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WO2024199167A1 - Sel de dérivé cyclique triaromatique, forme cristalline de celui-ci, procédé de préparation correspondant et utilisation associée - Google Patents

Sel de dérivé cyclique triaromatique, forme cristalline de celui-ci, procédé de préparation correspondant et utilisation associée Download PDF

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Publication number
WO2024199167A1
WO2024199167A1 PCT/CN2024/083481 CN2024083481W WO2024199167A1 WO 2024199167 A1 WO2024199167 A1 WO 2024199167A1 CN 2024083481 W CN2024083481 W CN 2024083481W WO 2024199167 A1 WO2024199167 A1 WO 2024199167A1
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Prior art keywords
formula
compound
salt
tartrate
hemifumarate
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PCT/CN2024/083481
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English (en)
Chinese (zh)
Inventor
周文波
陈煌
鲁健
童孝田
彭世鸿
刘明耀
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Shanghai Yuyaobiotech Ltd
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Shanghai Yuyaobiotech Ltd
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Priority to CN202480018966.XA priority Critical patent/CN120981455A/zh
Publication of WO2024199167A1 publication Critical patent/WO2024199167A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present application relates to the field of pharmaceutical chemistry. Specifically, the present application relates to a triaromatic ring derivative, specifically a salt of (6-((5-(3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrazin-2-yl)oxy)-1-methyl-1H-indol-2-yl)(4-(4-(2,2,2-trifluoroethoxy)benzyl)piperazin-1-yl)methanone, its crystal form and pharmaceutical composition, preparation method and use.
  • a triaromatic ring derivative specifically a salt of (6-((5-(3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrazin-2-yl)oxy)-1-methyl-1H-indol-2-yl)(4-(4-(2,2,2-trifluoroethoxy)benzyl)piperazin-1-yl)me
  • Cide patent application CN112300145A discloses a triaromatic ring compound, whose chemical name is (6-((5-(3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrazin-2-yl)oxy)-1-methyl-1H-indol-2-yl)(4-(4-(2,2,2-trifluoroethoxy)benzyl)piperazin-1-yl)methanone, and its structural formula is shown in formula (I):
  • the compound of formula (I) is an inhibitor targeting the bifunctional phosphorylation site of STAT3 and is used for preventing and/or treating diseases caused or regulated by the activation of the bifunctional phosphorylation site of STAT3, and has good clinical prospects.
  • salts For different active pharmaceutical molecules, especially oral solid drugs, different solid forms (salts, crystal forms) often affect the stability, solubility, purity, dissolution, and bioavailability of the drug, and only based on the molecular structure, it is usually impossible to accurately and reasonably predict whether it can be salified, whether it can be crystallized after salification, and how the properties after crystallization are.
  • some salts are solid at ambient temperature, while other salts are liquid or oily at ambient temperature.
  • some salt forms can remain stable under extreme conditions (such as heating), while other salts are easy to decompose under normal conditions (such as room temperature). Therefore, the development of salt forms for different active pharmaceutical molecules is an unpredictable process.
  • the salt of a compound may exist in one or more crystal forms, but its existence and characteristics cannot be specifically expected.
  • the present application provides salts of the compound of formula (I) and crystal forms of the salts.
  • the salts and crystal forms of the salts provided in the present application have at least one of the following advantages: good stability, high solubility, high bioavailability, good efficacy, good tablet dissolution, good tablet compressibility, good fluidity, good crystal morphology, good crystal size distribution, stable storage, simple and reliable preparation method, and great development value.
  • One aspect of the present application is to provide a salt of a compound of formula (I),
  • the salt is an acid salt, wherein the molar ratio of the compound of formula (I) to the acid is 0.5-2.
  • the salt of the compound of formula (I) is selected from fumarate, L-tartrate, hydrochloride, methanesulfonate and oxalate.
  • the salt of the compound of formula (I) is selected from fumarate.
  • the molar ratio of the compound of formula (I) to fumaric acid is 1:0.5-1; more preferably 1:0.5.
  • the salt of the compound of formula (I) is a hemifumarate, and the structural formula is shown in formula (II):
  • the hemifumarate salt of the compound of formula (I) is substantially in crystalline form or amorphous form; more preferably, it is substantially in crystalline form.
  • the hemifumarate salt of the compound of formula (I) may be in one or more crystalline forms; specifically, it may be at least one of an anhydrate, a hydrate or a solvate.
  • Another aspect of the present application is to provide a method for preparing the hemifumarate of the compound of formula (I), which comprises dissolving the compound of formula (I) in solvent 1, and then adding fumaric acid or a fumaric acid solution to react to obtain the hemifumarate.
  • the preparation method of the hemifumarate of the compound of formula (I) comprises the following steps:
  • Step A dissolving an appropriate amount of the compound of formula (I) in solvent 1;
  • Step B dissolving an appropriate amount of fumaric acid in an organic solvent
  • Step C combining the above two solutions, stirring to precipitate a solid or adding solvent 2 and stirring to precipitate a solid;
  • Step D Separate the solid to obtain the hemifumarate of the compound of formula (I).
  • the solvent 1 is selected from any one or a combination of alcohols, ethers, nitriles, esters and ketones; preferably, the alcohol is selected from any one or a combination of methanol, ethanol, n-propanol, sec-butanol, n-butanol and trifluoroethanol; the ether is selected from any one or a combination of diethyl ether and methyl tert-butyl ether; the nitriles are selected from acetonitrile; the esters are selected from any one or a combination of ethyl acetate, isopropyl acetate and n-butyl acetate; the ketones are selected from any one or a combination of acetone and butanone.
  • the alcohol is selected from any one or a combination of methanol, ethanol, n-propanol, sec-butanol, n-butanol and trifluoroethanol
  • the ether is selected from any one or
  • the solvent 1 is selected from any one of methanol, ethyl acetate, acetonitrile or a combination thereof.
  • the organic solvent is selected from alcohols.
  • the organic solvent is selected from methanol.
  • the solvent 2 is selected from any one of water, isopropyl ether, isopropyl alcohol, n-heptane and methylcyclohexane or a combination thereof.
  • the solvent 2 is selected from any one of water and isopropyl ether or a combination thereof.
  • the molar ratio of the compound of formula (I) to fumaric acid is 1:0.5-1.5; preferably, the molar ratio is 1:1.
  • the mass volume ratio (mg/ml) of the compound of formula (I) to solvent 1 is ⁇ 100:1; preferably ⁇ 80:1; more preferably ⁇ 50:1.
  • the mass volume ratio (mg/ml) of compound (I) to solvent 1 is 25:1.
  • the hemifumarate of the compound of formula (I) is in a crystalline form, and using Cu-K ⁇ radiation, the X-ray powder diffraction (XRPD) pattern of the hemifumarate crystalline form expressed in 2 ⁇ angles has a characteristic peak at at least one of 15.7° ⁇ 0.2°, 16.1° ⁇ 0.2° and 9.4° ⁇ 0.2°. Preferably, there are two or three characteristic peaks.
  • the XRPD spectrum of the hemi-fumarate crystalline form expressed in 2 ⁇ angle has characteristic peaks at 15.7° ⁇ 0.2°, 16.1° ⁇ 0.2° and 9.4° ⁇ 0.2°.
  • the XRPD spectrum of the hemi-fumarate crystalline form also has characteristic peaks at at least one of 14.0° ⁇ 0.2°, 17.1° ⁇ 0.2°, 17.9° ⁇ 0.2° and 19.2° ⁇ 0.2° 2 ⁇ .
  • the XRPD spectrum of the hemi-fumarate crystalline form also has characteristic peaks at at least one of 18.7° ⁇ 0.2°, 21.8° ⁇ 0.2°, 23.4° ⁇ 0.2 and 27.1° ⁇ 0.2°2 ⁇ .
  • the hemifumarate crystalline form is the hemifumarate Form 1 of the compound of formula (I) (referred to as hemifumarate Form 1).
  • the XRPD spectrum of the hemi-fumarate salt Form 1 also has characteristic peaks at at least one of 7.0° ⁇ 0.2°, 10.2° ⁇ 0.2°, 24.5° ⁇ 0.2° and 20.1° ⁇ 0.2°2 ⁇ .
  • the XRPD spectrum of Form 1 is 7.0° ⁇ 0.2°, 8.2° ⁇ 0.2°, 9.4° ⁇ 0.2°, 9.6° ⁇ 0.2°, 10.2° ⁇ 0.2°, 12.0° ⁇ 0.2°, 14.0° ⁇ 0.2°, 15.7° ⁇ 0.2°, 16.1° ⁇ 0.2°, 17.1° ⁇ 0.2°, 17.9° ⁇ 0.2°, 18.7° ⁇ 0.2°, 19.2° ⁇ 0.2°, 20.1° ⁇ 0.2°, 20.9° ⁇ 0.2°, 21.
  • the hemifumarate salt Form 1 has an XRPD pattern substantially the same as that of Figure 1.
  • the hemifumarate Form 1 has a TGA spectrum substantially the same as that of Figure 2.
  • the DSC spectrum of the hemi-fumarate Form 1 shows that its melting point is 156°C ⁇ 3°C.
  • the hemifumarate salt Form 1 has a DSC spectrum substantially the same as that of Figure 3.
  • the hemifumarate Form 1 has a DVS spectrum substantially the same as that of Figure 4.
  • the hemifumarate salt Form 1 is anhydrous.
  • the hemifumarate Form 1 has an XRD single crystal simulation pattern substantially as shown in Figure 20.
  • the crystalline form is hemifumarate Form 2 of the compound of formula (I) (referred to as hemifumarate Form 2).
  • the XRPD spectrum of the hemifumarate Form 2 also has characteristic peaks at at least one of 16.5° ⁇ 0.2°, 17.3° ⁇ 0.2°, 19.5° ⁇ 0.2°, 24.8° ⁇ 0.2° and 27.6° ⁇ 0.2°2 ⁇ .
  • the XRPD spectrum of the hemifumarate Form 2 is 4.2° ⁇ 0.2°, 5.0° ⁇ 0.2°, 9.3° ⁇ 0.2°, 9.9° ⁇ 0.2°, 11.2° ⁇ 0.2°, 12.6° ⁇ 0.2°, 14.0° ⁇ 0.2°, 15.1° ⁇ 0.2°, 15.6° ⁇ 0.2°, 16.2° ⁇ 0. 2°, 16.5° ⁇ 0.2°, 17.0° ⁇ 0.2°, 17.3° ⁇ 0.2°, 18.1° ⁇ 0.2°, 18.4° ⁇ 0.2°, 18.7° ⁇ 0.2°, 19.2° ⁇ 0.2°, 19.5° ⁇ 0.2°, 19.8° ⁇ 0.2°, 20.0° ⁇ 0.2°, 20.4° ⁇ 0.
  • the hemifumarate salt Form 2 has an XRPD pattern substantially the same as that of Figure 6.
  • the hemifumarate Form 2 has a TGA spectrum substantially the same as that of Figure 7.
  • the hemi-fumarate salt Form 2 has a DSC spectrum substantially the same as that of Figure 8.
  • the hemifumarate Form 2 has a DVS spectrum substantially the same as that of Figure 9.
  • the hemifumarate Form 2 is anhydrous.
  • Another aspect of the present application is to provide a method for preparing a hemifumarate of a compound of formula (I) in a crystalline form, the preparation method comprising any one of the following methods:
  • Step A dissolving an appropriate amount of the compound of formula (I) in solvent 3;
  • Step B dissolving an appropriate amount of fumaric acid in an organic solvent
  • Step C combining the above two solutions, stirring to precipitate or adding solvent 4 and stirring to precipitate to form a suspension;
  • Step D Continue stirring the suspension, and stir it under low temperature to crystallize, separate and dry to obtain the hemifumarate of the compound of formula (I) in crystalline form.
  • the solvent 3 is selected from one or a combination of alcohols, ethers, nitriles, esters and ketones; preferably, the alcohol is selected from any one or a combination of methanol, ethanol, n-propanol, sec-butanol, n-butanol and trifluoroethanol; the ether is selected from any one or a combination of diethyl ether and methyl tert-butyl ether; the nitrile is selected from acetonitrile; the ester is selected from any one or a combination of ethyl acetate, isopropyl acetate and n-butyl acetate; the ketone is selected from any one or a combination of acetone and butanone.
  • the alcohol is selected from any one or a combination of methanol, ethanol, n-propanol, sec-butanol, n-butanol and trifluoroethanol
  • the ether is selected from any one or a
  • the solvent 3 is selected from any one of methanol, ethyl acetate, acetonitrile or a mixture thereof.
  • the organic solvent is selected from alcohols.
