[go: up one dir, main page]

WO2025185706A1 - Sel pharmaceutiquement acceptable et forme cristalline d'un inhibiteur de kif18a, procédé de préparation correspondant et utilisation associée - Google Patents

Sel pharmaceutiquement acceptable et forme cristalline d'un inhibiteur de kif18a, procédé de préparation correspondant et utilisation associée

Info

Publication number
WO2025185706A1
WO2025185706A1 PCT/CN2025/081058 CN2025081058W WO2025185706A1 WO 2025185706 A1 WO2025185706 A1 WO 2025185706A1 CN 2025081058 W CN2025081058 W CN 2025081058W WO 2025185706 A1 WO2025185706 A1 WO 2025185706A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound represented
salt
characteristic peaks
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/081058
Other languages
English (en)
Chinese (zh)
Other versions
WO2025185706A8 (fr
Inventor
葛广存
张小兵
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
Original Assignee
Changchun Genescience Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Changchun Genescience Pharmaceutical Co Ltd filed Critical Changchun Genescience Pharmaceutical Co Ltd
Publication of WO2025185706A1 publication Critical patent/WO2025185706A1/fr
Publication of WO2025185706A8 publication Critical patent/WO2025185706A8/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the present invention belongs to the field of compounds, and specifically relates to a pharmaceutically acceptable salt, crystal form, preparation method and application of a KIF18A inhibitor.
  • 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 exhibits good KIF18A inhibition and OVCAR-3 cell activity in vitro, but also exhibits significantly improved physicochemical properties (solubility and permeability), significantly enhanced OVCAR-3 in vivo efficacy, and a good safety profile.
  • This compound can be used to treat KIF18A-mediated conditions and/or diseases, such as tumors, and to prepare medicaments for treating such conditions or diseases.
  • Salt formation is one of the effective means to improve the physicochemical properties of drug molecules and enhance their drugability. It can change the solubility of the drug, improve its compliance, enhance its stability and bioavailability, and reduce its adverse reactions.
  • the crystal structure of the active ingredient of the drug and its salt not only affects the physical and chemical stability of the drug itself, but also affects the difficulty of subsequent drug preparation and production costs. Different crystallization conditions and storage conditions may lead to changes in the crystal structure of the compound and its salt, and sometimes are accompanied by the production of other morphologies.
  • the present invention provides a pharmaceutically acceptable salt of a compound represented by formula (I), wherein the pharmaceutically acceptable salt is selected from one or more of the sodium salt, potassium salt, hydrochloride, p-toluenesulfonate, maleate, methanesulfonate, ethanesulfonate and hydrobromide of the compound represented by formula (I);
  • the molar ratio of the compound represented by formula (I) to the p-toluenesulfonic acid molecule is 1:1.8 to 1:2.5, for example, about 1:1.9, 1:2, 1:2.1, or 1:2.2.
  • the molar ratio of the compound represented by formula (I) to hydrogen chloride is 1:0.4 to 1:2.5, for example, about 1:0.7, 1:1.5, or 1:1.7.
  • the molar ratio of the compound represented by formula (I) to maleic acid is 1:0.9 to 1:1.3, for example, about 1:1.
  • the molar ratio of the compound represented by formula (I) to sodium ions is 1:1.8 to 1:2.5, for example, about 1:1.9.
  • the molar ratio of the compound represented by formula (I) to methanesulfonic acid is 1:0.9 to 1:2.5, for example, about 1:1.1 or 1:2.
  • the molar ratio of the compound represented by formula (I) to ethanesulfonic acid is 1:0.9 to 1:1.3, for example, about 1:1, 1:1.1, or 1:1.2.
  • the molar ratio of the compound represented by formula (I) to hydrogen bromide is 1:0.9 to 1:2.5, for example, about 1:1.1 or 1:2.1.
  • the present invention also provides crystals of the above-mentioned pharmaceutically acceptable salts, including crystal form A of the sodium salt of the compound represented by formula (I), crystal form A of the potassium salt of the compound represented by formula (I), crystal form A of the hydrochloride of the compound represented by formula (I), crystal form B of the hydrochloride of the compound represented by formula (I), crystal form C of the hydrochloride of the compound represented by formula (I), crystal form D of the hydrochloride of the compound represented by formula (I), crystal form A of the p-toluenesulfonate of the compound represented by formula (I), crystal form A of the methanesulfonate of the compound represented by formula (I), crystal form B of the methanesulfonate of the compound represented by formula (I), crystal form A of the maleate of the compound represented by formula (I), crystal form A of the ethanesulfonate of the compound represented by formula (I), crystal form B of the ethanesulfonate of the compound represented
  • the crystal form A of the sodium salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG3 .
  • the crystal form A of the sodium salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 2.
  • the weight loss of the crystal form A of the sodium salt of the compound represented by formula (I) in the range of room temperature to 230° C. is 12 to 20%, for example, 14 to 18%.
  • the crystal form A of the sodium salt of the compound represented by formula (I) has at least one broad endothermic peak with an onset temperature of 45-53°C and a peak temperature of 85-95°C; for example, the onset temperature is 48.5°C and the peak temperature is 90.3°C.
  • the crystal form A of the sodium salt of the compound represented by formula (I) also has an endothermic peak with an onset temperature of 222-228°C and a peak temperature of 232-238°C; for example, the onset temperature is 225.3°C and the peak temperature is 234.3°C.
  • the crystal form A of the sodium salt of the compound represented by formula (I) has a DSC and TGA overlay diagram substantially as shown in FIG4 .
  • the crystal form A of the sodium salt of the compound represented by formula (I) contains residual solvent, for example, the residual solvent is acetonitrile.
  • the A crystal form of the potassium salt of the compound represented by formula (I) uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks at 4.0 ⁇ 0.20°, 5.4 ⁇ 0.20°, 6.1 ⁇ 0.20°, 6.6 ⁇ 0.20°, 10.0 ⁇ 0.20°, 16.0 ⁇ 0.20°, and 18.8 ⁇ 0.20°; further, it can also have characteristic peaks at 12.1 ⁇ 0.20°, 14.0 ⁇ 0.20°, 16.5 ⁇ 0.20°, 16.9 ⁇ 0.20°, 18.8 ⁇ 0.20°, 19.1 ⁇ 0.20°, 20.
