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WO2025185704A1 - Crystal form of kif18a inhibitor, and preparation method therefor and use thereof - Google Patents

Crystal form of kif18a inhibitor, and preparation method therefor and use thereof

Info

Publication number
WO2025185704A1
WO2025185704A1 PCT/CN2025/081054 CN2025081054W WO2025185704A1 WO 2025185704 A1 WO2025185704 A1 WO 2025185704A1 CN 2025081054 W CN2025081054 W CN 2025081054W WO 2025185704 A1 WO2025185704 A1 WO 2025185704A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound represented
ray powder
powder diffraction
diffraction pattern
Prior art date
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Pending
Application number
PCT/CN2025/081054
Other languages
French (fr)
Chinese (zh)
Other versions
WO2025185704A8 (en
Inventor
张小兵
葛广存
杨方龙
王思勤
金磊
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Changchun Genescience Pharmaceutical Co Ltd
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Changchun Genescience Pharmaceutical Co Ltd
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Publication of WO2025185704A1 publication Critical patent/WO2025185704A1/en
Publication of WO2025185704A8 publication Critical patent/WO2025185704A8/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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

Definitions

  • the present invention belongs to the field of compounds, and specifically relates to a crystal form of a KIF18A inhibitor, a preparation method thereof, and an application thereof.
  • PCT/CN2023/117322 (filing date September 6, 2023) describes the compound 4-(2-hydroxyethanesulfonylamino)-2-(6-azaspiro[2.5]octane-6-yl)-N-((1S,4R)-1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-yl)benzamide, whose structure is shown in Formula (I).
  • This compound not only has good KIF18A inhibition and OVCAR-3 cell activity in vitro, but also has significantly improved physicochemical properties (solubility and permeability), significantly improved OVCAR-3 in vivo efficacy, and good safety.
  • This compound can be used to treat KIF18A-mediated conditions and/or diseases, such as tumor diseases, and to prepare drugs for treating such conditions or diseases.
  • the crystal structure of a pharmaceutically active ingredient often affects the chemical stability of the drug. Differences in crystallization and storage conditions can lead to variations in the compound's crystal structure, sometimes resulting in the formation of alternative crystalline forms. Therefore, in-depth research into the crystal forms of the compound of formula (I) and related preparation methods is essential to improve various properties of the compound of formula (I).
  • the present invention provides an amorphous or polymorphic compound of a compound represented by formula (I);
  • the amorphous form of the compound represented by formula (I) has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in Figure 1.
  • XRPD pattern X-ray powder diffraction pattern
  • DSC pattern differential scanning calorimetry pattern
  • TGA pattern thermogravimetric analysis pattern
  • the polymorph of the compound represented by formula (I) is selected from the Form A crystal form, Form B crystal form, Form C crystal form, Form D crystal form, Form E crystal form, Form F crystal form, Form G crystal form, Form H crystal form, and Form I crystal form of the compound represented by formula (I).
  • the X-ray powder diffraction pattern of the Form A crystal form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2 ⁇ angles: 14.97° ⁇ 0.20°, 17.87° ⁇ 0.20°, 18.82° ⁇ 0.20°, 19.07° ⁇ 0.20°, 19.56° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the Form A crystal form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at the following 2 ⁇ angles: 8.87° ⁇ 0.20°, 13.46° ⁇ 0.20°, 24.77° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the Form A crystal form of the compound represented by formula (I) further includes the following characteristic diffraction peaks at one, two or more 2 ⁇ angles: 6.81° ⁇ 0.20°, 13.20° ⁇ 0.20°, 16.18° ⁇ 0.20°, 20.32° ⁇ 0.20°, 21.11° ⁇ 0.20°, 21.56° ⁇ 0.20°, 22.38° ⁇ 0.20° , 22.82° ⁇ 0.20°, 23.35° ⁇ 0.20°, 23.78° ⁇ 0.20°, 24.01° ⁇ 0.20°, 25.12° ⁇ 0.20°, 25.68° ⁇ 0.20°, 26.48° ⁇ 0.20°, 26.67° ⁇ 0.20°, 27.02° ⁇ 0.20°, 28.01° ⁇ 0.20°, 28.75° ⁇ 0.20°, 30.72° ⁇ 0.20°.
  • the Form A crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 4.
  • the differential scanning calorimetry analysis spectrum (DSC graph) of the Form A crystal form of the compound represented by formula (I) contains an endothermic peak at 245.9°C ⁇ 2.0°C.
  • the differential scanning calorimetry analysis spectrum (DSC graph) of the Form A crystal form of the compound represented by formula (I) is shown in Figure 5.
  • the thermogravimetric analysis spectrum (TGA graph) of the Form A crystal form of the compound represented by formula (I) is shown in Figure 5.
  • the X-ray powder diffraction pattern of the Form B crystal form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2 ⁇ angles: 7.10° ⁇ 0.20°, 9.92° ⁇ 0.20°, 19.13° ⁇ 0.20°, 19.36° ⁇ 0.20°, 20.18° ⁇ 0.20°, 23.50° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the Form B crystal form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at the following 2 ⁇ angles: 15.48° ⁇ 0.20°, 17.34° ⁇ 0.20°, 17.87° ⁇ 0.20°, 21.13° ⁇ 0.20°, 23.66° ⁇ 0.20°, 26.69° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the Form B crystal form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at 2 ⁇ angles: 9.61° ⁇ 0.20°, 10.72° ⁇ 0.20°, 14.10° ⁇ 0.20°, 17.58° ⁇ 0.20°, 19.75° ⁇ 0.20°, 22.05° ⁇ 0.20°, 22.40° ⁇ 0.20° , 23.99° ⁇ 0.20°, 24.42° ⁇ 0.20°, 24.73° ⁇ 0.20°, 25.90° ⁇ 0.20°, 27.26° ⁇ 0.20°, 28.56° ⁇ 0.20°, 28.85° ⁇ 0.20°, 30.27° ⁇ 0.20°, 30.72° ⁇ 0.20°, 32.46° ⁇ 0.20°, 33.01° ⁇ 0.20°, 34.43° ⁇ 0.20°.
  • the X-ray powder diffraction pattern analysis data of the Form B crystal form of the compound represented by formula (I) further includes one, two or more characteristic diffraction
  • the Form B crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 7.
  • the differential scanning calorimetry analysis spectrum (DSC diagram) of the Form B crystal form of the compound represented by formula (I) includes endothermic peaks at 60.7°C ⁇ 2.0°C, 167.0°C ⁇ 2.0°C, and 245.8°C ⁇ 2.0°C.
  • the differential scanning calorimetry analysis spectrum (DSC diagram) of the Form B crystal form of the compound represented by formula (I) includes an exothermic peak at 172.1°C ⁇ 2.0°C.
  • the differential scanning calorimetry analysis spectrum (DSC diagram) of the Form B crystal form of the compound represented by formula (I) is shown in Figure 8.
  • the thermogravimetric analysis spectrum (TGA diagram) of the Form B crystal form of the compound represented by formula (I) is shown in Figure 8.
  • the X-ray powder diffraction pattern of the Form C crystal form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2 ⁇ angles: 9.51° ⁇ 0.20°, 18.32° ⁇ 0.20°, 19.09° ⁇ 0.20°, 19.35° ⁇ 0.20°, 23.10° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the Form C crystal form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at the following 2 ⁇ angles: 16.51° ⁇ 0.20°, 17.58° ⁇ 0.20°, 20.24° ⁇ 0.20°, 23.97° ⁇ 0.20°, 25.51° ⁇ 0.20°, 30.99° ⁇ 0.20°.
  • the X-ray powder diffraction pattern analysis data of the Form C crystal form of the compound represented by formula (I) is shown in Table 4, wherein the error range of each characteristic diffraction peak 2 ⁇ is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the Form D crystal form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2 ⁇ angles: 9.47° ⁇ 0.20°, 18.41° ⁇ 0.20°, 19.17° ⁇ 0.20°, 19.93° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the Form D crystal form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at the following 2 ⁇ angles: 6.93° ⁇ 0.20°, 17.60° ⁇ 0.20°, 22.94° ⁇ 0.20°, 23.60° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the Form D crystalline form of the compound represented by formula (I) further includes the following characteristic diffraction peaks at one, two or more 2 ⁇ angles: 9.14° ⁇ 0.20°, 15.21° ⁇ 0.20°, 16.57° ⁇ 0.20°, 17.21. ⁇ 0.20°, 20.57° ⁇ 0.20°, 21.00° ⁇ 0.20°, 21.81° ⁇ 0.20°, 23.19 ⁇ 0.20°, 23.84° ⁇ 0.20°, 26.46° ⁇ 0.20°, 28.09° ⁇ 0.20°, and 30.58° ⁇ 0.20°.
  • the X-ray powder diffraction pattern analysis data of the Form D crystal form of the compound represented by formula (I) is shown in Table 5, wherein the error range of each characteristic diffraction peak 2 ⁇ is ⁇ 0.2°.
  • the Form D crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 13.
  • the differential scanning calorimetry analysis spectrum (DSC diagram) of the Form D crystal form of the compound represented by formula (I) includes endothermic peaks at 148.7°C ⁇ 2.0°C, 166.7°C ⁇ 2.0°C, and 246.8°C ⁇ 2.0°C.
  • the differential scanning calorimetry analysis spectrum (DSC diagram) of the Form D crystal form of the compound represented by formula (I) includes an exothermic peak at 176.4°C ⁇ 2.0°C.
  • the differential scanning calorimetry analysis spectrum (DSC diagram) of the Form D crystal form of the compound represented by formula (I) is shown in Figure 14.
  • the thermogravimetric analysis spectrum (TGA diagram) of the Form D crystal form of the compound represented by formula (I) is shown in Figure 14.
  • the X-ray powder diffraction pattern of the Form E crystal form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2 ⁇ angles: 6.88° ⁇ 0.20°, 9.78° ⁇ 0.20°, 19.40° ⁇ 0.20°, 20.07° ⁇ 0.20°.
  • the Form E crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 16.
  • the differential scanning calorimetry analysis spectrum (DSC diagram) of the Form E crystal form of the compound represented by formula (I) includes endothermic peaks at 58.2°C ⁇ 2.0°C, 168.2°C ⁇ 2.0°C, and 246.8°C ⁇ 2.0°C.
  • the differential scanning calorimetry analysis spectrum (DSC diagram) of the Form E crystal form of the compound represented by formula (I) includes an exothermic peak at 182.9°C ⁇ 2.0°C.
  • the differential scanning calorimetry analysis spectrum (DSC diagram) of the Form E crystal form of the compound represented by formula (I) is shown in Figure 17.
  • the thermogravimetric analysis spectrum (TGA diagram) of the Form E crystal form of the compound represented by formula (I) is shown in Figure 17.
  • the X-ray powder diffraction pattern of the Form F crystal form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2 ⁇ angles: 6.88° ⁇ 0.20°, 9.71° ⁇ 0.20°, 17.65° ⁇ 0.20°, 18.79° ⁇ 0.20°, 19.44° ⁇ 0.20°, 20.01° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the Form F crystal form of the compound represented by formula (I) further includes the following one, two or more characteristic diffraction peaks at 2 ⁇ angles: 9.31° ⁇ 0.20°, 15.36° ⁇ 0.20°, 17.01° ⁇ 0.20°, 17.31° ⁇ 0.20°, 20.87° ⁇ 0.20°, 23.36° ⁇ 0.20°, 23.66° ⁇ 0.20°, 23.82° ⁇ 0.20°.
  • the analytical data of the X-ray powder diffraction pattern of the Form F crystal form of the compound represented by formula (I) are shown in Table 7, wherein the error range of 2 ⁇ of each characteristic diffraction peak is ⁇ 0.2°.
  • the Form F crystalline form of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 19.
  • the differential scanning calorimetry analysis spectrum (DSC spectrum) of the Form F crystalline form of the compound represented by formula (I) includes endothermic peaks at 56.4°C ⁇ 2.0°C, 150.7°C ⁇ 2.0°C, 167.8°C ⁇ 2.0°C, and 247.1°C ⁇ 2.0°C.
  • the differential scanning calorimetry analysis spectrum (DSC spectrum) of the Form F crystalline form of the compound represented by formula (I) includes an exothermic peak at 171.7°C ⁇ 2.0°C.
  • the differential scanning calorimetry analysis spectrum (DSC spectrum) of the Form F crystalline form of the compound represented by formula (I) is shown in Figure 20.
  • the thermogravimetric analysis spectrum (TGA spectrum) of the Form F crystalline form of the compound represented by formula (I) is shown in Figure 20.
  • the X-ray powder diffraction pattern of the Form G crystal form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2 ⁇ angles: 9.61° ⁇ 0.20°, 17.62° ⁇ 0.20°, 19.54° ⁇ 0.20°, 20.30° ⁇ 0.20°, 24.09° ⁇ 0.20°.
  • the Form G crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 22.
  • the differential scanning calorimetry analysis spectrum (DSC diagram) of the Form G crystal form of the compound represented by formula (I) comprises endothermic peaks at 97.5°C ⁇ 2.0°C and 246.4°C ⁇ 2.0°C.
  • the differential scanning calorimetry analysis spectrum (DSC diagram) of the Form G crystal form of the compound represented by formula (I) is shown in Figure 23.
  • the thermogravimetric analysis spectrum (TGA diagram) of the Form G crystal form of the compound represented by formula (I) is shown in Figure 23.
  • the X-ray powder diffraction pattern of the Form H crystal form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at 2 ⁇ angles: 6.95° ⁇ 0.20°, 9.14° ⁇ 0.20°, 16.57° ⁇ 0.20°, 17.30° ⁇ 0.20°, 17.54° ⁇ 0.20°, 20.59° ⁇ 0.20°, 21.08° ⁇ 0.20°, 25.60° ⁇ 0.20°, 26.26° ⁇ 0.20°, 28.19° ⁇ 0.20°, and 30.56° ⁇ 0.20°.
  • the X-ray powder diffraction pattern analysis data of the Form H crystal form of the compound represented by formula (I) are shown in Table 9, wherein the error range of each characteristic diffraction peak 2 ⁇ is ⁇ 0.2°.
  • the Form H crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 25.
  • the differential scanning calorimetry analysis spectrum (DSC spectrum) of the Form H crystal form of the compound represented by formula (I) includes endothermic peaks at 123.6°C ⁇ 2.0°C, 165.6°C ⁇ 2.0°C, and 246.6°C ⁇ 2.0°C.
  • the differential scanning calorimetry analysis spectrum (DSC spectrum) of the Form H crystal form of the compound represented by formula (I) includes an exothermic peak at 173.0°C ⁇ 2.0°C.
  • the differential scanning calorimetry analysis spectrum (DSC spectrum) of the Form H crystal form of the compound represented by formula (I) is shown in Figure 26.
  • the thermogravimetric analysis spectrum (TGA diagram) of the Form H crystal form of the compound represented by formula (I) is shown in Figure 26.
  • the X-ray powder diffraction pattern of the Form I crystal form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2 ⁇ angles: 13.55° ⁇ 0.20°, 17.22° ⁇ 0.20°, 18.27° ⁇ 0.20°, 18.91° ⁇ 0.20°, 20.8° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the Form I crystal form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at 2 ⁇ angles: 5.11° ⁇ 0.20°, 7.91° ⁇ 0.20°, 11.63° ⁇ 0.20°, 14.34° ⁇ 0.20°, 14.98° ⁇ 0.20°, 15.68° ⁇ 0.20°, 19.69° ⁇ 0.20°, 21.9° ⁇ 0.20°, 22.57° ⁇ 0.20°, 23.53° ⁇ 0.20°, 24.17° ⁇ 0.20°, 25.72° ⁇ 0.20°, 28.02° ⁇ 0.20°, and 32.21° ⁇ 0.20°.
  • the X-ray powder diffraction pattern analysis data of the Form I crystal form of the compound represented by formula (I) is shown in Table 10, wherein the error range of each characteristic diffraction peak 2 ⁇ is ⁇ 0.2°.
  • the Form I crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 28.
  • the differential scanning calorimetry analysis spectrum (DSC diagram) of the Form I crystal form of the compound represented by formula (I) includes endothermic peaks at 210.4°C ⁇ 2.0°C and 245.8°C ⁇ 2.0°C.
  • the differential scanning calorimetry analysis spectrum (DSC diagram) of the Form I crystal form of the compound represented by formula (I) includes an exothermic peak at 210.4°C ⁇ 2.0°C.
  • the present invention also provides a method for preparing the amorphous or polymorphic form of the compound represented by the above formula (I), wherein:
  • the preparation method of the amorphous form of the compound represented by formula (I) is as follows: dissolving the compound represented by formula (I) in a first solvent and freeze-drying to obtain the amorphous form of the compound represented by formula (I);
  • the preparation method of the polymorph of the compound represented by formula (I) is as follows: dissolving the compound represented by formula (I) in a solvent and crystallizing to obtain the polymorph of the compound represented by formula (I).
  • the first solvent is selected from a mixed solvent of an organic solvent (such as acetonitrile) and water.
  • the preparation method of the Form A crystal form of the compound represented by formula (I) is selected from the following method A or method B:
  • Method A dissolving the amorphous form of the compound of formula (I) in a second solvent, adding a third solvent, stirring, and crystallizing to obtain Form A of the compound of formula (I);
  • Method B The amorphous form of the compound of formula (I) is dissolved in a fourth solvent, suspended, and crystallized to obtain Form A of the compound of formula (I).
  • the method for preparing the amorphous form of the compound represented by formula (I) is as described above.
  • the method A is specifically as follows: the amorphous form of the compound of formula (I) is dissolved in a second solvent, and then a third solvent is added, stirred, crystallized, centrifuged, and dried to obtain the Form A crystal form of the compound represented by formula (I).
  • the second solvent is selected from dichloromethane and acetone.
  • the third solvent is selected from methyl tert-butyl ether.
  • the volume ratio of the second solvent to the third solvent is 1:1-20, for example, 1:15, 1:10, 1:8, 1:5, 1:2.
  • the mass volume ratio of the amorphous form of the compound of formula (I) to the second solvent is 1g:10mL-50mL, for example, 1g:40mL, 1g:30mL, 1g:20mL, 1g:15mL, 1g:10mL.
  • the method B is specifically as follows: the amorphous form of the compound of formula (I) is dissolved in a fourth solvent, suspended, crystallized, centrifuged, and dried to obtain the Form A crystal form of the compound represented by formula (I).
  • the fourth solvent is selected from n-hexane.
  • the suspension temperature is 40-60° C., for example, 50° C.
  • the suspension time is 10 h-50 h, for example, 24 h.
  • the mass volume ratio of the amorphous form of the compound of formula (I) to the fourth solvent is 1g:50mL-200mL, for example, 1g:80mL, 1g:100mL, 1g:120mL, 1g:150mL.
  • the preparation method of the Form B crystalline form of the compound represented by formula (I) is as follows:
  • the preparation method of the Form A crystal form of the compound represented by formula (I) is as described above.
  • the preparation method of the Form B crystal form is as follows: dissolve the Form A crystal form of the compound of formula (I) in a fifth solvent, then add a sixth solvent, stir, crystallize, centrifuge, and dry to obtain the Form B crystal form of the compound represented by formula (I).
  • the fifth solvent is selected from dichloromethane.
  • the sixth solvent is selected from n-heptane.
  • the volume ratio of the fifth solvent to the sixth solvent is 1:1-20, for example, 1:5, 1:8, 1:10, 1:12, 1:15.
  • the mass volume ratio of Form A crystalline form of the compound of formula (I) to the fifth solvent is 1g:10mL-50mL, for example, 1g:40mL, 1g:30mL, 1g:20mL, 1g:10mL.
  • the preparation method of the Form C crystalline form of the compound represented by formula (I) is as follows:
  • the Form A crystal form of the compound of formula (I) is dissolved in a seventh solvent, the seventh solvent is evaporated open, and crystallization is performed to obtain the Form C crystal form of the compound represented by formula (I).
  • the preparation method of Form A crystal form of the compound represented by formula (I) is as described above.
  • the preparation method of the Form C crystal form is as follows: the Form A crystal form of the compound represented by formula (I) is dissolved in a seventh solvent, the seventh solvent is evaporated at room temperature, and crystallization is performed to obtain the Form C crystal form of the compound represented by formula (I).
  • the seventh solvent is selected from ethyl acetate.
  • the mass volume ratio of the Form A crystalline form of the compound of formula (I) to the seventh solvent is 5 mg to 20 mg:1 mL, for example, 5 mg:1 mL, 8 mg:1 mL, 10 mg:1 mL, or 15 mg:1 mL.
  • the preparation method of the Form D crystal form of the compound represented by formula (I) is as follows: the Form A crystal form of the compound represented by formula (I) is dissolved in an eighth solvent, suspended, and crystallized to obtain the Form D crystal form of the compound represented by formula (I).
  • the preparation method of Form A crystal form of the compound represented by formula (I) is as described above.
  • the preparation method of the Form D crystal form is as follows: the Form A crystal form of the compound of formula (I) is dissolved in an eighth solvent, suspended, crystallized, centrifuged, and dried to obtain the Form D crystal form of the compound represented by formula (I).
  • the eighth solvent is selected from ethanol.
  • the suspension temperature is 10°C-30°C, for example, room temperature.
  • the suspension time is 5min-60min, for example, 20min.
  • the mass volume ratio of Form A crystalline form of the compound of formula (I) to the eighth solvent is 10mg-30mg:1mL, for example, 12mg:1mL, 15mg:1mL, 16mg:1mL, 20mg:1mL.
  • the preparation method of the Form E crystal form of the compound represented by formula (I) is as follows: the Form A crystal form of the compound represented by formula (I) is dissolved in a ninth solvent, suspended, and crystallized to obtain the Form E crystal form of the compound represented by formula (I).
  • the preparation method of Form A crystal form of the compound represented by formula (I) is as described above.
  • the preparation method of the Form E crystal form is as follows: the Form A crystal form of the compound of formula (I) is dissolved in a ninth solvent, suspended, crystallized, centrifuged, and dried to obtain the Form E crystal form of the compound represented by formula (I).
  • the ninth solvent is selected from methanol.
  • the suspension temperature is 10°C-30°C, for example, room temperature.
  • the mass volume ratio of the Form A crystalline form of the compound of formula (I) to the ninth solvent is 5 mg-30 mg:1 mL, for example, 8 mg:1 mL, 10 mg:1 mL, 10.2 mg:1 mL, 12 mg:1 mL, 15 mg:1 mL.
  • the preparation method of the Form F crystal form of the compound represented by formula (I) is as follows: the Form A crystal form of the compound represented by formula (I) is dissolved in a tenth solvent, suspended, and crystallized to obtain the Form F crystal form of the compound represented by formula (I).
  • the preparation method of the Form A crystal form of the compound represented by formula (I) is as described above.
  • the preparation method of the Form F crystal form is as follows: the Form A crystal form of the compound of formula (I) is dissolved in a tenth solvent, suspended, crystallized, centrifuged, and dried to obtain the Form F crystal form of the compound represented by formula (I).
  • the tenth solvent is selected from acetonitrile.
  • the suspension temperature is 10°C-30°C, for example, room temperature.
  • the mass volume ratio of Form A of the compound of formula (I) to the tenth solvent is 5 mg-30 mg:1 mL, for example, 8 mg:1 mL, 10 mg:1 mL, 10.2 mg:1 mL, 12 mg:1 mL, 15 mg:1 mL.
  • the preparation method of the Form G crystal form of the compound represented by formula (I) is as follows: the Form A crystal form of the compound represented by formula (I) is dissolved in an eleventh solvent, suspended, and crystallized to obtain the Form G crystal form of the compound represented by formula (I).
  • the preparation method of the Form A crystal form of the compound represented by formula (I) is as described above.
  • the preparation method of the Form G crystal form is as follows: the Form A crystal form of the compound of formula (I) is dissolved (completely dissolved) in an eleventh solvent, suspended, crystallized, centrifuged, and dried to obtain the Form G crystal form of the compound represented by formula (I).
  • the eleventh solvent is selected from ethylene glycol dimethyl ether.
  • the suspension temperature is 10°C-30°C, for example, room temperature.
  • the preparation method of the Form H crystalline form of the compound represented by formula (I) is as follows:
  • the Form A crystal form of the compound of formula (I) is dissolved in a twelfth solvent, cooled and crystallized to obtain the Form H crystal form of the compound represented by formula (I).
  • the preparation method of Form A crystal form of the compound represented by formula (I) is as described above.
  • the method for preparing the Form H crystal form is as follows: dissolving the Form A crystal form of the compound of formula (I) in a twelfth solvent (using a minimum amount of the twelfth solvent), cooling to crystallize, centrifuging, and drying to obtain the Form H crystal form of the compound of formula (I).
  • the twelfth solvent is selected from ethyl formate.
  • the preparation method of the Form I crystal form of the compound represented by formula (I) is as follows:
  • the Form D crystal form of the compound of formula (I) is dissolved in a thirteenth solvent, cooled and crystallized to obtain the Form I crystal form of the compound represented by formula (I).
  • the preparation method of Form D crystal form of the compound represented by formula (I) is as described above.
  • the preparation method of the Form I crystal form is as follows: Form D crystal form of the compound of formula (I) is dissolved by stirring in a thirteenth solvent, cooled and stirred, suspended, centrifuged, and dried to obtain Form I crystal form of the compound represented by formula (I).
  • the thirteenth solvent is selected from one or more of isopropyl alcohol, isopropyl acetate, acetone, methyl tert-butyl ether, and the like.
  • the mass volume ratio of Form D crystal form of the compound of formula (I) to the thirteenth solvent is 50 mg-200 mg:1 mL, for example, 80 mg:1 mL, 100 mg:1 mL, 125 mg:1 mL, 150 mg:1 mL, or 180 mg:1 mL.
  • the temperature for stirring and dissolving is 40°C-60°C, for example, 50°C.
  • the time for stirring and dissolving is 1 hour-3 hours, for example, 2 hours.
  • the temperature for stirring and cooling is 10°C-30°C, for example, room temperature.
  • the time for stirring and cooling is 1 day-3 days, for example, 2 days.
  • the drying method is vacuum drying.
  • the drying temperature is 40°C-60°C, for example 50°C.
  • the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the amorphous or polymorphic forms of the compound represented by the above formula (I).
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition may further contain one or more additional therapeutic agents.
  • the present invention also provides a method for treating tumor diseases, which comprises administering to a patient a preventive or therapeutically effective amount of at least one of the amorphous or polymorphic forms of the compound represented by formula (I) or the pharmaceutical composition.
  • the tumor disease includes colorectal cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head and neck cancer, cervical cancer and ovarian cancer.
  • the patient includes a mammal, preferably a human.
  • the present invention also provides a method for treating KIF18A-mediated disorders and/or diseases, comprising administering to a patient a preventive or therapeutically effective amount of at least one of the amorphous or polymorphic form of the compound represented by formula (I) or the pharmaceutical composition.
  • the KIF18A-mediated disorder and/or disease is cancer, such as bowel cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head and neck cancer, cervical cancer or ovarian cancer.
  • the present invention also provides an amorphous or polymorphic compound of the compound represented by the above formula (I) or the above pharmaceutical composition for treating tumor diseases.
  • the present invention also provides use of the amorphous or polymorphic form of the compound represented by the above formula (I) or the above pharmaceutical composition in preparing medicines.
  • the use may be use in preparing a medicament for treating KIF18A-mediated disorders and/or diseases, such as use in preparing a KIF18A inhibitor drug.
  • the disease is cancer, for example including bowel cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head and neck cancer, cervical cancer or ovarian cancer.
  • patient refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.
  • terapéuticaally effective amount refers to that amount of an active compound or drug that will elicit the biological or medical response that a researcher, veterinarian, physician, or other clinician is seeking in a tissue, system, animal, individual, or human, and includes one or more of the following: (1) prevents disease, e.g., prevents a disease, disorder, or condition in an individual who is susceptible to the disease, disorder, or condition but who is not yet experiencing or developing the pathology or symptoms of the disease. (2) inhibits disease, e.g., inhibits the disease, disorder, or condition (i.e., prevents further development of the pathology and/or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition. (3) alleviates disease, e.g., alleviates the disease, disorder, or condition (i.e., reverses the pathology and/or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition.
  • prevents disease e.g., prevents
  • the present invention provides an amorphous or polymorphic form of a compound represented by formula (I).
  • the amorphous and polymorphic forms have excellent hygroscopicity, solubility and stability, excellent drugability, and are suitable for industrial production, manufacturing and storage.
  • Figure 1 XRPD pattern of the amorphous form of the compound represented by formula (I);
  • Figure 8 Overlay of DSC and TGA images of Form B of the compound represented by formula (I);
  • FIG. 11 Overlay of DSC and TGA images of Form C of the compound represented by Formula (I);
  • Figure 14 Overlay of DSC and TGA images of Form D of the compound represented by formula (I);
  • Figure 17 Overlay of DSC and TGA images of Form E of the compound represented by Formula (I);
  • Figure 19 XRPD pattern of Form F crystalline form of the compound represented by formula (I);
  • Figure 20 Overlay of DSC and TGA images of Form F of the compound represented by Formula (I);
  • Figure 21 NMR spectrum of Form F, a crystalline form of the compound represented by Formula (I);
  • Figure 25 XRPD pattern of Form H crystalline form of the compound represented by formula (I);
  • Figure 26 Overlay of DSC and TGA images of Form H of the compound represented by Formula (I);
  • Figure 28 XRPD pattern of Form I of the compound represented by Formula (I);
  • FIG. 30 TGA chart of Form I crystal form of the compound represented by formula (I);
  • Figure 32 DVS image of Form A of the compound represented by formula (I);
  • Figure 33 XRPD comparison of Form A of the compound represented by Formula (I) before and after DVS testing;
  • Figure 35 XRPD comparison of Form E of the compound of formula (I) before and after DVS testing;
  • Figure 36 XRPD comparison chart of the stability study of Form A crystal form of the compound represented by formula (I).
  • Some solid samples obtained in the experiments were analyzed using a Bruker D8 Advance X-ray powder diffractometer (Bruker, GER).
  • the 2 ⁇ scan angle ranged from 3° to 45°, with a scan step size of 0.02° and an exposure time of 0.08 s.
  • the test method used Cu target K ⁇ 1 radiation, a voltage of 40 kV, a current of 40 mA, and a zero-background sample pan.
  • Some solid samples obtained in the experiments were analyzed using an X-ray powder diffractometer (PANalytical EMPYREAN, UK).
  • the 2 ⁇ scan angle ranged from 3° to 45°, with a scan step size of 0.013°, for a total measurement time of 3 minutes and 30 seconds.
  • the measurement method used K ⁇ 1 radiation from a Cu target, a voltage of 45 kV, a current of 40 mA, and a zero-background sample pan.
  • thermogravimetric analyzer was a TA Discovery 550 (TA, US). Samples (2–5 mg) were placed in a pre-equilibrated open aluminum sample pan and automatically weighed within the TGA furnace. The samples were heated to the final temperature at a rate of 10°C/min, with nitrogen purge rates of 60 mL/min at the sample and 40 mL/min at the balance.
  • DSC differential scanning calorimeter
  • TA TA Discovery 250
  • a 1–2 mg sample was accurately weighed and placed in a perforated DSC Tzero pan. The sample was heated to the final temperature at a rate of 10°C/min, with a nitrogen purge rate of 50 mL/min.
  • Dynamic moisture sorption/desorption analysis for preliminary hygroscopicity assessment was performed using a DVS Intrinsic Plus (SMS, UK).
  • the test used a gradient mode with humidity changes from 50% to 95% to 50%, with each step increasing by 15%.
  • the gradient endpoint was determined using the dm/dt method, with a dm/dt value of less than 0.002% maintained for 10 minutes, or a maximum of 60 minutes per step. After the test, the samples were analyzed by XRPD to confirm any changes in solid form.
  • Dynamic moisture sorption/desorption analysis was performed using a DVS Intrinsic Plus (SMS, UK).
  • the test used a gradient mode with humidity changes from 0% to 95% to 0%, with each step increasing by 10% within the 0% to 95% range.
  • the gradient endpoint was determined using the dm/dt method, with a dm/dt of less than 0.002% maintained for 10 minutes, or a maximum of 180 minutes per step.
  • the samples were analyzed by XRPD to confirm any changes in solid form.
  • HPLC model was SHIMADZU LC-20A (Shimadzu, JP), and the test conditions were shown in the table.
  • Step 4 Synthesis of 4-bromo-2-(6-azaspiro[2.5]octane-6-yl)-N-((1S,4R)-1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-yl)benzamide (Compound 3a)
  • HATU (10.36 g, 27 mmol, 1.3 eq.) and EDCI (5.22 g, 27 mmol, 1.3 eq.) were added to the system, the temperature was controlled at 25 ⁇ 5°C, and the mixture was stirred for at least 10 hours.
  • H2O 40.2 mL was added dropwise to the system. The mixture was stirred for at least 1 hour, centrifuged, and the filter cake was rinsed with H2O (13.4 mL) and collected. The wet filter cake and H2O (33.5 mL) were added to the autoclave.
  • the temperature in the autoclave was controlled at 25 ⁇ 5°C, and the mixture was stirred for at least 1 hour.
  • the mixture was centrifuged, and the filter cake was rinsed with H2O (13.4 mL) and collected.
  • the filter cake was dried in vacuo at 45 ⁇ 5°C to obtain a brown solid 3a (9.88 g, 93% yield).
  • compound 3a (9.50 g, 1.9 mmol, 1.0 eq.), 2-hydroxyethane-1-sulfonamide (compound 4) (3.14 g, 2.5 mmol, 1.3 eq.), K 3 PO 4 (10.26 g, 4.8 mmol, 2.5 eq.), DMF (38 mL), and trans-NN-dimethyl-1,2-cyclohexanediamine (2.75 g, 1.9 mmol, 1.0 eq.) were added to the reactor. The atmosphere was replaced with nitrogen three times. CuI (1.84 g, 0.95 mmol, 0.5 eq.) was added to the system. The reactor was rinsed with DMF (9.5 mL) and replaced with nitrogen three times.
  • the compound represented by the above formula (I) was dissolved in a certain amount of acetonitrile/water mixed solvent and lyophilized to obtain a white solid.
  • XRPD characterization of the solid was performed, and the XRPD pattern was shown in FIG1 . The results showed that the obtained white solid was amorphous.
  • the resulting Form C crystalline form of the compound represented by Formula (I) was subjected to TGA, DSC, and NMR analysis, with the spectra shown in Figures 11 and 12.
  • the NMR results revealed ethyl acetate signal peaks at 1.24 ppm, 2.01 ppm, and 4.09 ppm. Based on the integration results, the ratio of compound to ethyl acetate was 1:0.6, with a rough estimate of approximately 9.0% by mass.
  • the resulting Form F crystalline form of the compound represented by Formula (I) was subjected to TGA, DSC, and NMR analysis, with the spectra shown in Figures 20 and 21.
  • the NMR results showed an acetonitrile signal peak at 2.07 ppm. Based on the integration results, the ratio of compound to acetonitrile was 1:0.5, with a rough estimate of approximately 3.7% by mass.
  • the resulting Form G crystalline form of the compound represented by Formula (I) was subjected to TGA, DSC, and NMR analysis, with the spectra shown in Figures 23 and 24.
  • the NMR results showed visible peaks of ethylene glycol dimethyl ether at 3.65 ppm, 3.47 ppm, and 3.37 ppm. Based on the integration results, the ratio of compound to ethylene glycol dimethyl ether was 1:0.45, with a rough estimate of approximately 6.0% by mass.
  • the resulting Form H crystalline form of the compound represented by Formula (I) was subjected to TGA, DSC, and NMR analysis, with the spectra shown in Figures 26 and 27.
  • the NMR results showed peaks of ethyl formate at 8.06 ppm, 4.23 ppm, 4.17 ppm, and 1.28 ppm. Peaks at 1.18 ppm and 3.60 ppm are likely due to ethanol, suggesting that ethyl formate may have decomposed during the experiment.
  • the sample may be a solvate or hydrate.
  • SignalAve_PC The average value of the positive control (AM-5308) on the reaction plate.
  • SignalAve_VC the average value of the negative control (DMSO) on the reaction plate.
  • GraphPad 8.0 was used to obtain the IC50 of the compounds using a nonlinear fitting formula.
  • the preparation process of the biological medium is shown in Table 12. Samples of different crystalline forms were added to the biological medium and water and shaken at 37°C for 24 hours. Samples were taken at 0.5, 2, and 24 hours. The sampled solutions were filtered through a 0.22 ⁇ m water filter. Some samples with higher concentrations were appropriately diluted with diluent. The signal peak area of the solution was measured by HPLC. Finally, the concentration of the compound in the solution was calculated based on the peak area, the HPLC standard curve of the raw material, and the dilution factor. In addition, the pH value of the supernatant after 24 hours was tested.
  • Form A was subjected to stability studies under high temperature (60°C), high humidity (25°C/92.5% RH), light (25°C/4500 Lux), and accelerated conditions (40°C/75% RH). Samples were collected for XRPD characterization and HPLC analysis after 7 and 15 days, respectively. The results are shown in Table 14 and Figure 36. XRPD results showed that Form A maintained its crystalline form after 15 days under these conditions. Furthermore, there was no significant change in purity after 15 days under these conditions. However, under light exposure, the purity decreased slightly after 15 days, and the sample turned yellow.