  • the organic solvent is selected from methanol.
  • the solvent 4 is selected from one or a combination of water, isopropyl ether, isopropanol, n-heptane and methylcyclohexane.
  • the solvent 4 is selected from any one of water and isopropyl ether or a combination thereof.
  • the compound of formula (I) is heated and dissolved in solvent 3; the fumaric acid is heated and dissolved in an organic solvent; preferably, the temperature of the heating and dissolving is ⁇ 40°C; more preferably 50°C-60°C;
  • the stirring time in step C is ⁇ 1h.
  • the low temperature environment in step D is ⁇ 30°C; more preferably 0°C-20°C.
  • the low temperature environment in step D is 4°C.
  • the drying time is 8-24 hours; the drying temperature is 40°C.
  • the molar ratio of the compound of formula (I) to fumaric acid is 1:0.5-1.5.
  • the mass volume ratio (mg/ml) of the compound of formula (I) and the solvent 3 is ⁇ 100:1; preferably 80:1; more preferably 50:1.
  • the mass volume ratio (mg/ml) of compound (I) and solvent 3 is 25:1.
  • the solvent 5 is selected from one of alcohols, ketones, esters, ethers, dimethyl sulfoxide and tetrahydrofuran or a mixture thereof; more preferably, the solvent 5 is selected from tetrahydrofuran.
  • the solvent 6 is selected from one of water, n-heptane, isopropyl ether, dichloromethane, chloroform, toluene, methylcyclohexane or a mixture thereof; more preferably, the solvent 6 is selected from n-heptane.
  • the solvent 5 is selected from tetrahydrofuran, and the solvent 6 is selected from n-heptane.
  • the volume ratio of the solvent 6 to the solvent 5 is ⁇ 1:1; more preferably ⁇ 1.5:1.
  • the temperature of the heating dissolution is ⁇ 40°C; more preferably 50°C-60°C.
  • the drying time is ⁇ 4h; and the drying temperature is ⁇ 10°C.
  • the drying time is 8-24 hours; the drying temperature is 40°C.
  • the solvent 7 is selected from one of alcohols, ketones, esters, ethers, dimethyl sulfoxide and tetrahydrofuran or a mixture thereof; more preferably, the solvent 7 is selected from alcohols and ketones; most preferably, the alcohol is selected from one of ethanol and methanol or a combination thereof; the ketone is selected from acetone.
  • the solvent 8 is selected from one of water, n-heptane, isopropyl ether, dichloromethane, chloroform, toluene, methylcyclohexane or a mixture thereof; more preferably, it is one of water and n-heptane or a mixture thereof.
  • the crude product of the hemifumarate salt of the compound of formula (I) is dissolved in ethanol.
  • the compound of formula (I) is dissolved in a mixed solvent system of methanol and water, wherein the volume ratio of methanol to water is 1:0.1-0.2, preferably 1:0.15.
  • the compound of formula (I) is dissolved in a mixed solvent system of acetone and n-heptane, wherein the volume ratio of acetone to n-heptane is 1:0.5-1, preferably 1:0.8.
  • the temperature of the heating and dissolving is ⁇ 40°C; more preferably 50°C-60°C.
  • the temperature of the cooling and stirring is ⁇ 30°C; more preferably 0°C-20°C.
  • the drying time is ⁇ 4h; and the drying temperature is ⁇ 10°C.
  • the drying time is 8-24 hours; the drying temperature is 40°C.
  • the solvent 9 is selected from one or a combination of alcohols, alkanes, esters, nitriles, ethers, benzene rings, ketones and water; more preferably, the alcohol is selected from one or a combination of methanol, ethanol and isopropanol; the alkane is selected from one or a combination of dichloromethane, n-heptane and methylcyclohexane; the ester is selected from one or a combination of ethyl acetate and isopropyl acetate; the nitriles are selected from acetonitrile; the ethers are selected from one or a combination of diethyl ether and isopropyl ether; the benzene rings are selected from toluene; the ketones are selected from one or a combination of acetone and butanone.
  • the alcohol is selected from one or a combination of methanol, ethanol and isopropanol
  • the alkane is selected from one
  • the solvent 9 is selected from a single solvent system, such as one of methanol, water, isopropyl ether, dichloromethane, isopropanol, methyl tert-butyl ether, toluene, acetonitrile, and diethyl ether.
  • the solvent 9 is a mixed solvent system with a specific volume ratio, such as a mixed solvent system of methanol and water, with a volume ratio of 2:1; a mixed solvent system of ethanol and water, with a volume ratio of 3:1; a mixed solvent system of acetone and water, with a volume ratio of 1:2; a mixed solvent system of acetonitrile and water, with a volume ratio of 1:4; a saturated water mixed solvent system of ethyl acetate, a mixed solvent system of ethanol and isopropyl ether, with a volume ratio of 1:1; a mixed solvent system of isopropyl alcohol and n-heptane, with a volume ratio of 1:1; a mixed solvent system of butanone and methylcyclohexane, with a volume ratio of 1:5; isopropyl ether and ethyl acetate
  • the mixed solvent system is 5:1 in volume ratio; the mixed solvent system of ethyl acetate and dichloromethane is
  • the drying time is ⁇ 4h; and the drying temperature is ⁇ 10°C.
  • the drying time is 8-24 hours; the drying temperature is 40°C.
  • the mass volume ratio (mg/ml) of the crude product of the hemifumarate salt of the compound of formula (I) to the solvent 9 is ⁇ 150:1; more preferably ⁇ 120:1.
  • the mass volume ratio of the crude product of the hemifumarate salt of the compound of formula (I) and the solvent 9 is 100:1, 80:1, 60:1, 50:1, 25:1, or 20:1.
  • Another aspect of the present application is to provide a method for preparing hemifumarate Form 1, which comprises exposing the hemifumarate of the compound of formula (I) obtained in crystalline form by any of the above methods (1)-(4) to an environment with a relative humidity of ⁇ 75% for a sufficient period of time to obtain hemifumarate Form 1.
  • the exposure temperature is ⁇ 40°C.
  • the sufficient time refers to the time until the hemi-fumarate Form 1 is determined to be obtained after XRPD detection; in some embodiments, the sufficient time is generally more than 2 days.
  • Another aspect of the present application is to provide a method for preparing hemifumarate Form 2, which comprises exposing the hemifumarate of the compound of formula (I) obtained in crystalline form by any of the above methods (1)-(4) to an environment with a relative humidity of ⁇ 10% for a sufficient period of time to obtain hemifumarate Form 2.
  • the exposure temperature is ⁇ 30°C.
  • the sufficient time refers to the time until the hemi-fumarate Form 2 is determined to be obtained after XRPD detection; in some embodiments, the sufficient time is generally more than 2 days.
  • Another aspect of the present application is to provide a crystalline form of an ethanol solvate Form 3 of a hemifumarate of the compound of formula (I) (hereinafter referred to as hemifumarate Form 3).
  • the XRPD spectrum of the hemifumarate Form 3 expressed in 2 ⁇ angles has a characteristic peak at at least one of 6.8° ⁇ 0.2°, 9.4° ⁇ 0.2°, 15.7° ⁇ 0.2° and 15.9° ⁇ 0.2°; preferably, it has characteristic peaks at two, three or four locations.
  • the XRPD spectrum of the hemifumarate Form 3 also has characteristic peaks at at least one of 17.8° ⁇ 0.2°, 18.5° ⁇ 0.2°, 19.0° ⁇ 0.2° and 22.1° ⁇ 0.2°2 ⁇ .
  • the XRPD spectrum of the hemifumarate Form 3 also has characteristic peaks at at least one of 23.9° ⁇ 0.2°, 25.1° ⁇ 0.2°, 26.2° ⁇ 0.2° and 28.6° ⁇ 0.2°2 ⁇ .
  • the XRPD pattern of the Form 3 is at 4.1° ⁇ 0.2°, 6.8° ⁇ 0.2°, 8.0° ⁇ 0.2°, 9.4° ⁇ 0.2°, 10.0° ⁇ 0.2°, 11.2° ⁇ 0.2°, 13.0° ⁇ 0.2°, 13.6° ⁇ 0.2°, 14.5° ⁇ 0.2°, 15.7° ⁇ 0.2°, 16.0° ⁇ 0.2°, 16.5° ⁇ 0.2°, 17.4° ⁇ 0.2°, 17.8° ⁇ 0.2°, 18.5° ⁇ 0.2°, 19.0° ⁇ 0.2°, 20.0° ⁇ 0.2°, 20.4° ⁇ 0.2°, 20.6° ⁇ 0.2°, There are characteristic peaks at 0.2°, 22.1° ⁇ 0.2°, 22.9° ⁇ 0.2°, 23.6° ⁇ 0.2°, 23.9° ⁇ 0.2°, 24.2° ⁇ 0.2°, 24.5° ⁇ 0.2°, 25.1° ⁇ 0.2°, 26.2° ⁇ 0.2°, 27.4° ⁇ 0.2°, 27.7° ⁇ 0.2°, 28.6° ⁇ 0.2°, 29.2° ⁇ 0.2°, 31.0° ⁇ 0.2°, 31.6
  • the hemifumarate salt Form 3 has an XRPD spectrum substantially the same as that of Figure 11.
  • the hemifumarate Form 3 has a TGA spectrum substantially the same as that of Figure 12.
  • the hemifumarate Form 3 has a DSC spectrum substantially the same as that of Figure 13.
  • the hemifumarate salt Form 3 has a solid-state 1 H-NMR spectrum substantially the same as that of FIG. 14 .
  • the molar ratio of ethanol to the hemifumarate of the compound of formula (I) in the hemifumarate Form 3 is 1:1.
  • Another aspect of the present application is to provide a method for preparing hemifumarate Form 3, the preparation method comprising the following steps:
  • the crystalline form of the hemifumarate of the compound of formula (I) is diffused and crystallized in an ethanol atmosphere to obtain the ethanol solvate Form 3.
  • the diffusion crystallization time is ⁇ 1 day; more preferably ⁇ 5 days.
  • the diffusion crystallization time is 6 days.
  • hemifumarate Form 4 Another aspect of the present application is to provide a crystalline form of a hydrate Form 4 of the hemifumarate of the compound of formula (I) (hereinafter referred to as hemifumarate Form 4).
  • the XRPD spectrum of the hemifumarate Form 4 expressed in 2 ⁇ angles has a characteristic peak at at least one of 9.3° ⁇ 0.2°, 15.6° ⁇ 0.2°, 16.0° ⁇ 0.2°, and 21.9° ⁇ 0.2°; preferably, there are two, three, or four characteristic peaks.
  • the XRPD spectrum of the hemifumarate Form 4 also has characteristic peaks at at least one of 17.1° ⁇ 0.2°, 22.8° ⁇ 0.2°, 24.1° ⁇ 0.2° and 25.0° ⁇ 0.2°2 ⁇ .
  • the XRPD spectrum of the hemifumarate Form 4 also has characteristic peaks at at least one of 10.0° ⁇ 0.2°, 9.5° ⁇ 0.2°, 19.0° ⁇ 0.2° and 20.3° ⁇ 0.2°2 ⁇ .
  • the XRPD spectrum of the hemifumarate Form 4 is at 3.6° ⁇ 0.2°, 3.8° ⁇ 0.2°, 6.9° ⁇ 0.2°, 8.1° ⁇ 0.2°, 8.8° ⁇ 0.2°, 9.3° ⁇ 0.2°, 9.5° ⁇ 0.2°, 10.0° ⁇ 0.2°, 11.7° ⁇ 0.2°, 13.7° ⁇ 0.2°, 15.6° ⁇ 0.2°, 16.0° ⁇ 0.2°, 16.4° ⁇ 0.2°, 17.1° ⁇ 0.2°, 17.8° ⁇ 0.2°, 18.6° ⁇ 0.2°, 19.0° ⁇ 0.2°, 20.3° ⁇ 0.2°, 21.4° ⁇ 0.2°, 23.
  • the hemifumarate salt Form 4 has an XRPD pattern substantially the same as that of Figure 15.
  • the hemifumarate Form 4 has a TGA spectrum substantially the same as that of Figure 16.
  • the hemifumarate Form 4 has a DSC spectrum substantially the same as that of Figure 17.
  • the hemifumarate Form 4 has a DVS spectrum substantially the same as that of Figure 18.
  • the hemifumarate salt Form 4 has a solid-state 1 H-NMR spectrum substantially the same as that of FIG. 19 .
