WO2022206937A1 - 一种吡唑取代的烟酰胺类化合物的盐酸盐新晶型及其制备方法 - Google Patents

一种吡唑取代的烟酰胺类化合物的盐酸盐新晶型及其制备方法 Download PDF

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WO2022206937A1
WO2022206937A1 PCT/CN2022/084708 CN2022084708W WO2022206937A1 WO 2022206937 A1 WO2022206937 A1 WO 2022206937A1 CN 2022084708 W CN2022084708 W CN 2022084708W WO 2022206937 A1 WO2022206937 A1 WO 2022206937A1
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formula
compound
hydrochloride salt
crystal form
hydrochloride
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PCT/CN2022/084708
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English (en)
French (fr)
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鲁霞
陈智雄
张晓宇
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苏州晶云药物科技股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention relates to (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(1H-pyrazol-5-yl)
  • Bcr-Abl tyrosine kinase is a protein kinase expressed by the bcr-abl oncogene.
  • the persistent activity of Bcr-Abl tyrosine kinase is one of the causes of chronic myeloid leukaemia (CML).
  • CML chronic myeloid leukaemia
  • Enhanced kinase activity undertakes intracellular phosphorylation and activation of various signaling molecules, which accelerate cell proliferation while inhibiting cell apoptosis. Therefore, inhibition of Bcr-Abl tyrosine kinase activity is an effective way to target and treat CML.
  • Patent US20130310395A1 discloses compound (I) and its preparation method.
  • the disclosed synthesis method of the compound in formula (I) needs to be purified by chromatographic column or evaporated under reduced pressure to obtain the final product.
  • the chromatographic method takes a long time, consumes a large amount of solvent, and is industrially enlarged. It is difficult and expensive.
  • the evaporation under reduced pressure can relatively reduce the solvent consumption, it cannot achieve the effect of purifying the final product.
  • the free base crystal form and hydrochloride salt crystal form of compound (I) are disclosed in WO2020230099A1. Among them, the free base crystal form has lower solubility than hydrochloride, and its inherent dissolution rate in water and other media is lower than that of hydrochloride.
  • hydrochloride form A The preparation process of the hydrochloride form A is complicated, and it needs to go through multiple steps of heating and cooling, aging, and solvent addition before it can be prepared, and it is difficult to meet the requirements of industrial production.
  • the hydrochloride salt form A is unstable in water and readily converts to the free base forms A and HA.
  • the hydrochloride salt, Form B is less stable and undergoes transcrystallization under ambient conditions. Therefore, it is necessary to find other crystal forms of compound (I) to meet the needs of industrial production and clinical application.
  • Drug polymorphism is a common phenomenon in solid drugs, and the physicochemical properties of drugs in different crystal forms will be different. These properties can directly affect the production and storage of drugs, which may affect the effect of drugs in the human body. Therefore, in order to select the most suitable crystal form for development, it is necessary to conduct a comprehensive and systematic crystal form screening of the compound of formula (I).
  • the crystal forms described below are all the hydrochloride salt crystal forms of the compound (I).
  • the hydrochloride salt crystal form L of the compound of formula (I) using Cu-K ⁇ radiation to obtain an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , the powder X-ray diffraction pattern comprising: Characteristic peaks located at diffraction angles (2 ⁇ ) of 5.9° ⁇ 0.2°, 16.8° ⁇ 0.2°, 24.7° ⁇ 0.2°.
  • the powder X-ray diffraction pattern of the hydrochloride salt form L of the compound of formula (I) further comprises at least one characteristic peak at the following diffraction angle (2 ⁇ ): 19.5° ⁇ 0.2 °, 23.6° ⁇ 0.2°.
  • the powder X-ray diffraction pattern of the hydrochloride salt form L of the compound of formula (I) further comprises at least one characteristic peak at the following diffraction angle (2 ⁇ ): 22.1° ⁇ 0.2 °, 11.3° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the hydrochloride salt form L of the compound of formula (I) is substantially the same as FIG. 6 .
  • the X-ray powder diffraction pattern of the hydrochloride salt form L of the compound of formula (I) is substantially the same as that in FIG. 2 or FIG. 5 .
  • the alcoholic solvent in the method comprises isopropanol.
  • a pharmaceutical composition comprising the hydrochloride salt crystal form L of the compound represented by the formula (I) and one or more pharmaceutically acceptable carriers, diluents or excipients .