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Abstract

Provided in the present invention is an amorphous form or a polymorph of a compound as shown in formula (I). The amorphous form or polymorph has excellent hygroscopicity, solubility and stability, has good druggability, and is suitable for industrial production, manufacturing and storage.

Description

一种KIF18A抑制剂的晶型及其制备方法和应用A crystal form of a KIF18A inhibitor, its preparation method and application

本申请要求享有下列在先专利申请的优先权权益：This application claims the benefit of priority of the following prior patent applications:

申请人于2024年03月07日向中国国家知识产权局提交的，专利申请号为202410265564.1，名称为“一种KIF18A抑制剂的晶型及其制备方法和应用”的在先申请；The applicant's prior application, patent application number 202410265564.1, filed with the State Intellectual Property Office of China on March 7, 2024, entitled "A crystal form of a KIF18A inhibitor, its preparation method, and application";

上述在先专利申请的全文均通过引用的方式结合于本申请中。The entire contents of the above-mentioned prior patent applications are incorporated into this application by reference.

技术领域Technical Field

本发明属于化合物领域，具体涉及一种KIF18A抑制剂的晶型及其制备方法和应用。The present invention belongs to the field of compounds, and specifically relates to a crystal form of a KIF18A inhibitor, a preparation method thereof, and an application thereof.

背景技术Background Art

PCT/CN2023/117322(申请日2023年9月6日)描述了化合物4-(2-羟基乙磺酰氨基)-2-(6-氮杂螺[2.5]辛烷-6-基)-N-((1S,4R)-1,2，3,4-四氢-1,4-亚甲基苯并[4，5]咪唑并[1，2-a]吡啶-6-基)苯甲酰胺，其结构如式(I)所示，该化合物不仅具有良好的KIF18A抑制作用和OVCAR-3体外细胞活性，理化性质(溶解度、渗透性)显著提升，OVCAR-3体内药效显著提升，且安全性良好。该化合物可用以治疗KIF18A介导的病症和/或疾病，例如肿瘤疾病，以及制备用于治疗此类病症或疾病的药物。
PCT/CN2023/117322 (filing date September 6, 2023) describes the compound 4-(2-hydroxyethanesulfonylamino)-2-(6-azaspiro[2.5]octane-6-yl)-N-((1S,4R)-1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-yl)benzamide, whose structure is shown in Formula (I). This compound not only has good KIF18A inhibition and OVCAR-3 cell activity in vitro, but also has significantly improved physicochemical properties (solubility and permeability), significantly improved OVCAR-3 in vivo efficacy, and good safety. This compound can be used to treat KIF18A-mediated conditions and/or diseases, such as tumor diseases, and to prepare drugs for treating such conditions or diseases.

作为药用活性成分的晶型结构往往影响到该药物的化学稳定性，结晶条件及储存条件的不同有可能导致化合物的晶型结构的变化，有时还会伴随着产生其他形态的晶型。因此，深入研究式(I)化合物的晶型及相关制备方法，改善式(I)所示化合物的各方面性质是很有必要的。The crystal structure of a pharmaceutically active ingredient often affects the chemical stability of the drug. Differences in crystallization and storage conditions can lead to variations in the compound's crystal structure, sometimes resulting in the formation of alternative crystalline forms. Therefore, in-depth research into the crystal forms of the compound of formula (I) and related preparation methods is essential to improve various properties of the compound of formula (I).

发明内容Summary of the Invention

本发明提供了一种式(I)所示化合物的无定型或多晶型物；
The present invention provides an amorphous or polymorphic compound of a compound represented by formula (I);

根据本发明的实施方案，所述式(I)所示化合物的无定型具有基本上如图1所示的X射线粉末衍射图谱(XRPD图)。根据本发明的实施方案，所述式(I)所示化合物的无定型的差示扫描量热分析图谱(DSC图)如图2所示。根据本发明的实施方案，所述式(I)所示化合物的无定型的热重分析图谱(TGA图)如图2所示。According to an embodiment of the present invention, the amorphous form of the compound represented by formula (I) has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in Figure 1. According to an embodiment of the present invention, the differential scanning calorimetry pattern (DSC pattern) of the amorphous form of the compound represented by formula (I) is shown in Figure 2. According to an embodiment of the present invention, the thermogravimetric analysis pattern (TGA pattern) of the amorphous form of the compound represented by formula (I) is shown in Figure 2.

根据本发明的实施方案，式(I)所示化合物的多晶型物选自式(I)所示化合物的Form A晶型、Form B晶型、Form C晶型、Form D晶型、Form E晶型、Form F晶型、Form G晶型、Form H晶型、Form I晶型。According to an embodiment of the present invention, the polymorph of the compound represented by formula (I) is selected from the Form A crystal form, Form B crystal form, Form C crystal form, Form D crystal form, Form E crystal form, Form F crystal form, Form G crystal form, Form H crystal form, and Form I crystal form of the compound represented by formula (I).

根据本发明的实施方案，所述式(I)所示化合物的Form A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：14.97°±0.20°，17.87°±0.20°，18.82°±0.20°，19.07°±0.20°，19.56°±0.20°。根据本发明的实施方案，所述式(I)所示化合物的Form A晶型的X射线粉末衍射图谱进一步包括以下一个、两个或多个2θ角处的特征衍射峰：8.87°±0.20°，13.46°±0.20°，24.77°±0.20°。根据本发明的实施方案，所述式(I)所示化合物的Form A晶型的X射线粉末衍射图谱还进一步包括以下一个、两个或多个2θ角处的特征衍射峰：6.81°±0.20°，13.20°±0.20°，16.18°±0.20°，20.32°±0.20°，21.11°±0.20°，21.56°±0.20°，22.38°±0.20°，22.82°±0.20°，23.35°±0.20°，23.78°±0.20°，24.01°±0.20°，25.12°±0.20°，25.68°±0.20°，26.48°±0.20°，26.67°±0.20°，27.02°±0.20°，28.01°±0.20°，28.75°±0.20°，30.72°±0.20°。根据本发明的实施方案，所述式(I)所示化合物的Form A晶型的X射线粉末衍射图谱解析数据如表2所示，其中每个特征衍射峰2θ的误差范围为±0.2°。According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form A crystal form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles: 14.97°±0.20°, 17.87°±0.20°, 18.82°±0.20°, 19.07°±0.20°, 19.56°±0.20°. According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form A crystal form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at the following 2θ angles: 8.87°±0.20°, 13.46°±0.20°, 24.77°±0.20°. According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form A crystal form of the compound represented by formula (I) further includes the following characteristic diffraction peaks at one, two or more 2θ angles: 6.81°±0.20°, 13.20°±0.20°, 16.18°±0.20°, 20.32°±0.20°, 21.11°±0.20°, 21.56°±0.20°, 22.38°±0.20° , 22.82°±0.20°, 23.35°±0.20°, 23.78°±0.20°, 24.01°±0.20°, 25.12°±0.20°, 25.68°±0.20°, 26.48°±0.20°, 26.67°±0.20°, 27.02°±0.20°, 28.01°±0.20°, 28.75°±0.20°, 30.72°±0.20°. According to an embodiment of the present invention, the X-ray powder diffraction pattern analysis data of the Form A crystal form of the compound represented by formula (I) are shown in Table 2, wherein the error range of each characteristic diffraction peak 2θ is ±0.2°.