  • Another aspect of the present application is to provide a method for preparing hemifumarate Form 4, the preparation method comprising any one of the following methods:
  • the esters are selected from ethyl acetate; the alcohols are selected from isopropanol and sec-butyl alcohol or a mixture thereof; the ethers are selected from diethyl ether; the nitriles are selected from acetonitrile; and the ketones are selected from acetone.
  • the solvent 10 is ethyl acetate.
  • the solvent 10 is a mixed solvent system with a specific volume ratio, such as a mixed solvent system of acetone and isopropyl ether, with a volume ratio of 1:2; a mixed solvent system of isopropanol and acetonitrile, with a volume ratio of 5:2; a mixed solvent system of sec-butanol and ethyl acetate, with a volume ratio of 5:4.
  • a mixed solvent system of acetone and isopropyl ether with a volume ratio of 1:2
  • a mixed solvent system of isopropanol and acetonitrile with a volume ratio of 5:2
  • a mixed solvent system of sec-butanol and ethyl acetate with a volume ratio of 5:4.
  • the mass volume ratio (mg/ml) of the hemi-fumarate salt of the compound of formula (I) to the solvent 10 is ⁇ 150:1; more preferably ⁇ 120:1.
  • the mass volume ratio of the hemifumarate salt of the compound of formula (I) and the solvent 10 is 100:1, 70:1 or 50:1.
  • the solvent 11 is selected from one or a combination of ester and ketone solvents; more preferably, the ester is ethyl acetate; and the ketone is acetone.
  • the solvent 11 is ethyl acetate.
  • the solvent 11 is acetone.
  • the evaporation temperature is ⁇ 10°C.
  • the evaporation temperature is room temperature or 40°C.
  • the volume ratio of ethyl acetate to toluene is 5:1.
  • the temperature of the heating and dissolving is ⁇ 40°C; more preferably 50°C-60°C.
  • the temperature of the cooling and stirring is ⁇ 30°C; more preferably 0°C-20°C.
  • the drying time is ⁇ 4h; and the drying temperature is ⁇ 10°C.
  • the drying time is 8-24 hours; the drying temperature is 40°C.
  • the hemifumarate Form 1 of the present application is placed under high temperature (40°C and 60°C), high humidity (25°C/90% RH) and accelerated (40°C/75% RH) conditions for 30 days, and the crystal form remains basically unchanged, and the increase of related substances is less than 0.01%, which has good crystal stability and chemical stability; the hemifumarate Form 2 is placed under high temperature (open, 60°C, ⁇ 30% RH) conditions for 10 days, and the crystal form remains basically unchanged, and the increase of related substances is less than 0.05%, which has good crystal stability and chemical stability.
  • the hemifumarate Form 1 of the present application has good blood concentration and curve area and excellent oral absolute bioavailability in SD rats.
  • its blood concentration and curve area are 1.9 times and 1.8 times that of the free state of the compound of formula (I), respectively, and its oral absolute availability is 3.2 times that of the free state of the compound of formula (I); the oral absolute availability of the hemifumarate Form 2 is 2.7 times that of the free state of the compound of formula (I).
  • the hemi-fumarate Form 1 of the present application can significantly inhibit the growth of human breast cancer MDA-MB-231 cell Balb/c nude mouse xenograft tumors, the tumor volume inhibition rate TGI (%) is 75.46%, and the relative tumor proliferation rate T/C after administration is 23.91%; the hemi-fumarate Form 1 of the present application can significantly inhibit the growth of human leukemia MOLM16 cell CB-17SCID mouse xenograft tumors and significantly inhibit the growth of human leukemia MOLM16 cell CB-17SCID mouse xenograft tumors.
  • the tablets have good dissolution. Compared with the oxalate Form 2, the tablets with the hemi-fumarate Form 1 and hemi-fumarate Form 2 as active ingredients of the present application have better in vitro dissolution.
  • the salt of the compound of formula (I) is selected from L-tartrate.
  • the molar ratio of the compound of formula (I) to L-tartaric acid is 1:0.5-2; more preferably 1:1.
  • the salt of the compound of formula (I) is selected from L-tartrate, and the structural formula is shown in formula (III):
  • the L-tartrate salt of the compound of formula (I) is substantially in crystalline form or amorphous form; more preferably, it is substantially in crystalline form.
  • the crystalline form of the L-tartrate of the compound of formula (I) may be one or more; specifically, it may be at least one of an anhydrate, a hydrate or a solvate.
  • Another aspect of the present application is to provide a method for preparing L-tartrate of the compound of formula (I), which comprises dissolving the compound of formula (I) in a solvent 12, and then adding L-tartaric acid or an L-tartaric acid solution to react.
  • the preparation method of the L-tartrate of the compound of formula (I) comprises the following steps:
  • Step A dissolving an appropriate amount of the compound of formula (I) in solvent 12;
  • Step B dissolving an appropriate amount of L-tartaric acid in solvent 13;
  • Step C combining the above two solutions, stirring to precipitate solids to form a suspension
  • Step D separating the solid in the suspension to obtain L-tartrate of the compound of formula (I);
  • the solvent 12 is selected from any one or a combination of benzene rings, alkanes, esters, alcohols, ethers, ketones, halogens, tetrahydrofuran, 1,4-dioxane and dimethyl sulfoxide; more preferably, the benzene rings are selected from toluene; the alkanes are selected from dichloromethane; the alcohols are selected from any one or a combination of trifluoroethanol, methanol, ethanol, n-propanol, sec-butanol and n-butanol; the ethers are selected from any one or a combination of diethyl ether and methyl tert-butyl ether; the esters are selected from any one or a combination of ethyl acetate, isopropyl acetate and n-butyl acetate; the ketones are selected from any one or a combination of acetone and butanone; the halogens
  • the solvent 12 is selected from any one of toluene, dichloromethane, trifluoroethanol, ether, ethyl acetate, isopropyl acetate, acetone, butanone, chloroform, tetrahydrofuran and 1,4-dioxane, or a combination thereof.
  • the solvent 12 is selected from toluene.
  • the solvent 13 is selected from any one of alcohols, alkanes, ketones and tetrahydrofuran or a combination thereof; more preferably, the alcohol is selected from ethanol; the alkane is selected from dichloromethane; and the ketone is selected from acetone.
  • the solvent 13 is selected from ethanol or tetrahydrofuran.
  • the solvent 13 is selected from a mixed solvent of acetone/ethanol or a mixed solvent of dichloromethane/ethanol.
  • the solvent 14 may be added to the suspension in step D before solid separation.
  • the solvent 14 is selected from any one of isopropyl ether, n-heptane, water, isopropanol, and methylcyclohexane, or a combination thereof.
  • the solvent 14 is selected from any one of isopropyl ether and n-heptane or a combination thereof.
  • the molar ratio of the compound of formula (I) to L-tartaric acid is 1:1-2.5; more preferably, the molar ratio is 1:1.
  • the mass volume ratio (mg/ml) of the compound of formula (I) to the solvent 12 is ⁇ 300:1; more preferably ⁇ 200:1; most preferably ⁇ 150:1.
  • the mass volume ratio (mg/ml) of the compound of formula (I) and solvent 12 is 100:1.
  • L-tartrate Form 1 a crystalline form of Form 1 of L-tartrate of the compound of formula (I) (hereinafter referred to as L-tartrate Form 1).
  • L-tartrate Form 1 Using Cu-K ⁇ radiation, the XRPD spectrum of the L-tartrate Form 1 expressed in 2 ⁇ angles has a characteristic peak at at least one of 7.8° ⁇ 0.2°, 14.6° ⁇ 0.2°, 18.3° ⁇ 0.2° and 23.6° ⁇ 0.2°; preferably, there are two, three or four characteristic peaks.
  • the XRPD spectrum of the L-tartrate salt Form 1 also has characteristic peaks at at least one of 20.0° ⁇ 0.2°, 14.1° ⁇ 0.2°, 13.5° ⁇ 0.2° and 16.1° ⁇ 0.2°2 ⁇ .
  • the XRPD spectrum of the L-tartrate salt Form 1 also has characteristic peaks at at least one of 19.8° ⁇ 0.2°, 13.3° ⁇ 0.2°, 17.0° ⁇ 0.2° and 15.3° ⁇ 0.2°2 ⁇ .
  • the XRPD pattern of the L-tartrate salt Form 1 is at 3.9° ⁇ 0.2°, 6.1° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.2° ⁇ 0.2°, 11.7° ⁇ 0.2°, 13.3° ⁇ 0.2°, 13.5° ⁇ 0.2°, 14.1° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.3° ⁇ 0.2°, 16.1° ⁇ 0.2°, 17.0° ⁇ 0.2°, 17.7° ⁇ 0.2°, 18.3° ⁇ 0.2°, 18.6° ⁇ 0.2°, 18.8° ⁇ 0.2°, 19.1° ⁇ 0.
  • the L-tartrate salt Form 1 has an XRPD pattern substantially the same as that of Figure 21.
  • the L-tartrate salt Form 1 has a TGA spectrum substantially the same as that of Figure 22.
  • the L-tartrate salt Form 1 has a DSC spectrum substantially the same as that of Figure 23.
  • the L-tartrate salt Form 1 has a DVS spectrum substantially the same as that of Figure 24.
  • the L-tartrate salt Form 1 is a hydrate.
  • Another aspect of the present application is to provide a method for preparing L-tartrate Form 1, the preparation method comprising any one of the following methods:
  • Step A dissolving an appropriate amount of the compound of formula (I) in a solvent 15;
  • Step B dissolving an appropriate amount of L-tartaric acid in solvent 16;
  • Step C combining the above two solutions, stirring to precipitate solids to form a suspension
  • Step D Continue stirring or add solvent 17 to the suspension and continue stirring, crystallize, centrifuge, and dry to obtain L-tartrate salt Form 1.
  • the solvent 15 is selected from benzene rings; preferably, the benzene rings are selected from toluene.
  • the solvent 15 is selected from toluene.
  • the solvent 16 is selected from alcohols; more preferably, the alcohol is selected from ethanol.
  • the solvent 16 is selected from ethanol.
  • the solvent 17 is selected from isopropyl ether.
  • the solution merging in step C is performed by dropwise adding the solution of step B into the solution of step A.
  • the drying time in step D is ⁇ 5 h; preferably ⁇ 10 h.
  • the drying time is 12-24 hours.
  • the drying time is 16 hours.
  • the drying temperature is room temperature.
  • the stirring temperature in step D is low temperature, which is ⁇ 30°C; more preferably 0°C-20°C;
  • the stirring temperature in step D is 4°C.
  • the molar ratio of the compound of formula (I) to L-tartaric acid is 1:1-2.5; more preferably, the molar ratio is 1:1.
  • the mass volume ratio (mg/ml) of the compound of formula (I) and the solvent 15 is ⁇ 300:1; preferably ⁇ 200:1; and more preferably ⁇ 150:1.
  • the mass volume ratio (mg/ml) of the compound of formula (I) and solvent 15 is 100:1.
  • the solvent 18 is selected from any one or a combination of esters, alkanes, alcohols, ethers and water; the esters are selected from isopropyl acetate; the alkanes are selected from any one or a combination of dichloromethane, n-heptane, n-hexane and methylcyclohexane; the alcohols are selected from any one or a combination of methanol and ethanol; The ethers are selected from methyl tert-butyl ether.
  • the solvent 18 is a mixed solvent system with a specific volume ratio, such as a mixed solvent of isopropyl acetate and n-heptane, with a volume ratio of 1:4; or a mixed solvent of dichloromethane and n-hexane, with a volume ratio of 1:4; or a mixed solvent of ethanol and n-heptane, with a volume ratio of 1:4; or a mixed solvent of methanol and water, with a volume ratio of 1:2; or a mixed solvent of dichloromethane and methylcyclohexane, with a volume ratio of 1:6; or a mixed solvent of methyl tert-butyl ether and ethanol, with a volume ratio of 4:1; or a mixed solvent of isopropyl acetate and n-hexane, with a volume ratio of 1:6.
  • a specific volume ratio such as a mixed solvent of isopropyl acetate and n-heptane, with a
  • the stirring temperature is low temperature, room temperature or high temperature.
  • the low temperature is ⁇ 30°C; more preferably 0°C-20°C.
  • the low temperature is 4°C-8°C.
  • the high temperature is ⁇ 30°C; more preferably 40°C-60°C.
  • the elevated temperature is 50°C.
  • the mass volume ratio (mg/mL) of the L-tartrate salt of the compound of formula (I) and the solvent 18 is 40:1.
  • L-tartrate Form 2 a crystalline form of Form 2 of L-tartrate of the compound of formula (I) (hereinafter referred to as L-tartrate Form 2), using Cu-K ⁇ radiation, and the L-tartrate Form 2 has an XRPD spectrum substantially the same as that of Figure 26.