  • the invention discloses a novel nanostructured carbon foam having a nanostructured carbon foam and a nanostructured carbon foam.
  • the nanostructured carbon foam has characteristic peaks at 0.20°, 17.2 ⁇ 0.20°, 17.9 ⁇ 0.20°, 18.3 ⁇ 0.20° and/or 20.0 ⁇ 0.20°; further, the nanostructured carbon foam may have characteristic peaks at 7.0 ⁇ 0.20°, 8.5 ⁇ 0.20°, 9.2 ⁇ 0.20°, 11.0 ⁇ 0.20°, 13.6 ⁇ 0.20°, 14.6 ⁇ 0.20°, 14.9 ⁇ 0.20°, 15.3 ⁇ 0.20°, 19.5 ⁇ 0.20° and/or 21.3 ⁇ 0.20°.
  • the Form A of the potassium salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG6 .
  • the crystal form A of the potassium salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 3.
  • the weight loss of the potassium salt of the compound represented by formula (I) in the form A is 5-15%, for example, 7-10%, in the range of room temperature to 280°C.
  • the crystal form A of the potassium salt of the compound represented by formula (I) has at least one endothermic peak with a peak temperature of 52 to 60°C; for example, the peak temperature is 57.4°C.
  • the crystal form A of the potassium salt of the compound represented by formula (I) also has an endothermic peak with a peak temperature of 193 to 202°C; for example, the peak temperature is 197.7°C.
  • the crystal form A of the potassium salt of the compound represented by formula (I) has an exothermic peak with a peak temperature of 295 to 305°C; for example, the peak temperature is 299.5°C.
  • the crystal form A of the potassium salt of the compound represented by formula (I) has a DSC and TGA overlay diagram substantially as shown in FIG7 .
  • the crystal form A of the hydrochloride of the compound represented by formula (I) uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks at 6.3 ⁇ 0.20°, 12.6 ⁇ 0.20°, 19.0 ⁇ 0.20°, and 19.5 ⁇ 0.20°; further, it may also have characteristic peaks at 14.1 ⁇ 0.20°, 16.3 ⁇ 0.20° and/or 28.4 ⁇ 0.20°.
  • the Form A of the hydrochloride salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG9 .
  • the Form A of the hydrochloride salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 4.
  • the weight loss of form A of the hydrochloride salt of the compound represented by formula (I) in the range of room temperature to 110°C is 4 to 8%, for example, 5 to 7%; and/or, the weight loss in the range of 110 to 210°C is 4 to 8%, for example, 5 to 7%.
  • the crystal form A of the hydrochloride of the compound represented by formula (I) has at least one endothermic peak with a peak temperature of 72 to 85°C, for example, a peak temperature of 77.1°C.
  • the crystal form A of the hydrochloride salt of the compound represented by formula (I) also has an endothermic peak with an onset temperature of 172-180°C and a peak temperature of 193-202°C; for example, the onset temperature is 175.6°C and the peak temperature is 197.1°C.
  • the Form A of the hydrochloride salt of the compound represented by formula (I) has a DSC and TGA overlay diagram substantially as shown in FIG10 .
  • the crystal form A of the hydrochloride salt of the compound represented by formula (I) contains a solvent, for example, the solvent is ethanol.
  • the B crystal form of the hydrochloride of the compound represented by formula (I) uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks at 17.7 ⁇ 0.20°, 18.4 ⁇ 0.20°, 20.4 ⁇ 0.20°, 21.1 ⁇ 0.20° and 23.2 ⁇ 0.20°; further, it can also have characteristic peaks at 15.1 ⁇ 0.20°, 16.1 ⁇ 0.20°, 27.6 ⁇ 0.20°.
  • characteristic peaks may also be present at 10.4 ⁇ 0.20°, 12.8 ⁇ 0.20°, 24.6 ⁇ 0.20°, 25.7 ⁇ 0.20°, 30.2 ⁇ 0.20°, 32.1 ⁇ 0.20°, 33.1 ⁇ 0.20°, 35.6 ⁇ 0.20°, 37.1 ⁇ 0.20°, 38.3 ⁇ 0.20° and/or 43.6 ⁇ 0.20°.
  • the Form B of the hydrochloride salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG12 .
  • the Form B of the hydrochloride salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 5.
  • the weight loss of form B of the hydrochloride salt of the compound represented by formula (I) in the range of room temperature to 60°C is 1 to 5%, for example, 2 to 4%; and/or, the weight loss in the range of greater than 60°C and less than 125°C is 1.5 to 4%, for example, 2 to 3.5%; and/or, the weight loss in the range of 125 to 210°C is 5 to 8%, for example, 6 to 7%.
  • the B crystal form of the hydrochloride of the compound represented by formula (I) has at least one endothermic peak with an onset temperature of 80-90°C and a peak temperature of 105-115°C; for example, the onset temperature is 85.9°C and the peak temperature is 109.3°C;
  • the B crystal form of the hydrochloride salt of the compound represented by formula (I) also has an endothermic peak with an onset temperature of 165-180°C and a peak temperature of 183-193°C; for example, the onset temperature is 172.3°C and the peak temperature is 188.1°C.
  • the Form B of the hydrochloride salt of the compound represented by formula (I) has a DSC and TGA overlay diagram substantially as shown in FIG13 .
  • the C crystalline form of the hydrochloride of the compound represented by formula (I) uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks at 16.6 ⁇ 0.20°, 18.8 ⁇ 0.20°, 20.7 ⁇ 0.20°, 22.2 ⁇ 0.20°, 23.0 ⁇ 0.20° and 24.8 ⁇ 0.20°; further, it can also have characteristic peaks at 3.1 ⁇ 0.20°, 8.3 ⁇ 0.20°, 12.2 ⁇ 0.20°, 14.4 ⁇ 0.20°, 16.9 ⁇ 0.20°, 18.8 ⁇ 0.20°, 20.7 ⁇ 0.20°, 22.2 ⁇ 0.20°, 23.0 ⁇ 0.20° and 24.8 ⁇ 0.20°.
  • characteristic peaks may also be present at 2.3 ⁇ 0.20°, 5.2 ⁇ 0.20°, 7.3 ⁇ 0.20°, 10.4 ⁇ 0.20°, 21.5 ⁇ 0.20°, 25.5 ⁇ 0.20°, 27.8 ⁇ 0.20° and/or 31.6 ⁇ 0.20°.
  • the Form C of the hydrochloride salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG. 39 .
  • the Form C of the hydrochloride of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 10.
  • the hydrochloride salt of the compound represented by formula (I) in form C loses 8 to 11% of its weight at room temperature to 210° C., for example, loses 9 to 10.5% of its weight.
  • the C crystal form of the hydrochloride salt of the compound represented by formula (I) also has an endothermic peak with an onset temperature of 174-180°C and a peak temperature of 188-192°C; for example, the onset temperature is 177.23°C and the peak temperature is 190.51°C.
  • the Form C of the hydrochloride of the compound represented by formula (I) has a DSC spectrum substantially as shown in FIG40 .
  • the Form C of the hydrochloride of the compound represented by formula (I) has a TGA spectrum substantially as shown in FIG41 .
  • the D crystal form of the hydrochloride of the compound represented by formula (I) uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks at 8.2 ⁇ 0.20°, 16.3 ⁇ 0.20°, 19.3 ⁇ 0.20°, 20.1 ⁇ 0.20°, 20.9 ⁇ 0.20° and 27.0 ⁇ 0.20°; further, it can also have characteristic peaks at 13.3 ⁇ 0.20°, 15.1 ⁇ 0.20°, 18.2 ⁇ 0.
