁共振谱图相比，没有明显化学位移偏移，判断该晶型为共晶，其中，6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺与苹果酸的比例为1:1。29.0 mg of 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)benzene) Place methyl)amino)nicotinamide into a 4mL EP tube, add 1.0mL 4-methyl-2-pentanone and 8.1mg malic acid, suspend and stir at 25°C for 2 days, centrifuge the suspension, collect the solid, and The sample was obtained by vacuum drying at 25°C for 24 hours. The obtained sample was subjected to XRPD testing and proton nuclear magnetic resonance analysis, and its X-ray powder diffraction pattern was obtained as shown in Figure 60, and its proton nuclear magnetic resonance pattern was shown in Figure 61. Figure 61 It shows that the crystal contains malic acid, and the proton NMR spectrum has no obvious chemical shift shift compared with the proton NMR spectrum of crystal form A. It is judged that the crystal form is a eutectic, in which 6-(((2,6- The ratio of dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide to malic acid is 1:1.
实施例30：6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺的盐酸盐Type A的制备Example 30: 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of Phenyl)Amino)Nicotinamide Hydrochloride Type A
将29.2mg 6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺置于4mL EP管中，加入1.0mL 4-甲基-2-戊酮和60μL 1mol/L盐酸乙醇溶液，在25℃下悬浮搅拌2天后，将悬浮液离心分离，收集固体，于25℃下真空干燥24小时，得到样品。对所得样品进行XRPD测试和质子核磁共振分析，得到其X-射线粉末衍射图如图62所示，其质子核磁共振图谱如图63所示。图63显示该晶体含有盐酸，且质子核磁共振 图谱与E晶型质子核磁共振谱图相比，有明显的化学位移偏移，判断该晶型为盐酸盐晶体，其中，6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺与盐酸的比例为1:1。29.2 mg of 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)benzene) Base) amino) nicotinamide was placed in a 4mL EP tube, and 1.0 mL of 4-methyl-2-pentanone and 60 μL of 1 mol/L hydrochloric acid ethanol solution were added. After suspension and stirring at 25°C for 2 days, the suspension was centrifuged and collected. The solid was vacuum dried at 25°C for 24 hours to obtain a sample. The obtained sample was subjected to XRPD testing and proton nuclear magnetic resonance analysis, and its X-ray powder diffraction pattern was obtained as shown in Figure 62, and its proton nuclear magnetic resonance pattern was shown in Figure 63 . Figure 63 shows that the crystal contains hydrochloric acid, and the proton NMR Compared with the proton nuclear magnetic resonance spectrum of the E crystal form, there is an obvious chemical shift shift. It is judged that the crystal form is a hydrochloride crystal, in which 6-(((2,6-dimethylpyrimidin-4-yl The ratio of )amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide to hydrochloric acid is 1:1.
实施例31：6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺的盐酸盐Type B的制备Example 31: 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of phenyl) amino) nicotinamide hydrochloride Type B
将29.2mg 6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺置于4mL EP管中，加入1.0mL乙酸乙酯和60μL 1mol/L盐酸乙醇溶液，在25℃下悬浮搅拌2天后，将悬浮液离心分离，收集固体，于40℃下真空干燥24小时，得到样品。对所得样品进行XRPD测试和质子核磁共振分析，得到其X-射线粉末衍射图如图64所示，其质子核磁共振图谱如图65所示。图65显示其质子核磁共振图谱表明该晶体含有盐酸，且质子核磁共振图谱与E晶型质子核磁共振谱图相比，有明显的化学位移偏移，判断该晶型为成盐晶体，其中，6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺与盐酸的比例为1:1。29.2 mg of 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)benzene) Base) amino) nicotinamide was placed in a 4mL EP tube, added 1.0 mL ethyl acetate and 60 μL 1mol/L hydrochloric acid ethanol solution, suspended and stirred at 25°C for 2 days, centrifuged the suspension, collected the solid, and incubated at 40°C Dry under vacuum for 24 hours to obtain the sample. Perform XRPD test and proton NMR analysis on the obtained sample, and obtain its X-ray powder diffraction pattern as shown in Figure 64, and its proton NMR pattern as shown in Figure 65. Figure 65 shows its proton The nuclear magnetic resonance spectrum shows that the crystal contains hydrochloric acid, and the proton nuclear magnetic resonance spectrum has an obvious chemical shift shift compared with the proton nuclear magnetic resonance spectrum of the E crystal form. It is judged that the crystal form is a salt-forming crystal, among which, 6-((( 2,6-Dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide and hydrochloric acid The ratio is 1:1.
实施例32：6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺的乙醇酸共晶晶体Type A的制备Example 32: 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of glycolic acid eutectic crystal Type A of phenyl) amino) nicotinamide
将28.2mg 6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺置于10mL EP管中，加入4.8μL乙醇酸和0.5mL甲醇，在25℃下悬浮搅拌2天后，将悬浮液离心分离，收集固体，于25℃下真空干燥24小时，得到样品。对所得样品直接进行XRPD测试和质子核磁共振分析，得到其X-射线粉末衍射图如图66所示，其质子核磁共振图谱如图67所示。图67显示其质子核磁共振图谱表明该晶体含有乙醇酸，且质子核磁共振图谱与E晶型质子核磁共振谱图相比，没有明显化学位移偏移，判断该晶型为共晶，其中，6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺与乙醇酸的比例为1:1。28.2 mg of 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)benzene) Base) amino) nicotinamide was placed in a 10mL EP tube, added 4.8 μL glycolic acid and 0.5 mL methanol, suspended and stirred at 25°C for 2 days, centrifuged the suspension, collected the solid, and vacuum dried at 25°C for 24 hours. Obtain a sample. Directly perform XRPD testing and proton NMR analysis on the obtained sample, and obtain its X-ray powder diffraction pattern as shown in Figure 66, and its proton NMR spectrum as shown in Figure 67. Figure 67 shows its proton NMR spectrum. This crystal contains glycolic acid, and compared with the proton NMR spectrum of the E crystal form, there is no obvious chemical shift shift. It is judged that the crystal form is a eutectic, in which 6-(((2,6-di The ratio of methylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide to glycolic acid is 1 :1.
实施例33：6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺的乙醇酸共晶晶体Type B的制备Example 33: 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)) Preparation of glycolic acid eutectic crystal Type B of phenyl) amino) nicotinamide
将28.3mg 6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺置于10mL EP管中，加入4.9μL乙醇酸和1.0mL 4-甲基-2-戊酮，在25℃下悬浮搅拌2天后，将悬浮液离心分离，收集固体，于25℃下真空干燥24小时，得到样品。对所得样品进行XRPD测试和质子核磁共振分析，得到其X-射线粉末衍射图如图68所示，其质子核磁共振图谱如图69所示。图69显示该晶体含有乙醇酸，且质子核磁共振图谱与E晶型质子核磁共振谱图相比，没有明显化学位移偏移，判断该晶型为共晶，其中，6-(((2,6-二甲基嘧啶-4-基)氨基)-N-乙氧基-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)烟酰胺与乙醇酸的比例为1:1。28.3 mg of 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)benzene) Base) amino) nicotinamide was placed in a 10mL EP tube, added 4.9 μL glycolic acid and 1.0 mL 4-methyl-2-pentanone, suspended and stirred at 25°C for 2 days, centrifuged the suspension, collected the solid, and The sample was obtained by vacuum drying at 25°C for 24 hours. The obtained sample was subjected to XRPD testing and proton nuclear magnetic resonance analysis, and its X-ray powder diffraction pattern was obtained as shown in Figure 68, and its proton nuclear magnetic resonance pattern was shown in Figure 69. Figure 69 It shows that the crystal contains glycolic acid, and the proton NMR spectrum has no obvious chemical shift offset compared with the proton NMR spectrum of the E crystal form. It is judged that the crystal form is a eutectic, in which 6-(((2,6- The ratio of dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)nicotinamide to glycolic acid is 1:1.