  • the L-tartrate salt Form 2 has a TGA spectrum substantially the same as that of Figure 27.
  • the L-tartrate salt Form 2 has a DSC spectrum substantially the same as that of Figure 28.
  • the L-tartrate salt Form 2 is a hydrate.
  • Another aspect of the present application is to provide a method for preparing L-tartrate Form 2, which comprises exposing L-tartrate Form 1 to an environment with a relative humidity ⁇ 75% for a sufficient period of time to obtain L-tartrate Form 2.
  • the exposure temperature is ⁇ 40°C.
  • the relative humidity is 75% or 97%; and the exposure temperature is room temperature.
  • the sufficient time refers to the time until L-tartrate Form 2 is determined to be obtained after XRPD detection.
  • the sufficient period of time is 7 days.
  • L-tartrate Form 3 Another aspect of the present application is to provide a crystalline form of Form 3 of the L-tartrate salt of the compound of formula (I) (hereinafter referred to as L-tartrate Form 3), using Cu-K ⁇ radiation, and the L-tartrate Form 3 has an XRPD spectrum substantially the same as that of Figure 30.
  • the L-tartrate salt Form 3 has a TGA spectrum substantially the same as that of Figure 31.
  • the L-tartrate salt Form 3 has a DSC spectrum substantially the same as that of Figure 32.
  • the L-tartrate salt Form 3 is a hydrate.
  • Another aspect of the present application is to provide a method for preparing L-tartrate Form 3, the preparation method comprising:
  • L-tartrate salt Form 1 is suspended in solvent 19, stirred at low temperature to precipitate, and the crystals are separated to obtain L-tartrate salt Form 3; wherein solvent 19 is a mixed solvent of dimethyltetrahydrofuran and an alkane solvent.
  • the solvent 19 is a mixed solvent of dimethyltetrahydrofuran and methylcyclohexane, with a volume ratio of 1:4.
  • the temperature of the low-temperature stirring is ⁇ 30°C; preferably 0°C-20°C.
  • the low temperature stirring temperature is 4°C-8°C.
  • the stirring time is ⁇ 0.5 days; more preferably 1-10 days.
  • the stirring time is 3 days.
  • the mass volume ratio (mg/mL) of the L-tartrate salt Form 1 and the solvent 19 is 40:1.
  • L-tartrate Form 4 Another aspect of the present application is to provide a crystalline form of Form 4 of L-tartrate of the compound of formula (I) (hereinafter referred to as L-tartrate Form 4).
  • L-tartrate Form 4 Using Cu-K ⁇ radiation, the XRPD spectrum of the L-tartrate Form 4 expressed in 2 ⁇ angle has a characteristic peak at at least one of 3.6° ⁇ 0.2°, 11.0° ⁇ 0.2° and 14.3° ⁇ 0.2°; preferably, there are two or three characteristic peaks.
  • the XRPD spectrum of the L-tartrate salt Form 4 also has characteristic peaks at at least one of 6.6° ⁇ 0.2°, 7.3° ⁇ 0.2°, 8.4° ⁇ 0.2°, 17.7° ⁇ 0.2° and 18.0° ⁇ 0.2°2 ⁇ .
  • the XRPD spectrum of the L-tartrate salt Form 4 also has characteristic peaks at at least one of 13.2° ⁇ 0.2°, 13.8° ⁇ 0.2°, 18.5° ⁇ 0.2°19.9° ⁇ 0.2° and 21.8° ⁇ 0.2°2 ⁇ .
  • the XRPD pattern of the L-tartrate salt Form 4 is at 3.6° ⁇ 0.2°, 6.6° ⁇ 0.2°, 7.3° ⁇ 0.2°, 8.4° ⁇ 0.2°, 11.0° ⁇ 0.2°, 12.5° ⁇ 0.2°, 13.2° ⁇ 0.2°, 13.8° ⁇ 0.2°, 14.0° ⁇ 0.2°, 14. 3° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.6° ⁇ 0.2°, 16.0° ⁇ 0.2°, 16.9° ⁇ 0.2°, 17.5° ⁇ 0.2°, 17.7° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.5° ⁇ 0.2°, 18.8° ⁇ 0.2°, 19.2° ⁇ 0.2°, 19. 5° ⁇ 0.
  • the L-tartrate salt Form 4 has an XRPD pattern substantially the same as that of Figure 34.
  • the L-tartrate salt Form 4 has a TGA spectrum substantially the same as that of Figure 35.
  • the L-tartrate salt Form 4 has a DSC spectrum substantially the same as that of Figure 36.
  • the L-tartrate salt Form 4 is an anhydrate or a channel hydrate.
  • Another aspect of the present application is to provide a method for preparing L-tartrate Form 4, the preparation method comprising any one of the following methods:
  • the solvent 20 is selected from any one of ketones, esters, ethers and benzene rings or a mixture thereof; more preferably, the ketones are selected from any one of acetone and methyl isobutyl ketone or a combination thereof; the esters are selected from any one of ethyl acetate and isopropyl acetate or a combination thereof; the ethers are selected from methyl tert-butyl ether; and the benzene rings are selected from toluene.
  • the solvent 20 is a single solvent system, such as isopropyl acetate.
  • the solvent 20 is a mixed solvent system with a specific volume ratio, such as a mixed solvent of acetone and methyl tert-butyl ether, with a volume ratio of 1:1; or a mixed solvent system of ethyl acetate and toluene, with a volume ratio of 2:1.
  • the volatilization time is ⁇ 0.5 days; in some embodiments, the volatilization time is 1 day.
  • the slow volatilization is small pore volatilization.
  • the slow volatilization temperature is room temperature.
  • the solvent 21 is any one of ketones, alkanes, esters and ethers or a combination thereof; more preferably, the ketone is selected from any one of acetone and methyl isobutyl ketone or a combination thereof; the alkane is selected from n-heptane; the ester is selected from ethyl acetate; and the ether is selected from methyl tert-butyl ether.
  • the solvent 21 is a mixed solvent system with a specific volume ratio, such as a mixed solvent of acetone and n-heptane, with a volume ratio of 1:6; or a mixed solvent of ethyl acetate and n-heptane, with a volume ratio of 1:6; or a mixed solvent of isopropyl acetate and n-heptane, with a volume ratio of 1:4, or a mixed solvent of acetone and methyl tert-butyl ether, with a volume ratio of 1:4.
  • a specific volume ratio such as a mixed solvent of acetone and n-heptane, with a volume ratio of 1:6; or a mixed solvent of ethyl acetate and n-heptane, with a volume ratio of 1:6; or a mixed solvent of isopropyl acetate and n-heptane, with a volume ratio of 1:4, or a mixed solvent of acetone and methyl
  • the mass volume ratio (mg/mL) of the L-tartrate salt Form 1 and the solvent 21 is 40:1.
  • the solvent 22 is selected from any one or a combination of ketones, alkanes, esters and ethers; more preferably, the ketones are selected from any one or a combination of acetone and methyl isobutyl ketone; the alkanes are selected from n-heptane; the esters are selected from ethyl acetate; and the ethers are selected from methyl tert-butyl ether.
  • the solvent 22 is a mixed solvent system with a specific volume ratio, such as a mixed solvent of acetone and n-heptane, with a volume ratio of 1:6.
  • the molar ratio of the compound of formula (I) to L-tartaric acid is 1:1.
  • the mass volume ratio (mg/mL) of the compound of formula (I) and solvent 22 is 30:1.
  • the solvent 23 is selected from any one or a combination of alkanes, ketones and ethers; more preferably, the alkane is selected from n-heptane; the ketone is selected from butanone; and the ether is selected from methyl tert-butyl ether.
  • the solvent 23 is methyl tert-butyl ether.
  • the solvent 23 is a mixed solvent system with a specific volume ratio, such as a mixed solvent of butanone and n-heptane, with a volume ratio of 1:6.
  • the stirring temperature is low temperature or room temperature.
  • the low temperature is ⁇ 30°C; more preferably 0°C-20°C.
  • the low temperature is 4°C-8°C.
  • the mass volume ratio (mg/mL) of the L-tartrate salt of the compound of formula (I) and the solvent 23 is 40:1.
  • L-tartrate Form 5 Another aspect of the present application is to provide a crystalline form of Form 5 of L-tartrate of the compound of formula (I) (hereinafter referred to as L-tartrate Form 5), using Cu-K ⁇ radiation, the L-tartrate Form 5 has an XRPD pattern substantially the same as that of Figure 38.
  • Another aspect of the present application is to provide a method for preparing L-tartrate Form 5, which comprises forming a suspension of L-tartrate Form 1 in a mixed solvent of isopropanol and methyl tert-butyl ether, stirring to precipitate, separating the crystals, and obtaining L-tartrate Form 5.
  • the volume ratio of isopropanol to methyl tert-butyl ether is 1:1.
  • the stirring is stirring at room temperature.
  • the stirring time is 3 days.
  • the mass volume ratio (mg/mL) of the L-tartrate salt Form 1 and the mixed solvent is 40:1.
  • L-tartrate Form 6 Another aspect of the present application is to provide a crystalline form of L-tartrate Form 6 of the compound of formula (I) (hereinafter referred to as L-tartrate Form 6), using Cu-K ⁇ radiation, and the L-tartrate Form 6 has an XRPD spectrum substantially the same as that of Figure 39.
  • Another aspect of the present application is to provide a method for preparing L-tartrate Form 6, which comprises heating L-tartrate Form 1 to 70°C and maintaining the temperature for 10 minutes to obtain L-tartrate Form 6.
  • L-tartrate amorphous an amorphous form of L-tartrate of the compound of formula (I) (hereinafter referred to as L-tartrate amorphous), wherein the L-tartrate amorphous has no sharp diffraction peaks in the XRPD spectrum represented by 2 ⁇ using Cu-K ⁇ radiation.
  • the L-tartrate amorphous form has an XRPD pattern substantially the same as 40.
  • the L-tartrate amorphous form has a TGA pattern substantially the same as that of 41.
  • the L-tartrate amorphous form has a DSC spectrum substantially the same as that of 42.
  • the L-tartrate amorphous form has a DVS pattern substantially the same as that of Figure 43.
  • Another aspect of the present application is to provide a method for preparing amorphous L-tartrate, which comprises dissolving L-tartrate of the compound of formula (I) in dichloromethane, filtering, and concentrating the filtrate at high temperature to obtain amorphous L-tartrate.
  • the concentration is concentration under reduced pressure.
  • the high temperature is 40-70°C.
  • the elevated temperature is 60°C.
  • the mass volume ratio (mg/ml) of the L-tartrate salt of the compound of formula (I) and dichloromethane is 10:1.
  • the L-tartrate Form 1 of the present application was placed under long-term (25°C/60%RH) and accelerated (40°C/75%RH) conditions for 1 week, and the crystal form and purity remained basically unchanged. It was placed under high temperature (60°C, ⁇ 30%RH) conditions for 10 days, and its crystal form remained basically unchanged, and the increase of related substances was ⁇ 0.05%, which had good crystal stability and chemical stability; the L-tartrate Form 4 of the present application was placed under long-term (25°C/60%RH) and accelerated (40°C/75%RH) conditions for 1 week, and the crystal form and purity remained basically unchanged. It was placed under 40°C, 50°C and 55°C conditions for 30 days, and its crystal form remained basically unchanged, which had good crystal stability and chemical stability.
  • the L-tartrate salt Form 1 of the present application has good blood drug concentration and curve area and excellent oral absolute bioavailability in SD rats.
  • its blood drug concentration and curve area are 1.5 times and 1.8 times that of the free state of the compound of formula (I), respectively, and its oral absolute availability is 2.6 times that of the free state of the compound of formula (I);
  • the L-tartrate salt Form 4 of the present application has good blood drug concentration and curve area and excellent oral absolute bioavailability in SD rats.
  • the L-tartrate Form 1 of the present application has a significantly better tumor inhibition effect than the solvent in the NOD-SCID immunodeficient mouse Mol m16 subcutaneous tumor model, and at the same dose, its tumor inhibition effect is better than the free state of the compound of formula (I);
  • the L-tartrate Form 4 of the present application can significantly inhibit the growth of human breast cancer MDA-MB-231 cell Balb/c nude mouse xenograft tumors, the tumor volume inhibition rate TGI (%) is 79.43%, and the relative tumor proliferation rate T/C after administration is 20.37%;
  • the L-tartrate Form 4 of the present application significantly inhibits the growth of human breast cancer MDA-MB-231 cell Balb/c nude mouse xenograft tumors and the growth of human non-small cell lung cancer NCI-H460 cell Balb/c nude mouse xenograft tumors.