  • the invention discloses a novel nanostructured carbon foam having a nanostructured carbon foam and a nanostructured carbon foam.
  • the nanostructured carbon foam has characteristic peaks at 20°, 22.5 ⁇ 0.20°, 23.2 ⁇ 0.20°, 24.8 ⁇ 0.20° and/or 28.2 ⁇ 0.20°; further, the nanostructured carbon foam may have characteristic peaks at 5.7 ⁇ 0.20°, 8.8 ⁇ 0.20°, 9.6 ⁇ 0.20°, 10 ⁇ 0.20°, 10.5 ⁇ 0.20°, 11.2 ⁇ 0.20°, 12.4 ⁇ 0.20°, 24 ⁇ 0.20° and/or 26.1 ⁇ 0.20°.
  • the D crystal form of the hydrochloride salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in Figure 42.
  • the D crystal form of the hydrochloride salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 11.
  • the D-type hydrochloride of the compound represented by formula (I) loses 4-7% of its weight at room temperature to 200° C., for example, loses 5-6% of its weight.
  • the D crystal form of the hydrochloride salt of the compound represented by formula (I) has one, two or three of the following endothermic peaks:
  • the onset temperature is 33-38°C and the peak temperature is 60-65°C; for example, the onset temperature is 35.10°C and the peak temperature is 63.18°C;
  • Second endothermic peak the onset temperature is 112-116°C and the peak temperature is 120-125°C; for example, the onset temperature is 114.32°C and the peak temperature is 122.52°C;
  • the third endothermic peak the onset temperature is 155-160°C, and the peak temperature is 162-167°C; for example, the onset temperature is 157.36°C and the peak temperature is 164.36°C.
  • the D crystal form of the hydrochloride salt of the compound represented by formula (I) has a DSC spectrum substantially as shown in Figure 43.
  • the D crystal form of the hydrochloride salt of the compound represented by formula (I) has a TGA spectrum substantially as shown in Figure 44.
  • the crystalline form A of the p-toluenesulfonate salt of the compound represented by formula (I) uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks at 7.7 ⁇ 0.20°, 8.3 ⁇ 0.20°, 15.8 ⁇ 0.20°, (17.3 ⁇ 17.6) ⁇ 0.20° (for example, 17.3 ⁇ 0.20° or 17.6 ⁇ 0.20°), 20.0 ⁇ 0.20°, 20.6 ⁇ 0.20° and 21.8 ⁇ 0.20°.
  • the crystalline form A of the p-toluenesulfonate salt of the compound represented by formula (I) uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks at 7.7 ⁇ 0.20°, 8.3 ⁇ 0.20°, 15.8 ⁇ 0.20°, 17.3 ⁇ 0.20°, 20.0 ⁇ 0.20°, 20.6 ⁇ 0.20° and 21.8 ⁇ 0.20°; further, it may also have characteristic peaks at 15.5 ⁇ 0.20°, 17.6 ⁇ 0.20° and/or 18.7 ⁇ 0.20°; further, it may also have characteristic peaks at 6.2 ⁇ 0.20°, 7.1 ⁇ 0.20°, 12.0 ⁇ 0.20°, 12.4 ⁇ 0.20°, 14.1 ⁇ 0.20°, 14.7 ⁇ 0.20°, 15.3 ⁇ 0.20°, 16.7 ⁇ 0.20°, 18.3 ⁇ 0.20°, 18.9 ⁇ 0.20°, 19.2 ⁇ 0.20°, 19.7 ⁇ 0.20°, 21.2 ⁇ 0.20°, 21.5 ⁇ 0.2
  • the crystalline form A of the p-toluenesulfonate salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG15 .
  • the crystalline form A of the p-toluenesulfonate salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 6.
  • the weight loss of the p-toluenesulfonate salt of the compound represented by formula (I) in the crystal form A at room temperature to 140° C. is 0.5 to 5%, for example, 1 to 3%.
  • the crystalline form A of the p-toluenesulfonate salt of the compound represented by formula (I) also has an endothermic peak with an onset temperature of 205-210°C and a peak temperature of 210.5-215°C; for example, the onset temperature is 208.6°C and the peak temperature is 212.4°C.
  • the crystalline form A of the p-toluenesulfonate salt of the compound represented by formula (I) has a DSC and TGA overlay diagram substantially as shown in FIG16 .
  • the crystal form A of the methanesulfonate of the compound represented by formula (I) uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks at 14.3 ⁇ 0.20°, 18.5 ⁇ 0.20°, 18.6 ⁇ 0.20°, 20.4 ⁇ 0.20°, 21.5 ⁇ 0.20° and 21.6 ⁇ 0.20°; further, it can also have characteristic peaks at 18.7 ⁇ 0.20°, 18.9 ⁇ 0.20°, 20.0 ⁇ 0.20°, 21.
  • the invention discloses a novel nanostructured carbon foam having characteristic peaks at 0 ⁇ 0.20°, 22.0 ⁇ 0.20° and/or 23.0 ⁇ 0.20°; further, the nanostructured carbon foam may have characteristic peaks at 7.1 ⁇ 0.20°, 10.8 ⁇ 0.20°, 11.4 ⁇ 0.20°, 14.0 ⁇ 0.20°, 14.8 ⁇ 0.20°, 16.2 ⁇ 0.20°, 17.9 ⁇ 0.20°, 22.3 ⁇ 0.20°, 22.8 ⁇ 0.20°, 24.0 ⁇ 0.20° and/or 27.8 ⁇ 0.20°.
  • the crystal form A of the methanesulfonate salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG18 .
  • the crystal form A of the methanesulfonate salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 7.
  • the weight loss of the crystal form A of the methanesulfonate of the compound represented by formula (I) at room temperature to 145° C. does not exceed 0.3%, for example, does not exceed 0.1%.
  • the crystal form A of the methanesulfonate of the compound represented by formula (I) has an endothermic peak with an onset temperature of 210-213°C and a peak temperature of 213.5-216°C; for example, the onset temperature is 212.7°C and the peak temperature is 214.3°C.
  • the crystal form A of the methanesulfonate salt of the compound represented by formula (I) has a DSC and TGA overlay diagram substantially as shown in FIG19 .
  • the B crystalline form of the methanesulfonate of the compound represented by formula (I) uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks at 16.9 ⁇ 0.20°, 20.3 ⁇ 0.20°, 21 ⁇ 0.20° and 28.5 ⁇ 0.20°; further, it can also have characteristic peaks at 8.5 ⁇ 0.20°, 15.4 ⁇ 0.20°, 17.4 ⁇ It has characteristic peaks at 0.20° and/or 18.6 ⁇ 0.20°; further, it may also have characteristic peaks at 10.4 ⁇ 0.20°, 11.4 ⁇ 0.20°, 12.7 ⁇ 0.20°, 14.5 ⁇ 0.20°, 23.1 ⁇ 0.20°, 24.3 ⁇ 0.20°, 25.6 ⁇ 0.20°, 30.1 ⁇ 0.20° and/or 31.1 ⁇ 0.20°.
  • the Form B of the methanesulfonate salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG. 45 .
  • the Form B of the methanesulfonate salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 12.
  • the crystal form B of the methanesulfonate of the compound represented by formula (I) loses no more than 1.3% of its weight at room temperature to 160° C., for example, loses 0.8 to 1.0% of its weight.
  • the crystal form B of the methanesulfonate of the compound represented by formula (I) has one or two of the following endothermic peaks:
  • Endothermic peak 1 the onset temperature is 173-180°C, and the peak temperature is 181-185°C; for example, the onset temperature is 176.10°C and the peak temperature is 183.61°C;
  • Endothermic peak 2 the onset temperature is 207-210°C, and the peak temperature is 211-214°C; for example, the onset temperature is 208.90°C, and the peak temperature is 212.53°C.