根据本发明的实施方案，所述式(I)所示化合物的Form A晶型具有基本上如图4所示的X射线粉末衍射图谱。根据本发明的实施方案，所述式(I)所示化合物的Form A晶型的差示扫描量热分析图谱(DSC图)包含245.9℃±2.0℃的吸热峰。根据本发明的实施方案，所述式(I)所示化合物的Form A晶型的差示扫描量热分析图谱(DSC图)如图5所示。根据本发明的实施方案，所述式(I)所示化合物的Form A晶型的热重分析图谱(TGA图)如图5所示。According to an embodiment of the present invention, the Form A crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 4. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC graph) of the Form A crystal form of the compound represented by formula (I) contains an endothermic peak at 245.9°C±2.0°C. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC graph) of the Form A crystal form of the compound represented by formula (I) is shown in Figure 5. According to an embodiment of the present invention, the thermogravimetric analysis spectrum (TGA graph) of the Form A crystal form of the compound represented by formula (I) is shown in Figure 5.

根据本发明的实施方案，所述式(I)所示化合物的Form B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.10°±0.20°，9.92°±0.20°，19.13°±0.20°，19.36°±0.20°，20.18°±0.20°，23.50°±0.20°。根据本发明的实施方案，所述式(I)所示化合物的Form B晶型的X射线粉末衍射图谱进一步包括以下一个、两个或多个2θ角处的特征衍射峰：15.48°±0.20°，17.34°±0.20°，17.87°±0.20°，21.13°±0.20°，23.66°±0.20°，26.69°±0.20°。根据本发明的实施方案，所述式(I)所示化合物的Form B晶型的X射线粉末衍射图谱还进一步包括以下一个、两个或多个2θ角处的特征衍射峰：9.61°±0.20°，10.72°±0.20°，14.10°±0.20°，17.58°±0.20°，19.75°±0.20°，22.05°±0.20°，22.40°±0.20°，23.99°±0.20°，24.42°±0.20°，24.73°±0.20°，25.90°±0.20°，27.26°±0.20°，28.56°±0.20°，28.85°±0.20°，30.27°±0.20°，30.72°±0.20°，32.46°±0.20°，33.01°±0.20°，34.43°±0.20°。根据本发明的实施方案，所述式(I)所示化合物的Form B晶型的X射线粉末衍射图谱解析数据如表3所示，其中每个特征衍射峰2θ的误差范围为±0.2°。According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form B crystal form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles: 7.10°±0.20°, 9.92°±0.20°, 19.13°±0.20°, 19.36°±0.20°, 20.18°±0.20°, 23.50°±0.20°. According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form B crystal form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at the following 2θ angles: 15.48°±0.20°, 17.34°±0.20°, 17.87°±0.20°, 21.13°±0.20°, 23.66°±0.20°, 26.69°±0.20°. According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form B crystal form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at 2θ angles: 9.61°±0.20°, 10.72°±0.20°, 14.10°±0.20°, 17.58°±0.20°, 19.75°±0.20°, 22.05°±0.20°, 22.40°±0.20° , 23.99°±0.20°, 24.42°±0.20°, 24.73°±0.20°, 25.90°±0.20°, 27.26°±0.20°, 28.56°±0.20°, 28.85°±0.20°, 30.27°±0.20°, 30.72°±0.20°, 32.46°±0.20°, 33.01°±0.20°, 34.43°±0.20°. According to an embodiment of the present invention, the X-ray powder diffraction pattern analysis data of the Form B crystal form of the compound represented by formula (I) are shown in Table 3, wherein the error range of each characteristic diffraction peak 2θ is ±0.2°.

根据本发明的实施方案，所述式(I)所示化合物的Form B晶型具有基本上如图7所示的X射线粉末衍射图谱。根据本发明的实施方案，所述式(I)所示化合物的Form B晶型的差示扫描量热分析图谱(DSC图)包含60.7℃±2.0℃、167.0℃±2.0℃、245.8℃±2.0℃的吸热峰。根据本发明的实施方案，所述式(I)所示化合物的Form B晶型的差示扫描量热分析图谱(DSC图)包含172.1℃±2.0℃的放热峰。根据本发明的实施方案，所述式(I)所示化合物的Form B晶型的差示扫描量热分析图谱(DSC图)如图8所示。根据本发明的实施方案，所述式(I)所示化合物的Form B晶型的热重分析图谱(TGA图)如图8所示。According to an embodiment of the present invention, the Form B crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 7. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC diagram) of the Form B crystal form of the compound represented by formula (I) includes endothermic peaks at 60.7°C±2.0°C, 167.0°C±2.0°C, and 245.8°C±2.0°C. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC diagram) of the Form B crystal form of the compound represented by formula (I) includes an exothermic peak at 172.1°C±2.0°C. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC diagram) of the Form B crystal form of the compound represented by formula (I) is shown in Figure 8. According to an embodiment of the present invention, the thermogravimetric analysis spectrum (TGA diagram) of the Form B crystal form of the compound represented by formula (I) is shown in Figure 8.

根据本发明的实施方案，所述式(I)所示化合物的Form C晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.51°±0.20°，18.32°±0.20°，19.09°±0.20°，19.35°±0.20°，23.10°±0.20°。根据本发明的实施方案，所述式(I)所示化合物的Form C晶型的X射线粉末衍射图谱进一步包括以下一个、两个或多个2θ角处的特征衍射峰：16.51°±0.20°，17.58°±0.20°，20.24°±0.20°，23.97°±0.20°，25.51°±0.20°，30.99°±0.20°。根据本发明的实施方案，所述式(I)所示化合物的Form C晶型的X射线粉末衍射图谱解析数据如表4所示，其中每个特征衍射峰2θ的误差范围为±0.2°。According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form C crystal form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles: 9.51°±0.20°, 18.32°±0.20°, 19.09°±0.20°, 19.35°±0.20°, 23.10°±0.20°. According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form C crystal form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at the following 2θ angles: 16.51°±0.20°, 17.58°±0.20°, 20.24°±0.20°, 23.97°±0.20°, 25.51°±0.20°, 30.99°±0.20°. According to an embodiment of the present invention, the X-ray powder diffraction pattern analysis data of the Form C crystal form of the compound represented by formula (I) is shown in Table 4, wherein the error range of each characteristic diffraction peak 2θ is ±0.2°.

根据本发明的实施方案，所述式(I)所示化合物的Form C晶型具有基本上如图10所示的X射线粉末衍射图谱。根据本发明的实施方案，所述式(I)所示化合物的Form C晶型的差示扫描量热分析图谱(DSC图)包含91.7℃±2.0℃、245.4℃±2.0℃的吸热峰。根据本发明的实施方案，所述式(I)所示化合物的Form C晶型的差示扫描量热分析图谱(DSC图)如图11所示。根据本发明的实施方案，所述式(I)所示化合物的Form C晶型的热重分析图谱(TGA图)如图11所示。According to an embodiment of the present invention, the Form C crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 10. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC graph) of the Form C crystal form of the compound represented by formula (I) comprises endothermic peaks at 91.7°C±2.0°C and 245.4°C±2.0°C. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC graph) of the Form C crystal form of the compound represented by formula (I) is shown in Figure 11. According to an embodiment of the present invention, the thermogravimetric analysis spectrum (TGA graph) of the Form C crystal form of the compound represented by formula (I) is shown in Figure 11.

根据本发明的实施方案，所述式(I)所示化合物的Form D晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.47°±0.20°，18.41°±0.20°，19.17°±0.20°，19.93°±0.20°。根据本发明的实施方案，所述式(I)所示化合物的Form D晶型的X射线粉末衍射图谱进一步包括以下一个、两个或多个2θ角处的特征衍射峰：6.93°±0.20°，17.60°±0.20°，22.94°±0.20°，23.60°±0.20°。根据本发明的实施方案，所述式(I)所示化合物的Form D晶型的X射线粉末衍射图谱进一步包括以下一个、两个或多个2θ角处的特征衍射峰：9.14°±0.20°，15.21°±0.20°，16.57°±0.20°，17.21。±0.20°，20.57°±0.20°，21.00°±0.20°，21.81°±0.20°，23.19±0.20°，23.84°±0.20°，26.46°±0.20°，28.09°±0.20°，30.58°±0.20°。根据本发明的实施方案，所述式(I)所示化合物的Form D晶型的X射线粉末衍射图谱解析数据如表5所示，其中每个特征衍射峰2θ的误差范围为±0.2°。According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form D crystal form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles: 9.47°±0.20°, 18.41°±0.20°, 19.17°±0.20°, 19.93°±0.20°. According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form D crystal form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at the following 2θ angles: 6.93°±0.20°, 17.60°±0.20°, 22.94°±0.20°, 23.60°±0.20°. According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form D crystalline form of the compound represented by formula (I) further includes the following characteristic diffraction peaks at one, two or more 2θ angles: 9.14°±0.20°, 15.21°±0.20°, 16.57°±0.20°, 17.21.±0.20°, 20.57°±0.20°, 21.00°±0.20°, 21.81°±0.20°, 23.19±0.20°, 23.84°±0.20°, 26.46°±0.20°, 28.09°±0.20°, and 30.58°±0.20°. According to an embodiment of the present invention, the X-ray powder diffraction pattern analysis data of the Form D crystal form of the compound represented by formula (I) is shown in Table 5, wherein the error range of each characteristic diffraction peak 2θ is ±0.2°.

根据本发明的实施方案，所述式(I)所示化合物的Form D晶型具有基本上如图13所示的X射线粉末衍射图谱。根据本发明的实施方案，所述式(I)所示化合物的Form D晶型的差示扫描量热分析图谱(DSC图)包含148.7℃±2.0℃、166.7℃±2.0℃、246.8℃±2.0℃的吸热峰。根据本发明的实施方案，所述式(I)所示化合物的Form D晶型的差示扫描量热分析图谱(DSC图)包含176.4℃±2.0℃的放热峰。根据本发明的实施方案，所述式(I)所示化合物的Form D晶型的差示扫描量热分析图谱(DSC图)如图14所示。根据本发明的实施方案，所述式(I)所示化合物的Form D晶型的热重分析图谱(TGA图)如图14所示。According to an embodiment of the present invention, the Form D crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 13. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC diagram) of the Form D crystal form of the compound represented by formula (I) includes endothermic peaks at 148.7°C±2.0°C, 166.7°C±2.0°C, and 246.8°C±2.0°C. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC diagram) of the Form D crystal form of the compound represented by formula (I) includes an exothermic peak at 176.4°C±2.0°C. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC diagram) of the Form D crystal form of the compound represented by formula (I) is shown in Figure 14. According to an embodiment of the present invention, the thermogravimetric analysis spectrum (TGA diagram) of the Form D crystal form of the compound represented by formula (I) is shown in Figure 14.

根据本发明的实施方案，所述式(I)所示化合物的Form E晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.88°±0.20°，9.78°±0.20°，19.40°±0.20°，20.07°±0.20°。根据本发明的实施方案，所述式(I)所示化合物的Form E晶型的X射线粉末衍射图谱进一步包括以下一个、两个或多个2θ角处的特征衍射峰：9.40°±0.20°，15.33°±0.20°，17.26°±0.20°，17.48°±0.20°，17.62°±0.20°，18.98°±0.20°，23.49°±0.20°，23.66°±0.20°。根据本发明的实施方案，所述式(I)所示化合物的Form E晶型的X射线粉末衍射图谱解析数据如表6所示，其中每个特征衍射峰2θ的误差范围为±0.2°。According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form E crystal form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles: 6.88°±0.20°, 9.78°±0.20°, 19.40°±0.20°, 20.07°±0.20°. According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form E crystal form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at the following 2θ angles: 9.40°±0.20°, 15.33°±0.20°, 17.26°±0.20°, 17.48°±0.20°, 17.62°±0.20°, 18.98°±0.20°, 23.49°±0.20°, 23.66°±0.20°. According to an embodiment of the present invention, the X-ray powder diffraction pattern analysis data of the Form E crystal form of the compound represented by formula (I) is shown in Table 6, wherein the error range of each characteristic diffraction peak 2θ is ±0.2°.

根据本发明的实施方案，所述式(I)所示化合物的Form E晶型具有基本上如图16所示的X射线粉末衍射图谱。根据本发明的实施方案，所述式(I)所示化合物的Form E晶型的差示扫描量热分析图谱(DSC图)包含58.2℃±2.0℃、168.2℃±2.0℃、246.8℃±2.0℃的吸热峰。根据本发明的实施方案，所述式(I)所示化合物的Form E晶型的差示扫描量热分析图谱(DSC图)包含182.9℃±2.0℃的放热峰。根据本发明的实施方案，所述式(I)所示化合物的Form E晶型的差示扫描量热分析图谱(DSC图)如图17所示。根据本发明的实施方案，所述式(I)所示化合物的Form E晶型的热重分析图谱(TGA图)如图17所示。According to an embodiment of the present invention, the Form E crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 16. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC diagram) of the Form E crystal form of the compound represented by formula (I) includes endothermic peaks at 58.2°C±2.0°C, 168.2°C±2.0°C, and 246.8°C±2.0°C. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC diagram) of the Form E crystal form of the compound represented by formula (I) includes an exothermic peak at 182.9°C±2.0°C. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC diagram) of the Form E crystal form of the compound represented by formula (I) is shown in Figure 17. According to an embodiment of the present invention, the thermogravimetric analysis spectrum (TGA diagram) of the Form E crystal form of the compound represented by formula (I) is shown in Figure 17.

根据本发明的实施方案，所述式(I)所示化合物的Form F晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.88°±0.20°，9.71°±0.20°，17.65°±0.20°，18.79°±0.20°，19.44°±0.20°，20.01°±0.20°。根据本发明的实施方案，所述式(I)所示化合物的Form F晶型的X射线粉末衍射图谱进一步包括以下一个、两个或多个2θ角处的特征衍射峰：9.31°±0.20°，15.36°±0.20°，17.01°±0.20°，17.31°±0.20°，20.87°±0.20°，23.36°±0.20°，23.66°±0.20°，23.82°±0.20°。根据本发明的实施方案，所述式(I)所示化合物的Form F晶型的X射线粉末衍射图谱解析数据如表7所示，其中每个特征衍射峰2θ的误差范围为±0.2°。According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form F crystal form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles: 6.88°±0.20°, 9.71°±0.20°, 17.65°±0.20°, 18.79°±0.20°, 19.44°±0.20°, 20.01°±0.20°. According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form F crystal form of the compound represented by formula (I) further includes the following one, two or more characteristic diffraction peaks at 2θ angles: 9.31°±0.20°, 15.36°±0.20°, 17.01°±0.20°, 17.31°±0.20°, 20.87°±0.20°, 23.36°±0.20°, 23.66°±0.20°, 23.82°±0.20°. According to an embodiment of the present invention, the analytical data of the X-ray powder diffraction pattern of the Form F crystal form of the compound represented by formula (I) are shown in Table 7, wherein the error range of 2θ of each characteristic diffraction peak is ±0.2°.

根据本发明的实施方案，所述式(I)所示化合物的Form F晶型具有基本上如图19所示的X射线粉末衍射图谱。根据本发明的实施方案，所述式(I)所示化合物的Form F晶型的差示扫描量热分析图谱(DSC图)包含56.4℃±2.0℃、150.7℃±2.0℃、167.8℃±2.0℃、247.1℃±2.0℃的吸热峰。根据本发明的实施方案，所述式(I)所示化合物的Form F晶型的差示扫描量热分析图谱(DSC图)包含171.7℃±2.0℃的放热峰。根据本发明的实施方案，所述式(I)所示化合物的Form F晶型的差示扫描量热分析图谱(DSC图)如图20所示。根据本发明的实施方案，所述式(I)所示化合物的Form F晶型的热重分析图谱(TGA图)如图20所示。According to an embodiment of the present invention, the Form F crystalline form of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 19. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC spectrum) of the Form F crystalline form of the compound represented by formula (I) includes endothermic peaks at 56.4°C±2.0°C, 150.7°C±2.0°C, 167.8°C±2.0°C, and 247.1°C±2.0°C. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC spectrum) of the Form F crystalline form of the compound represented by formula (I) includes an exothermic peak at 171.7°C±2.0°C. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC spectrum) of the Form F crystalline form of the compound represented by formula (I) is shown in Figure 20. According to an embodiment of the present invention, the thermogravimetric analysis spectrum (TGA spectrum) of the Form F crystalline form of the compound represented by formula (I) is shown in Figure 20.

根据本发明的实施方案，所述式(I)所示化合物的Form G晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.61°±0.20°，17.62°±0.20°，19.54°±0.20°，20.30°±0.20°，24.09°±0.20°。根据本发明的实施方案，所述式(I)所示化合物的Form G晶型的X射线粉末衍射图谱进一步包括以下一个、两个或多个2θ角处的特征衍射峰：7.06°±0.20°，16.70°±0.20°，18.49°±0.20°，19.31°±0.20°，23.31°±0.20°，26.89°±0.20°，28.60°±0.20°。根据本发明的实施方案，所述式(I)所示化合物的Form G晶型的X射线粉末衍射图谱解析数据如表8所示，其中每个特征衍射峰2θ的误差范围为±0.2°。According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form G crystal form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles: 9.61°±0.20°, 17.62°±0.20°, 19.54°±0.20°, 20.30°±0.20°, 24.09°±0.20°. According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form G crystal form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at 2θ angles: 7.06°±0.20°, 16.70°±0.20°, 18.49°±0.20°, 19.31°±0.20°, 23.31°±0.20°, 26.89°±0.20°, 28.60°±0.20°. According to an embodiment of the present invention, the X-ray powder diffraction pattern analysis data of the Form G crystal form of the compound represented by formula (I) is shown in Table 8, wherein the error range of each characteristic diffraction peak 2θ is ±0.2°.

根据本发明的实施方案，所述式(I)所示化合物的Form G晶型具有基本上如图22所示的X射线粉末衍射图谱。根据本发明的实施方案，所述式(I)所示化合物的Form G晶型的差示扫描量热分析图谱(DSC图)包含97.5℃±2.0℃、246.4℃±2.0℃的吸热峰。根据本发明的实施方案，所述式(I)所示化合物的Form G晶型的差示扫描量热分析图谱(DSC图)如图23所示。根据本发明的实施方案，所述式(I)所示化合物的Form G晶型的热重分析图谱(TGA图)如图23所示。According to an embodiment of the present invention, the Form G crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 22. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC diagram) of the Form G crystal form of the compound represented by formula (I) comprises endothermic peaks at 97.5°C±2.0°C and 246.4°C±2.0°C. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC diagram) of the Form G crystal form of the compound represented by formula (I) is shown in Figure 23. According to an embodiment of the present invention, the thermogravimetric analysis spectrum (TGA diagram) of the Form G crystal form of the compound represented by formula (I) is shown in Figure 23.

根据本发明的实施方案，所述式(I)所示化合物的Form H晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.47°±0.20°，18.37°±0.20°，19.15°±0.20°，20.01°±0.20°，22.98°±0.20°，23.70°±0.20°。根据本发明的实施方案，所述式(I)所示化合物的Form H晶型的X射线粉末衍射图谱进一步包括以下一个、两个或多个2θ角处的特征衍射峰：6.95°±0.20°，9.14°±0.20°，16.57°±0.20°，17.30°±0.20°，17.54°±0.20°，20.59°±0.20°，21.08°±0.20°，25.60°±0.20°，26.26°±0.20°，28.19°±0.20°，30.56°±0.20°。According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form H crystal form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles: 9.47°±0.20°, 18.37°±0.20°, 19.15°±0.20°, 20.01°±0.20°, 22.98°±0.20°, 23.70°±0.20°. According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form H crystal form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at 2θ angles: 6.95°±0.20°, 9.14°±0.20°, 16.57°±0.20°, 17.30°±0.20°, 17.54°±0.20°, 20.59°±0.20°, 21.08°±0.20°, 25.60°±0.20°, 26.26°±0.20°, 28.19°±0.20°, and 30.56°±0.20°.

根据本发明的实施方案，所述式(I)所示化合物的Form H晶型的X射线粉末衍射图谱解析数据如表9所示，其中每个特征衍射峰2θ的误差范围为±0.2°。根据本发明的实施方案，所述式(I)所示化合物的Form H晶型具有基本上如图25所示的X射线粉末衍射图谱。根据本发明的实施方案，所述式(I)所示化合物的Form H晶型的差示扫描量热分析图谱(DSC图)包含123.6℃±2.0℃、165.6℃±2.0℃、246.6℃±2.0℃的吸热峰。根据本发明的实施方案，所述式(I)所示化合物的Form H晶型的差示扫描量热分析图谱(DSC图)包含173.0℃±2.0℃的放热峰。根据本发明的实施方案，所述式(I)所示化合物的Form H晶型的差示扫描量热分析图谱(DSC图)如图26所示。根据本发明的实施方案，所述式(I)所示化合物的Form H晶型的热重分析图谱(TGA图)如图26所示。According to an embodiment of the present invention, the X-ray powder diffraction pattern analysis data of the Form H crystal form of the compound represented by formula (I) are shown in Table 9, wherein the error range of each characteristic diffraction peak 2θ is ±0.2°. According to an embodiment of the present invention, the Form H crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 25. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC spectrum) of the Form H crystal form of the compound represented by formula (I) includes endothermic peaks at 123.6°C±2.0°C, 165.6°C±2.0°C, and 246.6°C±2.0°C. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC spectrum) of the Form H crystal form of the compound represented by formula (I) includes an exothermic peak at 173.0°C±2.0°C. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC spectrum) of the Form H crystal form of the compound represented by formula (I) is shown in Figure 26. According to an embodiment of the present invention, the thermogravimetric analysis spectrum (TGA diagram) of the Form H crystal form of the compound represented by formula (I) is shown in Figure 26.

根据本发明的实施方案，所述式(I)所示化合物的Form I晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：13.55°±0.20°，17.22°±0.20°，18.27°±0.20°，18.91°±0.20°，20.8°±0.20°。根据本发明的实施方案，所述式(I)所示化合物的Form I晶型的X射线粉末衍射图谱进一步包括以下一个、两个或多个2θ角处的特征衍射峰：5.11°±0.20°，7.91°±0.20°，11.63°±0.20°，14.34°±0.20°，14.98°±0.20°，15.68°±0.20°，19.69°±0.20°，21.9°±0.20°，22.57°±0.20°，23.53°±0.20°，24.17°±0.20°，25.72°±0.20°，28.02°±0.20°，32.21°±0.20°。根据本发明的实施方案，所述式(I)所示化合物的Form I晶型的X射线粉末衍射图谱解析数据如表10所示，其中每个特征衍射峰2θ的误差范围为±0.2°。According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form I crystal form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles: 13.55°±0.20°, 17.22°±0.20°, 18.27°±0.20°, 18.91°±0.20°, 20.8°±0.20°. According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form I crystal form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at 2θ angles: 5.11°±0.20°, 7.91°±0.20°, 11.63°±0.20°, 14.34°±0.20°, 14.98°±0.20°, 15.68°±0.20°, 19.69°±0.20°, 21.9°±0.20°, 22.57°±0.20°, 23.53°±0.20°, 24.17°±0.20°, 25.72°±0.20°, 28.02°±0.20°, and 32.21°±0.20°. According to an embodiment of the present invention, the X-ray powder diffraction pattern analysis data of the Form I crystal form of the compound represented by formula (I) is shown in Table 10, wherein the error range of each characteristic diffraction peak 2θ is ±0.2°.