  • L-tartrate Form 4 and L-tartrate Form 1 of the present application have good fluidity and are both better than the oxalate Form 2.
  • the salt of the compound of formula (I) is selected from hydrochloride, and the structural formula is shown in formula (IV):
  • the hydrochloride salt of the compound of formula (I) is substantially in crystalline form or amorphous form; more preferably, it is substantially in crystalline form.
  • the hydrochloride of the compound of formula (I) may be in one or more crystalline forms; specifically, it may be at least one of an anhydrate, a hydrate or a solvate.
  • hydrochloride salt Form 1 Another aspect of the present application is to provide a crystalline form of a hydrochloride salt of the compound of formula (I) Form 1 (hereinafter referred to as hydrochloride salt Form 1).
  • hydrochloride salt Form 1 Using Cu-K ⁇ radiation, the XRPD spectrum of the hydrochloride salt Form 1 expressed in 2 ⁇ angles has a characteristic peak at at least one of 13.5° ⁇ 0.2°, 15.4° ⁇ 0.2°, 15.7° ⁇ 0.2°, 32.6° ⁇ 0.2° and 35.3° ⁇ 0.2°; preferably, there are two, three, four or five characteristic peaks.
  • the hydrochloride salt Form 1 has an XRPD pattern substantially the same as that of Figure 45.
  • the hydrochloride salt Form 1 has a TGA spectrum substantially the same as that of Figure 46.
  • the hydrochloride salt Form 1 has a DSC spectrum substantially the same as that of Figure 47.
  • Another aspect of the present application is to provide a method for preparing hydrochloride Form 1, the preparation method comprising the following steps:
  • Step A dissolving an appropriate amount of the compound of formula (I) in an ester solvent
  • Step B dissolving an appropriate amount of hydrochloric acid in an alcohol solvent
  • Step C combining the two solutions, stirring to precipitate solids to form a suspension
  • Step D Stir the suspension to crystallize, centrifuge and dry to obtain hydrochloride Form 1.
  • the ester solvent is selected from butyl acetate.
  • the alcohol solvent is selected from methanol.
  • the stirring temperature in step D is 4°C.
  • the drying time is 16 hours.
  • the drying temperature is room temperature.
  • the molar ratio of the compound of formula (I) to hydrochloric acid is 1:1.2.
  • the mass volume ratio (mg/ml) of the compound of formula (I) and the ester solvent is 100:1.
  • the salt of the compound of formula (I) is selected from methanesulfonate, and the structural formula is shown in formula (V):
  • the methanesulfonate salt of the compound of formula (I) is substantially in crystalline form or amorphous form; more preferably, it is substantially in crystalline form.
  • the crystalline form of the methanesulfonate salt of the compound of formula (I) may be one or more; specifically, it may be at least one of an anhydrate, a hydrate or a solvate.
  • mesylate salt Form 1 a crystalline form of Form 1 of the mesylate salt of the compound of formula (I) (hereinafter referred to as mesylate salt Form 1), using Cu-K ⁇ radiation, and the mesylate salt Form 1 has an XRPD spectrum substantially the same as that of Figure 49.
  • methanesulfonate Form 2 Another aspect of the present application is to provide a crystalline form of Form 2 of the methanesulfonate of the compound of formula (I) (hereinafter referred to as methanesulfonate Form 2).
  • methanesulfonate Form 2 Using Cu-K ⁇ radiation, the XRPD spectrum of the methanesulfonate Form 2 expressed in 2 ⁇ angles has a characteristic peak at at least one of 6.5° ⁇ 0.2°, 13.8° ⁇ 0.2°, 15.2° ⁇ 0.2° and 17.0° ⁇ 0.2°; preferably, there are characteristic peaks at two, three or four locations.
  • the XRPD spectrum of the mesylate salt Form 2 is also at 3.9° ⁇ 0.2°, 4.6° ⁇ 0.2°, 4.9° ⁇ 0.2°, 10.5° ⁇ 0.2°, 10.7° ⁇ 0.2°, 12.8° ⁇ 0.2°, 13.0° ⁇ 0.2°, 16.3° ⁇ 0.2°, 16.7° ⁇ 0.2°, 17.4° ⁇ 0.2°, 18.3° ⁇ 0.2°, There is a characteristic peak at least one of 18.8° ⁇ 0.2°, 19.6° ⁇ 0.2°, 20.6° ⁇ 0.2°, 21.2° ⁇ 0.2°, 22.4° ⁇ 0.2°, 23.0° ⁇ 0.2°, 23.9° ⁇ 0.2°, 25.6° ⁇ 0.2°, 25.8° ⁇ 0.2°, 26.6° ⁇ 0.2°, 29.6° ⁇ 0.2° and 31.4° ⁇ 0.2°2 ⁇ .
  • the mesylate salt Form 2 has an XRPD spectrum substantially the same as that of Figure 50.
  • the mesylate salt Form 2 has a TGA spectrum substantially the same as that of Figure 51.
  • the mesylate salt Form 2 has a DSC spectrum substantially the same as that of Figure 52.
  • Another aspect of the present application is to provide a method for preparing mesylate Form 2, the preparation method comprising:
  • the benzene ring solvent is toluene.
  • the mass volume ratio (mg/ml) of methanesulfonic acid and toluene is 72.5:1.
  • the mass volume ratio (mg/ml) of the compound of formula (I) and toluene is 100:1.
  • the molar ratio of the compound of formula (I) to methanesulfonic acid is 1:1.1.
  • the ether solvent is isopropyl ether.
  • the low temperature stirring temperature is 4°C.
  • mesylate salt Form 3 Another aspect of the present application is to provide a crystalline form of Form 3 of the mesylate salt of the compound of formula (I) (hereinafter referred to as mesylate salt Form 3), using Cu-K ⁇ radiation, and the mesylate salt Form 3 has an XRPD spectrum substantially the same as that of Figure 54.
  • the salt of the compound of formula (I) is selected from oxalate, and the structural formula is shown in formula (VI):
  • the oxalate salt of the compound of formula (I) is substantially present in crystalline or amorphous form.
  • the crystalline form of the oxalate of the compound of formula (I) may be one or more; specifically, it may be at least one of an anhydrate, a hydrate or a solvate.
  • Another aspect of the present application is to provide a crystalline form of oxalate Form 1 of the compound of formula (I) (hereinafter referred to as oxalate Form 1), using Cu-K ⁇ radiation, and the oxalate Form 1 has an XRPD spectrum substantially the same as that of Figure 55.
  • Another aspect of the present application is to provide a crystalline form of oxalate Form 2 of the compound of formula (I) (hereinafter referred to as oxalate Form 2).
  • oxalate Form 2 a crystalline form of oxalate Form 2 of the compound of formula (I) (hereinafter referred to as oxalate Form 2).
  • the XRPD spectrum of the oxalate Form 2 expressed in 2 ⁇ angle has a characteristic peak at at least one of 15.5° ⁇ 0.2°, 17.2° ⁇ 0.2° and 23.8° ⁇ 0.2°; preferably, there are two or three characteristic peaks.
  • the XRPD spectrum of the oxalate Form 2 also has characteristic peaks at at least one of 13.9° ⁇ 0.2°, 16.9° ⁇ 0.2°, 19.8° ⁇ 0.2° and 16.0° ⁇ 0.2°2 ⁇ .
  • the oxalate Form 2 has an XRPD pattern substantially the same as that of Figure 56.
  • Another aspect of the present application is to provide a method for preparing oxalate Form 2, which comprises: dissolving the compound of formula (I) and oxalic acid in ketone solvents respectively, mixing the two solutions, stirring at room temperature, precipitating, adding an ether solvent, stirring, centrifuging, and drying to obtain oxalate Form 2.
  • the ketone solvent is acetone
  • the ether solvent is isopropyl ether.
  • the mass volume ratio (mg/ml) of the compound of formula (I) to acetone is >100:1.
  • the molar ratio of the compound of formula (I) to oxalic acid is 1:1-1.5.
  • the low temperature stirring temperature is 4°C.
  • Another aspect of the present application is to provide a pharmaceutical composition, which comprises a therapeutically effective amount of a salt of a compound of formula (I) or a crystalline form thereof, and at least one pharmaceutically acceptable carrier.
  • Another aspect of the present application is to provide a preparation prepared from the above-mentioned pharmaceutical composition, wherein the preparation form includes but is not limited to oral solid preparations, injections, and external preparations.
  • the preparation is in the form of tablets, capsules, powder injections, powders, syrups, solutions, suspensions, aerosols or suppositories.
  • the various dosage forms of the present application can be prepared according to conventional preparation methods in the pharmaceutical field.
  • the pharmaceutically acceptable carrier is an excipient commonly used in preparations in the art, including but not limited to any one of adhesives, surfactants, diluents, antiadhesives, hydrophilic or hydrophobic polymers, tranquilizers or stabilizers, disintegrants, antioxidants, defoaming agents, fillers, glidants/lubricants, adsorbents, preservatives, plasticizers, sweeteners, and mixtures of two or more thereof.
  • adhesives including but not limited to any one of adhesives, surfactants, diluents, antiadhesives, hydrophilic or hydrophobic polymers, tranquilizers or stabilizers, disintegrants, antioxidants, defoaming agents, fillers, glidants/lubricants, adsorbents, preservatives, plasticizers, sweeteners, and mixtures of two or more thereof.
  • the filler or diluent is selected from any one or a combination of lactose, D-mannitol, microcrystalline cellulose, starch, pregelatinized starch, calcium sulfate, calcium hydrogen phosphate, and calcium carbonate;
  • the disintegrant is selected from any one or a combination of sodium carboxymethyl starch, sodium hydroxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, and cross-linked polyvinyl pyrrolidone;
  • the lubricant/glidant is selected from any one or a combination of magnesium stearate, talc, and micro-powdered silica gel.
  • the pharmaceutical composition may also include one or more pH adjusters or buffers, for example: acids, such as any one or a combination of acetic acid, boric acid, citric acid, fumaric acid, maleic acid, tartaric acid, malic acid, lactic acid, phosphoric acid, and hydrochloric acid; or bases, such as any one or a combination of sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and trishydroxymethylaminomethane; or buffers, such as citrate/glucose, sodium bicarbonate, ammonium chloride, and the like; such buffers used as bases may have counter ions other than sodium, such as potassium, magnesium, calcium, ammonium, and other counter ions; and other amounts required to maintain the pH of the components within an acceptable range, comprising solutions or solids of such acids, bases, and buffers.
  • acids such as any one or a combination of acetic acid, boric acid, citric acid, fumaric acid, maleic acid
  • Another aspect of the present application is to provide a use of a salt of the compound of formula (I) or a crystal form thereof, or a pharmaceutical composition thereof, in the preparation of a drug for preventing and/or treating diseases caused or regulated by activation of the bifunctional phosphorylation site of STAT3.
  • the application is to inhibit the proliferation, growth, migration, infiltration, cloning and metastasis of cancer cells, promote the apoptosis of cancer cells, and/or prolong the survival of tumor patients.
  • the diseases include but are not limited to examples of malignant tumors, including astroglioma, malignant medulloblastoma, germ cell tumor, craniopharyngioma, ependymoma and other pediatric brain tumors; glioma, meningioma, pituitary adenoma, neurothecoma and other adult brain tumors; maxillary sinus cancer, pharyngeal cancer (nasopharyngeal cancer, middle pharyngeal cancer, laryngeal cancer), oral cancer, lip cancer, tongue cancer, parotid gland cancer and other head and neck cancers; small cell lung cancer, non-small cell lung cancer, thymoma, mesothelioma and other chest cancers and tumors; esophageal cancer, liver cancer, primary liver cancer, gallbladder cancer, bile duct cancer, gastric cancer, colorectal cancer, colon cancer, rectal cancer, an
  • the disease is selected from pancreatic cancer Capan-2, PANC-1, MIAPACA-2, BXPC3, SW1990, CFPAC-1, Pan02, ASPC-1, gastric cancer MKN45, BGC823, MGC803, liver cancer Huh7, PLC/PRF-5, HepG2, SK-hep1, SMMC7721, HCCC9810, lung cancer HCC827, A549, H460, H23, H1299, H522, H1975, PC-9, prostate cancer DU145, LNCAP, colon cancer HCT8, HT29, HCT-116.
  • Another aspect of the present application is to provide a use of a salt of the compound of formula (I) or a crystal form thereof, or a pharmaceutical composition thereof, in the preparation of an inhibitor that inhibits STAT3 phosphorylation, inhibits STAT3 transcriptional activity and mitochondrial oxidative phosphorylation.