  • the Form B of the methanesulfonate of the compound represented by formula (I) has a DSC spectrum substantially as shown in FIG46 .
  • the Form B of the methanesulfonate salt of the compound represented by formula (I) has a TGA spectrum substantially as shown in FIG47 .
  • the crystalline form A of the maleate salt of the compound represented by formula (I) uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks at 7.7 ⁇ 0.20°, 18.6 ⁇ 0.20°, 19.4 ⁇ 0.20°, 19.9 ⁇ 0.20° and 20.2 ⁇ 0.20°; further, it also has characteristic peaks at 11.4 ⁇ 0.20°, 13.8 ⁇ 0.20°, 14.9 ⁇ 0.20°, 15.4 ⁇ 0.20°, 15.6 ⁇ 0.20°, 21.1 ⁇ 0.20°, 25.4 ⁇ 0.20° and/or 27.9 ⁇ 0.20°.
  • the crystalline form A of the maleate salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG21 .
  • the crystalline form A of the maleate salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 8.
  • the crystalline form A of the maleate salt of the compound represented by formula (I) loses no more than 0.5% of its weight at room temperature to 110° C., for example, the weight loss is about 0;
  • the maleate salt of the compound represented by formula (I) in Form A loses 13-20% of its weight at a temperature greater than 110° C. and not exceeding 250° C., for example, loses 15-18% of its weight.
  • the maleate crystal form A of the compound represented by formula (I) has a DSC and TGA overlay diagram substantially as shown in FIG22 .
  • the crystalline form A of the ethanesulfonate of the compound represented by formula (I) uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks at 15.1 ⁇ 0.20°, 16.8 ⁇ 0.20°, 19.8 ⁇ 0.20° and 20.5 ⁇ 0.20°; further, it may also have characteristic peaks at 8.3 ⁇ 0.20°, 22.6 ⁇ 0.20°, 23.6 ⁇ 0.20°, 27.2 ⁇ 0.20° and/or 28.2 ⁇ 0.20°; further, it may also have characteristic peaks at 10.3 ⁇ 0.20°, 12.4 ⁇ 0.20°, 18.1 ⁇ 0.20°, 25.0 ⁇ 0.20°, 29.7 ⁇ 0.20° and/or 30.5 ⁇ 0.20°.
  • the crystalline form A of the ethanesulfonate salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG. 48 .
  • the crystalline form A of the ethanesulfonate salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 13.
  • the crystalline form A of the ethanesulfonate salt of the compound represented by formula (I) loses no more than 1.0% of its weight at room temperature to 150° C., for example, loses 0.5 to 0.7% of its weight.
  • the crystalline form A of the ethanesulfonate salt of the compound represented by formula (I) has one or two of the following endothermic peaks:
  • Endothermic peak 1 the onset temperature is 165-169°C, and the peak temperature is 170-175°C; for example, the onset temperature is 168.23°C and the peak temperature is 171.09°C;
  • Endothermic peak 2 the onset temperature is 207-210°C, and the peak temperature is 214-219°C; for example, the onset temperature is 209.37°C, and the peak temperature is 216.61°C.
  • the crystal form A of the ethanesulfonic acid salt of the compound represented by formula (I) has a DSC spectrum substantially as shown in Figure 49.
  • the crystal form A of the ethanesulfonic acid salt of the compound represented by formula (I) has a TGA spectrum substantially as shown in Figure 50.
  • the B crystalline form of the ethanesulfonate salt of the compound represented by formula (I) uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks at 8.5 ⁇ 0.20°, 15.2 ⁇ 0.20° and 17.5 ⁇ 0.20°; further, it may also have characteristic peaks at 20.8 ⁇ 0.20°, 22.8 ⁇ 0.20° and/or 23.6 ⁇ 0.20°; further, it may also have characteristic peaks at 9.9 ⁇ 0.20°, 10.8 ⁇ 0.20°, 14.7 ⁇ 0.20°, 19.0 ⁇ 0.20°, 19.5 ⁇ 0.20°, 21.4 ⁇ 0.20°, 22.1 ⁇ 0.20°, 24.9 ⁇ 0.20° and/or 26.8 ⁇ 0.20°.
  • the Form B of the ethanesulfonic acid salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG51 .
  • the Form B of the ethanesulfonic acid salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 14.
  • the crystalline form B of the ethanesulfonate salt of the compound represented by formula (I) loses 1.3-2.3% of its weight at room temperature to 160° C., for example, loses 1.5-1.9% of its weight.
  • the crystalline form B of the ethanesulfonate salt of the compound represented by formula (I) has one or two of the following endothermic peaks:
  • Endothermic peak 1 The onset temperature is 15-20°C and the peak temperature is 50-55°C; for example, the onset temperature is 17.23°C and the peak temperature is 52.50°C;
  • Endothermic peak 2 the onset temperature is 215-220°C, and the peak temperature is 221-225°C; for example, the onset temperature is 218.89°C, and the peak temperature is 222.29°C.
  • the Form B of the ethanesulfonic acid salt of the compound represented by formula (I) has a DSC spectrum substantially as shown in FIG52 .
  • the Form B of the ethanesulfonic acid salt of the compound represented by formula (I) has a TGA spectrum substantially as shown in FIG53 .
  • the A crystal form of the hydrobromide salt of the compound represented by formula (I) uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks at 15.6 ⁇ 0.20°, 20.9 ⁇ 0.20°, 25.5 ⁇ 0.20° and 28.2 ⁇ 0.20°; further, it can also have characteristic peaks at 8.0 ⁇ 0.20°, 11.4 ⁇ 0.20°, 17.0 ⁇ 0.20°, 18.0 ⁇ 0.20°, 20.0 ⁇ 0.20°, 25.0 ⁇ 0.20°, 26.0 ⁇ 0.20°, 27.0 ⁇ 0.20°, 28.0 ⁇ 0.20°, 29.0 ⁇ 0.20°, 30.0 ⁇ 0.20°, 31.0 ⁇ 0.20°, 32.0 ⁇ 0.20°, 33.0 ⁇ 0.20°, 34.0 ⁇ 0.20°, 35.0 ⁇ 0.20°, 36.0 ⁇ 0.20°, 37.0 ⁇ 0.20°, 38.0 ⁇ 0.20°, 39.0 ⁇ 0.20°, 40.0 ⁇ 0.20°, 41.0 ⁇ 0.20°, 42.0
  • the Form A of the hydrobromide salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG54 .
  • the crystal form A of the hydrobromide salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 15.
  • the crystal form A of the hydrobromide salt of the compound represented by formula (I) loses 4.0-5.0% of its weight at room temperature to 170° C., for example, loses 4.3-4.8% of its weight.
  • the crystalline form A of the hydrobromide salt of the compound represented by formula (I) has one or two of the following endothermic peaks:
  • Endothermic peak 1 the onset temperature is 35-40°C, and the peak temperature is 58-63°C; for example, the onset temperature is 38.99°C and the peak temperature is 60.49°C;
  • Endothermic peak 2 the onset temperature is 178-184°C, and the peak temperature is 190-195°C; for example, the onset temperature is 181.71°C, and the peak temperature is 192.83°C.
  • the Form A of the hydrobromide salt of the compound represented by formula (I) has a DSC spectrum substantially as shown in FIG55 .
  • the crystal form A of the hydrobromide salt of the compound represented by formula (I) has a TGA spectrum substantially as shown in Figure 56.