实施例34：非溶剂化晶型E的热力学稳定性 Example 34: Thermodynamic Stability of Unsolvated Crystalline Form E
取一定质量的甲醇溶剂化晶型A，加入1.0mL乙腈或者1.0mL甲基叔丁基醚(MTBE)，在不同温度下搅拌，形成饱和溶液，然后向饱和溶液中加入等量的非溶剂化晶型E和非溶剂化晶型AH，在所选取的特定温度下悬浮搅拌6天，离心得到其中的固体，再次用XRPD测定其晶型，结果如表1所示，搅拌后的XRPD对比图如图70所示。Take a certain mass of methanol solvated crystal form A, add 1.0 mL acetonitrile or 1.0 mL methyl tert-butyl ether (MTBE), stir at different temperatures to form a saturated solution, and then add an equal amount of non-solvated form A to the saturated solution. The crystal form E and the unsolvated crystal form AH were suspended and stirred at a specific selected temperature for 6 days, and the solid was obtained by centrifugation. The crystal form was determined again by XRPD. The results are shown in Table 1. The XRPD comparison chart after stirring As shown in Figure 70.
表1
Table 1
结果标明，在所测试的条件下，晶型E比晶型AH具有更高的稳定性。The results show that under the conditions tested, Form E has higher stability than Form AH.
实施例35：非溶剂化晶型E的引湿性Example 35: Hygroscopicity of Unsolvated Crystalline Form E
称取本发明非溶剂化晶型E 15～20mg，采用动态水分吸脱附(DVS)仪测定其引湿性。测试采用梯度模式，在湿度变化为50％-95％-0％-50％条件下循环一次，在0％至90％范围内每个梯度的湿度变化量为10％，梯度终点采用dm/dt方式进行判断，以dm/dt小于0.002％并维持10分钟为梯度终点。记录每个湿度下的质量变化，相应的质量变化如图71所示。测试完成后，对样品进行XRPD分析，其XRPD对比图如图72所示。Weigh 15 to 20 mg of the unsolvated crystalline form E of the present invention, and use a dynamic moisture adsorption and desorption (DVS) instrument to measure its hygroscopicity. The test adopts gradient mode, with one cycle under the condition of humidity change of 50%-95%-0%-50%. The humidity change amount of each gradient in the range of 0% to 90% is 10%, and the gradient end point adopts dm/dt The method is used to judge, and the gradient end point is when dm/dt is less than 0.002% and maintained for 10 minutes. The mass change at each humidity was recorded, and the corresponding mass change is shown in Figure 71. After the test is completed, XRPD analysis is performed on the sample, and its XRPD comparison chart is shown in Figure 72.
从DVS实验可以看出，晶型E无引湿性，其XRPD结果显示，非溶剂化晶型E在DVS测试前后没有发生晶型转变。It can be seen from the DVS experiment that the crystalline form E has no hygroscopicity, and its XRPD results show that the unsolvated crystalline form E does not undergo a crystalline transformation before and after the DVS test.
实施例36：非溶剂化晶型AH的引湿性Example 36: Hygroscopicity of Unsolvated Crystalline Form AH
称取本发明非溶剂化晶型AH 15～20mg，采用动态水分吸脱附(DVS)仪测定其引湿性。测试采用梯度模式，在湿度变化为50％-95％-0％-50％条件下循环一次，在0％至90％范围内每个梯度的湿度变化量为10％，梯度终点采用dm/dt方式进行判断，以dm/dt小于0.002％并维持10分钟为梯度终点。记录每个湿度下的质量变化，相应的质量变化如图73所示。测试完成后，对样品进行XRPD分析，其XRPD对比图如图74所示。Weigh 15 to 20 mg of the non-solvated crystalline form AH of the present invention, and use a dynamic moisture adsorption and desorption (DVS) instrument to measure its hygroscopicity. The test adopts gradient mode, with one cycle under the condition of humidity change of 50%-95%-0%-50%. The humidity change amount of each gradient in the range of 0% to 90% is 10%, and the gradient end point adopts dm/dt The method is used to judge, and the gradient end point is when dm/dt is less than 0.002% and maintained for 10 minutes. The mass change at each humidity was recorded, and the corresponding mass change is shown in Figure 73. After the test is completed, XRPD analysis is performed on the sample, and its XRPD comparison chart is shown in Figure 74.
从DVS实验可以看出，晶型AH有引湿性，其XRPD结果显示，非溶剂化晶型AH在DVS测试前后没有发生晶型转变。It can be seen from the DVS experiment that the crystalline form AH has hygroscopicity, and its XRPD results show that the unsolvated crystalline form AH did not undergo a crystalline transformation before and after the DVS test.
实施例37：式(I)化合物马来酸盐晶型Type A的引湿性Example 37: Hygroscopicity of the maleate crystal form Type A of the compound of formula (I)
称取式(I)化合物马来酸盐晶型Type A 15～20mg，采用动态水分吸脱附(DVS)仪测定其引湿性。测试采用梯度模式，在湿度变化为50％-95％-0％-50％条件下循环一次，在0％至90％范围内每个梯度的湿度变化量为10％，梯度终点采用dm/dt方式进行判断，以dm/dt小于0.002％并维持10分钟为梯度终点。记录每个湿度下的质量变化，相应的质量变化如图75所示。测试完成后，对样品进行XRPD分析，其XRPD对比图如图76所示。Weigh 15 to 20 mg of the maleate crystal form Type A of the compound of formula (I), and use a dynamic moisture adsorption and desorption (DVS) instrument to measure its hygroscopicity. The test adopts gradient mode, with one cycle under the condition of humidity change of 50%-95%-0%-50%. The humidity change amount of each gradient in the range of 0% to 90% is 10%, and the gradient end point adopts dm/dt The method is used to judge, and the gradient end point is when dm/dt is less than 0.002% and maintained for 10 minutes. Record the mass change at each humidity, and the corresponding mass change is shown in Figure 75. After the test is completed, XRPD analysis is performed on the sample, and its XRPD comparison chart is shown in Figure 76.
从DVS实验可以看出，式(I)化合物马来酸盐晶型Type A极有引湿性，其XRPD结 果显示，式(I)化合物马来酸盐晶型Type A在DVS测试前后没有发生晶型转变。It can be seen from the DVS experiment that the maleate crystal form Type A of the compound of formula (I) is extremely hygroscopic, and its XRPD structure The results show that the maleate crystal form Type A of the compound of formula (I) does not undergo crystalline transformation before and after the DVS test.
实施例38：式(I)化合物柠檬酸共晶晶型Type A的引湿性Example 38: Hygroscopicity of the citric acid eutectic crystal form Type A of the compound of formula (I)
称取式(I)化合物柠檬酸共晶晶型Type A 15～20mg，采用动态水分吸脱附(DVS)仪测定其引湿性。测试采用梯度模式，在湿度变化为50％-95％-0％-50％条件下循环一次，在0％至90％范围内每个梯度的湿度变化量为10％，梯度终点采用dm/dt方式进行判断，以dm/dt小于0.002％并维持10分钟为梯度终点。记录每个湿度下的质量变化，相应的质量变化如图77所示。测试完成后，对样品进行XRPD分析，其XRPD对比图如图78所示。Weigh 15 to 20 mg of the citric acid eutectic crystal form Type A of the compound of formula (I), and use a dynamic moisture adsorption and desorption (DVS) instrument to measure its hygroscopicity. The test adopts gradient mode, with one cycle under the condition of humidity change of 50%-95%-0%-50%. The humidity change amount of each gradient in the range of 0% to 90% is 10%, and the gradient end point adopts dm/dt The method is used to judge, and the gradient end point is when dm/dt is less than 0.002% and maintained for 10 minutes. Record the mass change at each humidity, and the corresponding mass change is shown in Figure 77. After the test is completed, XRPD analysis is performed on the sample, and its XRPD comparison chart is shown in Figure 78.
从DVS实验可以看出，式(I)化合物柠檬酸共晶晶型Type A几乎无引湿性，其XRPD结果显示，式(I)化合物柠檬酸共晶晶型Type A在DVS测试前后没有发生晶型转变。It can be seen from the DVS experiment that the citric acid eutectic crystal form Type A of the compound formula (I) has almost no hygroscopicity. The XRPD results show that the citric acid eutectic crystal form Type A of the compound formula (I) did not crystallize before and after the DVS test. type transformation.