  • Another aspect of the present application is to provide a method for preventing and/or treating diseases related to activation of the bifunctional phosphorylation site of STAT3, which comprises administering an effective amount of a salt of the compound of formula (I) or a crystalline form thereof, or a pharmaceutical composition thereof, to an individual in need.
  • the diseases include but are not limited to examples of malignant tumors, including astroglioma, malignant medulloblastoma, germ cell tumor, craniopharyngioma, ependymoma and other pediatric brain tumors; glioma, meningioma, pituitary adenoma, neurothecoma and other adult brain tumors; maxillary sinus cancer, pharyngeal cancer (nasopharyngeal cancer, middle pharyngeal cancer, laryngeal cancer), oral cancer, lip cancer, tongue cancer, parotid gland cancer and other head and neck cancers; small cell lung cancer, non-small cell lung cancer, thymoma, mesothelioma and other chest cancers and tumors; esophageal cancer, liver cancer, primary liver cancer, gallbladder cancer, bile duct cancer, gastric cancer, colorectal cancer, colon cancer, rectal cancer, an
  • the disease is selected from pancreatic cancer Capan-2, PANC-1, MIAPACA-2, BXPC3, SW1990, CFPAC-1, Pan02, ASPC-1, gastric cancer MKN45, BGC823, MGC803, liver cancer Huh7, PLC/PRF-5, HepG2, SK-hep1, SMMC7721, HCCC9810, lung cancer HCC827, A549, H460, H23, H1299, H522, H1975, PC-9, prostate cancer DU145, LNCAP, colon cancer HCT8, HT29 and HCT-116.
  • Another aspect of the present application is to provide a salt of the compound of formula (I) or its crystal form and its pharmaceutical composition for combined use with other drugs.
  • the other drug is a drug for preventing and/or treating cancer, renal fibrosis, pulmonary fibrosis, rheumatoid arthritis, psoriasis, lupus erythematosus, inflammatory lung disease, inflammatory bowel disease and the like.
  • the experimental operating temperature generally refers to room temperature, and "room temperature” refers to the temperature between 10°C and 30°C.
  • crystal or “crystalline form” refers to the one confirmed by the X-ray powder diffraction pattern shown. It is well known to those skilled in the art that the experimental error depends on the instrument conditions, sample preparation and sample purity, especially the X-ray powder diffraction pattern will usually change with the instrument conditions. It should be noted that the relative intensity of the X-ray powder diffraction pattern may also change with the experimental conditions, so the order of peak intensity cannot be used as the only or decisive factor. In addition, the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ⁇ 0.2° is usually allowed.
  • any crystal form having the same or similar characteristic peaks in the X-ray powder diffraction spectrum of the crystal form of the present application belongs to the scope of the present application.
  • “Stirring” can adopt conventional methods in the art, such as stirring methods including magnetic stirring and mechanical stirring, and the stirring speed is 50 to 1800 rpm, preferably 300 to 900 rpm.
  • Separatation can be carried out by conventional methods in the art, such as centrifugation or filtration.
  • the filtration is carried out under reduced pressure, generally at a pressure less than atmospheric pressure, preferably at a pressure less than 0.09 MPa.
  • Drying can be accomplished by conventional techniques in the art, such as room temperature drying, forced air drying or reduced pressure drying; it can be reduced pressure or normal pressure, preferably the pressure is less than 0.09 MPa.
  • the drying apparatus and method are not limited, and can be a fume hood, forced air oven, spray dryer, fluidized bed drying or vacuum oven; it can be carried out under reduced pressure or not, preferably the pressure is less than 0.09 MPa.
  • ratios involved in this application are mass-to-volume ratios between liquid and solid, and volume ratios between liquids.
  • substantially in crystalline form means that the crystallinity determined by X-ray powder diffraction data is greater than about 20%, more preferably greater than about 60%, even greater than about 80%, and more preferably greater than about 90%.
  • Figure 1 is the XRPD spectrum of hemifumarate Form 1 in Example 2;
  • Figure 2 is a TGA spectrum of hemifumarate Form 1 in Example 2;
  • Figure 3 is a DSC spectrum of hemifumarate Form 1 in Example 2;
  • Figure 4 is a DVS spectrum of hemifumarate Form 1 in Example 2;
  • FIG5 is a solid-state 1 H-NMR spectrum of the hemifumarate salt Form 1 in Example 2;
  • Figure 6 is the XRPD spectrum of hemifumarate Form 2 in Example 2.
  • Figure 7 is a TGA spectrum of hemifumarate Form 2 in Example 2.
  • Figure 8 is a DSC spectrum of hemifumarate Form 2 in Example 2.
  • Figure 9 is a DVS spectrum of hemifumarate Form 2 in Example 2.
  • FIG10 is a solid-state 1 H-NMR spectrum of the hemifumarate salt Form 2 in Example 2;
  • Figure 11 is the XRPD spectrum of hemifumarate Form 3 in Example 35;
  • Figure 12 is a TGA spectrum of hemifumarate Form 3 in Example 35;
  • Figure 13 is a DSC spectrum of hemifumarate Form 3 in Example 35;
  • FIG14 is a solid-state 1 H-NMR spectrum of the hemifumarate salt Form 3 in Example 35;
  • Figure 15 is the XRPD spectrum of hemifumarate Form 4 in Example 36;
  • Figure 16 is a TGA spectrum of hemifumarate Form 4 in Example 36;
  • Figure 17 is a DSC spectrum of hemifumarate Form 4 in Example 36;
  • Figure 18 is a DVS spectrum of hemifumarate Form 4 in Example 36;
  • FIG19 is a solid-state 1 H-NMR spectrum of the hemifumarate salt Form 4 in Example 36;
  • FIG20 is a single crystal simulation spectrum of hemifumarate Form 1 in Example 44;
  • Figure 21 is the XRPD spectrum of L-tartrate Form 1 in Example 46;
  • Figure 22 is a TGA spectrum of L-tartrate Form 1 in Example 46;
  • Figure 23 is a DSC spectrum of L-tartrate Form 1 in Example 46;
  • Figure 24 is a DVS spectrum of L-tartrate Form 1 in Example 46;
  • FIG25 is a solid-state 1 H-NMR spectrum of L-tartrate salt Form 1 in Example 46;
  • Figure 26 is the XRPD spectrum of L-tartrate Form 2 in Example 57;
  • Figure 27 is a TGA spectrum of L-tartrate Form 2 in Example 57;
  • Figure 28 is a DSC spectrum of L-tartrate Form 2 in Example 57;
  • FIG29 is a solid-state 1 H-NMR spectrum of L-tartrate salt Form 2 in Example 57;
  • Figure 30 is the XRPD spectrum of L-tartrate Form 3 in Example 58;
  • Figure 31 is a TGA spectrum of L-tartrate Form 3 in Example 58;
  • Figure 32 is a DSC spectrum of L-tartrate Form 3 in Example 58;
  • Figure 33 is a solid-state 1H-NMR spectrum of L-tartrate salt Form 3 in Example 58;
  • Figure 34 is an XRPD spectrum of L-tartrate Form 4 in Example 59;
  • Figure 35 is a TGA spectrum of L-tartrate Form 4 in Example 59;
  • Figure 36 is a DSC spectrum of L-tartrate Form 4 in Example 59;
  • FIG37 is a solid-state 1 H-NMR spectrum of L-tartrate salt Form 4 in Example 59;
  • Figure 38 is the XRPD spectrum of L-tartrate salt Form 5 in Example 74;
  • Figure 39 is an XRPD spectrum of L-tartrate Form 6 in Example 75;
  • FIG40 is an XRPD pattern of amorphous L-tartrate salt in Example 76;
  • FIG41 is a TGA spectrum of amorphous L-tartrate salt in Example 76;
  • FIG42 is a DSC spectrum of amorphous L-tartrate salt in Example 76;
  • FIG43 is a DVS spectrum of amorphous L-tartrate in Example 76;
  • FIG44 is a solid-state 1 H-NMR spectrum of the amorphous L-tartrate salt in Example 76;
  • Figure 45 is the XRPD spectrum of hydrochloride Form 1 in Example 77;
  • Figure 46 is a TGA spectrum of hydrochloride Form 1 in Example 77;
  • Figure 47 is a DSC spectrum of hydrochloride Form 1 in Example 77;
  • Figure 48 is a DVS spectrum of hydrochloride Form 1 in Example 77;
  • Figure 49 is the XRPD spectrum of mesylate Form 1 in Example 78;
  • Figure 50 is the XRPD spectrum of mesylate Form 2 in Example 79;
  • Figure 51 is a TGA spectrum of mesylate Form 2 in Example 79;
  • Figure 52 is a DSC spectrum of mesylate Form 2 in Example 79;
  • Figure 53 is a DVS spectrum of mesylate Form 2 in Example 79;
  • Figure 54 is the XRPD spectrum of mesylate Form 3 in Example 80;
  • Figure 55 is the XRPD spectrum of oxalate Form 1 in Example 81;
  • Figure 56 is the XRPD spectrum of oxalate Form 2 in Example 82;
  • Figure 57 is a TGA spectrum of oxalate Form 2 in Example 82;
  • Figure 58 is a DSC spectrum of oxalate Form 2 in Example 82;
  • Figure 59 is a DVS spectrum of oxalate Form 2 in Example 82;
  • FIG60 is an XRPD overlay of the hemifumarate Form 1 in Experimental Example 1 before and after being placed under high temperature (40°C and 60°C);
  • FIG61 is an XRPD overlay of the hemifumarate Form 1 in Experimental Example 1 before and after being placed under high humidity (25°C/90%RH) and accelerated (40°C/75%RH) conditions;
  • FIG62 is an XRPD overlay of the hemifumarate Form 2 in Experimental Example 1 before and after being placed under high temperature (open, 60°C, ⁇ 30% RH) conditions;
  • FIG63 is an XRPD overlay of L-tartrate Form 1 in Experimental Example 1 before and after long-term (25°C/60%RH) and accelerated (40°C/75%RH) conditions;
  • Figure 64 is an XRPD overlay of L-tartrate Form 1 in Experimental Example 1 before and after being placed under high temperature (60°C, ⁇ 30% RH) conditions;
  • Figure 65 is an XRPD overlay of L-tartrate Form 4 in Experimental Example 1 before and after long-term (25°C/60%RH) and accelerated (40°C/75%RH) conditions;
  • Figure 66 is an XRPD overlay of L-tartrate Form 4 in Experimental Example 1 before and after being placed at 40°C;
  • Figure 67 is an XRPD overlay of L-tartrate Form 4 in Experimental Example 1 before and after being placed at 50°C;
  • Figure 68 is an XRPD overlay of L-tartrate Form 4 in Experimental Example 1 before and after being placed at 55°C;
  • Figure 69 is a PSD graph of hemifumarate Form 1 in Experimental Example 2;
  • Figure 70 is a PSD graph of hemifumarate Form 2 in Experimental Example 2;
  • Figure 71 is the PSD graph of oxalate Form 2 in Experimental Example 2.
  • X-ray powder diffraction (XRPD) data were collected from a Bruker D8 Advance diffractometer; the parameters were as follows: Cu target; wavelength Current and voltage: 40KV, 40mA; Angle range: 3 ⁇ 40°2 ⁇ .
  • thermogravimetric analysis (TGA) data were collected from TA Instruments Q500TGA; the parameters were as follows: mode: high resolution mode; heating rate: 10°C/min; protective gas: N2; sample pan: platinum crucible.
  • DSC differential thermal analysis
  • vacuum drying adopts vacuum drying oven, model is D2F-6020.
  • the analytical balance model is BT125D.
  • HPLC high performance liquid chromatography
  • HPLC high performance liquid chromatography
  • the starting material compound of formula (I) can be prepared by the method mentioned in CN112300145A.
  • the results are as follows:
  • the results are as follows:
  • the results are as follows:
  • the hemifumarate of the compound of formula (I) (the compound of formula (II)) can be prepared in multiple solvent systems, and most of them are in a crystalline form with good crystallinity. Under the same conditions, most other acids cannot form salts, or the salts formed are in an amorphous state or have poor crystallinity.
  • Example 2 Preparation of the hemifumarate salt of the compound of formula (I) in crystalline form
  • the hemifumarate of the compound of formula (I) in crystalline form is exposed to an environment with a relative humidity of 75% RH and a temperature of 30°C for 2 days to obtain hemifumarate Form 1.
  • the hemifumarate of the compound of formula (I) in crystalline form is exposed to an environment with a relative humidity of ⁇ 10% RH and a temperature of 30°C for 2 days to obtain hemifumarate Form 2.