  • the B crystalline form of the hydrobromide salt of the compound represented by formula (I) uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks at 4.5 ⁇ 0.20°, 6.4 ⁇ 0.20°, 11.9 ⁇ 0.20°, 17.4 ⁇ 0.20°, 18.3 ⁇ 0.20°, 22.0 ⁇ 0.20° and 23.8 ⁇ 0.20°; further, it may also have characteristic peaks at 5.2 ⁇ 0.20°, 17.7 ⁇ 0.20°, 19.3 ⁇ 0.20°, 20.8 ⁇ 0.20° and/or 28.
  • the Form B of the hydrobromide salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG57 .
  • the B crystal form of the hydrobromide salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 16.
  • the B crystal form of the hydrobromide salt of the compound represented by formula (I) loses 2-5% of its weight at room temperature to 160° C., for example, loses 3-4% of its weight.
  • the B crystal form of the hydrobromide salt of the compound represented by formula (I) has one or two of the following endothermic peaks:
  • Endothermic peak 1 The onset temperature is 75-85°C and the peak temperature is 95-105°C; for example, the onset temperature is 79.68°C and the peak temperature is 99.13°C;
  • Endothermic peak 2 the onset temperature is 165-175°C, and the peak temperature is 180-190°C; for example, the onset temperature is 170.54°C, and the peak temperature is 184.28°C.
  • the B crystal form of the hydrobromide salt of the compound represented by formula (I) has a DSC spectrum substantially as shown in Figure 58.
  • the B crystal form of the hydrobromide salt of the compound represented by formula (I) has a TGA spectrum substantially as shown in Figure 59.
  • the present invention also provides a method for preparing a pharmaceutically acceptable salt of the compound represented by the above formula (I) or a crystal of the pharmaceutically acceptable salt, comprising: reacting the compound represented by the formula (I) with sodium hydroxide, potassium hydroxide, hydrochloric acid, p-toluenesulfonic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid or hydrobromic acid in a solvent to obtain the pharmaceutically acceptable salt of the compound represented by the formula (I) or a crystal of the pharmaceutically acceptable salt.
  • the compound represented by formula (I) may be in an amorphous or crystalline form, for example, in crystal form A or crystal form D of the compound represented by formula (I).
  • the crystal form A of the compound represented by formula (I) substantially has an XRPD pattern as shown in FIG2 .
  • the crystal form A of the compound represented by formula (I) is prepared by the following method: the amorphous form of the compound represented by formula (I) is dissolved in dichloromethane, methyl tert-butyl ether is added to the solution, stirred until a solid precipitates, separated, and dried to obtain the crystal form A of the compound represented by formula (I).
  • the D crystal form of the compound represented by formula (I) substantially has an XRPD pattern as shown in FIG. 38 .
  • the crystal form D of the compound represented by formula (I) is prepared by the following method: the crystal form A of the compound represented by formula (I) is dissolved in ethanol, suspended and crystallized at room temperature to obtain the crystal form D of the compound represented by formula (I).
  • the solvent contains at least an organic solvent, such as one or more of acetonitrile, ethanol, ethyl acetate, isopropyl alcohol, isopropyl acetate, acetone and methyl tert-butyl ether. Further, the solvent may also contain water.
  • organic solvent such as one or more of acetonitrile, ethanol, ethyl acetate, isopropyl alcohol, isopropyl acetate, acetone and methyl tert-butyl ether.
  • the solvent may also contain water.
  • the present invention also provides a method for preparing the crystal form A of the p-toluenesulfonate of the compound represented by formula (I), comprising: mixing the compound represented by formula (I), a first solvent, and p-toluenesulfonic acid, suspending at room temperature, centrifuging, and drying to obtain the crystal form A of the p-toluenesulfonate;
  • the compound represented by formula (I) may be in an amorphous or crystalline form, for example, in crystal form A of the compound represented by formula (I);
  • the first solvent is selected from ethanol, n-propanol, dimethylformamide, ethylene glycol dimethyl ether and dimethyl sulfoxide, or dichloromethane and chloroform, for example, ethyl acetate;
  • the mass volume ratio of the compound represented by formula (I) (e.g., crystal form A of the compound represented by formula (I)) to the first solvent is (100-200) mg:10 mL;
  • the suspension time at room temperature is 1 to 3 days;
  • the drying is vacuum drying at room temperature.
  • the present invention also provides a method for preparing the crystal form A of the methanesulfonate of the compound represented by formula (I), comprising: mixing the compound represented by formula (I), a second solvent, and methanesulfonic acid, suspending the mixture at room temperature, then adding a third solvent thereto, continuing to suspend the mixture at room temperature, centrifuging, and drying to obtain the crystal form A of the methanesulfonate of the compound represented by formula (I);
  • the second solvent is selected from ethanol, n-propanol, dimethylformamide, ethylene glycol dimethyl ether and dimethyl sulfoxide, or dichloromethane and chloroform, for example, ethanol;
  • the third solvent is selected from one or more of methyl tert-butyl ether, n-heptane, isopropyl ether, methyl cyclopentyl ether, tetrahydrofuran, 1,4-dioxane, acetone, and n-hexane, for example, methyl tert-butyl ether.
  • the volume ratio of the second solvent to the third solvent is 1:(1-5), for example, 1:(1.2-3);
  • the compound represented by formula (I) may be in an amorphous or crystalline form, for example, in crystal form A of the compound represented by formula (I);
  • the methanesulfonic acid is added in the form of a solution
  • the solvent for preparing the methanesulfonic acid solution is ethanol
  • the concentration of the methanesulfonic acid solution is 0.9 to 1.3 mol/L;
  • the compound represented by formula (I), the second solvent and methanesulfonic acid are mixed and suspended at room temperature for 1 to 4 hours;
  • the suspension time at room temperature after adding the third solvent is 1 to 3 days;
  • the drying is vacuum drying at room temperature.
  • the present invention also provides a method for preparing the crystal form B of the ethanesulfonate of the compound represented by formula (I), comprising: mixing the compound represented by formula (I), ethanesulfonic acid, and a fourth solvent, first heating and stirring, then cooling and stirring, centrifuging the suspension, and drying to obtain the crystal form B of the ethanesulfonate of the compound represented by formula (I);
  • the fourth solvent is selected from isopropyl acetate