根据本发明的实施方案，所述式(I)所示化合物的Form I晶型具有基本上如图28所示的X射线粉末衍射图谱。根据本发明的实施方案，所述式(I)所示化合物的Form I晶型的差示扫描量热分析图谱(DSC图)包含210.4℃±2.0℃、245.8℃±2.0℃的吸热峰。根据本发明的实施方案，所述式(I)所示化合物的Form I晶型的差示扫描量热分析图谱(DSC图)包含210.4℃±2.0℃的放热峰。根据本发明的实施方案，所述式(I)所示化合物的Form I晶型的差示扫描量热分析图谱(DSC图)如图29所示。根据本发明的实施方案，所述式(I)所示化合物的Form I晶型的热重分析图谱(TGA图)如图30所示。According to an embodiment of the present invention, the Form I crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 28. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC diagram) of the Form I crystal form of the compound represented by formula (I) includes endothermic peaks at 210.4°C±2.0°C and 245.8°C±2.0°C. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC diagram) of the Form I crystal form of the compound represented by formula (I) includes an exothermic peak at 210.4°C±2.0°C. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC diagram) of the Form I crystal form of the compound represented by formula (I) is shown in Figure 29. According to an embodiment of the present invention, the thermogravimetric analysis spectrum (TGA diagram) of the Form I crystal form of the compound represented by formula (I) is shown in Figure 30.

本发明还提供上述式(I)所示化合物的无定型或多晶型物的制备方法，其中，The present invention also provides a method for preparing the amorphous or polymorphic form of the compound represented by the above formula (I), wherein:

式(I)所示化合物的无定型的制备方法如下：将式(I)化合物用第一溶剂溶解，冻干，即得所述式(I)所示化合物的无定型；The preparation method of the amorphous form of the compound represented by formula (I) is as follows: dissolving the compound represented by formula (I) in a first solvent and freeze-drying to obtain the amorphous form of the compound represented by formula (I);

式(I)所示化合物的多晶型物的制备方法如下：将式(I)化合物用溶剂溶解，析晶，即得所述式(I)所示化合物的多晶型物。The preparation method of the polymorph of the compound represented by formula (I) is as follows: dissolving the compound represented by formula (I) in a solvent and crystallizing to obtain the polymorph of the compound represented by formula (I).

根据本发明的实施方案，式(I)所示化合物的无定型的制备方法中，第一溶剂选自有机溶剂(例如乙腈)与水的混合溶剂。According to an embodiment of the present invention, in the method for preparing the amorphous form of the compound represented by formula (I), the first solvent is selected from a mixed solvent of an organic solvent (such as acetonitrile) and water.

根据本发明的实施方案，式(I)所示化合物的Form A晶型的制备方法选自如下方法A或方法B：According to an embodiment of the present invention, the preparation method of the Form A crystal form of the compound represented by formula (I) is selected from the following method A or method B:

方法A)：将式(I)化合物的无定型用第二溶剂溶解，再加入第三溶剂，搅拌，析晶，即得所述式(I)所示化合物的Form A晶型；Method A): dissolving the amorphous form of the compound of formula (I) in a second solvent, adding a third solvent, stirring, and crystallizing to obtain Form A of the compound of formula (I);

方法B)：将式(I)化合物的无定型用第四溶剂溶解，悬浮，析晶，即得所述式(I)所示化合物的Form A晶型。Method B): The amorphous form of the compound of formula (I) is dissolved in a fourth solvent, suspended, and crystallized to obtain Form A of the compound of formula (I).

根据本发明的实施方案，式(I)所示化合物的无定型的制备方法如上所述。According to an embodiment of the present invention, the method for preparing the amorphous form of the compound represented by formula (I) is as described above.

根据本发明的实施方案，所述方法A具体如下：将式(I)化合物的无定型用第二溶剂溶解，再加入第三溶剂，搅拌，析晶，离心，干燥，即得所述式(I)所示化合物的Form A晶型。According to an embodiment of the present invention, the method A is specifically as follows: the amorphous form of the compound of formula (I) is dissolved in a second solvent, and then a third solvent is added, stirred, crystallized, centrifuged, and dried to obtain the Form A crystal form of the compound represented by formula (I).

根据本发明的实施方案，第二溶剂选自二氯甲烷、丙酮。根据本发明的实施方案，第三溶剂选自甲基叔丁基醚。根据本发明的实施方案，第二溶剂与第三溶剂的体积比为1：1-20，例如1：15、1：10、1：8、1：5、1：2。根据本发明的实施方案，式(I)化合物的无定型与第二溶剂的质量体积比为1g：10mL-50mL，例如1g：40mL、1g：30mL、1g：20mL、1g：15mL、1g：10mL。According to an embodiment of the present invention, the second solvent is selected from dichloromethane and acetone. According to an embodiment of the present invention, the third solvent is selected from methyl tert-butyl ether. According to an embodiment of the present invention, the volume ratio of the second solvent to the third solvent is 1:1-20, for example, 1:15, 1:10, 1:8, 1:5, 1:2. According to an embodiment of the present invention, the mass volume ratio of the amorphous form of the compound of formula (I) to the second solvent is 1g:10mL-50mL, for example, 1g:40mL, 1g:30mL, 1g:20mL, 1g:15mL, 1g:10mL.

根据本发明的实施方案，所述方法B具体如下：将式(I)化合物的无定型用第四溶剂溶解，悬浮，析晶，离心，干燥，即得所述式(I)所示化合物的Form A晶型。According to an embodiment of the present invention, the method B is specifically as follows: the amorphous form of the compound of formula (I) is dissolved in a fourth solvent, suspended, crystallized, centrifuged, and dried to obtain the Form A crystal form of the compound represented by formula (I).

根据本发明的实施方案，第四溶剂选自正己烷。根据本发明的实施方案，悬浮温度为40℃-60℃，例如50℃。根据本发明的实施方案，悬浮时间为10h-50h，例如24h。According to an embodiment of the present invention, the fourth solvent is selected from n-hexane. According to an embodiment of the present invention, the suspension temperature is 40-60° C., for example, 50° C. According to an embodiment of the present invention, the suspension time is 10 h-50 h, for example, 24 h.

根据本发明的实施方案，式(I)化合物的无定型与第四溶剂的质量体积比为1g：50mL-200mL，例如1g：80mL、1g：100mL、1g：120mL、1g：150mL。According to an embodiment of the present invention, the mass volume ratio of the amorphous form of the compound of formula (I) to the fourth solvent is 1g:50mL-200mL, for example, 1g:80mL, 1g:100mL, 1g:120mL, 1g:150mL.

根据本发明的实施方案，式(I)所示化合物的Form B晶型的制备方法如下：According to an embodiment of the present invention, the preparation method of the Form B crystalline form of the compound represented by formula (I) is as follows:

将式(I)化合物的Form A晶型用第五溶剂溶解，再加入第六溶剂，搅拌，析晶，即得所述式(I)所示化合物的Form B晶型。The Form A crystal form of the compound of formula (I) is dissolved in the fifth solvent, and then the sixth solvent is added, stirred, and crystallized to obtain the Form B crystal form of the compound represented by formula (I).

根据本发明的实施方案，式(I)所示化合物的Form A晶型的制备方法如上所述。According to an embodiment of the present invention, the preparation method of the Form A crystal form of the compound represented by formula (I) is as described above.

根据本发明的实施方案，所述Form B晶型的制备方法具体如下：将式(I)化合物的Form A晶型用第五溶剂溶解，再加入第六溶剂，搅拌，析晶，离心，干燥，即得所述式(I)所示化合物的Form B晶型。According to an embodiment of the present invention, the preparation method of the Form B crystal form is as follows: dissolve the Form A crystal form of the compound of formula (I) in a fifth solvent, then add a sixth solvent, stir, crystallize, centrifuge, and dry to obtain the Form B crystal form of the compound represented by formula (I).

根据本发明的实施方案，第五溶剂选自二氯甲烷。根据本发明的实施方案，第六溶剂选自正庚烷。根据本发明的实施方案，第五溶剂与第六溶剂的体积比为1：1-20，例如1：5、1：8、1：10、1：12、1：15。根据本发明的实施方案，式(I)化合物的Form A晶型与第五溶剂的质量体积比为1g：10mL-50mL，例如1g：40mL、1g：30mL、1g：20mL、1g：10mL。According to an embodiment of the present invention, the fifth solvent is selected from dichloromethane. According to an embodiment of the present invention, the sixth solvent is selected from n-heptane. According to an embodiment of the present invention, the volume ratio of the fifth solvent to the sixth solvent is 1:1-20, for example, 1:5, 1:8, 1:10, 1:12, 1:15. According to an embodiment of the present invention, the mass volume ratio of Form A crystalline form of the compound of formula (I) to the fifth solvent is 1g:10mL-50mL, for example, 1g:40mL, 1g:30mL, 1g:20mL, 1g:10mL.

根据本发明的实施方案，式(I)所示化合物的Form C晶型的制备方法如下：According to an embodiment of the present invention, the preparation method of the Form C crystalline form of the compound represented by formula (I) is as follows:

将式(I)化合物的Form A晶型用第七溶剂溶解，敞口挥发第七溶剂，析晶，即得所述式(I)所示化合物的Form C晶型。The Form A crystal form of the compound of formula (I) is dissolved in a seventh solvent, the seventh solvent is evaporated open, and crystallization is performed to obtain the Form C crystal form of the compound represented by formula (I).

根据本发明的实施方案，式(I)所示化合物的Form A晶型的制备方法如上所述。According to an embodiment of the present invention, the preparation method of Form A crystal form of the compound represented by formula (I) is as described above.

根据本发明的实施方案，所述Form C晶型的制备方法具体如下：将式(I)化合物的Form A晶型用第七溶剂溶解，室温敞口挥发第七溶剂，析晶，即得所述式(I)所示化合物的Form C晶型。According to an embodiment of the present invention, the preparation method of the Form C crystal form is as follows: the Form A crystal form of the compound represented by formula (I) is dissolved in a seventh solvent, the seventh solvent is evaporated at room temperature, and crystallization is performed to obtain the Form C crystal form of the compound represented by formula (I).

根据本发明的实施方案，第七溶剂选自乙酸乙酯。根据本发明的实施方案，式(I)化合物的Form A晶型与第七溶剂的质量体积比为5mg-20mg：1mL，例如5mg：1mL、8mg：1mL、10mg：1mL、15mg：1mL。According to an embodiment of the present invention, the seventh solvent is selected from ethyl acetate. According to an embodiment of the present invention, the mass volume ratio of the Form A crystalline form of the compound of formula (I) to the seventh solvent is 5 mg to 20 mg:1 mL, for example, 5 mg:1 mL, 8 mg:1 mL, 10 mg:1 mL, or 15 mg:1 mL.

根据本发明的实施方案，式(I)所示化合物的Form D晶型的制备方法如下：将式(I)化合物的Form A晶型用第八溶剂溶解，悬浮，析晶，即得所述式(I)所示化合物的Form D晶型。According to an embodiment of the present invention, the preparation method of the Form D crystal form of the compound represented by formula (I) is as follows: the Form A crystal form of the compound represented by formula (I) is dissolved in an eighth solvent, suspended, and crystallized to obtain the Form D crystal form of the compound represented by formula (I).

根据本发明的实施方案，式(I)所示化合物的Form A晶型的制备方法如上所述。According to an embodiment of the present invention, the preparation method of Form A crystal form of the compound represented by formula (I) is as described above.

根据本发明的实施方案，所述Form D晶型的制备方法具体如下：将式(I)化合物的Form A晶型用第八溶剂溶解，悬浮，析晶，离心，干燥，即得所述式(I)所示化合物的Form D晶型。According to an embodiment of the present invention, the preparation method of the Form D crystal form is as follows: the Form A crystal form of the compound of formula (I) is dissolved in an eighth solvent, suspended, crystallized, centrifuged, and dried to obtain the Form D crystal form of the compound represented by formula (I).

根据本发明的实施方案，第八溶剂选自乙醇。根据本发明的实施方案，悬浮温度为10℃-30℃，例如室温。根据本发明的实施方案，悬浮时间为5min-60min，例如如20min。根据本发明的实施方案，式(I)化合物的Form A晶型与第八溶剂的质量体积比为10mg-30mg：1mL，例如12mg：1mL、15mg：1mL、16mg：1mL、20mg：1mL。According to an embodiment of the present invention, the eighth solvent is selected from ethanol. According to an embodiment of the present invention, the suspension temperature is 10°C-30°C, for example, room temperature. According to an embodiment of the present invention, the suspension time is 5min-60min, for example, 20min. According to an embodiment of the present invention, the mass volume ratio of Form A crystalline form of the compound of formula (I) to the eighth solvent is 10mg-30mg:1mL, for example, 12mg:1mL, 15mg:1mL, 16mg:1mL, 20mg:1mL.

根据本发明的实施方案，式(I)所示化合物的Form E晶型的制备方法如下：将式(I)化合物的Form A晶型用第九溶剂溶解，悬浮，析晶，即得所述式(I)所示化合物的Form E晶型。According to an embodiment of the present invention, the preparation method of the Form E crystal form of the compound represented by formula (I) is as follows: the Form A crystal form of the compound represented by formula (I) is dissolved in a ninth solvent, suspended, and crystallized to obtain the Form E crystal form of the compound represented by formula (I).

根据本发明的实施方案，式(I)所示化合物的Form A晶型的制备方法如上所述。According to an embodiment of the present invention, the preparation method of Form A crystal form of the compound represented by formula (I) is as described above.

根据本发明的实施方案，所述Form E晶型的制备方法具体如下：将式(I)化合物的Form A晶型用第九溶剂溶解，悬浮，析晶，离心，干燥，即得所述式(I)所示化合物的Form E晶型。According to an embodiment of the present invention, the preparation method of the Form E crystal form is as follows: the Form A crystal form of the compound of formula (I) is dissolved in a ninth solvent, suspended, crystallized, centrifuged, and dried to obtain the Form E crystal form of the compound represented by formula (I).

根据本发明的实施方案，第九溶剂选自甲醇。根据本发明的实施方案，悬浮温度为10℃-30℃，例如室温。根据本发明的实施方案，式(I)化合物的Form A晶型与第九溶剂的质量体积比为5mg-30mg：1mL，例如8mg：1mL、10mg：1mL、10.2mg：1mL、12mg：1mL、15mg：1mL。According to an embodiment of the present invention, the ninth solvent is selected from methanol. According to an embodiment of the present invention, the suspension temperature is 10°C-30°C, for example, room temperature. According to an embodiment of the present invention, the mass volume ratio of the Form A crystalline form of the compound of formula (I) to the ninth solvent is 5 mg-30 mg:1 mL, for example, 8 mg:1 mL, 10 mg:1 mL, 10.2 mg:1 mL, 12 mg:1 mL, 15 mg:1 mL.

根据本发明的实施方案，式(I)所示化合物的Form F晶型的制备方法如下：将式(I)化合物的Form A晶型用第十溶剂溶解，悬浮，析晶，即得所述式(I)所示化合物的Form F晶型。According to an embodiment of the present invention, the preparation method of the Form F crystal form of the compound represented by formula (I) is as follows: the Form A crystal form of the compound represented by formula (I) is dissolved in a tenth solvent, suspended, and crystallized to obtain the Form F crystal form of the compound represented by formula (I).

根据本发明的实施方案，式(I)所示化合物的Form A晶型的制备方法如上所述。According to an embodiment of the present invention, the preparation method of the Form A crystal form of the compound represented by formula (I) is as described above.

根据本发明的实施方案，所述Form F晶型的制备方法具体如下：将式(I)化合物的Form A晶型用第十溶剂溶解，悬浮，析晶，离心，干燥，即得所述式(I)所示化合物的Form F晶型。According to an embodiment of the present invention, the preparation method of the Form F crystal form is as follows: the Form A crystal form of the compound of formula (I) is dissolved in a tenth solvent, suspended, crystallized, centrifuged, and dried to obtain the Form F crystal form of the compound represented by formula (I).

根据本发明的实施方案，第十溶剂选自乙腈。根据本发明的实施方案，悬浮温度为10℃-30℃，例如室温。根据本发明的实施方案，式(I)化合物的Form A晶型与第十溶剂的质量体积比为5mg-30mg：1mL，例如8mg：1mL、10mg：1mL、10.2mg：1mL、12mg：1mL、15mg：1mL。According to an embodiment of the present invention, the tenth solvent is selected from acetonitrile. According to an embodiment of the present invention, the suspension temperature is 10°C-30°C, for example, room temperature. According to an embodiment of the present invention, the mass volume ratio of Form A of the compound of formula (I) to the tenth solvent is 5 mg-30 mg:1 mL, for example, 8 mg:1 mL, 10 mg:1 mL, 10.2 mg:1 mL, 12 mg:1 mL, 15 mg:1 mL.

根据本发明的实施方案，式(I)所示化合物的Form G晶型的制备方法如下：将式(I)化合物的Form A晶型用第十一溶剂溶解，悬浮，析晶，即得所述式(I)所示化合物的Form G晶型。According to an embodiment of the present invention, the preparation method of the Form G crystal form of the compound represented by formula (I) is as follows: the Form A crystal form of the compound represented by formula (I) is dissolved in an eleventh solvent, suspended, and crystallized to obtain the Form G crystal form of the compound represented by formula (I).

根据本发明的实施方案，式(I)所示化合物的Form A晶型的制备方法如上所述。According to an embodiment of the present invention, the preparation method of the Form A crystal form of the compound represented by formula (I) is as described above.

根据本发明的实施方案，所述Form G晶型的制备方法具体如下：将式(I)化合物的Form A晶型用第十一溶剂溶解(完全溶解)，悬浮，析晶，离心，干燥，即得所述式(I)所示化合物的Form G晶型。根据本发明的实施方案，第十一溶剂选自乙二醇二甲醚。根据本发明的实施方案，悬浮温度为10℃-30℃，例如室温。According to an embodiment of the present invention, the preparation method of the Form G crystal form is as follows: the Form A crystal form of the compound of formula (I) is dissolved (completely dissolved) in an eleventh solvent, suspended, crystallized, centrifuged, and dried to obtain the Form G crystal form of the compound represented by formula (I). According to an embodiment of the present invention, the eleventh solvent is selected from ethylene glycol dimethyl ether. According to an embodiment of the present invention, the suspension temperature is 10°C-30°C, for example, room temperature.

根据本发明的实施方案，式(I)所示化合物的Form H晶型的制备方法如下：According to an embodiment of the present invention, the preparation method of the Form H crystalline form of the compound represented by formula (I) is as follows:

将式(I)化合物的Form A晶型用第十二溶剂溶解，降温析晶，即得所述式(I)所示化合物的Form H晶型。The Form A crystal form of the compound of formula (I) is dissolved in a twelfth solvent, cooled and crystallized to obtain the Form H crystal form of the compound represented by formula (I).

根据本发明的实施方案，式(I)所示化合物的Form A晶型的制备方法如上所述。According to an embodiment of the present invention, the preparation method of Form A crystal form of the compound represented by formula (I) is as described above.

根据本发明的实施方案，所述Form H晶型的制备方法具体如下：将式(I)化合物的Form A晶型用第十二溶剂溶解(用最少量第十二溶剂溶解)，降温析晶，离心，干燥，即得所述式(I)所示化合物的Form H晶型。根据本发明的实施方案，第十二溶剂选自甲酸乙酯。According to an embodiment of the present invention, the method for preparing the Form H crystal form is as follows: dissolving the Form A crystal form of the compound of formula (I) in a twelfth solvent (using a minimum amount of the twelfth solvent), cooling to crystallize, centrifuging, and drying to obtain the Form H crystal form of the compound of formula (I). According to an embodiment of the present invention, the twelfth solvent is selected from ethyl formate.

根据本发明的实施方案，式(I)所示化合物的Form I晶型的制备方法如下：According to an embodiment of the present invention, the preparation method of the Form I crystal form of the compound represented by formula (I) is as follows:

将式(I)化合物的Form D晶型用第十三溶剂溶解，降温析晶，即得所述式(I)所示化合物的Form I晶型。The Form D crystal form of the compound of formula (I) is dissolved in a thirteenth solvent, cooled and crystallized to obtain the Form I crystal form of the compound represented by formula (I).

根据本发明的实施方案，式(I)所示化合物的Form D晶型的制备方法如上所述。According to an embodiment of the present invention, the preparation method of Form D crystal form of the compound represented by formula (I) is as described above.

根据本发明的实施方案，所述Form I晶型的制备方法具体如下：将式(I)化合物的Form D晶型用第十三溶剂搅拌溶解，降温搅拌，悬浮，离心，干燥，即得所述式(I)所示化合物的Form I晶型。根据本发明的实施方案，第十三溶剂选自异丙醇、醋酸异丙酯、丙酮、甲基叔丁基醚等一种或多种。根据本发明的实施方案，式(I)化合物的Form D晶型与第十三溶剂的质量体积比为50mg-200mg：1mL，例如80mg：1mL、100mg：1mL、125mg：1mL、150mg：1mL、180mg：1mL。根据本发明的实施方案，搅拌溶解的温度为40℃-60℃，例如50℃。根据本发明的实施方案，搅拌溶解的时间为1小时-3小时，例如2小时。根据本发明的实施方案，降温搅拌的温度为10℃-30℃，例如室温。根据本发明的实施方案，降温搅拌的时间为1天-3天，例如2天。根据本发明的实施方案，干燥方式为真空干燥。根据本发明的实施方案，干燥温度为40℃-60℃，例如50℃。According to an embodiment of the present invention, the preparation method of the Form I crystal form is as follows: Form D crystal form of the compound of formula (I) is dissolved by stirring in a thirteenth solvent, cooled and stirred, suspended, centrifuged, and dried to obtain Form I crystal form of the compound represented by formula (I). According to an embodiment of the present invention, the thirteenth solvent is selected from one or more of isopropyl alcohol, isopropyl acetate, acetone, methyl tert-butyl ether, and the like. According to an embodiment of the present invention, the mass volume ratio of Form D crystal form of the compound of formula (I) to the thirteenth solvent is 50 mg-200 mg:1 mL, for example, 80 mg:1 mL, 100 mg:1 mL, 125 mg:1 mL, 150 mg:1 mL, or 180 mg:1 mL. According to an embodiment of the present invention, the temperature for stirring and dissolving is 40°C-60°C, for example, 50°C. According to an embodiment of the present invention, the time for stirring and dissolving is 1 hour-3 hours, for example, 2 hours. According to an embodiment of the present invention, the temperature for stirring and cooling is 10°C-30°C, for example, room temperature. According to an embodiment of the present invention, the time for stirring and cooling is 1 day-3 days, for example, 2 days. According to an embodiment of the present invention, the drying method is vacuum drying. According to an embodiment of the present invention, the drying temperature is 40°C-60°C, for example 50°C.