实施例39：式(I)化合物苹果酸共晶晶型Type A的引湿性Example 39: Hygroscopicity of the malic acid eutectic crystal form Type A of the compound of formula (I)
称取式(I)化合物苹果酸共晶晶型Type A 15～20mg，采用动态水分吸脱附(DVS)仪测定其引湿性。测试采用梯度模式，在湿度变化为50％-95％-0％-50％条件下循环一次，在0％至90％范围内每个梯度的湿度变化量为10％，梯度终点采用dm/dt方式进行判断，以dm/dt小于0.002％并维持10分钟为梯度终点。记录每个湿度下的质量变化，相应的质量变化如图79所示。测试完成后，对样品进行XRPD分析，其XRPD对比图如图80所示。Weigh 15 to 20 mg of the malic acid eutectic crystal form Type A of the compound of formula (I), and use a dynamic moisture adsorption and desorption (DVS) instrument to measure its hygroscopicity. The test adopts gradient mode, with one cycle under the condition of humidity change of 50%-95%-0%-50%. The humidity change amount of each gradient in the range of 0% to 90% is 10%, and the gradient end point adopts dm/dt The method is used to judge, and the gradient end point is when dm/dt is less than 0.002% and maintained for 10 minutes. Record the mass change at each humidity, and the corresponding mass change is shown in Figure 79. After the test is completed, XRPD analysis is performed on the sample, and its XRPD comparison chart is shown in Figure 80.
从DVS实验可以看出，式(I)化合物苹果酸共晶晶型Type A略有引湿性，其XRPD结果显示，式(I)化合物苹果酸共晶晶型Type A在DVS测试前后没有发生晶型转变。It can be seen from the DVS experiment that the malic acid eutectic crystal form Type A of the compound formula (I) is slightly hygroscopic. The XRPD results show that the malic acid eutectic crystal form Type A of the compound formula (I) did not crystallize before and after the DVS test. type transformation.
实施例40：非溶剂化晶型E的稳定性Example 40: Stability of Unsolvated Form E
称取本发明晶非溶剂化晶型E 15mg左右样品置于称量瓶中，分别敞口放置在高温(60℃)、高湿(25℃/92.5％RH)、光照(25℃/4500Lux)、加速(40℃/75％RH)和室温(25℃/60％RH)下，于特定时间点取样进行XRPD表征。结果如表2所示，XRPD对比图如图81所示。Weigh about 15 mg samples of the non-solvated crystal form E of the present invention and place them in weighing bottles, and place them with their mouths exposed at high temperature (60°C), high humidity (25°C/92.5%RH), and light (25°C/4500Lux). , accelerated (40℃/75%RH) and room temperature (25℃/60%RH), samples were taken at specific time points for XRPD characterization. The results are shown in Table 2, and the XRPD comparison chart is shown in Figure 81.
表2
Table 2
根据以上实验结果可知，非溶剂化晶型E在高温、高湿、加速和室温条件下保持稳定，稳定性高。 According to the above experimental results, it can be seen that the unsolvated crystalline form E remains stable under high temperature, high humidity, acceleration and room temperature conditions, and has high stability.
实施例41：非溶剂化晶型AH的稳定性Example 41: Stability of Unsolvated Crystalline Form AH
称取本发明非溶剂化晶型AH 15mg左右样品置于称量瓶中，分别敞口放置在高温(60℃)、高湿(25℃/92.5％RH)、光照(25℃/4500Lux)、加速(40℃/75％RH)和室温(25℃/60％RH)下，于特定时间点取样进行XRPD表征。结果如表3所示，XRPD对比图如图82所示。Weigh about 15 mg of samples of the non-solvated crystalline form AH of the present invention and place them in weighing bottles, respectively, and place them exposed at high temperature (60°C), high humidity (25°C/92.5%RH), light (25°C/4500Lux), Samples were taken at specific time points for XRPD characterization under accelerated conditions (40°C/75%RH) and room temperature (25°C/60%RH). The results are shown in Table 3, and the XRPD comparison chart is shown in Figure 82.
表3
table 3
根据以上实验结果可知，非溶剂化晶型AH在高温、高湿、光照、加速和室温条件下保持稳定，稳定性高。According to the above experimental results, it can be seen that the unsolvated crystalline form AH remains stable under high temperature, high humidity, light, acceleration and room temperature conditions, and has high stability.
实施例42：式(I)化合物马来酸盐晶型Type A的稳定性Example 42: Stability of the maleate crystal form Type A of the compound of formula (I)
称取本发明式(I)化合物马来酸盐晶型Type A 15mg左右样品置于称量瓶中，分别敞口放置在高温(60℃)、高湿(25℃/92.5％RH)、光照(25℃/4500Lux)、加速(40℃/75％RH)和室温(25℃/60％RH)下，于特定时间点取样进行XRPD表征。结果如表4所示，XRPD对比图如图83所示。Weigh about 15 mg of the maleate crystal form Type A of the compound of formula (I) of the present invention, place it in a weighing bottle, and place it open to high temperature (60°C), high humidity (25°C/92.5%RH), and light. (25℃/4500Lux), accelerated (40℃/75%RH) and room temperature (25℃/60%RH), samples were taken at specific time points for XRPD characterization. The results are shown in Table 4, and the XRPD comparison chart is shown in Figure 83.
表4
Table 4
根据以上实验结果可知，马来酸盐晶型Type A在高温、高湿、加速和室温条件下保持稳定，稳定性高。According to the above experimental results, it can be seen that the maleate crystal form Type A remains stable under high temperature, high humidity, acceleration and room temperature conditions, and has high stability.
实施例43：式(I)化合物柠檬酸共晶晶型Type A的稳定性Example 43: Stability of the citric acid eutectic crystal form Type A of the compound of formula (I)
称取本发明式(I)化合物柠檬酸盐共晶晶型Type A 15mg左右样品置于称量瓶中，分别敞口放置在高温(60℃)、高湿(25℃/92.5％RH)、光照(25℃/4500Lux)、加速(40℃/75％RH)和室温(25℃/60％RH)下，于特定时间点取样进行XRPD表征。结果如表5所示，XRPD对比图如图84所示。Weigh about 15 mg of the citrate eutectic crystal form Type A of the compound of formula (I) of the present invention and place it in a weighing bottle, and place it open at high temperature (60°C), high humidity (25°C/92.5%RH), Samples were taken at specific time points for XRPD characterization under illumination (25°C/4500Lux), acceleration (40°C/75%RH) and room temperature (25°C/60%RH). The results are shown in Table 5, and the XRPD comparison chart is shown in Figure 84.
表5
table 5
根据以上实验结果可知，柠檬酸盐共晶晶型Type A在高温、高湿、加速和室温条件下保持稳定，稳定性高。According to the above experimental results, it can be seen that the citrate eutectic crystal form Type A remains stable under high temperature, high humidity, acceleration and room temperature conditions and has high stability.
实施例44：式(I)化合物苹果酸共晶晶型Type A的稳定性Example 44: Stability of the malic acid eutectic crystal form Type A of the compound of formula (I)
称取本发明式(I)化合物苹果酸盐共晶晶型Type A 15mg左右样品置于称量瓶中，分别敞口放置在高温(60℃)、高湿(25℃/92.5％RH)、光照(25℃/4500Lux)、加速(40℃/75％RH)和室温(25℃/60％RH)下，于特定时间点取样进行XRPD表征。结果如表6所示，XRPD对比图如图85所示。Weigh about 15 mg of the malate eutectic crystal form Type A of the compound of formula (I) of the present invention and place it in a weighing bottle, and place it open at high temperature (60°C), high humidity (25°C/92.5%RH), Samples were taken at specific time points for XRPD characterization under illumination (25°C/4500Lux), acceleration (40°C/75%RH) and room temperature (25°C/60%RH). The results are shown in Table 6, and the XRPD comparison chart is shown in Figure 85.
表6
Table 6
根据以上实验结果可知，苹果酸盐共晶晶型Type A在高温、高湿、加速和室温条件下保持稳定，稳定性高。 According to the above experimental results, it can be seen that the malate eutectic crystal form Type A remains stable under high temperature, high humidity, acceleration and room temperature conditions, and has high stability.