  • the compound represented by formula (I) may be in the form of an amorphous or crystalline form, for example, the D crystal form of the compound represented by formula (I);
  • the ethanesulfonic acid is added in the form of a solution
  • the solvent for preparing the ethanesulfonic acid solution is ethyl acetate; preferably, the concentration of the ethanesulfonic acid solution is 0.9 to 1.3 mol/L;
  • the mass volume ratio of the compound represented by formula (I) (e.g., crystal form D of the compound represented by formula (I)) to the fourth solvent is 1 g: (8-15) mL;
  • the heating and stirring temperature is 40 to 60° C., and the time is 15 to 24 hours;
  • the temperature of the cooling and stirring is room temperature, and the time is 2 to 6 hours;
  • the drying is vacuum drying at 40-60°C.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable salt or a crystal of the pharmaceutically acceptable salt 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 the use of the pharmaceutically acceptable salt, crystal of the pharmaceutically acceptable salt or pharmaceutical composition in the preparation of a drug for treating KIF18A-mediated conditions and/or diseases, such as the use in the preparation of a KIF18A inhibitor drug.
  • 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 the pharmaceutically acceptable salt, crystal of the pharmaceutically acceptable salt, or pharmaceutical composition.
  • the disease is, for example, cancer, 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
  • room temperature refers to 15 to 40°C, preferably 20 to 30°C, for example 25°C.
  • (17.3-17.6) ⁇ 0.20° refers to X-ray powder diffraction peaks expressed in 2 ⁇ angles at any one or more positions within the range of (17.3-17.6) ⁇ 0.20° (e.g., 17.3 ⁇ 0.20°, 17.4 ⁇ 0.20°, 17.5 ⁇ 0.20°, or 17.6 ⁇ 0.20°).
  • (17.3-17.6) ⁇ 0.20° e.g. 17.3 ⁇ 0.20°, 17.4 ⁇ 0.20°, 17.5 ⁇ 0.20°, or 17.6 ⁇ 0.20°.
  • the present invention provides pharmaceutically acceptable salts of the compound represented by formula (I) and crystals of the salts, which have good hygroscopicity, solubility and/or stability and are suitable for pharmaceutical preparation.
  • Figure 1 XRPD pattern of the amorphous form of the compound represented by formula (I);
  • FIG. 4 Overlay of DSC and TGA images of Form A of the sodium salt of the compound represented by formula (I);
  • FIG. 10 Overlay of DSC and TGA images of Form A of the hydrochloride salt of the compound represented by formula (I);
  • Figure 12 XRPD pattern of Form B of the hydrochloride salt of the compound represented by formula (I);
  • Figure 15 XRPD pattern of Form A of p-toluenesulfonate salt of the compound represented by formula (I);
  • Figure 16 Overlay of DSC and TGA images of Form A of the p-toluenesulfonate salt of the compound represented by formula (I);
  • Figure 17 NMR spectrum of Form A of p-toluenesulfonate salt of the compound represented by formula (I);
  • Figure 20 NMR spectrum of Form A of the methanesulfonate salt of the compound represented by formula (I);
  • Figure 22 Overlay of DSC and TGA images of Form A of the maleate salt of the compound represented by formula (I);
  • Figure 25 XRPD patterns of Form A of the sodium salt of the compound represented by formula (I) before and after DVS testing;
  • FIG. 26 DVS spectrum of Form A of the hydrochloride salt of the compound represented by formula (I);
  • Figure 27 XRPD patterns of Form A of the hydrochloride salt of the compound represented by formula (I) before and after DVS testing;
  • Figure 28 DVS spectrum of Form B of the hydrochloride salt of the compound represented by formula (I);
  • Figure 29 XRPD patterns of Form B hydrochloride of the compound represented by formula (I) before and after DVS testing;
  • Figure 30 DVS spectrum of Form A of p-toluenesulfonate salt of the compound represented by formula (I);
  • Figure 31 XRPD patterns of Form A of the p-toluenesulfonate salt of the compound represented by formula (I) before and after DVS testing;
  • Figure 32 DVS spectrum of Form A of the mesylate salt of the compound represented by formula (I);
  • Figure 33 XRPD patterns of Form A of the mesylate salt of the compound represented by formula (I) before and after DVS testing;
  • Figure 35 XRPD patterns of Form A of the maleate salt of the compound represented by formula (I) before and after DVS testing;
  • Figure 36 XRPD pattern of stability study of Form A of p-toluenesulfonate salt of the compound represented by formula (I);
  • Figure 37 XRPD pattern of stability study of Form A of the methanesulfonate salt of the compound represented by formula (I);
  • Figure 38 XRPD pattern of the crystalline form D of the compound represented by formula (I);
  • Figure 40 DSC chart of Form C of the hydrochloride salt of the compound represented by formula (I);
  • FIG 41 TGA chart of Form C of the hydrochloride salt of the compound represented by formula (I);
  • Figure 42 XRPD pattern of Form D of the hydrochloride salt of the compound represented by formula (I);
  • Figure 43 DSC chart of Form D of the hydrochloride salt of the compound represented by formula (I);
  • Figure 45 XRPD pattern of Form B of the methanesulfonate salt of the compound represented by formula (I);
  • Figure 46 DSC chart of Form B of the methanesulfonate salt of the compound represented by formula (I);
  • Figure 47 TGA chart of Form B of the methanesulfonate salt of the compound represented by formula (I);
  • Figure 48 XRPD pattern of Form A of the ethanesulfonate salt of the compound represented by formula (I);
  • Figure 49 DSC chart of Form A of the ethanesulfonic acid salt of the compound represented by formula (I);
  • Figure 50 TGA chart of Form A of the ethanesulfonic acid salt of the compound represented by formula (I);
  • Figure 51 XRPD pattern of Form B of the ethanesulfonate salt of the compound represented by formula (I);
  • Figure 52 DSC graph of Form B of the ethanesulfonic acid salt of the compound represented by formula (I);
  • Figure 53 TGA chart of Form B of ethanesulfonic acid salt of the compound represented by formula (I);
  • Figure 54 XRPD pattern of Form A of the hydrobromide salt of the compound represented by formula (I);
  • Figure 55 DSC chart of Form A of the hydrobromide salt of the compound represented by formula (I);
  • Figure 56 TGA chart of Form A of the hydrobromide salt of the compound represented by formula (I);
  • Figure 58 DSC chart of Form B of the hydrobromide salt of the compound represented by formula (I);
  • Figure 60 DVS spectrum of Form B of ethanesulfonic acid salt 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 K ⁇ 1 radiation, a voltage of 40 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.