本发明还提供一种药物组合物，所述药物组合物包含治疗有效量的上述式(I)所示化合物的无定型或多晶型物中的至少一种。The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the amorphous or polymorphic forms of the compound represented by the above formula (I).

根据本发明的实施方案，所述药物组合物还包括一种或多种药学上可接受的辅料。According to an embodiment of the present invention, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

根据本发明的实施方案，所述药物组合物还可以进一步含有一种或多种额外的治疗剂。According to an embodiment of the present invention, the pharmaceutical composition may further contain one or more additional therapeutic agents.

本发明还提供一种治疗肿瘤疾病的方法，所述方法包括给予患者预防或治疗有效量的上述式(I)所示化合物的无定型或多晶型物或上述药物组合物中的至少一种。The present invention also provides a method for treating tumor diseases, which comprises administering to a patient a preventive or therapeutically effective amount of at least one of the amorphous or polymorphic forms of the compound represented by formula (I) or the pharmaceutical composition.

根据本发明的实施方案，所述肿瘤疾病包括肠癌、乳腺癌、肺癌、胰腺癌、前列腺癌、膀胱癌、头颈部癌、宫颈癌和卵巢癌。根据本发明的实施方案，所述患者包括哺乳动物，优选是人。According to an embodiment of the present invention, the tumor disease includes colorectal cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head and neck cancer, cervical cancer and ovarian cancer. According to an embodiment of the present invention, the patient includes a mammal, preferably a human.

本发明还提供一种治疗KIF18A介导的病症和/或疾病的方法，所述方法包括给予患者预防或治疗有效量的上述式(I)所示化合物的无定型或多晶型物或上述药物组合物中的至少一种。The present invention also provides a method for treating KIF18A-mediated disorders and/or diseases, comprising administering to a patient a preventive or therapeutically effective amount of at least one of the amorphous or polymorphic form of the compound represented by formula (I) or the pharmaceutical composition.

根据本发明的实施方案，KIF18A介导的病症和/或疾病为癌症，例如肠癌、乳腺癌、肺癌、胰腺癌、前列腺癌、膀胱癌、头颈部癌、宫颈癌或卵巢癌。According to an embodiment of the present invention, the KIF18A-mediated disorder and/or disease is cancer, such as bowel cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head and neck cancer, cervical cancer or ovarian cancer.

本发明还提供一种用于治疗肿瘤疾病的上述式(I)所示化合物的无定型或多晶型物或上述药物组合物。The present invention also provides an amorphous or polymorphic compound of the compound represented by the above formula (I) or the above pharmaceutical composition for treating tumor diseases.

本发明还提供上述式(I)所示化合物的无定型或多晶型物或上述药物组合物在制备药物中的用途。The present invention also provides use of the amorphous or polymorphic form of the compound represented by the above formula (I) or the above pharmaceutical composition in preparing medicines.

根据本发明的实施方案，所述用途可以为在制备治疗KIF18A介导的病症和/或疾病的药物中的用途，如在制备KIF18A抑制剂药物中的用途。According to an embodiment of the present invention, the use may be use in preparing a medicament for treating KIF18A-mediated disorders and/or diseases, such as use in preparing a KIF18A inhibitor drug.

根据本发明的实施方案，所述疾病为癌症，例如包括肠癌、乳腺癌、肺癌、胰腺癌、前列腺癌、膀胱癌、头颈部癌、宫颈癌或卵巢癌。According to an embodiment of the present invention, the disease is cancer, for example including bowel cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head and neck cancer, cervical cancer or ovarian cancer.

术语“患者”是指包括哺乳动物在内的任何动物，优选小鼠、大鼠、其它啮齿类动物、兔、狗、猫、猪、牛、羊、马或灵长类动物，最优选人。The term "patient" refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

术语“治疗有效量”是指研究人员、兽医、医师或其它临床医师正在组织、系统、动物、个体或人中寻找的引起生物学或医学反应的活性化合物或药物的量，它包括以下一项或多项：(1)预防疾病：例如在易感染疾病、紊乱或病症但尚未经历或出现疾病病理或症状的个体中预防疾病、紊乱或病症。(2)抑制疾病：例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中抑制疾病、紊乱或病症(即阻止病理和/或症状的进一步发展)。(3)缓解疾病：例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中缓解疾病、紊乱或病症(即逆转病理和/或症状)。The term "therapeutically effective amount" refers to that amount of an active compound or drug that will elicit the biological or medical response that a researcher, veterinarian, physician, or other clinician is seeking in a tissue, system, animal, individual, or human, and includes one or more of the following: (1) prevents disease, e.g., prevents a disease, disorder, or condition in an individual who is susceptible to the disease, disorder, or condition but who is not yet experiencing or developing the pathology or symptoms of the disease. (2) inhibits disease, e.g., inhibits the disease, disorder, or condition (i.e., prevents further development of the pathology and/or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition. (3) alleviates disease, e.g., alleviates the disease, disorder, or condition (i.e., reverses the pathology and/or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition.

有益效果Beneficial effects

本发明提供了式(I)所示化合物的无定型或多晶型物，所述无定型和多晶型物具有优异的引湿性、溶解度和稳定性，具有优良的成药性，适合产业上的生产制造保存。The present invention provides an amorphous or polymorphic form of a compound represented by formula (I). The amorphous and polymorphic forms have excellent hygroscopicity, solubility and stability, excellent drugability, and are suitable for industrial production, manufacturing and storage.

附图说明BRIEF DESCRIPTION OF THE DRAWINGS

图1：式(I)所示化合物无定型的XRPD图谱；Figure 1: XRPD pattern of the amorphous form of the compound represented by formula (I);

图2：式(I)所示化合物无定型的DSC和TGA叠图；Figure 2: Overlay of DSC and TGA images of the amorphous form of the compound represented by formula (I);

图3：式(I)所示化合物无定型的NMR图谱；Figure 3: NMR spectrum of the amorphous form of the compound represented by formula (I);

图4：式(I)所示化合物Form A晶型的XRPD图谱；Figure 4: XRPD pattern of Form A of the compound represented by formula (I);

图5：式(I)所示化合物Form A晶型的DSC和TGA叠图；Figure 5: Overlay of DSC and TGA images of Form A of the compound represented by formula (I);

图6：式(I)所示化合物Form A晶型的NMR图谱；Figure 6: NMR spectrum of Form A of the compound represented by formula (I);

图7：式(I)所示化合物Form B晶型的XRPD图谱；Figure 7: XRPD pattern of Form B of the compound represented by formula (I);

图8：式(I)所示化合物Form B晶型的DSC和TGA叠图；Figure 8: Overlay of DSC and TGA images of Form B of the compound represented by formula (I);

图9：式(I)所示化合物Form B晶型的NMR图谱；Figure 9: NMR spectrum of Form B of the compound represented by formula (I);

图10：式(I)所示化合物Form C晶型的XRPD图谱；Figure 10: XRPD pattern of Form C of the compound represented by formula (I);

图11：式(I)所示化合物Form C晶型的DSC和TGA叠图；Figure 11: Overlay of DSC and TGA images of Form C of the compound represented by Formula (I);

图12：式(I)所示化合物Form C晶型的NMR图谱；Figure 12: NMR spectrum of Form C of the compound represented by Formula (I);

图13：式(I)所示化合物Form D晶型的XRPD图谱；Figure 13: XRPD pattern of Form D of the compound represented by formula (I);

图14：式(I)所示化合物Form D晶型的DSC和TGA叠图；Figure 14: Overlay of DSC and TGA images of Form D of the compound represented by formula (I);

图15：式(I)所示化合物Form D晶型的NMR图谱；Figure 15: NMR spectrum of the compound represented by formula (I) Form D;

图16：式(I)所示化合物Form E晶型的XRPD图谱；Figure 16: XRPD pattern of Form E of the compound represented by formula (I);

图17：式(I)所示化合物Form E晶型的DSC和TGA叠图；Figure 17: Overlay of DSC and TGA images of Form E of the compound represented by Formula (I);

图18：式(I)所示化合物Form E晶型的NMR图谱；Figure 18: NMR spectrum of Form E of the compound represented by formula (I);

图19：式(I)所示化合物Form F晶型的XRPD图谱；Figure 19: XRPD pattern of Form F crystalline form of the compound represented by formula (I);

图20：式(I)所示化合物Form F晶型的DSC和TGA叠图；Figure 20: Overlay of DSC and TGA images of Form F of the compound represented by Formula (I);

图21：式(I)所示化合物Form F晶型的NMR图谱；Figure 21: NMR spectrum of Form F, a crystalline form of the compound represented by Formula (I);

图22：式(I)所示化合物Form G晶型的XRPD图谱；Figure 22: XRPD pattern of Form G of the compound represented by formula (I);

图23：式(I)所示化合物Form G晶型的DSC和TGA叠图；Figure 23: Overlay of DSC and TGA images of Form G of the compound of formula (I);

图24：式(I)所示化合物Form G晶型的NMR图谱；Figure 24: NMR spectrum of the Form G crystalline form of the compound represented by formula (I);

图25：式(I)所示化合物Form H晶型的XRPD图谱；Figure 25: XRPD pattern of Form H crystalline form of the compound represented by formula (I);

图26：式(I)所示化合物Form H晶型的DSC和TGA叠图；Figure 26: Overlay of DSC and TGA images of Form H of the compound represented by Formula (I);

图27：式(I)所示化合物Form H晶型的NMR图谱；Figure 27: NMR spectrum of Form H crystalline form of the compound represented by formula (I);

图28：式(I)所示化合物Form I晶型的XRPD图谱；Figure 28: XRPD pattern of Form I of the compound represented by Formula (I);

图29：式(I)所示化合物Form I晶型的DSC图；Figure 29: DSC graph of Form I crystalline form of the compound represented by formula (I);

图30：式(I)所示化合物Form I晶型的TGA图；Figure 30: TGA chart of Form I crystal form of the compound represented by formula (I);

图31：式(I)所示化合物Form I晶型的NMR图谱；Figure 31: NMR spectrum of Form I of the compound represented by Formula (I);

图32：式(I)所示化合物Form A晶型的DVS图；Figure 32: DVS image of Form A of the compound represented by formula (I);

图33：式(I)所示化合物Form A晶型在DVS测试前后的XRPD对比图；Figure 33: XRPD comparison of Form A of the compound represented by Formula (I) before and after DVS testing;

图34：式(I)所示化合物Form E晶型的DVS图；Figure 34: DVS image of the Form E crystalline form of the compound represented by formula (I);

图35：式(I)所示化合物Form E晶型在DVS测试前后的XRPD对比图；Figure 35: XRPD comparison of Form E of the compound of formula (I) before and after DVS testing;

图36：式(I)所示化合物Form A晶型稳定性研究的XRPD对比图。Figure 36: XRPD comparison chart of the stability study of Form A crystal form of the compound represented by formula (I).

具体实施方式DETAILED DESCRIPTION

下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection that the present invention is intended to protect.

除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

以下为实施例所用的仪器、参数、表征及测试方法：The following are the instruments, parameters, characterizations and test methods used in the examples:

(1)核磁分析(1H NMR)(1) Nuclear magnetic resonance analysis ( 1 H NMR)

将若干毫克固体样品溶解于二甲基亚砜-d6或氘代甲醇溶剂中，在Bruker AVANCE NEO 400(Bruker，GER)上进行核磁分析。Several milligrams of solid sample were dissolved in dimethyl sulfoxide-d6 or deuterated methanol solvent and analyzed by nuclear magnetic resonance on a Bruker AVANCE NEO 400 (Bruker, GER).

(2)X射线粉末衍射(XRPD)(2) X-ray powder diffraction (XRPD)

部分实验所得固体样品用X射线粉末衍射仪Bruker D8 Advance(Bruker，GER)进行分析。2θ扫描角度从3°到45°，扫描步长为0.02°，曝光时间为0.08秒。测试方法为Cu靶Kɑ1射线，电压40kV，电流40m A，样品盘为零背景样品盘。Some solid samples obtained in the experiments were analyzed using a Bruker D8 Advance X-ray powder diffractometer (Bruker, GER). The 2θ scan angle ranged from 3° to 45°, with a scan step size of 0.02° and an exposure time of 0.08 s. The test method used Cu target Kα1 radiation, a voltage of 40 kV, a current of 40 mA, and a zero-background sample pan.

部分实验所得固体样品用X射线粉末衍射仪Panalytical EMPYREAN(PANalytical，UK)进行分析。2θ扫描角度从3°到45°，扫描步长为0.013°，总测试时间3分30秒。测试方法为Cu靶Kɑ1射线，电压45kV，电流40m A，样品盘为零背景样品盘。Some solid samples obtained in the experiments were analyzed using an X-ray powder diffractometer (PANalytical EMPYREAN, UK). The 2θ scan angle ranged from 3° to 45°, with a scan step size of 0.013°, for a total measurement time of 3 minutes and 30 seconds. The measurement method used Kα1 radiation from a Cu target, a voltage of 45 kV, a current of 40 mA, and a zero-background sample pan.

(3)热重分析(TGA)(3) Thermogravimetric analysis (TGA)

热重分析仪的型号为TA Discovery 550(TA，US)。将2-5mg样品置于已平衡的开口铝制样品盘中，在TGA加热炉内自动称量。样品以10℃/min的速率加热至最终温度，样品处氮气吹扫速度为60mL/min，天平处氮气吹扫速度为40mL/min。The thermogravimetric analyzer (TGA) was a TA Discovery 550 (TA, US). Samples (2–5 mg) were placed in a pre-equilibrated open aluminum sample pan and automatically weighed within the TGA furnace. The samples were heated to the final temperature at a rate of 10°C/min, with nitrogen purge rates of 60 mL/min at the sample and 40 mL/min at the balance.

(4)差示扫描量热分析(DSC)(4) Differential Scanning Calorimetry (DSC)

差示扫描量热分析仪的型号为TA Discovery 250(TA，US)。1-2mg样品经精确称重后置于扎孔的DSC Tzero样品盘中，以10℃/min的速率加热至最终温度，炉内氮气吹扫速度为50mL/min。A differential scanning calorimeter (DSC) was used, a TA Discovery 250 (TA, US). A 1–2 mg sample was accurately weighed and placed in a perforated DSC Tzero pan. The sample was heated to the final temperature at a rate of 10°C/min, with a nitrogen purge rate of 50 mL/min.

(5)动态水分吸脱附分析(DVS)(5) Dynamic moisture adsorption and desorption analysis (DVS)

引湿性初步评估的动态水分吸脱附分析采用DVS Intrinsic Plus(SMS，UK)进行测定。测试采用梯度模式，湿度变化为50％-95％-50％，每个梯度的湿度变化量为15％，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，或每个梯度最长的维持时间为60分钟。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 sorption/desorption analysis for preliminary hygroscopicity assessment was performed using a DVS Intrinsic Plus (SMS, UK). The test used a gradient mode with humidity changes from 50% to 95% to 50%, with each step increasing by 15%. The gradient endpoint was determined using the dm/dt method, with a dm/dt value of less than 0.002% maintained for 10 minutes, or a maximum of 60 minutes per step. After the test, the samples were analyzed by XRPD to confirm any changes in solid form.

动态水分吸脱附分析采用DVS Intrinsic Plus(SMS，UK)进行测定。测试采用梯度模式，湿度变化为0％-95％-0％，在0％至95％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，或每个梯度最长维持180分钟。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 sorption/desorption analysis was performed using a DVS Intrinsic Plus (SMS, UK). The test used a gradient mode with humidity changes from 0% to 95% to 0%, with each step increasing by 10% within the 0% to 95% range. The gradient endpoint was determined using the dm/dt method, with a dm/dt of less than 0.002% maintained for 10 minutes, or a maximum of 180 minutes per step. After the test, the samples were analyzed by XRPD to confirm any changes in solid form.

(6)高效液相色谱(HPLC)(6) High performance liquid chromatography (HPLC)

高效液相色谱型号为SHIMADZU LC-20A(Shimadzu，JP)，测试条件如表所示。The HPLC model was SHIMADZU LC-20A (Shimadzu, JP), and the test conditions were shown in the table.

表1 HPLC测试条件
Table 1 HPLC test conditions

实施例1
Example 1

第一步(1S,4R)-N-(2，6-二溴苯基)-2-氮杂双环[2.2.1]庚烷-3-亚胺(化合物2c)的合成Step 1 Synthesis of (1S,4R)-N-(2,6-dibromophenyl)-2-azabicyclo[2.2.1]heptane-3-imine (Compound 2c)

在氮气氛围下，将(1S,4R)-2-氮杂双环[2.2.1]庚烷-3-酮2b(2.76g，25mmol，1.0eq.)溶解在60mL乙腈中，将反应液温度降至0℃，滴加入POCl3(3.73g，25mmol，1.0eq.)，保持0℃反应2h，加入2，6-二溴苯胺2a(6.20g，25mmol，1.0eq.)继续反应2h，TLC检测反应完成，加入20mL饱和NaHCO3淬灭反应液，加入2×20mL乙酸乙酯萃取，分液，合并有机层，用2×20mL食盐水洗涤，有机相旋干，用乙酸乙酯/石油醚＝1/1混合溶液打浆，得到产品化合物2c粗品(5.60g)，未经纯化直接用于下一步反应。Under nitrogen atmosphere, (1S,4R)-2-azabicyclo[2.2.1]heptan-3-one 2b (2.76 g, 25 mmol, 1.0 eq.) was dissolved in 60 mL of acetonitrile. The reaction temperature was lowered to 0°C, and POCl 3 (3.73 g, 25 mmol, 1.0 eq.) was added dropwise. The reaction was maintained at 0°C for 2 h. 2,6-dibromoaniline 2a (6.20 g, 25 mmol, 1.0 eq.) was added and the reaction was continued for 2 h. After TLC detection, the reaction was completed. 20 mL of saturated NaHCO 3 was added to quench the reaction solution. 2×20 mL of ethyl acetate was added for extraction. The layers were separated, and the organic layers were combined and washed with 2×20 mL of brine. The organic phase was spin-dried and slurried with a 1/1 mixture of ethyl acetate/petroleum ether to give the crude product compound 2c (5.60 g), which was used directly in the next reaction without purification.

化合物2c表征如下：Compound 2c was characterized as follows:

1H NMR(400MHz，CDCl3)δ7.52-7.49(m，2H)，6.5(t,J＝8.0，1H)，3.85(d，1H)，3.20(s，1H)，1.98-1.95(m，2H)，1.85(t，1H)，1.48(d，1H)，1.46-1.44(m，1H)，1.37-1.36(m，2H)； 1 H NMR (400MHz, CDCl 3 )δ7.52-7.49 (m, 2H), 6.5 (t, J = 8.0, 1H), 3.85 (d, 1H), 3.20 (s, 1H), 1.98-1. 95(m, 2H), 1.85(t, 1H), 1.48(d, 1H), 1.46-1.44(m, 1H), 1.37-1.36(m, 2H);

MS：(ESI，m/z)：345.1[M+H]+。MS: (ESI, m/z): 345.1[M+H] + .

第二步(1S,4R)-6-溴-1,2，3，4-四氢-1，4-亚甲基苯并[4，5]咪唑并[1，2-a]吡啶(化合物2d)的合成Step 2 Synthesis of (1S,4R)-6-bromo-1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridine (Compound 2d)

称量上述化合物2c粗品(1.50g，4.4mmol，1.0eq.)溶于30mL DMSO中，加入碳酸钾(1.21g，8.8mmol，2eq.)、碘化亚铜(0.08g，0.44mmol，0.1eq.)，加热至80℃反应2h，HPLC检测反应完成，冷却至室温，加入600mL水，用2×30mL乙酸乙酯萃取，合并有机层，浓缩干得到粗品2d(0.48g)。The crude product of compound 2c (1.50 g, 4.4 mmol, 1.0 eq.) was weighed and dissolved in 30 mL of DMSO. Potassium carbonate (1.21 g, 8.8 mmol, 2 eq.) and cuprous iodide (0.08 g, 0.44 mmol, 0.1 eq.) were added. The mixture was heated to 80°C for 2 h. The reaction was completed after HPLC detection. The mixture was cooled to room temperature and added with 600 mL of water. The mixture was extracted with 2×30 mL of ethyl acetate. The organic layers were combined and concentrated to dryness to give the crude product 2d (0.48 g).

化合物2d表征如下：MS：(ESI，m/z)：262.8[M+H]+。Compound 2d was characterized as follows: MS: (ESI, m/z): 262.8 [M+H] + .

第三步化合物2的合成Step 3 Synthesis of Compound 2

将化合物2d(0.50g，1.9mmol，1.0eq.)、氧化亚铜(100mg，0.07mmol，0.35eq.)、氢氧化钾(0.12g，1.9mmol，1.0eq.)和氨乙醇溶液10mL(20％的氨/乙醇溶液)80℃搅拌反应12小时。HPLC检测反应完成，过滤后滤液减压浓缩干，加入20mL水，并用二氯甲烷萃取2×10mL，有机相浓缩干，加入乙酸乙酯/正庚烷＝1/3结晶，得到化合物2(250mg，收率66％)。Compound 2d (0.50 g, 1.9 mmol, 1.0 eq.), cuprous oxide (100 mg, 0.07 mmol, 0.35 eq.), potassium hydroxide (0.12 g, 1.9 mmol, 1.0 eq.), and 10 mL of ethanolic ammonia solution (20% ammonia in ethanol) were stirred at 80°C for 12 hours. HPLC confirmed the reaction was complete, and the filtrate was filtered and concentrated to dryness under reduced pressure. 20 mL of water was added, and the mixture was extracted with dichloromethane (2 × 10 mL). The organic phase was concentrated to dryness and crystallized by adding ethyl acetate/n-heptane (1/3) to afford compound 2 (250 mg, 66% yield).