  • the hydrochloride salt crystal form L of the compound represented by the formula (I) and the pharmaceutical composition are provided in the preparation of the prevention and/or treatment of Bcr-Abl tyrosine kinase-mediated diseases use in medicines.
  • a method for preventing and/or treating a disease mediated by Bcr-Abl tyrosine kinase comprising administering to the patient a therapeutically effective amount of the compound represented by the formula (I)
  • the hydrochloride salt crystal form L or the pharmaceutical composition comprising administering to the patient a therapeutically effective amount of the compound represented by the formula (I)
  • the hydrochloride salt crystal form L or the pharmaceutical composition comprising administering to the patient a therapeutically effective amount of the compound represented by the formula (I)
  • the hydrochloride salt crystal form L or the pharmaceutical composition comprising administering to the patient a therapeutically effective amount of the compound represented by the formula (I)
  • the hydrochloride salt crystal form L or the pharmaceutical composition comprising administering to the patient a therapeutically effective amount of the compound represented by the formula (I)
  • the hydrochloride salt crystal form L or the pharmaceutical composition comprising administering to the patient a therapeutically effective amount of the compound represented by the formula (I)
  • a medicine for preventing and/or treating the disease mediated by Bcr-Abl tyrosine kinase which comprises the hydrochloric acid of the compound shown in the formula (I) in a therapeutically effective amount.
  • Salt crystal form L or the pharmaceutical composition which comprises the hydrochloric acid of the compound shown in the formula (I) in a therapeutically effective amount.
  • the Bcr-Abl tyrosine kinase mediated disease comprises chronic myeloid leukemia.
  • the hydrochloride salt crystal form F of the compound of formula (I) using Cu-K ⁇ radiation to obtain an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , the powder X-ray diffraction pattern comprising: Characteristic peaks located at diffraction angles (2 ⁇ ) of 16.9° ⁇ 0.2°, 9.6° ⁇ 0.2°, 10.4° ⁇ 0.2°.
  • the powder X-ray diffraction pattern of the hydrochloride salt form F of the compound of formula (I) further comprises at least one characteristic peak at the following diffraction angle (2 ⁇ ): 20.4° ⁇ 0.2 °, 16.1° ⁇ 0.2°, 23.5° ⁇ 0.2°.
  • the powder X-ray diffraction pattern of the hydrochloride salt form F of the compound of formula (I) further comprises at least one characteristic peak at the following diffraction angle (2 ⁇ ): 22.0° ⁇ 0.2 °, 11.0° ⁇ 0.2°, 12.7° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the hydrochloride salt form F of the compound of formula (I) is substantially the same as FIG. 7 .
  • a method for preparing the hydrochloride salt form F of the compound of formula (I) comprising: using the compound of formula (I) as an amorphous sample of hydrochloride at room temperature
  • the starting material is stirred into a suspended state by adding an ether solvent, and the suspension is centrifuged and evaporated to dryness at room temperature to obtain the hydrochloride salt crystal form F.
  • the ether solvent in the method includes methyl tert-butyl ether.
  • a pharmaceutical composition which comprises the hydrochloride salt crystal form F of the compound represented by the formula (I) and one or more pharmaceutically acceptable carriers, diluents or excipients .
  • the hydrochloride salt crystal form F of the compound represented by the formula (I) and the pharmaceutical composition are provided in the preparation of the prevention and/or treatment of Bcr-Abl tyrosine kinase-mediated diseases use in medicines.
  • a method for preventing and/or treating a disease mediated by Bcr-Abl tyrosine kinase comprising administering to the patient a therapeutically effective amount of the compound represented by the formula (I)
  • the hydrochloride salt crystal form F or the pharmaceutical composition comprising administering to the patient a therapeutically effective amount of the compound represented by the formula (I)
  • the hydrochloride salt crystal form F or the pharmaceutical composition comprising administering to the patient a therapeutically effective amount of the compound represented by the formula (I)
  • the hydrochloride salt crystal form F or the pharmaceutical composition comprising administering to the patient a therapeutically effective amount of the compound represented by the formula (I)
  • the hydrochloride salt crystal form F or the pharmaceutical composition comprising administering to the patient a therapeutically effective amount of the compound represented by the formula (I)
  • the hydrochloride salt crystal form F or the pharmaceutical composition comprising administering to the patient a therapeutically effective amount of the compound represented by the formula (I)
  • a medicine for preventing and/or treating the disease mediated by Bcr-Abl tyrosine kinase which comprises the hydrochloric acid of the compound shown in the formula (I) in a therapeutically effective amount.