  • Example 3-5 Preparation of the hemifumarate salt of the compound of formula (I) in crystalline form
  • Example 6 Preparation of the hemifumarate salt of the compound of formula (I) in crystalline form
  • Example 7 Preparation of the hemifumarate salt of the compound of formula (I) in crystalline form
  • Example 11-34 Preparation of the hemifumarate salt of the compound of formula (I) in crystalline form
  • hemifumarate Form 2 Take about 100 mg of hemifumarate Form 2, put it in a centrifuge tube, place it in a bottle filled with ethanol at room temperature for 6 days, and after testing, hemifumarate Form 3 was obtained.
  • L-tartrate Form 2 Take about 20 mg of L-tartrate Form 1 into a 3 ml vial and place it under RT-97% relative humidity conditions for 7 days to obtain L-tartrate Form 2.
  • L-tartrate salt Form 1 About 20 mg of L-tartrate salt Form 1 was suspended in 0.5 mL of a mixed solvent of dimethyltetrahydrofuran and an alkane solvent in a volume ratio of 1:4. The suspension was stirred at 4-8°C for about 3 days, and the solid was separated to obtain L-tartrate salt Form 3.
  • L-tartrate Form 1 Take about 200 mg of L-tartrate Form 1 and dissolve it in 1 mL of a mixed solvent of acetone and methyl tert-butyl ether in a volume ratio of 1:1, filter to obtain a clear solution, and then put the clear solution into a 20 mL vial sealed with a sealing film with a pinhole on the sealing film. Leave it at room temperature to allow the pinhole to evaporate slowly. After 1 day, a solid precipitates and is separated to obtain L-tartrate Form 4.
  • L-tartrate Form 1 Take about 1.0 g of L-tartrate Form 1, suspend it in 25 mL of a mixed solvent of acetone/n-heptane with a volume ratio of 1:6, and introduce a small amount of L-tartrate Form 4 as a seed crystal. The suspension agglomerates and stirs at room temperature overnight (about 16 hours). Separate the solid to obtain L-tartrate Form 4.
  • L-tartrate Form 4 About 1.5 g of the compound of formula (I) and about 320.58 mg of L-tartaric acid are suspended in 50 mL of a 1:6 acetone/n-heptane mixed solvent, and a small amount of L-tartrate Form 4 is introduced as a seed crystal. The mixture is stirred at room temperature for about 2 days, and the solid is separated to obtain L-tartrate Form 4.
  • L-tartrate Form 1 Take about 20 mg of L-tartrate Form 1 and suspend it in 0.5 mL of methyl tert-butyl ether. After stirring the suspension at 4-8°C for about 3 days, separate the solid to obtain L-tartrate Form 4.
  • L-tartrate salt Form 1 About 20 mg was suspended in 0.5 mL of a mixed solvent of butanone and n-heptane in a volume ratio of 1:6. After the suspension was stirred at room temperature for about 3 days, the solid was separated to obtain L-tartrate salt Form 4.
  • L-tartrate Form 1 Take about 20 mg of L-tartrate Form 1 into a 3 mL vial, place it in a 20 mL vial containing 3 mL of acetone or ethyl acetate, seal the 20 mL vial with a lid, and keep it at room temperature for 7 days to allow the solvent vapor to interact with the sample and separate the solid to obtain L-tartrate Form 4.
  • L-tartrate Form 1 Take about 20 mg of L-tartrate Form 1 and dissolve it in 0.1-3.0 mL of ethyl acetate. Filter the filtrate and add about 1-2 mg of ethyl cellulose into a vial. Seal the vial containing the filtrate with a sealing film and pierce a small hole. Slowly evaporate at room temperature to separate the solid and obtain L-tartrate Form 4.
  • L-tartrate salt Form 1 About 20 mg of L-tartrate salt Form 1 was suspended in 0.5 mL of a 1:1 volume ratio isopropanol/methyl tert-butyl ether mixed solvent. After the suspension was stirred at room temperature for about 3 days, the solid was separated to obtain L-tartrate salt Form 5.
  • the high performance liquid chromatography (HPLC) detection result shows that the molar ratio of the compound of formula (I) to hydrochloric acid is 1:1.
  • L-tartrate Form 1 is placed under long-term (25°C/60%RH) and accelerated (40°C/75%RH) conditions for 1 week, and the crystal form and purity remain basically unchanged, showing good crystal stability and chemical stability.
  • L-tartrate Form 1 is placed under high temperature (60°C, ⁇ 30%RH) conditions for 10 days, and its crystal form remains basically unchanged (the results are shown in Figure 64), and the increase of related substances is ⁇ 0.05%, showing good crystal stability and chemical stability.
  • L-tartrate Form 4 remains basically unchanged in crystal form and purity after being placed under long-term (25°C/60%RH) and accelerated (40°C/75%RH) conditions for 1 week, and has good crystal stability and chemical stability.
  • an appropriate amount of L-tartrate Form 4 was placed at high temperatures of 40°C, 50°C and 55°C for 30 days in two conditions: with packaging materials and exposed, and its crystal form remained basically unchanged (the results are shown in Figures 66-68), and it has good crystal stability.
  • the repose angle of the crystal form was tested using the HYL-1001 multifunctional powder physical property analyzer of Haoyu Technology Co., Ltd. The results showed that the repose angle of oxalate Form 2 was 58.10°, and the repose angles of L-tartrate Form 1 and L-tartrate Form 4 were 40.20° and 32.73°, respectively. According to the evaluation criteria of powder indicators in Table 6, the fluidity of L-tartrate Form 4 and L-tartrate Form 1 were better than that of oxalate Form 2.
  • Tablets containing each salt form and its crystal form were prepared according to the tablet formulation in Table 8. Specifically, the components were mixed, vortexed and mixed, and all the mixtures were pressed (pressed into tablets at a pressure of 2 MPa for 2 min) using an infrared tablet press to prepare tablets.
  • the prepared hemi-fumarate Form 1 tablets, hemi-fumarate Form 2 tablets and oxalate Form 2 tablets were taken respectively, and the diameter and hardness were tested with a hardness tester, the thickness was tested with a vernier caliper, and the tensile strength was calculated.
  • the results showed that the average tensile strength of hemi-fumarate Form 1 tablets was 1.20MPa, the average tensile strength of hemi-fumarate Form 2 was 1.34MPa, and the average tensile strength of oxalate Form 2 was 1.14MPa. Under a certain pressure, the greater the tensile strength, the better the compressibility. Therefore, compared with the tablets prepared from oxalate Form 2, the tablets prepared from hemi-fumarate Form 1 and the tablets prepared from hemi-fumarate Form 2 have better compressibility.
  • Dissolution medium pH 1.2 solution (containing 0.5% Tween 80)
  • Dissolution method Paddle method, 75rpm
  • Gender and age Male, 6 to 8 weeks.
  • the blood concentration and curve area of hemifumarate Form 1, hemifumarate Form 2 and L-tartrate Form 4 have obvious advantages over the free state of the compound of formula (I), and the oral absolute bioavailability of hemifumarate Form 1, hemifumarate Form 2 and L-tartrate Form 4 has obvious advantages over the free state of the compound of formula (I).
  • Gender and age Male, 6 to 8 weeks.
  • the blood concentration and curve area of L-tartrate Form 1 have obvious advantages over the free state of the compound of formula (I), and the oral absolute bioavailability of L-tartrate Form 1 has obvious advantages over the free state of the compound of formula (I).
  • mice Animal species and strain: Balb/c nude mice
  • Gender and age Female, 7-9 weeks old.
  • Preparation and storage of dosing solution Weigh a certain amount of hemi-fumarate Form 1 (based on the free base content) into a suitable container, add the calculated amount of solvent, stir, vortex or ultrasonically mix to obtain the dosing solution of desired concentration, record the physical properties, and store at 4°C for use immediately after preparation.
  • MDA-MB-231 cells were cultured in L-15 medium containing 10% fetal bovine serum (FBS) (GIBCO, USA) in a closed culture flask without carbon dioxide and placed in an incubator at 37°C.
  • FBS fetal bovine serum
  • MDA-MB-231 cells in the logarithmic growth phase were collected, resuspended in serum-free L-15 basal medium, added to Matrigel at a ratio of 1:1, and the concentration of the cell suspension was adjusted to 6.67 ⁇ 107/ml. Under sterile conditions, 0.15 mL of the cell suspension was inoculated subcutaneously on the right back of the mouse, with an inoculation concentration of 1 ⁇ 107/0.15 mL/mouse.
  • the animals were randomly divided into groups according to the tumor volume so that the difference in tumor volume between groups was less than 10% of the mean.
  • the day of grouping was designated as Day 0, and drug administration was started according to the animal weight or the fixed dosage volume for each animal.
  • the dosing schedule is shown in Table 14.
  • the experimental period was 4 weeks. During the experiment, the animal body weight and tumor volume were measured twice a week, and the clinical symptoms of the animals were observed and recorded once a day.
  • the calculation formula for tumor volume (TV) is: 1/2 ⁇ a ⁇ b2, where a and b are the measured length and width of the tumor, respectively.
  • the relative tumor volume (RTV) calculation formula is: Vt/V0, where V0 is the tumor volume at the time of grouping and Vt is the tumor volume at each measurement.
  • the relative tumor proliferation rate T/C was calculated as follows: TRTV/CRTV ⁇ 100%, where TRTV was the RTV of the treatment group and CRTV was the RTV of the negative control group.
  • TGI tumor volume inhibition rate
  • the tumor inhibition rate (%) was calculated as follows: (TWC-TWT)/TWC ⁇ 100%, where TWC was the average tumor weight of the negative control group and TWT was the average tumor weight of the treatment group.
  • BWC (%) (BWt-BW0)/BW0 ⁇ 100%, where BWt is the animal weight at each measurement and BW0 is the animal weight when grouped.
  • the tumor growth curve was drawn with time point as X-axis and tumor volume (mm 3 ) as Y-axis; the animal weight change curve was drawn with time point as X-axis and animal weight (g) as Y-axis.
  • the two-tailed t-test was used for comparison between groups, with P ⁇ 0.05 as significant difference and P ⁇ 0.01 as extremely significant difference.
  • the average tumor volume of the vehicle control group was 564.69 ⁇ 26.44mm 3
  • the average tumor volume of the hemi-fumarate Form 1 (10mg/kg) group was 138.60 ⁇ 14.36mm 3
  • the tumor volume inhibition rate TGI (%) was 75.46%
  • the relative tumor proliferation rate T/C after administration was 23.91%, which was less than 40%, and it could significantly inhibit the growth of human breast cancer MDA-MB-231 cell Balb/c nude mouse xenograft tumors.
  • the average tumor volume of the L-tartrate Form 4 (10mg/kg) group was 116.17 ⁇ 7.25, the tumor volume inhibition rate TGI (%) was 79.43%, and the relative tumor proliferation rate T/C after administration was 20.37%, which was less than 40%, and it could significantly inhibit the growth of human breast cancer MDA-MB-231 cell Balb/c nude mouse xenograft tumors.
  • Gender and age Female, 6-7 weeks old.
  • Preparation and storage of dosing solution Weigh a certain amount of hemi-fumarate Form 1 (based on the free base content) into a suitable container, add the calculated amount of solvent, stir, vortex or ultrasonically mix to obtain the dosing solution of desired concentration, record the physical properties, and prepare and use at room temperature.
  • MOLM16 cells were cultured in RPMI-1640 medium containing 20% FBS and maintained in a 37°C saturated humidity incubator with 5% CO 2 .
  • MOLM16 cells in logarithmic growth phase were collected, resuspended in RPMI-1640 basal medium, and matrigel was added at a ratio of 1:1 to adjust the cell concentration to 1 ⁇ 10 7 /mL.
  • 0.1mL of cell suspension was inoculated subcutaneously on the right back of nude mice at an inoculation concentration of 1 ⁇ 10 6 /0.1mL/mouse.
  • the animals were randomly divided into groups according to the tumor volume so that the difference in tumor volume between groups was less than 10% of the mean.
  • the day of grouping was designated as Day 0, and drug administration was started according to the animal weight or the fixed administration volume for each animal.
  • the administration schedule is shown in Table 16.
  • the experimental period was 2 weeks. During the experiment, the animal body weight and tumor volume were measured twice a week, and the clinical symptoms of the animals were observed and recorded once a day.
  • the average tumor volume of the vehicle control group was 1788.88 ⁇ 132.86mm 3
  • the average tumor volume of the hemi-fumarate Form 1 (1mg/kg, 3mg/kg and 10mg/kg) groups was 172.85 ⁇ 14.02mm 3 , 120.33 ⁇ 3.15mm 3 and 64.08 ⁇ 7.11mm 3 , respectively
  • mice Animal species and strain: CB-17 SCID mice.