化合物2表征如下：Compound 2 is characterized as follows:

1H NMR(400MHz，CDCl3)δ7.18(t，1H)，6.83(dd，1H)，6.54(dd，1H)，4.95(qd，1H)，4.31(s，2H)，3.62(d，1H)，2.22-2.16(m，1H)，2.10-2.07(m，3H)，1.37-1.36(m，2H)； 1 H NMR (400MHz, CDCl 3 )δ7.18(t, 1H), 6.83(dd, 1H), 6.54(dd, 1H), 4.95(qd, 1H), 4.31(s, 2H), 3.62(d, 1H), 2.22-2.16(m, 1H), 2.10-2.07(m, 3H), 1.37-1.36(m, 2H);

MS：(ESI，m/z)：199.9[M+H]+。MS: (ESI, m/z): 199.9[M+H] + .

第四步4-溴-2-(6-氮杂螺[2.5]辛烷-6-基)-N-((1S,4R)-1,2，3，4-四氢-1，4-亚甲基苯并[4，5]咪唑并[1，2-a]吡啶-6-基)苯甲酰胺(化合物3a)的合成Step 4: Synthesis of 4-bromo-2-(6-azaspiro[2.5]octane-6-yl)-N-((1S,4R)-1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-yl)benzamide (Compound 3a)

在氮气保护下，向反应釜中加入4-溴-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酸(化合物1a)(6.70g，21.6mmol，1.0eq.)、化合物2(4.38g，22mmol，1.02eq.)、DMF(33.5mL)，控制温度25±5℃，向体系中滴加DIEA(5.42g，47mmol，2.2eq.)，滴加完毕后，向体系中加入HATU(10.36g，27mmol，1.3eq.)、EDCI(5.22g，27mmol，1.3eq.)，控温25±5℃，搅拌至少10小时。HPLC检测反应结束后，控制釜内温度25±5℃，向体系中滴加H2O(40.2mL)，搅拌至少1小时，离心，滤饼用H2O(13.4mL)淋洗，收集滤饼。向反应釜中加入上述湿滤饼和H2O(33.5mL)，控制釜内温度25±5℃，搅拌至少1小时，离心，滤饼用H2O(13.4mL)淋洗，收集滤饼。滤饼于45±5℃真空干燥，得棕色固体3a(9.88g，收率93％)。Under nitrogen protection, 4-bromo-2-(6-azaspiro[2.5]octane-6-yl)benzoic acid (compound 1a) (6.70 g, 21.6 mmol, 1.0 eq.), compound 2 (4.38 g, 22 mmol, 1.02 eq.), and DMF (33.5 mL) were added to the reactor, and the temperature was controlled at 25±5°C. DIEA (5.42 g, 47 mmol, 2.2 eq.) was added dropwise to the system. After the addition was complete, HATU (10.36 g, 27 mmol, 1.3 eq.) and EDCI (5.22 g, 27 mmol, 1.3 eq.) were added to the system, the temperature was controlled at 25±5°C, and the mixture was stirred for at least 10 hours. After the reaction was completed by HPLC, the temperature in the autoclave was controlled at 25±5°C, and H2O (40.2 mL) was added dropwise to the system. The mixture was stirred for at least 1 hour, centrifuged, and the filter cake was rinsed with H2O (13.4 mL) and collected. The wet filter cake and H2O (33.5 mL) were added to the autoclave. The temperature in the autoclave was controlled at 25±5°C, and the mixture was stirred for at least 1 hour. The mixture was centrifuged, and the filter cake was rinsed with H2O (13.4 mL) and collected. The filter cake was dried in vacuo at 45±5°C to obtain a brown solid 3a (9.88 g, 93% yield).

化合物3a表征如下：Compound 3a was characterized as follows:

1H NMR(400MHz，CDCl3)δ12.28(s，1H)，8.46(d，1H)，8.10(d，1H)，7.44-7.39(m，1H)，7.36-7.30(m，1H)，7.24(dd，1H)，7.14-7.12(m，1H)，4.97(s，1H)，3.79(t，1H)，3.67(s，1H)，3.13-3.11(m，4H)，2.40(d，1H)，2.38-2.37(m，1H)，2.36-2.35(m，2H)，2.16-2.13(m，2H)，2.02-1.96(m，3H)，1.94-1.58(m，4H)，1.22-1.14(m，4H)，0.31(s，4H).MS(EI，m/z)：492.5[M+H]+。 1 H NMR (400MHz, CDCl 3 )δ12.28(s, 1H), 8.46(d, 1H), 8.10(d, 1H), 7.44-7.39(m, 1H), 7.36-7.30(m, 1H), 7.2 4(dd, 1H), 7.14-7.12(m, 1H), 4.97(s, 1H), 3.79(t, 1H), 3.67(s, 1H), 3.13-3.11(m, 4 H), 2.40 (d, 1H), 2.38-2.37 (m, 1H), 2.36-2.35 (m, 2H), 2.16-2.13 (m, 2H), 2.02-1.96 (m, 3H), 1.94-1.58 (m, 4H), 1.22-1.14 (m, 4H), 0.31 (s, 4H).MS (EI, m/z): 492.5[M+H] + .

第五步式(I)化合物的合成Step 5: Synthesis of the compound of formula (I)

在氮气保护下，向反应釜中加入化合物3a(9.50g，1.9mmol，1.0eq.)、2-羟基乙烷-1-磺酰胺(化合物4)(3.14g，2.5mmol，1.3eq.)、K3PO4(10.26g，4.8mmol，2.5eq.)、DMF(38mL)，反-N-N-二甲基-1，2-环已二胺(2.75g，1.9mmol，1.0eq.)，氮气置换三次，向体系中加入CuI(1.84g，0.95mmol，0.5eq.)，用DMF(9.5mL)淋洗反应釜，氮气置换3次，升温至85℃反应，搅拌至少2小时。HPLC监控反应结束，降温至25℃，反应液处理后柱层析纯化，得到式(I)化合物(白色固体，7.55g，纯度99.0％，ee值99.5％，收率73％)。Under nitrogen protection, compound 3a (9.50 g, 1.9 mmol, 1.0 eq.), 2-hydroxyethane-1-sulfonamide (compound 4) (3.14 g, 2.5 mmol, 1.3 eq.), K 3 PO 4 (10.26 g, 4.8 mmol, 2.5 eq.), DMF (38 mL), and trans-NN-dimethyl-1,2-cyclohexanediamine (2.75 g, 1.9 mmol, 1.0 eq.) were added to the reactor. The atmosphere was replaced with nitrogen three times. CuI (1.84 g, 0.95 mmol, 0.5 eq.) was added to the system. The reactor was rinsed with DMF (9.5 mL) and replaced with nitrogen three times. The temperature was raised to 85°C for reaction and stirred for at least 2 hours. After the reaction was completed under HPLC monitoring, the temperature was lowered to 25° C. The reaction solution was treated and purified by column chromatography to obtain the compound of formula (I) (white solid, 7.55 g, purity 99.0%, ee value 99.5%, yield 73%).

式(I)化合物表征如下：The compound of formula (I) is characterized as follows:

1H NMR(400MHz，Methanol-d4)δ12.28(s，1H)，10.16(s，1H)，8.20(d，1H)，8.00(d，1H)，7.30-7.25(m，2H)，7.19-7.15(m，1H)，7.08(dd，1H)，5.18(s，1H)，3.77(t，2H)，3.63(d，1H)，3.36(t，2H)，2.98(q，4H)，2.51-2.49(m，1H)，2.25(d，1H)，2.16-2.13(m，1H)，2.02-1.96(m，2H)，1.94-1.58(m，3H)，1.22-1.14(m，2H)，0.28(s，4H)； 1H NMR (400MHz, Methanol-d4) δ12.28 (s, 1H), 10.16 (s, 1H), 8.20 (d, 1H), 8.00 (d, 1 H), 7.30-7.25(m, 2H), 7.19-7.15(m, 1H), 7.08(dd, 1H), 5.18(s, 1H), 3.77(t, 2H) , 3.63(d, 1H), 3.36(t, 2H), 2.98(q, 4H), 2.51-2.49(m, 1H), 2.25(d, 1H), 2.16-2. 13(m, 1H), 2.02-1.96(m, 2H), 1.94-1.58(m, 3H), 1.22-1.14(m, 2H), 0.28(s, 4H);

HPLC：Chiralpak IC柱，254nm，35℃，0.1％二乙胺(正己烷：乙醇：二氯甲烷＝75：15：10)/乙醇＝70/30，流速＝1.0mL/min，保留时间9.4min和12.0min(主要峰)；HPLC: Chiralpak IC column, 254 nm, 35°C, 0.1% diethylamine (n-hexane:ethanol:dichloromethane=75:15:10)/ethanol=70/30, flow rate=1.0 mL/min, retention times 9.4 min and 12.0 min (main peak);

MS(EI，m/z)：536.6[M+H]+。MS (EI, m/z): 536.6[M+H] + .

用一定量的乙腈/水混合溶剂溶解上述式(I)所示化合物，冻干得到白色固体。对其进行XRPD表征，其图谱如图1所示，结果表明得到的白色固体为无定型形态。The compound represented by the above formula (I) was dissolved in a certain amount of acetonitrile/water mixed solvent and lyophilized to obtain a white solid. XRPD characterization of the solid was performed, and the XRPD pattern was shown in FIG1 . The results showed that the obtained white solid was amorphous.

对得到的式(I)所示化合物无定型形态进行TGA、DSC、NMR检测，图谱如图2、图3所示。The amorphous form of the compound represented by formula (I) was subjected to TGA, DSC and NMR detection, and the spectra are shown in Figures 2 and 3.

实施例2 Form A的制备及表征Example 2 Preparation and characterization of Form A

称取式(I)化合物无定型原料2g，室温下滴加60mL二氯甲烷使样品完全溶解，将溶液滴加至10倍体积的甲基叔丁基醚中，搅拌约30min后，将有固体析出的体系离心分离后，并将固体室温真空干燥，得到Form A晶型，XRPD图谱如图4所示，其解析数据如表2所示。2 g of amorphous raw material of the compound of formula (I) was weighed, and 60 mL of dichloromethane was added dropwise at room temperature to completely dissolve the sample. The solution was added dropwise to 10 times the volume of methyl tert-butyl ether and stirred for about 30 min. The system with solid precipitation was centrifuged and the solid was vacuum-dried at room temperature to obtain Form A crystal form. The XRPD spectrum is shown in Figure 4, and the analytical data are shown in Table 2.

表2

Table 2

对得到的式(I)所示化合物Form A晶型进行TGA、DSC、NMR检测，图谱如图5、图6所示。NMR结果显示，无明显溶剂信号峰，样品为无溶剂物。The obtained Form A crystalline form of the compound represented by Formula (I) was subjected to TGA, DSC, and NMR analysis, and the spectra are shown in Figures 5 and 6. The NMR results showed that there was no obvious solvent signal peak, indicating that the sample was solvent-free.

实施例3Example 3

称取式(I)化合物无定型原料2g，室温下滴加30mL丙酮使样品完全溶解，缓慢滴加60mL甲基叔丁基醚，搅拌约30min后，将有固体析出的体系离心分离后，并将固体室温真空干燥，收集固体。对固体进行XRPD表征，经X-射线粉末衍射检测，XRPD谱图与实施例2中Form A基本一致，表明得到的晶体为Form A晶型。Weigh 2 g of the amorphous raw material of the compound of formula (I) and add 30 mL of acetone dropwise at room temperature to completely dissolve the sample. Slowly add 60 mL of methyl tert-butyl ether dropwise and stir for approximately 30 min. The system with the precipitated solid is centrifuged and dried under vacuum at room temperature to collect the solid. XRPD analysis of the solid revealed that the XRPD spectrum was consistent with that of Form A in Example 2, indicating that the resulting crystals were Form A.

实施例4Example 4

称取式(I)化合物无定型原料2g，加入200mL环己烷，50℃悬浮24h后，将有固体析出的体系离心分离后，将固体室温真空干燥，收集固体。对固体进行XRPD表征，经X-射线粉末衍射检测，XRPD谱图与实施例2中Form A基本一致，表明得到的晶体为Form A晶型。2 g of the amorphous starting material of the compound of formula (I) was weighed and added to 200 mL of cyclohexane. The mixture was suspended at 50°C for 24 h. The precipitated solid was centrifuged and then dried under vacuum at room temperature. The solid was collected. XRPD analysis of the solid revealed that the XRPD spectrum was consistent with that of Form A in Example 2, indicating that the resulting crystals were Form A.

实施例5 Form B的制备及表征Example 5 Preparation and characterization of Form B

称取式(I)化合物Form A原料2g，室温下滴加60mL二氯甲烷使样品完全溶解，将溶液滴加至10倍体积的正庚烷中，搅拌约30min后，将有固体析出的体系离心分离后，并将固体室温真空干燥，得到Form B晶型，XRPD图谱如图7所示，其解析数据如表3所示。Weigh 2 g of the raw material Form A of the compound of formula (I), add 60 mL of dichloromethane dropwise at room temperature to completely dissolve the sample, add the solution dropwise into 10 times the volume of n-heptane, stir for about 30 minutes, centrifuge the system with solid precipitation, and vacuum dry the solid at room temperature to obtain Form B crystal form. The XRPD spectrum is shown in Figure 7, and the analytical data are shown in Table 3.

表3

Table 3

对得到的式(I)所示化合物Form B晶型进行TGA、DSC、NMR检测，图谱如图8、图9所示。NMR结果显示，在5.49ppm可见二氯甲烷的信号峰，根据积分结果，化合物与二氯甲烷的摩尔比例为1：0.3，粗估质量占比为4.5％左右。The resulting Form B crystalline form of the compound represented by Formula (I) was subjected to TGA, DSC, and NMR analysis, with the spectra shown in Figures 8 and 9. The NMR results revealed a dichloromethane signal peak at 5.49 ppm. Based on the integration results, the molar ratio of the compound to dichloromethane was 1:0.3, with a rough estimate of approximately 4.5% by mass.

实施例6 Form C的制备及表征Example 6 Preparation and Characterization of Form C

称取式(I)化合物Form A原料20mg，滴加2.5mL乙酸乙酯至完全溶解，将溶液在室温敞口静置挥发，直至出现足量固体析出，得到Form C晶型，XRPD图谱如图10所示，其解析数据如表4所示。Weigh 20 mg of the raw material Form A of the compound of formula (I), add 2.5 mL of ethyl acetate dropwise until completely dissolved, and let the solution stand open at room temperature to evaporate until sufficient solid precipitates to obtain Form C. The XRPD spectrum is shown in Figure 10, and the analytical data are shown in Table 4.

表4

Table 4

对得到的式(I)所示化合物Form C晶型进行TGA、DSC、NMR检测，图谱如图11、图12所示。NMR结果显示，在1.24ppm、2.01ppm、4.09ppm可见乙酸乙酯的信号峰，根据积分结果，化合物与乙酸乙酯的比例为1：0.6，粗估质量占比为9.0％左右。The resulting Form C crystalline form of the compound represented by Formula (I) was subjected to TGA, DSC, and NMR analysis, with the spectra shown in Figures 11 and 12. The NMR results revealed ethyl acetate signal peaks at 1.24 ppm, 2.01 ppm, and 4.09 ppm. Based on the integration results, the ratio of compound to ethyl acetate was 1:0.6, with a rough estimate of approximately 9.0% by mass.

实施例7 Form D的制备及表征Example 7 Preparation and characterization of Form D

称取式(I)化合物Form A原料20.4mg，向样品中加入1.3mL的乙醇使样品完全溶解，室温悬浮20min后有足量白色固体析出，将悬浮液离心分离，并将固体室温真空干燥表征，得到Form D晶型，XRPD图谱如图13所示，其解析数据如表5所示。Weigh 20.4 mg of the raw material Form A of the compound of formula (I), add 1.3 mL of ethanol to the sample to completely dissolve the sample. After suspending at room temperature for 20 minutes, sufficient white solid precipitates. The suspension is centrifuged and the solid is vacuum-dried at room temperature to obtain Form D crystal form. The XRPD spectrum is shown in Figure 13, and the analytical data are shown in Table 5.

表5
Table 5

对得到的式(I)所示化合物Form D晶型进行TGA、DSC、NMR检测，图谱如图14、图15所示。NMR结果显示，在1.18ppm、3.60ppm可见乙醇的信号峰，根据积分结果，化合物与乙醇的比例为1：0.9，粗估质量占比为7.2％左右。The resulting Form D crystalline form of the compound represented by Formula (I) was subjected to TGA, DSC, and NMR analysis, with the spectra shown in Figures 14 and 15 . The NMR results revealed visible ethanol signal peaks at 1.18 ppm and 3.60 ppm. Based on the integration results, the compound-to-ethanol ratio was 1:0.9, with a rough estimate of approximately 7.2% by mass.

实施例8 Form E的制备及表征Example 8 Preparation and Characterization of Form E

称取式(I)化合物Form A原料20.4mg，向样品中加入2mL的甲醇使样品完全溶解，室温悬浮至足量白色固体析出，将悬浮液离心分离，并将固体室温真空干燥表征，得到Form E晶型，XRPD图谱如图16所示，其解析数据如表6所示。Weigh 20.4 mg of the raw material Form A of the compound of formula (I), add 2 mL of methanol to the sample to completely dissolve the sample, and suspend it at room temperature until sufficient white solid precipitates. The suspension is centrifuged and the solid is vacuum-dried at room temperature to obtain Form E crystal form. The XRPD spectrum is shown in Figure 16, and the analytical data are shown in Table 6.

表6
Table 6

对得到的式(I)所示化合物Form E晶型进行TGA、DSC、NMR检测，图谱如图17、图18所示。NMR结果显示，无明显溶剂信号峰。The resulting Form E crystalline form of the compound represented by Formula (I) was subjected to TGA, DSC, and NMR analysis, and the spectra are shown in Figures 17 and 18. The NMR results showed no obvious solvent signal peak.

实施例9 Form F的制备及表征Example 9 Preparation and characterization of Form F

称取式(I)化合物Form A原料20.4mg，向样品中加入2mL的乙腈使样品完全溶解，室温悬浮至足量白色固体析出，将悬浮液离心分离，并将固体室温真空干燥后进行表征，得到Form F晶型，XRPD图谱如图19所示，其解析数据如表7所示。Weigh 20.4 mg of the raw material Form A of the compound of formula (I), add 2 mL of acetonitrile to the sample to completely dissolve the sample, and suspend it at room temperature until sufficient white solid precipitates. The suspension is centrifuged and the solid is vacuum-dried at room temperature and characterized to obtain Form F crystal form. The XRPD spectrum is shown in Figure 19, and the analytical data are shown in Table 7.

表7

Table 7

对得到的式(I)所示化合物Form F晶型进行TGA、DSC、NMR检测，图谱如图20、图21所示。NMR结果显示，在2.07ppm可见乙腈的信号峰，根据积分结果，化合物与乙腈的比例为1：0.5，粗估质量占比为3.7％左右。The resulting Form F crystalline form of the compound represented by Formula (I) was subjected to TGA, DSC, and NMR analysis, with the spectra shown in Figures 20 and 21. The NMR results showed an acetonitrile signal peak at 2.07 ppm. Based on the integration results, the ratio of compound to acetonitrile was 1:0.5, with a rough estimate of approximately 3.7% by mass.

实施例10 Form G的制备及表征Example 10 Preparation and Characterization of Form G

称取式(I)化合物Form A原料20.4mg，向样品中加入足量乙二醇二甲醚使样品完全溶解，室温悬浮挥发至足量白色固体析出，将悬浮液离心分离，并将固体室温真空干燥后进行表征，得到Form G晶型，XRPD图谱如图22所示，其解析数据如表8所示。Weigh 20.4 mg of the raw material Form A of the compound of formula (I), add sufficient ethylene glycol dimethyl ether to the sample to completely dissolve the sample, and suspend and evaporate at room temperature until sufficient white solid precipitates. Centrifuge the suspension, and vacuum dry the solid at room temperature and characterize it to obtain Form G crystal form. The XRPD spectrum is shown in Figure 22, and the analytical data are shown in Table 8.

表8
Table 8

对得到的式(I)所示化合物Form G晶型进行TGA、DSC、NMR检测，图谱如图23、图24所示。NMR结果显示，在3.65ppm、3.47ppm、3.37ppm可见乙二醇二甲醚的信号峰，根据积分结果，化合物与乙二醇二甲醚的比例为1：0.45，粗估质量占比为6.0％左右。The resulting Form G crystalline form of the compound represented by Formula (I) was subjected to TGA, DSC, and NMR analysis, with the spectra shown in Figures 23 and 24. The NMR results showed visible peaks of ethylene glycol dimethyl ether at 3.65 ppm, 3.47 ppm, and 3.37 ppm. Based on the integration results, the ratio of compound to ethylene glycol dimethyl ether was 1:0.45, with a rough estimate of approximately 6.0% by mass.

实施例11 Form H的制备及表征Example 11 Preparation and characterization of Form H

称取式(I)化合物Form A原料134.0mg，加入最少量甲酸乙酯使其完全溶解，然后降温析晶，离心，将固体室温真空干燥过夜，表征得到Form H晶型，XRPD图谱如图25所示，其解析数据如表9所示。Weigh 134.0 mg of the compound of formula (I) Form A raw material, add a minimum amount of ethyl formate to completely dissolve it, then cool and crystallize, centrifuge, and dry the solid in vacuum at room temperature overnight to obtain Form H crystal form. The XRPD spectrum is shown in Figure 25, and the analytical data are shown in Table 9.

表9
Table 9

对得到的式(I)所示化合物Form H晶型进行TGA、DSC、NMR检测，图谱如图26、图27所示。NMR结果显示，在8.06ppm、4.23ppm、4.17ppm、1.28ppm可见甲酸乙酯的信号峰，在1.18ppm、3.60ppm可能是乙醇的信号峰，可能实验过程中甲酸乙酯发生分解。样品可能是溶剂合物或水合物。The resulting Form H crystalline form of the compound represented by Formula (I) was subjected to TGA, DSC, and NMR analysis, with the spectra shown in Figures 26 and 27. The NMR results showed peaks of ethyl formate at 8.06 ppm, 4.23 ppm, 4.17 ppm, and 1.28 ppm. Peaks at 1.18 ppm and 3.60 ppm are likely due to ethanol, suggesting that ethyl formate may have decomposed during the experiment. The sample may be a solvate or hydrate.