Claims (50)

  1. 式(I)所示化合物的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：
    Unsolvated crystals, hydrate crystals, solvated crystals, eutectic crystals, and salt-form crystals of the compound represented by formula (I) are characterized by:
    所述非溶剂化晶体选自：The unsolvated crystals are selected from:
    非溶剂化晶体AH，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：7.65°、11.26°、11.43°、15.07°、15.32°、19.07°、20.12°和20.78°；The X-ray powder diffraction pattern of unsolvated crystalline AH has characteristic diffraction peaks at the following 2θ angles (±0.2°): 7.65°, 11.26°, 11.43°, 15.07°, 15.32°, 19.07°, 20.12° and 20.78 °;
    非溶剂化晶体E，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：7.19°、9.59°、14.46°、18.15°、20.41°、23.44°、23.67°、24.01°、24.34°和24.60°；The X-ray powder diffraction pattern of unsolvated crystal E has characteristic diffraction peaks at the following 2θ angles (±0.2°): 7.19°, 9.59°, 14.46°, 18.15°, 20.41°, 23.44°, 23.67°, 24.01 °, 24.34° and 24.60°;
    所述水合物晶体选自：The hydrate crystals are selected from:
    水合物晶体AA，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：7.85°、10.35°、12.74°、14.95°、17.94°、18.05°、19.01°、20.90°和27.26°；Hydrate crystal AA, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles (±0.2°): 7.85°, 10.35°, 12.74°, 14.95°, 17.94°, 18.05°, 19.01°, 20.90° and 27.26°;
    水合物晶体T，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：4.31°、6.09°、6.82°、11.05°、18.49°、19.74°、24.32°和26.78°；Hydrate crystal T, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles (±0.2°): 4.31°, 6.09°, 6.82°, 11.05°, 18.49°, 19.74°, 24.32° and 26.78° ;
    水合物晶体V，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：6.34°、7.48°、7.95°、10.27°、12.97°、17.90°、20.71°和23.98°；Hydrate crystal V, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles (±0.2°): 6.34°, 7.48°, 7.95°, 10.27°, 12.97°, 17.90°, 20.71° and 23.98° ;
    水合物晶体L，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：6.69°、8.02°、9.93°、14.23°、16.13°、16.29°、18.13°、19.18°和24.32°；Hydrate crystal L, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles (±0.2°): 6.69°, 8.02°, 9.93°, 14.23°, 16.13°, 16.29°, 18.13°, 19.18° and 24.32°;
    所述溶剂化晶体选自：The solvated crystals are selected from:
    甲醇溶剂化物晶体A，其中，式(I)所示化合物与甲醇的比例为1:1；其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：4.56°、9.16°、9.34°、12.91°、13.78°、14.66°、15.25°、18.52°和23.12°；Methanol solvate crystal A, in which the ratio of the compound represented by formula (I) to methanol is 1:1; its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles (±0.2°): 4.56°, 9.16 °, 9.34°, 12.91°, 13.78°, 14.66°, 15.25°, 18.52° and 23.12°;
    甲醇溶剂化晶体AE，其中，式(I)所示化合物与甲醇的比例为1:0.4；其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：9.08°、9.63°、13.11°、13.70°、14.80°、15.29°、17.88°、18.78°、22.94°和23.46°；Methanol solvated crystal AE, in which the ratio of the compound represented by formula (I) to methanol is 1:0.4; its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles (±0.2°): 9.08°, 9.63 °, 13.11°, 13.70°, 14.80°, 15.29°, 17.88°, 18.78°, 22.94° and 23.46°;
    甲酸溶剂化晶体F，其中，式(I)所示化合物与甲酸的比例为1:1，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：4.96°、5.30°、7.25°、8.44°、12.14°、15.04°、15.83°、19.47°和20.11°；Formic acid solvated crystal F, in which the ratio of the compound represented by formula (I) to formic acid is 1:1, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles (±0.2°): 4.96°, 5.30 °, 7.25°, 8.44°, 12.14°, 15.04°, 15.83°, 19.47° and 20.11°;
    甲酸溶剂化晶体O，其中，式(I)所示化合物与甲酸的比例为1:1，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.30°、10.68°、11.72°、15.25°、16.09°、17.99 °、20.50°、22.30°、25.78°和26.57°；Formic acid solvates crystal O, in which the ratio of the compound represented by formula (I) to formic acid is 1:1, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.30°, 10.68 °, 11.72°, 15.25°, 16.09°, 17.99 °, 20.50°, 22.30°, 25.78° and 26.57°;
    甲酸溶剂化晶体AF，其中，式(I)所示化合物与甲酸的比例为1:1，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：6.19°、7.48°、8.32°、12.49°、13.46°和14.76°；Formic acid solvated crystal AF, in which the ratio of the compound represented by formula (I) to formic acid is 1:1, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles (±0.2°): 6.19°, 7.48 °, 8.32°, 12.49°, 13.46° and 14.76°;
    乙醇溶剂化晶体R，其中，式(I)所示化合物与乙醇的比例为1:0.3，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：8.37°、12.51°、16.14°、17.56°、17.69°、18.36°、18.68°、19.45°、21.71°、23.01°和24.14°；Ethanol solvated crystal R, in which the ratio of the compound represented by formula (I) to ethanol is 1:0.3, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles (±0.2°): 8.37°, 12.51 °, 16.14°, 17.56°, 17.69°, 18.36°, 18.68°, 19.45°, 21.71°, 23.01° and 24.14°;
    所述共晶晶体选自：The eutectic crystal is selected from:
    草酸共晶晶体Type A，式(I)化合物与草酸的比例为1:1；其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：6.07°、11.01°、12.23°、12.80°、14.28°、16.93°和21.76°；Oxalic acid eutectic crystal Type A, the ratio of the compound of formula (I) to oxalic acid is 1:1; its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles (±0.2°): 6.07°, 11.01°, 12.23 °, 12.80°, 14.28°, 16.93° and 21.76°;
    草酸共晶晶体Type B，式(I)化合物与草酸的比例为1:1；其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：6.01°、8.19°、11.55°、12.34°、13.79°、17.36°、18.14°、20.56°、23.27°、23.94°和25.24°；Oxalic acid eutectic crystal Type B, the ratio of the compound of formula (I) to oxalic acid is 1:1; its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles (±0.2°): 6.01°, 8.19°, 11.55 °, 12.34°, 13.79°, 17.36°, 18.14°, 20.56°, 23.27°, 23.94° and 25.24°;
    富马酸共晶晶体Type B，式(I)化合物与富马酸的比例为1:1，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.18°、6.43°、10.93°、11.46°、12.39°、15.96°、16.22°、19.28°和22.09°；Fumaric acid eutectic crystal Type B, the ratio of the compound of formula (I) to fumaric acid is 1:1, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.18°, 6.43°, 10.93°, 11.46°, 12.39°, 15.96°, 16.22°, 19.28° and 22.09°;
    富马酸共晶晶体Type C，式(I)化合物与富马酸的比例为1:1，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：7.14°、7.49°、10.87°、12.17°、17.38°、19.81°、20.63°、21.58°、23.27°、24.38°和25.39°；Fumaric acid eutectic crystal Type C, the ratio of the compound of formula (I) to fumaric acid is 1:1, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles (±0.2°): 7.14°, 7.49°, 10.87°, 12.17°, 17.38°, 19.81°, 20.63°, 21.58°, 23.27°, 24.38° and 25.39°;
    柠檬酸共晶晶体Type A，式(I)化合物与柠檬酸的比例为1:1，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.56°、6.52°、9.85°、14.27°、14.62°、16.60°、17.73°、19.71°、19.86°、24.36°和26.42°；Citric acid eutectic crystal Type A, the ratio of the compound of formula (I) to citric acid is 1:1, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.56°, 6.52° , 9.85°, 14.27°, 14.62°, 16.60°, 17.73°, 19.71°, 19.86°, 24.36° and 26.42°;
    苹果酸共晶晶体Type A，式(I)化合物与苹果酸的比例为1:1，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：7.14°、8.77°、8.99°、9.90°、11.59°、11.84°、17.27°、19.91°、20.22°、21.09°、23.74°和25.22°；Malic acid eutectic crystal Type A, the ratio of the compound of formula (I) to malic acid is 1:1, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles (±0.2°): 7.14°, 8.77° , 8.99°, 9.90°, 11.59°, 11.84°, 17.27°, 19.91°, 20.22°, 21.09°, 23.74° and 25.22°;
    乙醇酸共晶晶体Type A，式(I)化合物与乙醇的比例为1:1，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.61°、6.83°、8.27°、11.25°、13.73°、14.63°、16.94°、19.79°和23.23°；Glycolic acid eutectic crystal Type A, the ratio of the compound of formula (I) to ethanol is 1:1, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.61°, 6.83°, 8.27°, 11.25°, 13.73°, 14.63°, 16.94°, 19.79° and 23.23°;