  • Salt crystal form F or the pharmaceutical composition which comprises the hydrochloric acid of the compound shown in the formula (I) in a therapeutically effective amount.
  • the Bcr-Abl tyrosine kinase mediated disease comprises chronic myeloid leukemia.
  • a hydrochloride salt crystal form J of the compound of formula (I) using Cu-K ⁇ radiation to obtain an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , the powder X-ray diffraction pattern comprising: Characteristic peaks located at diffraction angles (2 ⁇ ) of 20.8° ⁇ 0.2°, 21.2° ⁇ 0.2°, 7.3° ⁇ 0.2°.
  • the powder X-ray diffraction pattern of the hydrochloride salt form J of the compound of formula (I) further comprises at least one characteristic peak at the following diffraction angle (2 ⁇ ): 19.9° ⁇ 0.2 °, 12.8° ⁇ 0.2°.
  • the powder X-ray diffraction pattern of the hydrochloride salt form J of the compound of formula (I) further comprises at least one characteristic peak at the following diffraction angle (2 ⁇ ): 8.8° ⁇ 0.2 °, 21.6° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the hydrochloride salt form J of the compound of formula (I) is substantially the same as FIG. 10 .
  • a method for preparing the hydrochloride salt form J of the compound of formula (I) is provided.
  • the sample was dissolved in a nitrogen-containing solvent, added to a ketone solvent pre-cooled at -20°C to 5°C, and the solid was precipitated to obtain the hydrochloride salt crystal form J.
  • the nitrogen-based solvent in the method includes N,N-dimethylacetamide
  • the ketone-based solvent includes methyl isobutyl ketone
  • a pharmaceutical composition comprising the hydrochloride salt crystal form J of the compound represented by the formula (I) and one or more pharmaceutically acceptable carriers, diluents or excipients .
  • hydrochloride salt crystal form J of the compound represented by the formula (I) and the pharmaceutical composition in the preparation of preventing and/or treating Bcr-Abl tyrosine kinase-mediated diseases use in medicines.
  • a method for preventing and/or treating a disease mediated by Bcr-Abl tyrosine kinase comprising administering to the patient a therapeutically effective amount of the compound represented by the formula (I)
  • the hydrochloride salt crystal form J or the pharmaceutical composition comprising administering to the patient a therapeutically effective amount of the compound represented by the formula (I)
  • the hydrochloride salt crystal form J or the pharmaceutical composition comprising administering to the patient a therapeutically effective amount of the compound represented by the formula (I)
  • the hydrochloride salt crystal form J or the pharmaceutical composition comprising administering to the patient a therapeutically effective amount of the compound represented by the formula (I)
  • the hydrochloride salt crystal form J or the pharmaceutical composition comprising administering to the patient a therapeutically effective amount of the compound represented by the formula (I)
  • the hydrochloride salt crystal form J or the pharmaceutical composition comprising administering to the patient a therapeutically effective amount of the compound represented by the formula (I)
  • a medicine for preventing and/or treating the disease mediated by Bcr-Abl tyrosine kinase which comprises the hydrochloric acid of the compound shown in the formula (I) in a therapeutically effective amount.
  • Salt crystal form J or the pharmaceutical composition which comprises the hydrochloric acid of the compound shown in the formula (I) in a therapeutically effective amount.
  • the Bcr-Abl tyrosine kinase mediated disease comprises chronic myeloid leukemia.
  • a pharmaceutical composition comprising a plurality of the hydrochloride salt crystal form L, the hydrochloride salt crystal form F, the hydrochloride salt crystal form J, and a one or more pharmaceutically acceptable carriers, diluents or excipients.
  • a method for preventing and/or treating a disease mediated by Bcr-Abl tyrosine kinase comprising administering to the patient a therapeutically effective amount of the hydrochloride crystal form L, A plurality of the hydrochloride salt crystal form F, the hydrochloride salt crystal form J or the pharmaceutical composition.
  • a medicament for preventing and/or treating a disease mediated by Bcr-Abl tyrosine kinase comprising a therapeutically effective amount of the hydrochloride crystal form L, the The hydrochloride salt crystal form F, a plurality of the hydrochloride salt crystal form J or the pharmaceutical composition.
  • the Bcr-Abl tyrosine kinase mediated disease comprises chronic myeloid leukemia.