实施例12 Form I的制备及表征Example 12 Preparation and Characterization of Form I

制备方法：称取50mg的式I所示化合物的晶型D，加入0.4mL醋酸异丙酯，50℃搅拌2小时后降至室温搅拌2天，悬浮液离心分离后样品在50℃真空干燥，得到式I所示化合物的晶型Form I，XRPD图谱如图28所示，其解析数据如表10所示。化合物Form I晶型的DSC图、TGA图、NMR图谱分别如图29-31所示。Preparation: Weigh 50 mg of Form D of the compound of Formula I, add 0.4 mL of isopropyl acetate, and stir at 50°C for 2 hours, then cool to room temperature and stir for 2 days. The suspension is centrifuged and the sample is dried in vacuo at 50°C to obtain Form I of the compound of Formula I. The XRPD pattern is shown in Figure 28, and the analytical data are shown in Table 10. The DSC pattern, TGA pattern, and NMR spectrum of Form I are shown in Figures 29-31, respectively.

化合物Form I晶型的NMR数据如下：1H NMR(400MHz，DMSO-d6)δ12.32(s，1H)，10.16(s，1H)，8.27(dd，J＝7.9，1.0Hz，1H)，8.00(d，J＝8.5Hz，1H)，7.31-7.17(m，2H)，7.17-7.03(m，2H)，5.15(d，J＝2.2Hz，1H)，4.95(t，J＝5.7Hz，1H)，3.76(q，J＝6.3Hz，2H)，3.58(d，J＝3.7Hz，1H)，3.37-3.36(m，4H)，2.99(d，J＝9.8Hz，3H)，2.23(d，J＝9.5Hz，1H)，2.18-2.08(m，1H)，1.98(dd，J＝13.8，8.4Hz，2H)，1.34-1.06(m，4H)，0.29(s，4H)。The NMR data of the Form I crystalline form of the compound are as follows: 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.32 (s, 1H), 10.16 (s, 1H), 8.27 (dd, J=7.9, 1.0 Hz, 1H), 8.00 (d, J=8.5 Hz, 1H), 7.31-7.17 (m, 2H), 7.17-7.03 (m, 2H), 5.15 (d, J=2.2 Hz, 1H), 4.95 (t, J=5.7 Hz, 1H), 3.76 (q, J=6 .3Hz, 2H), 3.58 (d, J=3.7Hz, 1H), 3.37-3.36 (m, 4H), 2.99 (d, J=9.8Hz, 3H), 2.23 (d, J=9.5 Hz, 1H), 2.18-2.08 (m, 1H), 1.98 (dd, J=13.8, 8.4Hz, 2H), 1.34-1.06 (m, 4H), 0.29 (s, 4H).

表10

Table 10

不同晶型性质总结Summary of properties of different crystal forms

表11
Table 11

实施例13生物学评价Example 13 Biological Evaluation

(1)测试名称：KIF18A酶活检测(1) Test name: KIF18A enzyme activity assay

(2)操作步骤：(2) Operation steps:

1)化合物稀释及处理：AM-5308最终测试浓度为：10000、3333.3、1111.1、370.3、123.4、41.1、13.7、4.5、1.5、0.5nM，测试化合物最终测试浓度为：10000、3333.3、1111.1、370.3、123.4、41.1、13.7、4.5、1.5、0.5nM。1) Compound dilution and treatment: The final test concentrations of AM-5308 are: 10000, 3333.3, 1111.1, 370.3, 123.4, 41.1, 13.7, 4.5, 1.5, 0.5 nM, and the final test concentrations of the test compounds are: 10000, 3333.3, 1111.1, 370.3, 123.4, 41.1, 13.7, 4.5, 1.5, 0.5 nM.

2)用Echo 655向反应板每孔转移100nL稀释好的化合物储液。DMSO的最终浓度为1％。2) Using an Echo 655, transfer 100 nL of the diluted compound stock solution to each well of the reaction plate. The final DMSO concentration is 1%.

3)用封板膜封住反应板，1000g离心1分钟。3) Seal the reaction plate with sealing film and centrifuge at 1000g for 1 minute.

4)用1×反应缓冲液配制2×酶溶液。4) Prepare 2× enzyme solution using 1× reaction buffer.

5)向反应板中每孔加入5μL 2×酶溶液。用封板膜封住板子1000g离心1分钟，室温放置15分钟。5) Add 5 μL of 2× enzyme solution to each well of the reaction plate. Seal the plate with film and centrifuge at 1000 g for 1 minute. Incubate at room temperature for 15 minutes.

6)用1×反应缓冲液配制2×ATP溶液。6) Prepare 2× ATP solution using 1× reaction buffer.

7)向反应板中加入5μL 2×ATP溶液，1000g离心1分钟，开始反应。7) Add 5 μL 2× ATP solution to the reaction plate and centrifuge at 1000 g for 1 minute to start the reaction.

8)室温反应60分钟。8) React at room temperature for 60 minutes.

9)加入10μL ADP Glo试剂。1000g离心1分钟，在室温下孵育60分钟。9) Add 10 μL of ADP-Glo reagent. Centrifuge at 1000 g for 1 minute and incubate at room temperature for 60 minutes.

10)加入20μL激酶检测试剂。1000g离心1分钟，室温下孵育60分钟。10) Add 20 μL of kinase assay reagent, centrifuge at 1000 g for 1 minute, and incubate at room temperature for 60 minutes.

11)1000g离心1分钟。11) Centrifuge at 1000g for 1 minute.

12)在Envision 2104读取发光信号。12) Read the luminescence signal on Envision 2104.

(3)数据分析：(3) Data analysis:

抑制百分率计算如下：The percentage inhibition was calculated as follows:

％inhibition＝100-(Signalcmpd-SignalAve_PC)/(SignalAve_VC-SignalAve_PC)×100%inhibition=100-(Signalcmpd-SignalAve_PC)/(SignalAve_VC-SignalAve_PC)×100

Signalcmpd：反应板上测试化合物的平均值。Signalcmpd: Average value of test compounds on the reaction plate.

SignalAve_PC：反应板上阳性对照(AM-5308)的平均值。SignalAve_PC: The average value of the positive control (AM-5308) on the reaction plate.

SignalAve_VC：反应板上阴性对照(DMSO)的平均值。SignalAve_VC: the average value of the negative control (DMSO) on the reaction plate.

(4)计算IC50以及拟合化合物量效曲线：(4) Calculate IC50 and fit compound dose-effect curve:

用GraphPad 8.0，利用非线性拟合公式来得到化合物的IC50。GraphPad 8.0 was used to obtain the IC50 of the compounds using a nonlinear fitting formula.

质量控制Z factor＞0.5；S/B＞2。Quality control Z factor＞0.5; S/B＞2.

(5)实验结果：式(I)所示化合物KIF18A的IC50为5.35nM。(5) Experimental results: The IC 50 of the compound KIF18A represented by formula (I) is 5.35 nM.

实施例14引湿性评估Example 14 Evaluation of Moisture Absorption

对实施例中得到的式(I)所示化合物Form A进行动态水分吸脱附分析，并对测试前后固体进行XRPD分析，结果如图32-33所示。结果显示Form A在80％RH下，吸湿增重约为0.17％，再回到0％湿度下失重0.01％，表明Form A几乎无引湿性。Form A经DVS测试后晶型不变。Dynamic moisture sorption/desorption analysis was performed on Form A, the compound represented by Formula (I) obtained in the Example, and XRPD analysis of the solid before and after the test was performed. The results are shown in Figures 32-33. The results show that Form A gained approximately 0.17% in weight upon moisture absorption at 80% relative humidity, and lost 0.01% in weight upon returning to 0% humidity, indicating that Form A is virtually non-hygroscopic. Form A maintained its crystalline form after DVS testing.

对实施例中得到的式(I)所示化合物Form E进行引湿性初步评估的动态水分吸脱附分析，并对测试前后固体进行XRPD分析，结果如图34-35所示。结果显示Form E在吸附过程中在80％湿度下增重0.98％；在脱附过程中在80％湿度下增重0.93％，在50％湿度下失重0.15％。Form E经DVS测试后晶型不变。Dynamic moisture sorption/desorption analysis was performed on Form E, the compound of Formula (I) obtained in this Example, to initially assess its hygroscopicity. XRPD analysis of the solid before and after the test was performed, as shown in Figures 34-35. The results show that Form E gained 0.98% weight at 80% humidity during the sorption process; during the desorption process, it gained 0.93% weight at 80% humidity and lost 0.15% weight at 50% humidity. Form E maintained its crystalline form after DVS analysis.

实施例15生物介质和水中的动态溶解度测试Example 15 Dynamic Solubility Test in Biological Media and Water

生物介质的配制过程如表12所示。不同晶型的样品加入生物介质和水中在37℃恒温震荡24h，分别于0.5h，2h和24h取样，将取样的溶液用0.22μm水系滤膜过滤，对部分浓度较高的样品用稀释剂进行适当稀释，用HPLC测量溶液的信号峰面积，最后根据峰面积、原料的HPLC标准曲线和稀释倍数计算溶液中化合物的浓度。此外，取24h上清液测试其pH值。The preparation process of the biological medium is shown in Table 12. Samples of different crystalline forms were added to the biological medium and water and shaken at 37°C for 24 hours. Samples were taken at 0.5, 2, and 24 hours. The sampled solutions were filtered through a 0.22 μm water filter. Some samples with higher concentrations were appropriately diluted with diluent. The signal peak area of the solution was measured by HPLC. Finally, the concentration of the compound in the solution was calculated based on the peak area, the HPLC standard curve of the raw material, and the dilution factor. In addition, the pH value of the supernatant after 24 hours was tested.

表12生物介质的配制过程
Table 12 Preparation process of biological medium

对Form A和无定型在3种生物介质(FaSSIF、FeSSIF和FaSSGF)和水中进行动态溶解度测定。相应结果见表13。结果显示，Form A和无定型在生物介质和水中的24h溶解度从大到小均为：FaSSGF＞FeSSIF＞FaSSIF＞水，两者溶解度基本一致。Dynamic solubility measurements were performed on Form A and the amorphous form in three biological media (FaSSIF, FeSSIF, and FaSSGF) and in water. The corresponding results are shown in Table 13. The results show that the 24-h solubility of Form A and the amorphous form in both biological media and water is generally consistent, with the order of FaSSGF > FeSSIF > FaSSIF > water.

表13生物介质和水中的动态溶解度测试

Table 13 Dynamic solubility test in biological media and water

实施例16稳定性试验Example 16 Stability Test

对Form A进行高温(60℃)、高湿(25℃/92.5％RH)、光照(25℃/4500Lux)、加速(40℃/75％RH)条件下的稳定性研究，分别于7天和15天取样进行XRPD表征和HPLC测试，结果如表14、图36所示。XRPD结果显示，Form A在高温、高湿、光照、加速条件下15天晶型均未发生变化；在高温、高湿、加速条件下15天纯度无明显变化，在光照条件下15天纯度略有下降且样品颜色变黄。Form A was subjected to stability studies under high temperature (60°C), high humidity (25°C/92.5% RH), light (25°C/4500 Lux), and accelerated conditions (40°C/75% RH). Samples were collected for XRPD characterization and HPLC analysis after 7 and 15 days, respectively. The results are shown in Table 14 and Figure 36. XRPD results showed that Form A maintained its crystalline form after 15 days under these conditions. Furthermore, there was no significant change in purity after 15 days under these conditions. However, under light exposure, the purity decreased slightly after 15 days, and the sample turned yellow.

表14
Table 14

以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.

Claims (11)