    乙醇酸共晶晶体Type B，式(I)化合物与乙醇的比例为1:1，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.44°、6.70°、8.29°、10.96°、13.50°、14.25°、16.48°、20.83°和25.06°；Glycolic acid eutectic crystal Type B, the ratio of the compound of formula (I) to ethanol is 1:1, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.44°, 6.70°, 8.29°, 10.96°, 13.50°, 14.25°, 16.48°, 20.83° and 25.06°;
    所述盐型晶体选自：The salt form crystals are selected from:
    对甲苯磺酸盐晶体Type A，式(I)所示化合物与对甲苯磺酸的比例为1:1；其X-射线 粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：7.41°、9.57°、9.92°、16.06°、16.94°、19.70°、20.44°、22.07°和26.24°；p-toluenesulfonate crystal Type A, the ratio of the compound represented by formula (I) to p-toluenesulfonic acid is 1:1; its X-ray The powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles (±0.2°): 7.41°, 9.57°, 9.92°, 16.06°, 16.94°, 19.70°, 20.44°, 22.07° and 26.24°;
    对甲苯磺酸盐晶体Type B，式(I)所示化合物与对甲苯磺酸的比例为1:1；其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：6.35°、6.93°、7.63°、14.59°、16.79°和20.79°；p-Toluenesulfonate crystal Type B, the ratio of the compound represented by formula (I) to p-toluenesulfonic acid is 1:1; its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angle (±0.2°): 6.35°, 6.93°, 7.63°, 14.59°, 16.79° and 20.79°;
    对甲苯磺酸盐晶体Type C，式(I)所示化合物与对甲苯磺酸的比例为1:1；其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.19°、6.87°、10.06°、13.79°、16.62°、16.93°、20.44°、24.53°和26.12°；p-Toluenesulfonate crystal Type C, the ratio of the compound represented by formula (I) to p-toluenesulfonic acid is 1:1; its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angle (±0.2°): 5.19°, 6.87°, 10.06°, 13.79°, 16.62°, 16.93°, 20.44°, 24.53° and 26.12°;
    甲磺酸盐晶体Type A，式(I)所示化合物与甲磺酸的比例为1:1；其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：8.09°、9.60°、11.06°、12.57°、14.33°、14.55°、16.93°、19.32°、19.64°、20.19°、20.31°、21.05°和26.42°；Methanesulfonate crystal Type A, the ratio of the compound represented by formula (I) to methanesulfonic acid is 1:1; its X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2θ angle (±0.2°): 8.09° , 9.60°, 11.06°, 12.57°, 14.33°, 14.55°, 16.93°, 19.32°, 19.64°, 20.19°, 20.31°, 21.05° and 26.42°;
    甲磺酸盐晶体Type B，式(I)所示化合物与甲磺酸的比例为1:1.2；其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.74°、5.89°、11.53°、11.93°、12.47°、12.90°、14.06°、15.01°、17.14°和25.52°；Methanesulfonate crystal Type B, the ratio of the compound represented by formula (I) to methanesulfonic acid is 1:1.2; its X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2θ angle (±0.2°): 5.74° , 5.89°, 11.53°, 11.93°, 12.47°, 12.90°, 14.06°, 15.01°, 17.14° and 25.52°;
    甲磺酸盐晶体Type C，式(I)所示化合物与对甲苯磺酸的比例为1:1；其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.32°、8.45°、11.84°、17.01°、18.49°、21.30°和22.98°；Mesylate crystal Type C, the ratio of the compound represented by formula (I) to p-toluenesulfonic acid is 1:1; its X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2θ angle (±0.2°): 5.32 °, 8.45°, 11.84°, 17.01°, 18.49°, 21.30° and 22.98°;
    钾盐晶体Type A，其具有结构其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.74°、6.68°、7.96°、13.54°、14.04°、17.78°、20.14°和23.29°；Potash salt crystal Type A, which has the structure Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.74°, 6.68°, 7.96°, 13.54°, 14.04°, 17.78°, 20.14° and 23.29°;
    马来酸盐晶体Type A，式(I)所示化合物与马来酸的比例为1:1，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：4.26°、4.76°、7.08°、7.96°、8.54°、9.53°、10.18°、10.93°、14.34°、15.03°、15.99°和20.50°；Maleate crystal Type A, the ratio of the compound represented by formula (I) to maleic acid is 1:1, and its X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2θ angle (±0.2°): 4.26° , 4.76°, 7.08°, 7.96°, 8.54°, 9.53°, 10.18°, 10.93°, 14.34°, 15.03°, 15.99° and 20.50°;
    马来酸盐晶体Type B，式(I)所示化合物与马来酸的比例为1:1，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：4.34°、4.79°、5.27°、7.20°、7.86°、10.22°、10.56°、11.08°、14.73°、15.20°、16.14°和20.50°； Maleate crystal Type B, the ratio of the compound represented by formula (I) to maleic acid is 1:1, and its X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2θ angle (±0.2°): 4.34° , 4.79°, 5.27°, 7.20°, 7.86°, 10.22°, 10.56°, 11.08°, 14.73°, 15.20°, 16.14° and 20.50°;
    钠盐晶体Type B，其具有结构其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：6.01°、6.61°、7.94°、11.88°、12.48°、13.10°、13.70°、18.31°、19.98°、21.19°、22.35°、25.36°和26.27°；Sodium salt crystal Type B, which has the structure Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles (±0.2°): 6.01°, 6.61°, 7.94°, 11.88°, 12.48°, 13.10°, 13.70°, 18.31°, 19.98°, 21.19 °, 22.35°, 25.36° and 26.27°;
    盐酸盐晶体Type A，式(I)所示化合物与盐酸的比例为1:1，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.90°、7.42°、7.74°、10.96°、14.07°、14.96°、18.01°、25.14°和26.42°；Hydrochloride crystal Type A, the ratio of the compound represented by formula (I) to hydrochloric acid is 1:1, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.90°, 7.42° , 7.74°, 10.96°, 14.07°, 14.96°, 18.01°, 25.14° and 26.42°;
    盐酸盐晶体Type B，式(I)所示化合物与盐酸的比例为1:1，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：6.48°、7.20°、7.90°、14.16°、14.48°、15.68°、17.31°、21.76°和26.53°。Hydrochloride crystal Type B, the ratio of the compound represented by formula (I) to hydrochloric acid is 1:1, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles (±0.2°): 6.48°, 7.20° , 7.90°, 14.16°, 14.48°, 15.68°, 17.31°, 21.76° and 26.53°.
  2. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)所示化合物的非溶剂化晶体AH，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：7.65°、11.26°、11.43°、15.07°、15.32°、16.60°、19.07°、20.12°、20.78°和23.02°。The nonsolvated crystal, hydrate crystal, solvated crystal, eutectic crystal, and salt type crystal as described in claim 1, characterized by: the nonsolvated crystal AH of the compound represented by formula (I), and its X-ray powder The diffraction pattern has characteristic diffraction peaks at the following 2θ angles (±0.2°): 7.65°, 11.26°, 11.43°, 15.07°, 15.32°, 16.60°, 19.07°, 20.12°, 20.78° and 23.02°.
  3. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)所示化合物的非溶剂化晶体AH，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：7.65°、9.47°、11.26°、11.43°、15.07°、15.32°、16.31°、16.60°、19.07°、20.12°、20.78°、23.02°和25.77°。The nonsolvated crystal, hydrate crystal, solvated crystal, eutectic crystal, and salt type crystal as described in claim 1, characterized by: the nonsolvated crystal AH of the compound represented by formula (I), and its X-ray powder The diffraction pattern has characteristic diffraction peaks at the following 2θ angles (±0.2°): 7.65°, 9.47°, 11.26°, 11.43°, 15.07°, 15.32°, 16.31°, 16.60°, 19.07°, 20.12°, 20.78°, 23.02° and 25.77°.
  4. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)化合物的非溶剂化晶体AH，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：7.65°、8.36°、9.47°、9.80°、11.26°、11.43°、11.55°、11.80°、12.95°、13.64°、14.34°、14.74°、15.07°、15.32°、15.91°、16.31°、16.60°、16.87°、18.72°、19.07°、19.73°、20.12°、20.78°、21.30°、21.45°、21.95°、22.31°、23.02°、23.30°、23.67°、23.84°、24.65°、25.77°、26.57°、26.90°、28.29°、28.85°、29.54°。The unsolvated crystal, hydrate crystal, solvated crystal, eutectic crystal, and salt-type crystal as described in claim 1 is characterized by: the unsolvated crystal AH of the compound of formula (I) and its X-ray powder diffraction pattern It has characteristic diffraction peaks at the following 2θ angles (±0.2°): 7.65°, 8.36°, 9.47°, 9.80°, 11.26°, 11.43°, 11.55°, 11.80°, 12.95°, 13.64°, 14.34°, 14.74° , 15.07°, 15.32°, 15.91°, 16.31°, 16.60°, 16.87°, 18.72°, 19.07°, 19.73°, 20.12°, 20.78°, 21.30°, 21.45°, 21.95°, 22.31°, 23.02°, 23.30 °, 23.67°, 23.84°, 24.65°, 25.77°, 26.57°, 26.90°, 28.29°, 28.85°, 29.54°.