  • Gender and age Female, 6-8 weeks old.
  • Body weight 18-22 g, deviation is ⁇ 20% of the mean body weight.
  • Preparation and storage of dosing solution Weigh a certain amount of hemi-fumarate Form 1 (based on the free base content) into a suitable container, add the calculated amount of solvent, stir, vortex or ultrasonically mix to obtain the dosing solution of desired concentration, record the physical properties, and store at 4°C for use immediately after preparation.
  • SU-DHL-1 cells were cultured in RPMI-1640 medium containing 10% FBS and maintained in a 37°C humidified incubator with 5% CO 2 .
  • SU-DHL-1 cells in the logarithmic growth phase were collected, resuspended in RPMI-1640 basal medium, and matrigel was added at a ratio of 1:1 to adjust the cell concentration to 3 ⁇ 10 7 /mL.
  • matrigel was added at a ratio of 1:1 to adjust the cell concentration to 3 ⁇ 10 7 /mL.
  • 0.1 mL of the cell suspension was inoculated subcutaneously on the right back of nude mice at an inoculation concentration of 3 ⁇ 10 6 /0.1 mL/mouse.
  • the animals were randomly divided into groups according to the tumor volume so that the difference in tumor volume between groups was less than 10% of the mean.
  • the day of grouping was designated as Day 0, and drug administration was started according to the animal weight or the fixed administration volume for each animal.
  • the administration schedule is shown in Table 18.
  • the experimental period was 3 weeks. During the experiment, the animal body weight and tumor volume were measured twice a week, and the clinical symptoms of the animals were observed and recorded once a day.
  • the average tumor volume of the vehicle control group was 2029.90 ⁇ 204.72 mm 3
  • the average tumor volume of the hemi-fumarate Form 1 (10 mg/kg) group was 316.83 ⁇ 97.40 mm 3
  • Hemi-fumarate Form 1 could significantly inhibit the growth of human metastatic large cell lymphoma SU-DHL-1 cell CB-17 SCID mouse xenograft tumors.
  • mice Animal species and strains: mice, NOD-SCID
  • Gender and age Male, 6-8 weeks.
  • Preparation of test compound Preparation of solvent: Take an appropriate amount of Tween80 and add 99ml of 0.5% MC, vortex mix, and set aside;
  • Preparation of dosing solution Weigh a certain amount of the free form of the compound of formula (I) and L-tartrate Form 1 (based on the content of free base) into a suitable container, add a calculated amount of solvent, stir and mix to obtain a dosing solution of the desired concentration, which is prepared and used immediately.
  • Molm16 cells were cultured in 1640 medium containing 20% inactivated fetal bovine serum (Gbico-10099141) and 1% penicillin/streptomycin, and cultured continuously in a cell culture flask in a cell culture incubator at 37°C containing 5% CO2; when the cells grew to the logarithmic growth phase, the cells were collected and washed once with PBS, the cells were counted, centrifuged, and finally resuspended with PBS, 50% Matrigel (Cultrex PathClear BM, 3432-010-01P) was added, and the cell concentration was adjusted for subsequent inoculation; 3 ⁇ 10 6 cells were inoculated in the right axilla of each mouse, and the inoculation volume was 100ul.
  • Gbico-10099141 inactivated fetal bovine serum
  • penicillin/streptomycin penicillin/streptomycin
  • the tumor volume calculation formula: 0.5a ⁇ b 2
  • a and b represent the length and width of the tumor, respectively, and the tumor volume was used to calculate the tumor volume, and the grouping was based on the tumor volume.
  • Tumors with a volume of 80 mm 3 to 120 mm 3 were randomly grouped, and the mean tumor volume of each group was 93 mm 3 , and then the drug was administered.
  • the drug administration scheme is shown in Table 20.
  • the health status and mortality of animals were monitored daily. Routine inspections included observing the effects of the test substances and drugs on the daily behavior of animals, such as behavioral activities, food and water intake, body weight changes (body weight was measured twice a week), physical signs or other abnormal conditions.
  • Tumor diameters were measured twice a week, and tumor volumes were calculated.
  • TGI% (1-T/C) ⁇ 100%
  • Two-way ANOVA was used to compare body weight and tumor volume.
  • One-way ANOVA was used to compare tumor weight at the end point of the experiment. All data will be analyzed using GraphPad Prism 8, and p ⁇ 0.05 indicated statistical significance.
  • Experimental Example 13 Study on the inhibitory effect of L-tartrate Form 4 on the growth of human pancreatic cancer BxPC-3 cell Balb/c nude mouse xenograft tumors.
  • Experimental purpose To evaluate the anti-tumor activity of L-tartrate Form 4 using a human pancreatic cancer BxPC-3 cell Balb/c nude mouse xenograft tumor model.
  • mice Animal species and strain: Balb/c nude mice
  • Gender and age Female, 9-11 weeks old.
  • Body weight 21-24 g, with a deviation of ⁇ 20% from the mean body weight.
  • Solution preparation and storage Preparation of solvent (0.5% MC solution): Pipette an appropriate amount of MC into a suitable container, add a calculated amount of ddH2O, stir, vortex or sonicate to fully dissolve, and seal for later use.
  • Preparation and storage of dosing solution Weigh a certain amount of L-tartrate Form 4 (based on the content of free base) into a suitable container, add the calculated amount of solvent, stir, vortex or ultrasonically mix to obtain the desired concentration of dosing solution, and record the physical properties. 4°C, prepare and use immediately.
  • BxPC-3 cells were cultured in RPMI-1640 medium containing 10% FBS and maintained in a 37°C saturated humidity incubator with 5% CO 2 .
  • BxPC-3 cells in logarithmic growth phase were collected, resuspended in RPMI-1640 basal medium, and matrigel was added at a ratio of 1:1 to adjust the cell concentration to 5 ⁇ 10 7 /mL.
  • matrigel was added at a ratio of 1:1 to adjust the cell concentration to 5 ⁇ 10 7 /mL.
  • 0.1 mL of cell suspension was inoculated subcutaneously on the right back of nude mice at an inoculation concentration of 5 ⁇ 10 6 /0.1 mL/mouse.
  • the animals were randomly divided into groups according to the tumor volume so that the difference in tumor volume between groups was less than 10% of the mean.
  • the day of grouping was designated as Day 0, and drug administration was started according to the animal weight or the fixed administration volume for each animal.
  • the administration schedule is shown in Table 22.
  • the experimental period was 4 weeks. During the experiment, the animal body weight and tumor volume were measured twice a week, and the clinical symptoms of the animals were observed and recorded once a day.
  • the average tumor volume of the vehicle control group was 1175.00 ⁇ 147.32mm 3
  • the average tumor volume of the 3mg/kg group and the 10mg/kg group of L-tartrate Form 4 was 379.47 ⁇ 65.56mm 3 and 307.27 ⁇ 49.38mm 3 , respectively.
  • the tumor volume inhibition rate TGI (%) was 67.70% and 73.85%, respectively.
  • the relative tumor proliferation rate T/C after administration was 32.44% and 26.78%, respectively, which was less than 40%.
  • L-tartrate Form 4 can significantly inhibit the growth of human pancreatic cancer BxPC-3 cell Balb/c nude mouse xenograft tumors.
  • mice Animal species and strain: Balb/c nude mice
  • Gender and age female, 8-9 weeks old.
  • Body weight 18-22 g, deviation is ⁇ 20% of the mean body weight.
  • Solution preparation and storage Preparation of solvent (0.5% MC solution): Pipette an appropriate amount of MC into a suitable container, add a calculated amount of ddH 2 O, stir, vortex or ultrasonicate to fully dissolve, and seal for later use.
  • Preparation and storage of dosing solution Weigh a certain amount of L-tartrate Form 4 (based on the content of free base) into a suitable container, add the calculated amount of solvent, stir, vortex or ultrasonically mix to obtain the desired concentration of dosing solution, and record the physical properties. 4°C, prepare and use immediately.
  • NCI-H460 cells were cultured in RPMI-1640 medium containing 10% FBS and maintained in a 37°C saturated humidity incubator with 5% CO2.
  • NCI-H460 cells in the logarithmic growth phase, resuspend them in RPMI-1640 basal medium, add matrix gel at a ratio of 1:1, and adjust the cell concentration to 2 ⁇ 107/mL. Under sterile conditions, inoculate 0.1mL of the cell suspension subcutaneously on the right back of nude mice at an inoculation concentration of 2 ⁇ 106/0.1mL/mouse.
  • the animals were randomly divided into groups according to the tumor volume so that the difference in tumor volume between groups was less than 10% of the mean.
  • the day of grouping was designated as Day 0, and drug administration was started according to the animal weight or the fixed administration volume for each animal.
  • the administration schedule is shown in Table 24.
  • the experimental period was 17 days. During the experiment, the animal body weight and tumor volume were measured twice a week, and the clinical symptoms of the animals were observed and recorded once a day.
  • the average tumor volume of the vehicle control group was 2109.69 ⁇ 113.70 mm 3
  • the average tumor volume of the 3 mg/kg group and the 10 mg/kg group of L-tartrate Form 4 were 803.58 ⁇ 42.42 and 710.49 ⁇ 52.36, respectively
  • the tumor volume inhibition rate TGI (%) was 61.91% and 66.32%, respectively
  • the relative tumor growth rate TGI (%) after administration was 38.29% and 33.68%, respectively, which was less than 40%.
  • L-tartrate Form 4 can significantly inhibit the growth of human non-small cell lung cancer NCI-H460 cell Balb/c nude mouse xenograft tumors.

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Abstract

La présente demande relève du domaine de la chimie pharmaceutique. Plus particulièrement, la présente demande concerne un dérivé de cycle triaromatique, en particulier un sel de (6-((5-(3-(4-(trifluorométhyl)phényl)-1,2,4-oxadiazole-5-yl)pyrazine-2-yl)oxy)-1-méthyl-1H-indol-2-yl)(4-(4-(2,2,2-trifluoroéthoxy)benzyl)pipérazin-1-yl)méthanone, une forme cristalline de celui-ci, une composition pharmaceutique de celui-ci, un procédé de préparation correspondant et une utilisation associée. Le sel et la forme cristalline de celui-ci selon la présente demande ont une bonne stabilité, une solubilité élevée, une haute biodisponibilité, une bonne efficacité, une bonne dissolution de comprimé, une bonne compressibilité de comprimé, une bonne fluidité, une bonne morphologie cristalline, une bonne distribution de taille de particule cristalline, peuvent être stockés de manière stable, et ont un procédé de préparation simple et fiable et une grande valeur de développement.
PCT/CN2024/083481 2023-03-27 2024-03-25 Sel de dérivé cyclique triaromatique, forme cristalline de celui-ci, procédé de préparation correspondant et utilisation associée Pending WO2024199167A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101842367A (zh) * 2007-10-30 2010-09-22 大塚制药株式会社 杂环化合物及其药物组合物
JP2010275302A (ja) * 2009-04-28 2010-12-09 Otsuka Pharmaceut Co Ltd 医薬組成物
CN104736535A (zh) * 2012-08-24 2015-06-24 德州大学系统董事会 用于治疗疾病的hif活性的杂环调节剂
CN112300145A (zh) * 2019-07-31 2021-02-02 上海宇耀生物科技有限公司 一类靶向stat3双功能磷酸化位点的三芳香环类化合物及其应用

Patent Citations (4)

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Publication number Priority date Publication date Assignee Title
CN101842367A (zh) * 2007-10-30 2010-09-22 大塚制药株式会社 杂环化合物及其药物组合物
JP2010275302A (ja) * 2009-04-28 2010-12-09 Otsuka Pharmaceut Co Ltd 医薬組成物
CN104736535A (zh) * 2012-08-24 2015-06-24 德州大学系统董事会 用于治疗疾病的hif活性的杂环调节剂
CN112300145A (zh) * 2019-07-31 2021-02-02 上海宇耀生物科技有限公司 一类靶向stat3双功能磷酸化位点的三芳香环类化合物及其应用

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Title
ZHAO LI-PING, SONG DAN-QING, WANG YAN-XIANG: "Advances in small molecular inhibitors of IL-6/STAT3 signaling pathway", ACTA PHARMACEUTICA SINICA, YAOXUE XUEBAO, CN, vol. 56, no. 9, 22 June 2021 (2021-06-22), CN , pages 2472 - 2484, XP093217023, ISSN: 0513-4870, DOI: 10.16438/j.0513-4870.2021-0233 *

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