  • Figure 1 shows the XRPD pattern of the hydrochloride salt crystal form A described in the present application
  • Figure 2 shows the XRPD pattern of Example 2 hydrochloride crystal form L described in the application
  • FIG. 3 shows the TGA curve of Example 2 hydrochloride crystal form L described in the application
  • Figure 4 shows the DSC curve of Example 2 hydrochloride crystal form L described in this application
  • Figure 5 shows the XRPD pattern of Example 3 hydrochloride crystal form L described in the application
  • Figure 6 shows the XRPD pattern of Example 4 hydrochloride crystal form L described in the present application
  • Figure 7 shows the XRPD pattern of the hydrochloride salt crystal form F described in the present application.
  • Figure 8 shows the TGA curve of the hydrochloride salt crystal form F described in the present application.
  • Figure 9 shows the DSC curve of the hydrochloride salt crystal form F described in the present application.
  • Figure 10 shows the XRPD pattern of the hydrochloride salt crystal form J described in the present application.
  • Figure 11 shows the solubility comparison curves of different crystal forms described in the present application in pure water
  • Figure 12 shows the PLM diagram of the hydrochloride salt crystal form L described in the present application
  • Figure 13 shows the particle size distribution diagram of the hydrochloride Form A described in the present application
  • Figure 14 shows the particle size distribution of the hydrochloride crystal form L described in the present application
  • Figure 15 shows the XRPD comparison chart of the stability test of the hydrochloride crystal form L described in the present application at 25°C/60% relative humidity
  • amorphous or “amorphous form” is intended to mean that the substance, component or product in question lacks a characteristic crystalline shape or crystalline structure, eg, is not substantially crystalline or all
  • the substance, component or product in question for example, is not birefringent when viewed using a polarized light microscope, or the X-ray powder diffraction pattern has no sharp peaks.
  • a sample comprising an amorphous form of a substance may be substantially free of other amorphous and/or crystalline forms.
  • polymorphic or "polymorphism” as used herein is defined as the possibility of at least two different crystallographic arrangements for the same chemical molecule.
  • polymorph refers to solid crystalline forms of compounds or complexes, including, but not limited to, single component or multiple Component crystals, and/or polymorphs, solvates, hydrates, clathrates, co-crystals, salts, solvates of salts, hydrates of salts of the compounds.
  • Polymorphs can be detected, identified, classified and characterized using techniques well known to those skilled in the art such as, but not limited to: Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), X-ray Powder Diffraction method (XRPD), single crystal X-ray diffraction method, vibrational spectroscopy, solution calorimetry, solid state nuclear magnetic resonance (SSNMR), Fourier transform-infrared spectroscopy (FT-IRspectrum) method, Raman spectroscopy (Ramanspectrum) method, thermal Stage optical microscopy, scanning electron microscopy (SEM), electron crystallography, and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility and dissolution rate.
  • DSC Differential Scanning Calorimetry
  • TGA Thermogravimetric Analysis
  • XRPD X-ray Powder Diffraction method
  • FT-IRspectrum Fourier transform-infrared spectroscopy
  • Raman spectroscopy Raman
  • Polymorphism can be described as the ability of a particular compound to crystallize in different crystal modifications while maintaining the same chemical structural formula. Polymorphs of a given substance are chemically equivalent, containing the same atoms bonded to each other in the same way, but in different crystalline forms that affect one or more physical properties, such as dissolution rate ), melting point, bulk density, stability, flow properties, etc.
  • the graphical representation of such data may vary slightly (eg, peak relative intensities and peak positions) due to factors such as changes in instrument response and changes in sample concentration and purity, which are well known to those skilled in the art. Nonetheless, those skilled in the art are able to compare the pattern data in the graph of the present invention with the pattern data generated for the unknown crystal form, and can confirm whether the two sets of pattern data represent the same crystal form.
  • XRPD X-ray powder diffraction
  • the equipment used to obtain the X-ray powder diffraction pattern, humidity, temperature, orientation of powder crystals, and other parameters may cause diffraction
  • Some variability in the appearance, intensity, and position of peaks in the graph See, for example, The United States Pharmacopeia #23, National Formulary #18, pp. 1843-1844, 1995.
  • the variability of ⁇ 0.2° 2 ⁇ peak positions takes into account these possible variations without preventing unambiguous identification of the crystal forms shown. Identification of a crystalline form can be based on any unique difference peak (in °2 ⁇ units) or a combination thereof, typically the more pronounced peaks.
  • crystalline compounds of the present invention are characterized by XRPD patterns having certain peak positions having substantially the same characteristics as the XRPD patterns provided in the accompanying figures of the present invention.