  5. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)所示化合物的非溶剂化晶体AH，其X-射线粉末衍射图如图7所示。The nonsolvated crystal, hydrate crystal, solvated crystal, eutectic crystal, and salt type crystal as described in claim 1, characterized by: the nonsolvated crystal AH of the compound represented by formula (I), and its X-ray powder The diffraction pattern is shown in Figure 7.
  6. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)所示化合物的非溶剂化晶体E，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：7.19°、9.59°、13.64°、14.46°、18.15°、19.19°、20.41°、23.44°、23.67°、24.01°、24.34°和24.60°。 The unsolvated crystal, hydrate crystal, solvated crystal, eutectic crystal, and salt form crystal as described in claim 1, characterized by: unsolvated crystal E of the compound represented by formula (I), and its X-ray powder The diffraction pattern has characteristic diffraction peaks at the following 2θ angles (±0.2°): 7.19°, 9.59°, 13.64°, 14.46°, 18.15°, 19.19°, 20.41°, 23.44°, 23.67°, 24.01°, 24.34° and 24.60°.
  7. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)所示化合物的非溶剂化晶体E，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：7.19°、8.93°、9.59°、12.72°、13.64°、14.46°、18.15°、19.19°、19.96°、20.41°、23.44°、23.67°、24.01°、24.34°、24.60°和28.60°。The unsolvated crystal, hydrate crystal, solvated crystal, eutectic crystal, and salt form crystal as described in claim 1, characterized by: unsolvated crystal E of the compound represented by formula (I), and its X-ray powder The diffraction pattern has characteristic diffraction peaks at the following 2θ angles (±0.2°): 7.19°, 8.93°, 9.59°, 12.72°, 13.64°, 14.46°, 18.15°, 19.19°, 19.96°, 20.41°, 23.44°, 23.67°, 24.01°, 24.34°, 24.60° and 28.60°.
  8. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)化合物的非溶剂化晶体E，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：7.19°、8.93°、9.59°、10.14°、10.52°、11.74°、12.31°、12.72°、13.64°、14.46°、15.33°、15.85°、16.62°、17.02°、18.03°、18.15°、18.72°、19.19°、19.36°、19.96°、20.41°、20.90°、23.44°、23.67°、24.01°、24.34°、24.60°、25.69°、26.66°、28.60°、29.19°、32.08°。The unsolvated crystal, hydrate crystal, solvated crystal, eutectic crystal, and salt form crystal as described in claim 1, characterized by: the unsolvated crystal E of the compound of formula (I) and its X-ray powder diffraction pattern It has characteristic diffraction peaks at the following 2θ angles (±0.2°): 7.19°, 8.93°, 9.59°, 10.14°, 10.52°, 11.74°, 12.31°, 12.72°, 13.64°, 14.46°, 15.33°, 15.85° , 16.62°, 17.02°, 18.03°, 18.15°, 18.72°, 19.19°, 19.36°, 19.96°, 20.41°, 20.90°, 23.44°, 23.67°, 24.01°, 24.34°, 24.60°, 25.69°, 26.66 °, 28.60°, 29.19°, 32.08°.
  9. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)所示化合物的非溶剂化晶体E，其X-射线粉末衍射图如图11所示。The unsolvated crystal, hydrate crystal, solvated crystal, eutectic crystal, and salt form crystal as described in claim 1, characterized by: unsolvated crystal E of the compound represented by formula (I), and its X-ray powder The diffraction pattern is shown in Figure 11.
  10. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)所示化合物的水合物晶体AA，其X-射线粉末衍射图如图3所示。The unsolvated crystal, hydrate crystal, solvated crystal, eutectic crystal, and salt-type crystal as described in claim 1 is characterized by: hydrate crystal AA of the compound represented by formula (I), and its X-ray powder diffraction The diagram is shown in Figure 3.
  11. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)所示化合物的水合物晶体T，其X-射线粉末衍射图如图20所示。The unsolvated crystal, hydrate crystal, solvated crystal, eutectic crystal, and salt type crystal as described in claim 1 is characterized by: the hydrate crystal T of the compound represented by formula (I), and its X-ray powder diffraction The diagram is shown in Figure 20.
  12. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)化合物的水合物晶体V，其X-射线粉末衍射图如图22所示。Non-solvated crystals, hydrate crystals, solvated crystals, eutectic crystals, and salt-type crystals as described in claim 1 are characterized in that: the hydrate crystal V of the compound of formula (I) has an X-ray powder diffraction pattern as follows As shown in Figure 22.
  13. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)化合物的水合物晶体L，其X-射线粉末衍射图如图26所示。The unsolvated crystal, hydrate crystal, solvated crystal, eutectic crystal, and salt type crystal as described in claim 1 is characterized in that: the hydrate crystal L of the compound of formula (I) has an X-ray powder diffraction pattern as follows As shown in Figure 26.
  14. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)所示化合物的甲醇溶剂化物晶体A，其X-射线粉末衍射图如图1所示。Unsolvated crystals, hydrate crystals, solvated crystals, eutectic crystals, and salt-type crystals as described in claim 1, characterized by: methanol solvate crystal A of the compound represented by formula (I), and its X-ray powder The diffraction pattern is shown in Figure 1.
  15. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)所示化合物的甲醇溶剂化物晶体AE，其X-射线粉末衍射图如图5所示。The unsolvated crystal, hydrate crystal, solvated crystal, eutectic crystal, and salt form crystal as described in claim 1, characterized by: methanol solvate crystal AE of the compound represented by formula (I), and its X-ray powder The diffraction pattern is shown in Figure 5.
  16. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)所示化合物的甲酸溶剂化晶体F，其X-射线粉末衍射图如图16所示。Unsolvated crystals, hydrate crystals, solvated crystals, eutectic crystals, and salt-type crystals as described in claim 1, characterized by: formic acid solvated crystal F of the compound represented by formula (I), and its X-ray powder The diffraction pattern is shown in Figure 16.
  17. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)所示化合物的甲酸溶剂化晶体O，其X-射线粉末衍射图如图18所示。Unsolvated crystals, hydrate crystals, solvated crystals, eutectic crystals, and salt-type crystals as described in claim 1, characterized by: formic acid solvated crystal O of the compound represented by formula (I), and its X-ray powder The diffraction pattern is shown in Figure 18.
  18. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)所示化合物的甲酸溶剂化晶体AF，其X-射线粉末衍射图如图24所示。Unsolvated crystals, hydrate crystals, solvated crystals, eutectic crystals, and salt-type crystals as described in claim 1, characterized by: formic acid solvated crystals AF of the compound represented by formula (I), and its X-ray powder The diffraction pattern is shown in Figure 24.
  19. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)所示化合物的乙醇溶剂化物晶体R，其X-射线粉末衍射图如图28所示。Unsolvated crystals, hydrate crystals, solvated crystals, eutectic crystals, and salt-type crystals as described in claim 1, characterized by: ethanol solvate crystal R of the compound represented by formula (I), and its X-ray powder The diffraction pattern is shown in Figure 28.
  20. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)化合物的草酸共晶晶体Type A，其X-射线粉末衍射图如图30所示。 The unsolvated crystal, hydrate crystal, solvated crystal, eutectic crystal, and salt type crystal as described in claim 1 is characterized by: oxalic acid eutectic crystal Type A of the compound of formula (I), and its X-ray powder diffraction The diagram is shown in Figure 30.
  21. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)化合物的草酸共晶晶体Type B，其X-射线粉末衍射图如图32所示。Unsolvated crystals, hydrate crystals, solvated crystals, eutectic crystals, and salt-type crystals as described in claim 1, characterized by: oxalic acid eutectic crystal Type B of the compound of formula (I), and its X-ray powder diffraction The diagram is shown in Figure 32.