  • the test method for Figures 24-35 uses a gradient mode with a humidity ramp of 50%-95%-50%, with each ramp increasing by 15%.
  • the gradient endpoint is determined using the dm/dt method, with a dm/dt of less than 0.002% maintained for 10 minutes, or a maximum ramp duration of 60 minutes.
  • the sample is analyzed by XRPD to confirm any change in solid form.
  • Test method of Figure 60 The test adopts gradient mode, the humidity changes from 50% to 95% to 0% to 95%, the humidity change of each gradient is 10% in the range of 0% to 90%, and the gradient end point is judged by dm/dt method, and the gradient end point is when dm/dt is less than 0.002% and maintained for 10 minutes.
  • HPLC model was SHIMADZU LC-20A (Shimadzu, JP), and the test conditions are shown in Table 1.
  • the reaction was extracted with 2 ⁇ 20 mL of ethyl acetate. 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 and petroleum ether to give the crude product compound 2c (5.60 g), which was used directly in the next reaction without purification.
  • 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 , indicating that the white solid was amorphous.
  • Form A of the compound represented by Formula (I) obtained in Example 2 was added to 6.0 mL of acetonitrile and 0.2 mL of a 1 M sodium hydroxide aqueous solution, and the mixture was suspended at room temperature for 2 days. The mixture was centrifuged and the solid was dried under vacuum at room temperature overnight to obtain Form A of the sodium salt.
  • the XRPD pattern is shown in Figure 3, and the analytical data are shown in Table 2 below.
  • the resulting Form A hydrochloride of the compound represented by Formula (I) was subjected to TGA, DSC, and 1 H NMR analysis, with the spectra shown in Figures 10 and 11 .
  • the 1 H NMR results showed that the integration results were essentially consistent with those of the free form; ethanol solvent peaks were visible at 3.60 ppm and 1.18 ppm. Based on the integration results, the ratio of compound to ethanol was calculated to be 1:0.2, suggesting a small amount of residual solvent in the sample.
  • the resulting Form A methanesulfonate of the compound represented by Formula (I) was subjected to TGA, DSC, and 1H NMR analysis, with the spectra shown in Figures 19 and 20.
  • the 1H NMR results showed that the integration results were essentially consistent with those of the free form; ethanol signal peaks were visible at 1.18 ppm and 3.60 ppm, suggesting a small amount of residual solvent in the sample.
  • a methanesulfonic acid peak was visible at 2.65 ppm, suggesting a possible salt ratio of 1:2.
  • Form A of the compound represented by formula (I) was weighed, 1.3 mL of ethanol was added to completely dissolve the sample, and after suspending at room temperature for 20 minutes, a sufficient amount of white solid precipitated. The suspension was centrifuged, and the solid was vacuum dried at room temperature for characterization to obtain Form D of the compound represented by formula (I).
  • the XRPD spectrum is shown in Figure 38, and the analytical data are shown in Table 9 below.
  • the salt formation ratio of the compound represented by formula (I) and hydrochloric acid was calculated to be 1:0.7.
  • the salt ratio of the compound represented by formula (I) and methanesulfonic acid was calculated to be 1:1.1.
  • the salt ratio of the compound represented by formula (I) and ethanesulfonic acid was calculated to be 1:1.0.
  • the salt ratio of the compound represented by formula (I) and ethanesulfonic acid was calculated to be 1:1.0.
  • SignalAve_PC Average value of positive control (AM-5308) on the reaction plate.
  • SignalAve_VC Average value of negative control (DMSO) on the reaction plate.
  • GraphPad 8.0 was used to obtain the IC50 of the compounds using a nonlinear fitting formula.
  • Form A of the hydrochloride salt gained approximately 1.12% weight at 80% humidity.
  • Form A lost approximately 3.31% weight at 80% humidity and approximately 3.55% weight at 50% humidity.
  • DVS testing revealed that Form A of the hydrochloride salt transformed into Form B of the hydrochloride salt.
  • Form A of the p-toluenesulfonate salt gained approximately 0.87% weight at 80% humidity.
  • Form A gained approximately 0.85% weight at 80% humidity and lost approximately 0.06% weight at 50% humidity. DVS testing revealed no change in the crystal form of Form A.
  • Form A of the maleate salt gained approximately 0.86% weight at 80% humidity.
  • Form A gained approximately 2.17% weight at 80% humidity and approximately 1.39% weight at 50% humidity.
  • DVS testing of Form A of the maleate salt revealed changes in its crystalline form.
  • Form A of the p-toluenesulfonate salt did not undergo a phase transition under high temperature and accelerated conditions for 15 days, and its purity may have slightly increased due to the degradation of some impurities.
  • Form A of the methanesulfonate salt did not undergo a phase transition under high temperature, accelerated conditions for 15 days, and its chemical purity did not change significantly.
  • Form A of the ethanesulfonate salt did not undergo a phase transition under high temperature, accelerated conditions for 15 days, and its chemical purity did not change significantly.
  • Form B of the ethanesulfonate salt did not undergo a phase transition under high temperature, high humidity, and accelerated conditions for 14 days, and its chemical purity did not change significantly.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un sel pharmaceutiquement acceptable et une forme cristalline d'un inhibiteur de KIF18A, un procédé de préparation correspondant et une utilisation associée. Le sel pharmaceutiquement acceptable est choisi parmi un ou plusieurs éléments parmi un sel de sodium, un sel de potassium, un chlorhydrate, un p-toluènesulfonate, un maléate, un méthanesulfonate, un éthanesulfonate et un bromhydrate d'un composé représenté par la formule (I). La présente invention concerne le sel pharmaceutiquement acceptable du composé représenté par la formule (I) et un cristal du sel, qui présentent une excellente hygroscopicité, une excellente solubilité et/ou une excellente stabilité, et sont appropriés pour une utilisation pharmaceutique.
PCT/CN2025/081058 2024-03-07 2025-03-06 Sel pharmaceutiquement acceptable et forme cristalline d'un inhibiteur de kif18a, procédé de préparation correspondant et utilisation associée Pending WO2025185706A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202410265587.2 2024-03-07
CN202410265587 2024-03-07
CN202510227785 2025-02-27
CN202510227785.4 2025-02-27