  • XRPD patterns having certain peak positions having substantially the same characteristics as the XRPD patterns provided in the accompanying figures of the present invention.
  • an X-ray powder diffraction pattern "substantially consistent" with Figures 3, 7 or 8 provided by the present invention may be the same as the XRPD pattern in the accompanying figures, or more likely it may be slightly different.
  • Such XRPD patterns may not necessarily show every peak in the diffractogram presented by the present invention, and/or may show slight changes in the appearance, intensity or displacement of the peaks due to differences in the conditions involved in obtaining the data.
  • a sample of a crystalline compound has the same crystal form or a different crystal form than the one disclosed herein.
  • a given diffraction peak position (in °2 ⁇ ) from an XRPD pattern is at approximately the same position as the values presented herein.
  • the 2 ⁇ values in an X-ray powder diffraction pattern are all in degrees (°).
  • the melting peak height of a DSC curve depends on many related factors such as sample preparation and testing instrument conditions, while peak position is relatively insensitive to experimental details. Accordingly, in some embodiments, the crystalline compounds of the present invention are characterized by DSC patterns having characteristic peak positions having substantially the same properties as the DSC patterns provided in the accompanying drawings of the present invention. Depending on the condition of the instrument used for this test, there is an error tolerance of ⁇ 3°C, ⁇ 4°C or ⁇ 5°C for the melting temperature.
  • the position and shape of the absorption peaks of the infrared spectrum depend on the transitions in the kinetic energy levels of covalent bonds in the sample molecules. Accordingly, in some embodiments, the crystalline compounds of the present invention are characterized by Fourier transform-infrared spectrograms having characteristic peak positions and shapes, having substantially the same properties as the Fourier transform-infrared spectrograms provided in the accompanying drawings of the present invention .
  • the absorption peak has an error tolerance of ⁇ 5cm -1 near 3000cm -1 and ⁇ 2cm near 1000cm -1 -1 error tolerance.
  • X-ray powder diffractograms, DSC graphs, Raman spectra and Fourier transform-infrared spectra “substantially identical” or “substantially identical” means X-ray powder diffractograms, DSC graphs, Raman spectra and Fourier Transform-Infrared Spectrum at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks shown in the graph.
  • an X-ray powder diffraction pattern in the present invention that is "substantially the same” is meant to take into account typical X-ray diffraction peak positions and intensity variability.
  • peak position (2 ⁇ ) will vary from XRPD instrument to measurements, sometimes by as much as 0.2°.
  • factors such as XRPD sample preparation method, XRPD instrument, sample crystallinity, sample amount, and preferred crystallographic orientation will cause changes in relative peak intensities in the XRPD diffractogram of the sample.
  • nicotinamide (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(1H-pyrazole-5-
  • the new crystalline forms of nicotinamide include hydrochloride salt form L, hydrochloride salt form F, hydrochloride salt form J, all of which exist in substantially pure crystalline form.
  • substantially pure refers to chemical purity and crystalline form purity, more specifically, a crystalline form is substantially free of another crystalline form or forms, ie, the crystalline form is at least 60% pure, or at least 70% pure %, or at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7 %, or at least 99.8%, or at least 99.9%, or the crystal form contains other crystal forms whose percentage in the total volume or total weight of the crystal form is less than 30%, or less than 20%, or Less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.
  • the purity of the crystals of the present invention can be determined, for example, by known methods such as X-ray powder diffraction, thermal analysis and the like.
  • the purity of the crystals or mixed crystals of the present invention does not need to be 100%, and may be not lower than 70%, or not lower than 80%, or not lower than 90%, or not lower than 95%, or not lower than 98% . And the purity within this range can guarantee the quality.
  • solution refers to a mixture comprising at least one solvent and at least one compound in which the compound is at least partially soluble.
  • solvate means having a solvent on the surface, in the crystal lattice or on the surface and in the crystal lattice, such as water, acetic acid, acetone, acetonitrile, benzene, chloroform, tetrachloride Carbon, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-diol Methylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, l-methyl-2-pyrrolidone, nitromethane, polyethylene glycol, propanol, 2-propanone, pyridine, tetrahydrofuran, toluene, xylene, mixtures
  • a specific example of a solvate is a hydrate, wherein the solvent on the surface, in the lattice or both on the surface and in the lattice is water. Hydrates may or may not have solvents other than water on the surface of the substance, in the lattice, or both on the surface and in the lattice.