  22. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)化合物的富马酸共晶晶体Type B，其X-射线粉末衍射图如图40所示。Unsolvated crystals, hydrate crystals, solvated crystals, eutectic crystals, and salt-type crystals as described in claim 1, characterized by: fumaric acid eutectic crystal Type B of the compound of formula (I), and its X-ray The powder diffraction pattern is shown in Figure 40.
  23. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：所述富马酸共晶晶体Type C，其X-射线粉末衍射图如图42所示。The unsolvated crystal, hydrate crystal, solvated crystal, eutectic crystal, and salt type crystal as described in claim 1 is characterized in that: the fumaric acid eutectic crystal Type C has an X-ray powder diffraction pattern as follows As shown in Figure 42.
  24. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)化合物的柠檬酸共晶晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.56°、6.52°、9.85°、13.20°、13.46°、14.27°、14.62°、15.78°、16.60°、17.73°、19.71°、19.86°、24.36°、25.16°和26.42°。Non-solvated crystals, hydrate crystals, solvated crystals, eutectic crystals, and salt-type crystals as described in claim 1, characterized by: citric acid eutectic crystal Type A of the compound of formula (I), and its X-ray powder The diffraction pattern has characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.56°, 6.52°, 9.85°, 13.20°, 13.46°, 14.27°, 14.62°, 15.78°, 16.60°, 17.73°, 19.71°, 19.86°, 24.36°, 25.16° and 26.42°.
  25. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)化合物的柠檬酸共晶晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.56°、6.52°、7.10°、9.85°、13.20°、13.46°、14.27°、14.62°、15.41°、15.78°、16.29°、16.60°、17.73°、19.31°、19.71°、19.86°、23.15°、24.36°、25.16°和26.42°。Non-solvated crystals, hydrate crystals, solvated crystals, eutectic crystals, and salt-type crystals as described in claim 1, characterized by: citric acid eutectic crystal Type A of the compound of formula (I), and its X-ray powder The diffraction pattern has characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.56°, 6.52°, 7.10°, 9.85°, 13.20°, 13.46°, 14.27°, 14.62°, 15.41°, 15.78°, 16.29°, 16.60°, 17.73°, 19.31°, 19.71°, 19.86°, 23.15°, 24.36°, 25.16° and 26.42°.
  26. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)化合物的柠檬酸共晶晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：5.56°、6.52°、7.10°、9.85°、11.00°、12.76°、13.20°、13.46°、14.27°、14.62°、15.41°、15.78°、16.29°、16.60°、17.73°、19.31°、19.71°、19.86°、23.15°、23.51°、24.36°、25.16°、25.56°、25.70°、26.42°、27.08°、27.53°、27.74°、28.08°、32.03°。Non-solvated crystals, hydrate crystals, solvated crystals, eutectic crystals, and salt-type crystals as described in claim 1, characterized by: citric acid eutectic crystal Type A of the compound of formula (I), and its X-ray powder The diffraction pattern has characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.56°, 6.52°, 7.10°, 9.85°, 11.00°, 12.76°, 13.20°, 13.46°, 14.27°, 14.62°, 15.41°, 15.78°、16.29°、16.60°、17.73°、19.31°、19.71°、19.86°、23.15°、23.51°、24.36°、25.16°、25.56°、25.70°、26.42°、27.08°、27.53°、27.74° , 28.08°, 32.03°.
  27. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)化合物的柠檬酸共晶晶体Type A，其X-射线粉末衍射图如图58所示。Non-solvated crystals, hydrate crystals, solvated crystals, eutectic crystals, and salt-type crystals as described in claim 1, characterized by: citric acid eutectic crystal Type A of the compound of formula (I), and its X-ray powder The diffraction pattern is shown in Figure 58.
  28. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)化合物的苹果酸共晶晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：7.14°、8.77°、8.99°、9.90°、11.59°、11.84°、17.27°、18.02°、19.21°、19.91°、20.22°、21.09°、22.98°、23.74°、24.42°和25.22°。Non-solvated crystals, hydrate crystals, solvated crystals, eutectic crystals, and salt-type crystals as described in claim 1, characterized by: malic acid eutectic crystal Type A of the compound of formula (I), and its X-ray powder The diffraction pattern has characteristic diffraction peaks at the following 2θ angles (±0.2°): 7.14°, 8.77°, 8.99°, 9.90°, 11.59°, 11.84°, 17.27°, 18.02°, 19.21°, 19.91°, 20.22°, 21.09°, 22.98°, 23.74°, 24.42° and 25.22°.
  29. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)化合物的苹果酸共晶晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：7.14°、8.77°、8.99°、9.90°、11.59°、11.84°、13.90°、14.72°、15.83°、17.27°、18.02°、19.21°、19.91°、20.22°、21.09°、22.98°、23.74°、24.42°和25.22°。Non-solvated crystals, hydrate crystals, solvated crystals, eutectic crystals, and salt-type crystals as described in claim 1, characterized by: malic acid eutectic crystal Type A of the compound of formula (I), and its X-ray powder The diffraction pattern has characteristic diffraction peaks at the following 2θ angles (±0.2°): 7.14°, 8.77°, 8.99°, 9.90°, 11.59°, 11.84°, 13.90°, 14.72°, 15.83°, 17.27°, 18.02°, 19.21°, 19.91°, 20.22°, 21.09°, 22.98°, 23.74°, 24.42° and 25.22°.
  30. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)化合物的苹果酸共晶晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：7.14°、8.77°、8.99°、9.90°、11.59°、11.84°、13.90°、14.72°、15.83 °、17.27°、18.02°、18.49°、19.21°、19.91°、20.22°、20.49°、21.09°、22.32°、22.98°、23.74°、24.42°、25.22°、25.58°、26.30°、27.04°、27.86°、28.46°、29.20°、29.84°、31.18°、31.42°、34.27°、34.82°。Unsolvated crystals, hydrate crystals, solvated crystals, eutectic crystals, and salt-type crystals as described in claim 1, characterized by: malic acid eutectic crystal Type A of the compound of formula (I), and its X-ray powder The diffraction pattern has characteristic diffraction peaks at the following 2θ angles (±0.2°): 7.14°, 8.77°, 8.99°, 9.90°, 11.59°, 11.84°, 13.90°, 14.72°, 15.83 °, 17.27°, 18.02°, 18.49°, 19.21°, 19.91°, 20.22°, 20.49°, 21.09°, 22.32°, 22.98°, 23.74°, 24.42°, 25.22°, 25.58°, 26.30°, 27.04°, 27.86°, 28.46°, 29.20°, 29.84°, 31.18°, 31.42°, 34.27°, 34.82°.
  31. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)化合物的苹果酸共晶晶体Type A，其X-射线粉末衍射图如图60所示。Non-solvated crystals, hydrate crystals, solvated crystals, eutectic crystals, and salt-type crystals as described in claim 1, characterized by: malic acid eutectic crystal Type A of the compound of formula (I), and its X-ray powder The diffraction pattern is shown in Figure 60.
  32. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)化合物的乙醇酸共晶晶体Type A，其X-射线粉末衍射图如图66所示。Non-solvated crystals, hydrate crystals, solvated crystals, eutectic crystals, and salt-type crystals as described in claim 1, characterized by: glycolic acid eutectic crystal Type A of the compound of formula (I), and its X-ray powder The diffraction pattern is shown in Figure 66.
  33. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)化合物的乙醇酸共晶晶体Type B，其X-射线粉末衍射图如图68所示。Non-solvated crystals, hydrate crystals, solvated crystals, eutectic crystals, and salt-type crystals as described in claim 1, characterized by: glycolic acid eutectic crystal Type B of the compound of formula (I), and its X-ray powder The diffraction pattern is shown in Figure 68.
  34. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)化合物的对甲苯磺酸盐晶体Type A，其X-射线粉末衍射图如图34所示。Unsolvated crystals, hydrate crystals, solvated crystals, eutectic crystals, and salt-type crystals as described in claim 1, characterized by: p-toluenesulfonate crystal Type A of the compound of formula (I), and its X-ray The powder diffraction pattern is shown in Figure 34.
  35. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)化合物的对甲苯磺酸盐晶体Type B，其X-射线粉末衍射图如图36所示。Non-solvated crystals, hydrate crystals, solvated crystals, eutectic crystals, and salt-type crystals as described in claim 1, characterized by: p-toluenesulfonate crystal Type B of the compound of formula (I), and its X-ray The powder diffraction pattern is shown in Figure 36.