Publications (2)

Publication Number Publication Date
WO2025185706A1 true WO2025185706A1 (fr) 2025-09-12
WO2025185706A8 WO2025185706A8 (fr) 2025-10-02

Family

ID=96929794

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2025/081058 Pending WO2025185706A1 (fr) 2024-03-07 2025-03-06 Sel pharmaceutiquement acceptable et forme cristalline d'un inhibiteur de kif18a, procédé de préparation correspondant et utilisation associée

Country Status (2)

Country Link
CN (1) CN120607535A (fr)
WO (1) WO2025185706A1 (fr)

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113226473A (zh) * 2018-12-20 2021-08-06 美国安进公司 Kif18a抑制剂
WO2022268230A1 (fr) * 2021-06-25 2022-12-29 杭州英创医药科技有限公司 Composé destiné à être utilisé en tant qu'inhibiteur de kif18a
CN115772159A (zh) * 2021-09-06 2023-03-10 微境生物医药科技(上海)有限公司 Kif18a抑制剂
CN115947717A (zh) * 2023-03-09 2023-04-11 英矽智能科技(上海)有限公司 一类kif18a抑制剂
CN116554151A (zh) * 2022-05-13 2023-08-08 上海湃隆生物科技有限公司 驱动蛋白kif18a抑制剂及其应用
CN116903589A (zh) * 2022-04-15 2023-10-20 武汉人福创新药物研发中心有限公司 Kif18a抑制剂及用途
CN117510463A (zh) * 2022-08-05 2024-02-06 长春金赛药业有限责任公司 Kif18a抑制剂化合物、药物组合物及其制备方法和应用
WO2024051755A1 (fr) * 2022-09-08 2024-03-14 长春金赛药业有限责任公司 Composé inhibiteur de kif18a, composition pharmaceutique et son procédé de préparation et son utilisation

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113226473A (zh) * 2018-12-20 2021-08-06 美国安进公司 Kif18a抑制剂
WO2022268230A1 (fr) * 2021-06-25 2022-12-29 杭州英创医药科技有限公司 Composé destiné à être utilisé en tant qu'inhibiteur de kif18a
CN115772159A (zh) * 2021-09-06 2023-03-10 微境生物医药科技(上海)有限公司 Kif18a抑制剂
CN116903589A (zh) * 2022-04-15 2023-10-20 武汉人福创新药物研发中心有限公司 Kif18a抑制剂及用途
CN116554151A (zh) * 2022-05-13 2023-08-08 上海湃隆生物科技有限公司 驱动蛋白kif18a抑制剂及其应用
CN117510463A (zh) * 2022-08-05 2024-02-06 长春金赛药业有限责任公司 Kif18a抑制剂化合物、药物组合物及其制备方法和应用
WO2024051755A1 (fr) * 2022-09-08 2024-03-14 长春金赛药业有限责任公司 Composé inhibiteur de kif18a, composition pharmaceutique et son procédé de préparation et son utilisation
CN115947717A (zh) * 2023-03-09 2023-04-11 英矽智能科技(上海)有限公司 一类kif18a抑制剂

Also Published As

Publication number Publication date
WO2025185706A8 (fr) 2025-10-02
CN120607535A (zh) 2025-09-09

Similar Documents

Publication Publication Date Title
US20240317687A1 (en) Salt of omecamtiv mecarbil and process for preparing salt
CA2900322C (fr) Formes solides de compose d'acetyle -8-cyclopentyl-5-methyl -2-(5-p-piperazin-1-yl-pyridin-2-ylamino)-8h-pyrido[2,3-d]pyrimidin-7-one inhibiteur selectif de cdk4/6
ES2550771T3 (es) Sal de bismesilato etexilato de dabigatrán, formas en estado sólido y proceso para la preparación de las mismas
JP2019526605A (ja) 置換２−ｈ−ピラゾール誘導体の結晶形、塩型及びその製造方法
TW202430184A (zh) Kras g12d抑制劑的結晶形式及製備方法
US10689361B2 (en) Quinoline derivative and use thereof
JP2025538371A (ja) 含窒素複素環系化合物の薬用可能な塩、結晶型及び調製方法
TW202120509A (zh) 活化素受體樣激酶抑制劑之鹽及晶體形式
CN109438362B (zh) 一种取代的苯并咪唑化合物及包含该化合物的组合物
WO2023093861A1 (fr) Mono-p-toluènesulfonate d'inhibiteur de kinase axl et forme cristalline de celui-ci
WO2025185706A1 (fr) Sel pharmaceutiquement acceptable et forme cristalline d'un inhibiteur de kif18a, procédé de préparation correspondant et utilisation associée
EP4512808A1 (fr) Cristal de dérivé de 7h-pyrrolo[2,3-d]pyrimidine-4-amine
JP7702752B2 (ja) チアゾール－ラクタム－スピロ複素環化合物及びその適用
WO2024234619A1 (fr) Forme cristalline d'un composé, composition pharmaceutique et utilisation de celles-ci
EP4361140A1 (fr) Sel pharmaceutiquement acceptable et forme cristalline de dérivé cyclique de pyridine fusionné et son procédé de préparation
TW202313604A (zh) 吡唑並雜芳基類衍生物的可藥用鹽及其結晶形式
EP4183788A1 (fr) Cristal de composé pyrimidine
WO2025185704A1 (fr) Forme cristalline d'un inhibiteur de kif18a, son procédé de préparation et son utilisation
EP4501927A1 (fr) Cristal de dérivé tricyclique fusionné ou de sel pharmaceutiquement acceptable de celui-ci
CN112830919B (zh) 苯并哌啶衍生物可药用盐及其制备方法
WO2025223483A1 (fr) Composé azoté à cycle condensé, forme cristalline de celui-ci, procédé de préparation et utilisation de celui-ci
WO2025237404A1 (fr) Polymorphe d'antagoniste de mc4r, son procédé de préparation et son utilisation
JP2025533592A (ja) テトラリン系誘導体の薬学的に許容される塩、結晶型及び調製方法
WO2025237405A1 (fr) Composé, son procédé de préparation et son utilisation
RU2772274C2 (ru) Селективные ингибиторы hdac6, способ их получения и их применение

Legal Events

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

Ref document number: 25767446

Country of ref document: EP

Kind code of ref document: A1