式(I)所示化合物的无定型或多晶型物；
Amorphous or polymorphic forms of the compound represented by formula (I);
根据权利要求1所述的无定型或多晶型物，其特征在于，所述式(I)所示化合物的无定型具有基本上如图1所示的X射线粉末衍射图谱；The amorphous form or polymorph according to claim 1, wherein the amorphous form of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 1; 优选地，所述式(I)所示化合物的无定型的差示扫描量热分析图谱如图2所示。Preferably, the differential scanning calorimetry analysis spectrum of the amorphous form of the compound represented by formula (I) is shown in FIG2 . 优选地，所述式(I)所示化合物的无定型的热重分析图谱如图2所示。Preferably, the thermogravimetric analysis spectrum of the amorphous compound represented by formula (I) is shown in Figure 2. 根据权利要求1所述的无定型或多晶型物，其特征在于，式(I)所示化合物的多晶型物选自式(I)所示化合物的Form A晶型、Form B晶型、Form C晶型、Form D晶型、Form E晶型、Form F晶型、Form G晶型、Form H晶型、Form I晶型。The amorphous or polymorphic form according to claim 1, characterized in that the polymorph of the compound represented by formula (I) is selected from the Form A crystal form, Form B crystal form, Form C crystal form, Form D crystal form, Form E crystal form, Form F crystal form, Form G crystal form, Form H crystal form, and Form I crystal form of the compound represented by formula (I). 根据权利要求3所述的无定型或多晶型物，其特征在于，所述式(I)所示化合物的Form A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：14.97°±0.20°，17.87°±0.20°，18.82°±0.20°，19.07°±0.20°，19.56°±0.20°；The amorphous or polymorphic form according to claim 3, wherein the Form A crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 14.97°±0.20°, 17.87°±0.20°, 18.82°±0.20°, 19.07°±0.20°, and 19.56°±0.20°; 优选地，所述式(I)所示化合物的Form A晶型的X射线粉末衍射图谱进一步包括以下一个、两个或多个2θ角处的特征衍射峰：8.87°±0.20°，13.46°±0.20°，24.77°±0.20°；Preferably, the X-ray powder diffraction pattern of the Form A crystal form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at 2θ angles: 8.87°±0.20°, 13.46°±0.20°, 24.77°±0.20°; 优选地，所述式(I)所示化合物的Form A晶型的X射线粉末衍射图谱还进一步包括以下一个、两个或多个2θ角处的特征衍射峰：6.81°±0.20°，13.20°±0.20°，16.18°±0.20°，20.32°±0.20°，21.11°±0.20°，21.56°±0.20°，22.38°±0.20°，22.82°±0.20°，23.35°±0.20°，23.78°±0.20°，24.01°±0.20°，25.12°±0.20°，25.68°±0.20°，26.48°±0.20°，26.67°±0.20°，27.02°±0.20°，28.01°±0.20°，28.75°±0.20°，30.72°±0.20°；Preferably, the X-ray powder diffraction pattern of the Form A crystal form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at 2θ angles: 6.81°±0.20°, 13.20°±0.20°, 16.18°±0.20°, 20.32°±0.20°, 21.11°±0.20°, 21.56°±0.20°, 22.38°±0.20°, 22 .82°±0.20°, 23.35°±0.20°, 23.78°±0.20°, 24.01°±0.20°, 25.12°±0.20°, 25.68°±0.20°, 26.48°±0.20°, 26.67°±0.20°, 27.02°±0.20°, 28.01°±0.20°, 28.75°±0.20°, 30.72°±0.20°; 优选地，所述式(I)所示化合物的Form A晶型的X射线粉末衍射图谱解析数据如表2所示，其中每个特征衍射峰2θ的误差范围为±0.2°；Preferably, the X-ray powder diffraction pattern analysis data of the Form A crystal form of the compound represented by formula (I) is shown in Table 2, wherein the error range of 2θ of each characteristic diffraction peak is ±0.2°; 优选地，所述式(I)所示化合物的Form A晶型具有基本上如图4所示的X射线粉末衍射图谱；Preferably, the Form A crystalline form of the compound of formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 4; 优选地，所述式(I)所示化合物的Form A晶型的差示扫描量热分析图谱包含245.9℃±2.0℃的吸热峰；Preferably, the differential scanning calorimetry analysis spectrum of the Form A crystal form of the compound represented by formula (I) comprises an endothermic peak at 245.9°C ± 2.0°C; 优选地，所述式(I)所示化合物的Form A晶型的差示扫描量热分析图谱如图5所示；Preferably, the differential scanning calorimetry analysis spectrum of the Form A crystal form of the compound represented by formula (I) is shown in Figure 5; 优选地，所述式(I)所示化合物的Form A晶型的热重分析图谱如图5所示。Preferably, the thermogravimetric analysis spectrum of the Form A crystal form of the compound represented by formula (I) is shown in Figure 5. 根据权利要求3所述的无定型或多晶型物，其特征在于，所述式(I)所示化合物的Form B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.10°±0.20°，9.92°±0.20°，19.13°±0.20°，19.36°±0.20°，20.18°±0.20°,23.50°±0.20°；The amorphous or polymorphic form according to claim 3, wherein the X-ray powder diffraction pattern of the Form B crystal form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles: 7.10°±0.20°, 9.92°±0.20°, 19.13°±0.20°, 19.36°±0.20°, 20.18°±0.20°, 23.50°±0.20°; 优选地，所述式(I)所示化合物的Form B晶型的X射线粉末衍射图谱进一步包括以下一个、两个或多个2θ角处的特征衍射峰：15.48°±0.20°，17.34°±0.20°，17.87°±0.20°，21.13°±0.20°，23.66°±0.20°，26.69°±0.20°；Preferably, the X-ray powder diffraction pattern of the Form B crystalline form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at 2θ angles: 15.48°±0.20°, 17.34°±0.20°, 17.87°±0.20°, 21.13°±0.20°, 23.66°±0.20°, 26.69°±0.20°; 优选地，所述式(I)所示化合物的Form B晶型的X射线粉末衍射图谱还进一步包括以下一个、两个或多个2θ角处的特征衍射峰：9.61°±0.20°，10.72°±0.20°，14.10°±0.20°，17.58°±0.20°，19.75°±0.20°，22.05°±0.20°，22.40°±0.20°，23.99°±0.20°，24.42°±0.20°，24.73°±0.20°，25.90°±0.20°，27.26°±0.20°，28.56°±0.20°，28.85°±0.20°，30.27°±0.20°，30.72°±0.20°，32.46°±0.20°，33.01°±0.20°，34.43°±0.20°；Preferably, the X-ray powder diffraction pattern of the Form B crystalline form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at 2θ angles: 9.61°±0.20°, 10.72°±0.20°, 14.10°±0.20°, 17.58°±0.20°, 19.75°±0.20°, 22.05°±0.20°, 22.40°±0.20°, 23 .99°±0.20°, 24.42°±0.20°, 24.73°±0.20°, 25.90°±0.20°, 27.26°±0.20°, 28.56°±0.20°, 28.85°±0.20°, 30.27°±0.20°, 30.72°±0.20°, 32.46°±0.20°, 33.01°±0.20°, 34.43°±0.20°; 优选地，所述式(I)所示化合物的Form B晶型的X射线粉末衍射图谱解析数据如表3所示，其中每个特征衍射峰2θ的误差范围为±0.2°；Preferably, the X-ray powder diffraction pattern analysis data of the Form B crystal form of the compound represented by formula (I) is shown in Table 3, wherein the error range of 2θ of each characteristic diffraction peak is ±0.2°; 优选地，所述式(I)所示化合物的Form B晶型具有基本上如图7所示的X射线粉末衍射图谱；Preferably, the Form B crystalline form of the compound of formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 7; 优选地，所述式(I)所示化合物的Form B晶型的差示扫描量热分析图谱包含60.7℃±2.0℃、167.0℃±2.0℃、245.8℃±2.0℃的吸热峰；Preferably, the differential scanning calorimetry analysis spectrum of the Form B crystalline form of the compound represented by formula (I) comprises endothermic peaks at 60.7°C±2.0°C, 167.0°C±2.0°C, and 245.8°C±2.0°C; 优选地，所述式(I)所示化合物的Form B晶型的差示扫描量热分析图谱包含172.1℃±2.0℃的放热峰；Preferably, the differential scanning calorimetry analysis spectrum of the Form B crystalline form of the compound represented by formula (I) comprises an exothermic peak at 172.1°C ± 2.0°C; 优选地，所述式(I)所示化合物的Form B晶型的差示扫描量热分析图谱如图8所示；Preferably, the differential scanning calorimetry analysis spectrum of the Form B crystal form of the compound represented by formula (I) is shown in Figure 8; 优选地，所述式(I)所示化合物的Form B晶型的热重分析图谱如图8所示；Preferably, the thermogravimetric analysis spectrum of the Form B crystal form of the compound represented by formula (I) is shown in Figure 8; 优选地，所述式(I)所示化合物的Form C晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.51°±0.20°，18.32°±0.20°，19.09°±0.20°，19.35°±0.20°，23.10°±0.20°；Preferably, the Form C crystalline form of the compound represented by formula (I) has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 9.51°±0.20°, 18.32°±0.20°, 19.09°±0.20°, 19.35°±0.20°, 23.10°±0.20°; 优选地，所述式(I)所示化合物的Form C晶型的X射线粉末衍射图谱进一步包括以下一个、两个或多个2θ角处的特征衍射峰：16.51°±0.20°，17.58°±0.20°，20.24°±0.20°，23.97°±0.20°，25.51°±0.20°，30.99°±0.20°；Preferably, the X-ray powder diffraction pattern of the Form C crystalline form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at 2θ angles: 16.51°±0.20°, 17.58°±0.20°, 20.24°±0.20°, 23.97°±0.20°, 25.51°±0.20°, 30.99°±0.20°; 优选地，所述式(I)所示化合物的Form C晶型的X射线粉末衍射图谱解析数据如表4所示，其中每个特征衍射峰2θ的误差范围为±0.2°；Preferably, the X-ray powder diffraction pattern analysis data of the Form C crystal form of the compound represented by formula (I) is shown in Table 4, wherein the error range of 2θ of each characteristic diffraction peak is ±0.2°; 优选地，所述式(I)所示化合物的Form C晶型具有基本上如图10所示的X射线粉末衍射图谱；Preferably, the Form C crystalline form of the compound of formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 10; 优选地，所述式(I)所示化合物的Form C晶型的差示扫描量热分析图谱包含91.7℃±2.0℃、245.4℃±2.0℃的吸热峰；Preferably, the differential scanning calorimetry analysis spectrum of the Form C crystalline form of the compound represented by formula (I) comprises endothermic peaks at 91.7°C ± 2.0°C and 245.4°C ± 2.0°C; 优选地，所述式(I)所示化合物的Form C晶型的差示扫描量热分析图谱如图11所示；Preferably, the differential scanning calorimetry analysis spectrum of the Form C crystalline form of the compound represented by formula (I) is shown in Figure 11; 优选地，所述式(I)所示化合物的Form C晶型的热重分析图谱如图11所示；Preferably, the thermogravimetric analysis spectrum of the Form C crystal form of the compound represented by formula (I) is shown in Figure 11; 优选地，所述式(I)所示化合物的Form D晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.47°±0.20°，18.41°±0.20°，19.17°±0.20°，19.93°±0.20°；Preferably, the Form D crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 9.47°±0.20°, 18.41°±0.20°, 19.17°±0.20°, and 19.93°±0.20°; 优选地，所述式(I)所示化合物的Form D晶型的X射线粉末衍射图谱进一步包括以下一个、两个或多个2θ角处的特征衍射峰：6.93°±0.20°，17.60°±0.20°，22.94°±0.20°，23.60°±0.20°；Preferably, the X-ray powder diffraction pattern of the Form D crystalline form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at 2θ angles: 6.93°±0.20°, 17.60°±0.20°, 22.94°±0.20°, 23.60°±0.20°; 优选地，所述式(I)所示化合物的Form D晶型的X射线粉末衍射图谱进一步包括以下一个、两个或多个2θ角处的特征衍射峰：9.14°±0.20°，15.21°±0.20°，16.57°±0.20°，17.21°±0.20°，20.57°±0.20°，21.00°±0.20°，21.81°±0.20°，23.19±0.20°，23.84°±0.20°，26.46°±0.20°，28.09°±0.20°，30.58°±0.20°；Preferably, the X-ray powder diffraction pattern of the Form D crystalline form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at 2θ angles: 9.14°±0.20°, 15.21°±0.20°, 16.57°±0.20°, 17.21°±0.20°, 20.57°±0.20°, 21.00°±0.20°, 21.81°±0.20°, 23.19±0.20°, 23.84°±0.20°, 26.46°±0.20°, 28.09°±0.20°, 30.58°±0.20°; 优选地，所述式(I)所示化合物的Form D晶型的X射线粉末衍射图谱解析数据如表5所示，其中每个特征衍射峰2θ的误差范围为±0.2°；Preferably, the X-ray powder diffraction pattern analysis data of the Form D crystal form of the compound represented by formula (I) is shown in Table 5, wherein the error range of 2θ of each characteristic diffraction peak is ±0.2°; 优选地，所述式(I)所示化合物的Form D晶型具有基本上如图13所示的X射线粉末衍射图谱；Preferably, the Form D crystalline form of the compound of formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 13; 优选地，所述式(I)所示化合物的Form D晶型的差示扫描量热分析图谱包含148.7℃±2.0℃、166.7℃±2.0℃、246.8℃±2.0℃的吸热峰；Preferably, the differential scanning calorimetry analysis spectrum of the Form D crystalline form of the compound represented by formula (I) comprises endothermic peaks at 148.7°C ± 2.0°C, 166.7°C ± 2.0°C, and 246.8°C ± 2.0°C; 优选地，所述式(I)所示化合物的Form D晶型的差示扫描量热分析图谱包含176.4℃±2.0℃的放热峰；Preferably, the differential scanning calorimetry analysis spectrum of the Form D crystalline form of the compound represented by formula (I) comprises an exothermic peak at 176.4°C ± 2.0°C; 优选地，所述式(I)所示化合物的Form D晶型的差示扫描量热分析图谱如图14所示；Preferably, the differential scanning calorimetry analysis spectrum of the Form D crystal form of the compound represented by formula (I) is shown in Figure 14; 优选地，所述式(I)所示化合物的Form D晶型的热重分析图谱如图14所示；Preferably, the thermogravimetric analysis spectrum of the Form D crystal form of the compound represented by formula (I) is shown in Figure 14; 优选地，所述式(I)所示化合物的Form E晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.88°±0.20°，9.78°±0.20°，19.40°±0.20°，20.07°±0.20°；Preferably, the Form E crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 6.88°±0.20°, 9.78°±0.20°, 19.40°±0.20°, and 20.07°±0.20°; 优选地，所述式(I)所示化合物的Form E晶型的X射线粉末衍射图谱进一步包括以下一个、两个或多个2θ角处的特征衍射峰：9.40°±0.20°，15.33°±0.20°，17.26°±0.20°，17.48°±0.20°，17.62°±0.20°，18.98°±0.20°，23.49°±0.20°，23.66°±0.20°；Preferably, the X-ray powder diffraction pattern of the Form E crystalline form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at 2θ angles: 9.40°±0.20°, 15.33°±0.20°, 17.26°±0.20°, 17.48°±0.20°, 17.62°±0.20°, 18.98°±0.20°, 23.49°±0.20°, 23.66°±0.20°; 优选地，所述式(I)所示化合物的Form E晶型的X射线粉末衍射图谱解析数据如表6所示，其中每个特征衍射峰2θ的误差范围为±0.2°；Preferably, the X-ray powder diffraction pattern analysis data of the Form E crystal form of the compound represented by formula (I) is shown in Table 6, wherein the error range of 2θ of each characteristic diffraction peak is ±0.2°; 优选地，所述式(I)所示化合物的Form E晶型具有基本上如图16所示的X射线粉末衍射图谱；Preferably, the Form E crystalline form of the compound of formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 16; 优选地，所述式(I)所示化合物的Form E晶型的差示扫描量热分析图谱包含58.2℃±2.0℃、168.2℃±2.0℃、246.8℃±2.0℃的吸热峰；Preferably, the differential scanning calorimetry analysis spectrum of the Form E crystalline form of the compound represented by formula (I) comprises endothermic peaks at 58.2°C±2.0°C, 168.2°C±2.0°C, and 246.8°C±2.0°C; 优选地，所述式(I)所示化合物的Form E晶型的差示扫描量热分析图谱包含182.9℃±2.0℃的放热峰；Preferably, the differential scanning calorimetry analysis spectrum of the Form E crystalline form of the compound represented by formula (I) comprises an exothermic peak at 182.9°C ± 2.0°C; 优选地，所述式(I)所示化合物的Form E晶型的差示扫描量热分析图谱如图17所示；Preferably, the differential scanning calorimetry analysis spectrum of the Form E crystal form of the compound represented by formula (I) is shown in Figure 17; 优选地，所述式(I)所示化合物的Form E晶型的热重分析图谱如图17所示；Preferably, the thermogravimetric analysis spectrum of the Form E crystal form of the compound represented by formula (I) is shown in Figure 17; 优选地，所述式(I)所示化合物的Form F晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.88°±0.20°，9.71°±0.20°，17.65°±0.20°，18.79°±0.20°，19.44°±0.20°，20.01°±0.20°；Preferably, the X-ray powder diffraction pattern of the Form F crystalline form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles: 6.88°±0.20°, 9.71°±0.20°, 17.65°±0.20°, 18.79°±0.20°, 19.44°±0.20°, 20.01°±0.20°; 优选地，所述式(I)所示化合物的Form F晶型的X射线粉末衍射图谱进一步包括以下一个、两个或多个2θ角处的特征衍射峰：9.31°±0.20°，15.36°±0.20°，17.01°±0.20°，17.31°±0.20°，20.87°±0.20°，23.36°±0.20°，23.66°±0.20°，23.82°±0.20°；Preferably, the X-ray powder diffraction pattern of the Form F crystalline form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at 2θ angles: 9.31°±0.20°, 15.36°±0.20°, 17.01°±0.20°, 17.31°±0.20°, 20.87°±0.20°, 23.36°±0.20°, 23.66°±0.20°, 23.82°±0.20°; 优选地，所述式(I)所示化合物的Form F晶型的X射线粉末衍射图谱解析数据如表7所示，其中每个特征衍射峰2θ的误差范围为±0.2°；Preferably, the X-ray powder diffraction pattern analysis data of the Form F crystal form of the compound represented by formula (I) is shown in Table 7, wherein the error range of 2θ of each characteristic diffraction peak is ±0.2°; 优选地，所述式(I)所示化合物的Form F晶型具有基本上如图19所示的X射线粉末衍射图谱；Preferably, the Form F crystalline form of the compound of formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 19; 优选地，所述式(I)所示化合物的Form F晶型的差示扫描量热分析图谱包含56.4℃±2.0℃、150.7℃±2.0℃、167.8℃±2.0℃、247.1℃±2.0℃的吸热峰；Preferably, the differential scanning calorimetry analysis spectrum of the Form F crystalline form of the compound represented by formula (I) comprises endothermic peaks at 56.4°C ± 2.0°C, 150.7°C ± 2.0°C, 167.8°C ± 2.0°C, and 247.1°C ± 2.0°C; 优选地，所述式(I)所示化合物的Form F晶型的差示扫描量热分析图谱包含171.7℃±2.0℃的放热峰；Preferably, the differential scanning calorimetry analysis spectrum of the Form F crystalline form of the compound represented by formula (I) comprises an exothermic peak at 171.7°C ± 2.0°C; 优选地，所述式(I)所示化合物的Form F晶型的差示扫描量热分析图谱如图20所示；Preferably, the differential scanning calorimetry analysis spectrum of the Form F crystal form of the compound represented by formula (I) is shown in Figure 20; 优选地，所述式(I)所示化合物的Form F晶型的热重分析图谱如图20所示；Preferably, the thermogravimetric analysis spectrum of the Form F crystal form of the compound represented by formula (I) is shown in Figure 20; 优选地，所述式(I)所示化合物的Form G晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.61°±0.20°，17.62°±0.20°，19.54°±0.20°，20.30°±0.20°，24.09°±0.20°；Preferably, the Form G crystalline form of the compound represented by formula (I) has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 9.61°±0.20°, 17.62°±0.20°, 19.54°±0.20°, 20.30°±0.20°, 24.09°±0.20°; 优选地，所述式(I)所示化合物的Form G晶型的X射线粉末衍射图谱进一步包括以下一个、两个或多个2θ角处的特征衍射峰：7.06°±0.20°，16.70°±0.20°，18.49°±0.20°，19.31°±0.20°，23.31°±0.20°，26.89°±0.20°，28.60°±0.20°；Preferably, the X-ray powder diffraction pattern of the Form G crystalline form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at 2θ angles: 7.06°±0.20°, 16.70°±0.20°, 18.49°±0.20°, 19.31°±0.20°, 23.31°±0.20°, 26.89°±0.20°, 28.60°±0.20°; 优选地，所述式(I)所示化合物的Form G晶型的X射线粉末衍射图谱解析数据如表8所示，其中每个特征衍射峰2θ的误差范围为±0.2°；Preferably, the X-ray powder diffraction pattern analysis data of the Form G crystal form of the compound represented by formula (I) is shown in Table 8, wherein the error range of 2θ of each characteristic diffraction peak is ±0.2°; 优选地，所述式(I)所示化合物的Form G晶型具有基本上如图22所示的X射线粉末衍射图谱；Preferably, the Form G crystalline form of the compound of formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 22; 优选地，所述式(I)所示化合物的Form G晶型的差示扫描量热分析图谱包含97.5℃±2.0℃、246.4℃±2.0℃的吸热峰；Preferably, the differential scanning calorimetry analysis spectrum of the Form G crystalline form of the compound represented by formula (I) comprises endothermic peaks at 97.5°C ± 2.0°C and 246.4°C ± 2.0°C; 优选地，所述式(I)所示化合物的Form G晶型的差示扫描量热分析图谱如图23所示；Preferably, the differential scanning calorimetry analysis spectrum of the Form G crystal form of the compound represented by formula (I) is shown in Figure 23; 优选地，所述式(I)所示化合物的Form G晶型的热重分析图谱如图23所示；Preferably, the thermogravimetric analysis spectrum of the Form G crystal form of the compound represented by formula (I) is shown in Figure 23; 优选地，所述式(I)所示化合物的Form H晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.47°±0.20°，18.37°±0.20°，19.15°±0.20°，20.01°±0.20°，22.98°±0.20°，23.70°±0.20°；Preferably, the X-ray powder diffraction pattern of the Form H crystalline form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles: 9.47°±0.20°, 18.37°±0.20°, 19.15°±0.20°, 20.01°±0.20°, 22.98°±0.20°, 23.70°±0.20°; 优选地，所述式(I)所示化合物的Form H晶型的X射线粉末衍射图谱进一步包括以下一个、两个或多个2θ角处的特征衍射峰：6.95°±0.20°，9.14°±0.20°，16.57°±0.20°，17.30°±0.20°，17.54°±0.20°，20.59°±0.20°，21.08°±0.20°，25.60°±0.20°，26.26°±0.20°，28.19°±0.20°，30.56°±0.20°；Preferably, the X-ray powder diffraction pattern of the Form H crystalline form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at 2θ angles: 6.95°±0.20°, 9.14°±0.20°, 16.57°±0.20°, 17.30°±0.20°, 17.54°±0.20°, 20.59°±0.20°, 21.08°±0.20°, 25.60°±0.20°, 26.26°±0.20°, 28.19°±0.20°, 30.56°±0.20°; 优选地，所述式(I)所示化合物的Form H晶型的X射线粉末衍射图谱解析数据如表9所示，其中每个特征衍射峰2θ的误差范围为±0.2°；Preferably, the X-ray powder diffraction pattern analysis data of the Form H crystal form of the compound represented by formula (I) is shown in Table 9, wherein the error range of 2θ of each characteristic diffraction peak is ±0.2°; 优选地，所述式(I)所示化合物的Form H晶型具有基本上如图25所示的X射线粉末衍射图谱；Preferably, the Form H crystalline form of the compound of formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 25; 优选地，所述式(I)所示化合物的Form H晶型的差示扫描量热分析图谱包含123.6℃±2.0℃、165.6℃±2.0℃、246.6℃±2.0℃的吸热峰；Preferably, the differential scanning calorimetry analysis spectrum of the Form H crystalline form of the compound represented by formula (I) comprises endothermic peaks at 123.6°C±2.0°C, 165.6°C±2.0°C, and 246.6°C±2.0°C; 优选地，所述式(I)所示化合物的Form H晶型的差示扫描量热分析图谱包含173.0℃±2.0℃的放热峰；Preferably, the differential scanning calorimetry analysis spectrum of the Form H crystalline form of the compound represented by formula (I) comprises an exothermic peak at 173.0°C ± 2.0°C; 优选地，所述式(I)所示化合物的Form H晶型的差示扫描量热分析图谱如图26所示；Preferably, the differential scanning calorimetry analysis spectrum of the Form H crystal form of the compound represented by formula (I) is shown in Figure 26; 优选地，所述式(I)所示化合物的Form H晶型的热重分析图谱如图26所示；Preferably, the thermogravimetric analysis spectrum of the Form H crystal form of the compound represented by formula (I) is shown in Figure 26; 优选地，所述式(I)所示化合物的Form I晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：13.55°±0.20°，17.22°±0.20°，18.27°±0.20°，18.91°±0.20°，20.8°±0.20°；优选地，所述式(I)所示化合物的Form I晶型的X射线粉末衍射图谱进一步包括以下一个、两个或多个2θ角处的特征衍射峰：5.11°±0.20°，7.91°±0.20°，11.63°±0.20°，14.34°±0.20°，14.98°±0.20°，15.68°±0.20°，19.69°±0.20°，21.9°±0.20°，22.57°±0.20°，23.53°±0.20°，24.17°±0.20°，25.72°±0.20°，28.02°±0.20°，32.21°±0.20°；Preferably, the X-ray powder diffraction pattern of the Form I crystal form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles: 13.55°±0.20°, 17.22°±0.20°, 18.27°±0.20°, 18.91°±0.20°, 20.8°±0.20°; preferably, the X-ray powder diffraction pattern of the Form I crystal form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at the following 2θ angles: 5.1 1°±0.20°, 7.91°±0.20°, 11.63°±0.20°, 14.34°±0.20°, 14.98°±0.20°, 15.68°±0.20°, 19.69°±0.20°, 21.9°±0.20°, 22.57°±0.20°, 23.53°±0.20°, 24.17°±0.20°, 25.72°±0.20°, 28.02°±0.20°, 32.21°±0.20°; 优选地，所述式(I)所示化合物的Form I晶型的X射线粉末衍射图谱解析数据如表10所示，其中每个特征衍射峰2θ的误差范围为±0.2°；优选地，所述式(I)所示化合物的Form I晶型具有基本上如图28所示的X射线粉末衍射图谱；优选地，所述式(I)所示化合物的Form I晶型的差示扫描量热分析图谱包含210.4℃±2.0℃、245.8℃±2.0℃的吸热峰；优选地，所述式(I)所示化合物的Form I晶型的差示扫描量热分析图谱包含210.4℃±2.0℃的放热峰；优选地，所述式(I)所示化合物的Form I晶型的差示扫描量热分析图谱如图29所示；优选地，所述式(I)所示化合物的Form I晶型的热重分析图谱如图30所示。Preferably, the X-ray powder diffraction pattern analysis data of the Form I crystal form of the compound represented by formula (I) are as shown in Table 10, wherein the error range of each characteristic diffraction peak 2θ is ±0.2°; preferably, the Form I crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 28; preferably, the differential scanning calorimetry analysis pattern of the Form I crystal form of the compound represented by formula (I) includes endothermic peaks at 210.4℃±2.0℃ and 245.8℃±2.0℃; preferably, the differential scanning calorimetry analysis pattern of the Form I crystal form of the compound represented by formula (I) includes an exothermic peak at 210.4℃±2.0℃; preferably, the differential scanning calorimetry analysis pattern of the Form I crystal form of the compound represented by formula (I) is as shown in Figure 29; preferably, the thermogravimetric analysis pattern of the Form I crystal form of the compound represented by formula (I) is as shown in Figure 30. 权利要求1-5任一项所述的式(I)所示化合物的无定型或多晶型物的制备方法，其中，The method for preparing the amorphous or polymorphic form of the compound represented by formula (I) according to any one of claims 1 to 5, wherein: 式(I)所示化合物的无定型的制备方法如下：将式(I)化合物用第一溶剂溶解，冻干，即得所述式(I)所示化合物的无定型；The preparation method of the amorphous form of the compound represented by formula (I) is as follows: dissolving the compound represented by formula (I) in a first solvent and freeze-drying to obtain the amorphous form of the compound represented by formula (I); 式(I)所示化合物的多晶型物的制备方法如下：将式(I)化合物用溶剂溶解，析晶，即得所述式(I)所示化合物的多晶型物。The preparation method of the polymorph of the compound represented by formula (I) is as follows: dissolving the compound represented by formula (I) in a solvent and crystallizing to obtain the polymorph of the compound represented by formula (I). 一种药物组合物，所述药物组合物包含治疗有效量的权利要求1-5任一项所述的式(I)所示化合物的无定型或多晶型物中的至少一种；A pharmaceutical composition comprising a therapeutically effective amount of at least one of the amorphous or polymorphic forms of the compound of formula (I) according to any one of claims 1 to 5; 优选地，所述药物组合物还包括一种或多种药学上可接受的辅料；Preferably, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients; 优选地，所述药物组合物还可以进一步含有一种或多种额外的治疗剂。Preferably, the pharmaceutical composition may further contain one or more additional therapeutic agents. 一种治疗肿瘤疾病的方法，所述方法包括给予患者预防或治疗有效量的权利要求1-5任一项所述的式(I)所示化合物的无定型或多晶型物、或者权利要求7所述的药物组合物中的至少一种；A method for treating a tumor disease, comprising administering to a patient a preventively or therapeutically effective amount of at least one of the amorphous or polymorphic form of the compound of formula (I) according to any one of claims 1 to 5, or the pharmaceutical composition according to claim 7; 优选地，所述肿瘤疾病包括肠癌、乳腺癌、肺癌、胰腺癌、前列腺癌、膀胱癌、头颈部癌、宫颈癌和卵巢癌。Preferably, the tumor disease includes colorectal cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head and neck cancer, cervical cancer and ovarian cancer. 一种用于治疗肿瘤疾病的权利要求1-5任一项所述的式(I)所示化合物的无定型或多晶型物、或者权利要求7所述的药物组合物。An amorphous or polymorphic form of the compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutical composition according to claim 7 for treating tumor diseases. 权利要求1-5任一项所述的式(I)所示化合物的无定型或多晶型物、或者权利要求7所述的药物组合物在制备药物中的用途；Use of the amorphous or polymorphic form of the compound of formula (I) according to any one of claims 1 to 5, or the pharmaceutical composition according to claim 7 in the preparation of a medicament; 优选地，所述用途可以为在制备治疗KIF18A介导的病症和/或疾病的药物中的用途，如在制备KIF18A抑制剂药物中的用途；Preferably, the use can be for the preparation of a medicament for treating KIF18A-mediated disorders and/or diseases, such as for the preparation of a KIF18A inhibitor drug; 优选地，所述疾病为癌症，例如包括肠癌、乳腺癌、肺癌、胰腺癌、前列腺癌、膀胱癌、头颈部癌、宫颈癌或卵巢癌。Preferably, the disease is cancer, including, for example, bowel cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head and neck cancer, cervical cancer or ovarian cancer. 一种治疗KIF18A介导的病症和/或疾病的方法，所述方法包括给予患者预防或治疗有效量的权利要求1-5任一项所述的式(I)所示化合物的无定型或多晶型物或权利要求7所述的药物组合物中的至少一种；A method for treating KIF18A-mediated conditions and/or diseases, comprising administering to a patient a preventively or therapeutically effective amount of at least one of the amorphous or polymorphic form of the compound of formula (I) according to any one of claims 1 to 5 or the pharmaceutical composition according to claim 7; 优选地，KIF18A介导的病症和/或疾病为癌症，例如肠癌、乳腺癌、肺癌、胰腺癌、前列腺癌、膀胱癌、头颈部癌、宫颈癌或卵巢癌。Preferably, the KIF18A-mediated disorder and/or disease is cancer, such as bowel cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head and neck cancer, cervical cancer or ovarian cancer.
PCT/CN2025/081054 2024-03-07 2025-03-06 Crystal form of kif18a inhibitor, and preparation method therefor and use thereof Pending WO2025185704A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113226473A (en) * 2018-12-20 2021-08-06 美国安进公司 KIF18A inhibitors
WO2023004075A1 (en) * 2021-07-21 2023-01-26 Amgen Inc. Salts and solid state forms of a kif18a inhibitor compound
CN115772159A (en) * 2021-09-06 2023-03-10 微境生物医药科技(上海)有限公司 KIF18A inhibitor
CN117510463A (en) * 2022-08-05 2024-02-06 长春金赛药业有限责任公司 KIF18A inhibitor compounds, pharmaceutical compositions and preparation methods and applications thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113226473A (en) * 2018-12-20 2021-08-06 美国安进公司 KIF18A inhibitors
WO2023004075A1 (en) * 2021-07-21 2023-01-26 Amgen Inc. Salts and solid state forms of a kif18a inhibitor compound
CN115772159A (en) * 2021-09-06 2023-03-10 微境生物医药科技(上海)有限公司 KIF18A inhibitor
CN117510463A (en) * 2022-08-05 2024-02-06 长春金赛药业有限责任公司 KIF18A inhibitor compounds, pharmaceutical compositions and preparation methods and applications thereof

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