  36. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)化合物的对甲苯磺酸盐晶体Type C，其X-射线粉末衍射图如图38所示。Unsolvated crystals, hydrate crystals, solvated crystals, eutectic crystals, and salt-type crystals as described in claim 1, characterized by: p-toluenesulfonate crystal Type C of the compound of formula (I), and its X-ray The powder diffraction pattern is shown in Figure 38.
  37. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)化合物的甲磺酸盐晶体Type A，其X-射线粉末衍射图如图44所示。Non-solvated crystals, hydrate crystals, solvated crystals, eutectic crystals, and salt-type crystals as described in claim 1, characterized by: methanesulfonate crystal Type A of the compound of formula (I), and its X-ray powder The diffraction pattern is shown in Figure 44.
  38. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)化合物的甲磺酸盐晶体Type B，其X-射线粉末衍射图如图46所示。Non-solvated crystals, hydrate crystals, solvated crystals, eutectic crystals, and salt-type crystals as described in claim 1, characterized by: methanesulfonate crystal Type B of the compound of formula (I), and its X-ray powder The diffraction pattern is shown in Figure 46.
  39. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)化合物的甲磺酸盐晶体Type C，其X-射线粉末衍射图如图48所示。Non-solvated crystals, hydrate crystals, solvated crystals, eutectic crystals, and salt-type crystals as described in claim 1, characterized by: methanesulfonate crystal Type C of the compound of formula (I), and its X-ray powder The diffraction pattern is shown in Figure 48.
  40. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)化合物的钾盐晶体Type A，其X-射线粉末衍射图如图50所示。The unsolvated crystal, hydrate crystal, solvated crystal, eutectic crystal, and salt type crystal as described in claim 1 is characterized by: potassium salt crystal Type A of the compound of formula (I), and its X-ray powder diffraction pattern As shown in Figure 50.
  41. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)化合物的马来酸盐晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：4.26°、4.76°、7.08°、7.96°、8.54°、9.53°、10.18°、10.93°、13.89°、14.34°、15.03°、15.99°、20.50°、21.49°和24.03°。Non-solvated crystals, hydrate crystals, solvated crystals, eutectic crystals, and salt-type crystals as described in claim 1, characterized by: maleate crystal Type A of the compound of formula (I), and its X-ray powder The diffraction pattern has characteristic diffraction peaks at the following 2θ angles (±0.2°): 4.26°, 4.76°, 7.08°, 7.96°, 8.54°, 9.53°, 10.18°, 10.93°, 13.89°, 14.34°, 15.03°, 15.99°, 20.50°, 21.49° and 24.03°.
  42. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)化合物的马来酸盐晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：4.26°、4.76°、7.08°、7.96°、8.54°、9.53°、10.18°、10.93°、12.41°、13.89°、14.34°、15.03°、15.99°、17.93°、20.50°、21.49°、23.55°和24.03°。Non-solvated crystals, hydrate crystals, solvated crystals, eutectic crystals, and salt-type crystals as described in claim 1, characterized by: maleate crystal Type A of the compound of formula (I), and its X-ray powder The diffraction pattern has characteristic diffraction peaks at the following 2θ angles (±0.2°): 4.26°, 4.76°, 7.08°, 7.96°, 8.54°, 9.53°, 10.18°, 10.93°, 12.41°, 13.89°, 14.34°, 15.03°, 15.99°, 17.93°, 20.50°, 21.49°, 23.55° and 24.03°.
  43. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)化合物的马来酸盐晶体Type A，其X-射线粉末衍射图在下列2θ角处(±0.2°)具有特征衍射峰：4.26°、4.76°、7.08°、7.96°、8.54°、9.53°、10.18°、10.93°、12.41°、 13.89°、14.34°、15.03°、15.99°、17.93°、20.50°、21.49°、21.97°、23.55°、24.03°、25.19°、25.57°、26.00°。Unsolvated crystals, hydrate crystals, solvated crystals, eutectic crystals, and salt-type crystals as described in claim 1, characterized by: maleate crystal Type A of the compound of formula (I), and its X-ray powder The diffraction pattern has characteristic diffraction peaks at the following 2θ angles (±0.2°): 4.26°, 4.76°, 7.08°, 7.96°, 8.54°, 9.53°, 10.18°, 10.93°, 12.41°, 13.89°, 14.34°, 15.03°, 15.99°, 17.93°, 20.50°, 21.49°, 21.97°, 23.55°, 24.03°, 25.19°, 25.57°, 26.00°.
  44. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)化合物的马来酸盐晶体Type A，其X-射线粉末衍射图如图52所示。Non-solvated crystals, hydrate crystals, solvated crystals, eutectic crystals, and salt-type crystals as described in claim 1, characterized by: maleate crystal Type A of the compound of formula (I), and its X-ray powder The diffraction pattern is shown in Figure 52.
  45. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)化合物的马来酸盐晶体Type B，其X-射线粉末衍射图如图54所示。Non-solvated crystals, hydrate crystals, solvated crystals, eutectic crystals, and salt-type crystals as described in claim 1, characterized by: maleate crystal Type B of the compound of formula (I), and its X-ray powder The diffraction pattern is shown in Figure 54.
  46. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)化合物的钠盐晶体Type B，其X-射线粉末衍射图如图56所示。Non-solvated crystals, hydrate crystals, solvated crystals, eutectic crystals, and salt-type crystals as described in claim 1, characterized by: sodium salt crystal Type B of the compound of formula (I), and its X-ray powder diffraction pattern As shown in Figure 56.
  47. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)化合物的盐酸盐晶体Type A，其X-射线粉末衍射图如图62所示。The unsolvated crystal, hydrate crystal, solvated crystal, eutectic crystal, and salt form crystal as described in claim 1 is characterized by: hydrochloride crystal Type A of the compound of formula (I), and its X-ray powder diffraction The diagram is shown in Figure 62.
  48. 如权1所述的非溶剂化晶体，水合物晶体，溶剂化晶体，共晶晶体，盐型晶体，其特征在于：式(I)化合物的盐酸盐晶体Type B，其X-射线粉末衍射图如图64所示。Unsolvated crystals, hydrate crystals, solvated crystals, eutectic crystals, and salt-type crystals as described in claim 1, characterized by: hydrochloride crystal Type B of the compound of formula (I), and its X-ray powder diffraction The diagram is shown in Figure 64.
  49. 式(I)所示化合物的非溶剂化晶体E，其晶型为三斜晶系，晶胞参数值为： α＝76.404(2)°；β＝86.6962(16)°；γ＝70.126(2)°；空间群：P-1；每个晶胞中的分子(Z)：2；晶胞体积：计算密度：1.376g/cm3；
    The unsolvated crystal E of the compound represented by formula (I) has a crystal form of triclinic system and the unit cell parameter values are: α=76.404(2)°; β=86.6962(16)°; γ=70.126(2)°; Space group: P-1; Molecules (Z) in each unit cell: 2; Unit cell volume: Calculated density: 1.376g/cm 3 ;
  50. 式(I)所示化合物的非溶剂化晶体E，其X-射线单晶衍射图谱如图15；
    The X-ray single crystal diffraction pattern of the unsolvated crystal E of the compound represented by formula (I) is shown in Figure 15;
PCT/CN2023/096974 2022-06-01 2023-05-30 Crystal forms of hydroxamic acid ester compound and salt thereof, and preparation method WO2023231996A1 (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101405283A (en) * 2006-03-30 2009-04-08 泰博特克药品有限公司 HIV inhibiting 5-amido substituted pyrimidines
CN113563309A (en) * 2020-04-28 2021-10-29 浙江海正药业股份有限公司 Pyridine derivative and preparation method and application thereof
CN114901656A (en) * 2020-12-02 2022-08-12 深圳微芯生物科技股份有限公司 Hydroximic acid ester compound, preparation method and application thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101405283A (en) * 2006-03-30 2009-04-08 泰博特克药品有限公司 HIV inhibiting 5-amido substituted pyrimidines
CN113563309A (en) * 2020-04-28 2021-10-29 浙江海正药业股份有限公司 Pyridine derivative and preparation method and application thereof
CN114901656A (en) * 2020-12-02 2022-08-12 深圳微芯生物科技股份有限公司 Hydroximic acid ester compound, preparation method and application thereof

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