  • positive solvent used in the present invention means that the compound represented by formula (I) of the present invention has good solubility in the solvent, for example, methanol, ethanol, N,N-dimethylformamide, N-methylformamide One or more of pyrrolidone and dimethyl sulfoxide;
  • anti-solvent means that the compound represented by formula (I) of the present invention has poor solubility in this solvent, such as n-heptane, cyclopentyl methyl ether, One or more of tetrahydrofuran, diethyl ether, propylene glycol methyl ether, methyl tert-butyl ether, acetone, acetophenone, methyl isobutyl ketone, ethyl acetate, acetonitrile, and dichloromethane.
  • Hygroscopicity is an important physical property of the drug substance, which directly affects the storage stability, processability and process preparation of the drug.
  • the dynamic water adsorption instrument (DVS) was used to investigate the adsorption and desorption experiments of water on the samples at a temperature of 25 °C in 0-95% relative humidity, so as to determine the moisture-inducing performance of various crystal forms.
  • the following table is the definition and scope of the hygroscopicity of the Chinese Pharmacopoeia 2015 edition for the drug after equilibration at 25°C and 80% RH.
  • composition refers to a mixture of one or more of the compounds of the invention, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable salts or prodrugs.
  • the purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.
  • compositions of the present invention further comprise pharmaceutically acceptable excipients, such as those used in the present invention, including any solvents, solid excipients, diluents, binders agents, disintegrating agents, or other liquid excipients, dispersing agents, flavoring or suspending agents, surfactants, isotonic agents, thickening agents, emulsifiers, preservatives, solid binders or lubricants, etc. etc., suitable for the unique target dosage form.
  • pharmaceutically acceptable excipients such as those used in the present invention, including any solvents, solid excipients, diluents, binders agents, disintegrating agents, or other liquid excipients, dispersing agents, flavoring or suspending agents, surfactants, isotonic agents, thickening agents, emulsifiers, preservatives, solid binders or lubricants, etc. etc., suitable for the unique target dosage form.
  • Substances that can be used as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances, such as phosphate; glycine; sorbic acid; Potassium sorbate; partial glyceride mixture of saturated vegetable fatty acids; water; salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica; magnesium trisilicate; Vinylpyrrolidones; polyacrylates; waxes; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxylate Sodium methylcellulose, ethylcellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients
  • compositions of the present invention may be administered orally, by injection, topically, bucally, or via an implantable kit.
  • administration by injection includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial (cavity), intrasternal, intramembranous, intraocular, intrahepatic, focal intracranial, and intracranial injection or infusion techniques.
  • the pharmaceutically acceptable compositions of the present invention may be orally administered in any acceptable oral dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • Sterile injectable forms of the compositions of the present invention may be aqueous or oleaginous suspensions. These suspensions may be formulated according to the known art using suitable dispersing, wetting and suspending agents.
  • an "effective amount,” “therapeutically effective amount,” or “effective dose” of a crystalline compound or pharmaceutically acceptable pharmaceutical composition of the present invention refers to an amount that treats or lessens the severity of one or more of the disorders referred to in the present invention. effective amount.
  • the crystalline compounds or pharmaceutically acceptable pharmaceutical compositions of the present invention are effective over a fairly wide range of dosages. For example, the daily dose is in the range of about 0.1 mg-1000 mg/person, divided into one or several administrations.
  • the methods, crystalline compounds and pharmaceutical compositions according to the present invention can be used in any amount and by any route of administration to be effective for treating or reducing the severity of a disease.
  • a compound or pharmaceutical composition of the present invention may be administered in combination with one or more other therapeutic agents, as discussed herein.
  • the term “treating" any disease or disorder refers to ameliorating the disease or disorder (ie, slowing or arresting or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, “treating” refers to alleviating/or improving at least one physical parameter, including a physical parameter that may not be perceived by a patient. In other embodiments, “treating” refers to modulating a disease or disorder physically (eg, stabilizing an observable symptom), physiologically (eg, stabilizing a physical parameter), or both. In other embodiments, “treating” refers to preventing or delaying the onset, occurrence or worsening of a disease or disorder.
  • the crystalline compound of the present invention can also be used in veterinary therapy for pets, introduced species and farm animals, including mammals, rodents, and the like. Examples of other animals include horses, dogs and cats.
  • the compounds of the present invention include pharmaceutically acceptable derivatives thereof.
  • the present invention provides the hydrochloride salt crystal form L of the compound of formula (I), using Cu-K ⁇ radiation to obtain an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , the powder X-ray diffraction pattern comprising the Characteristic peaks at diffraction angles (2 ⁇ ) of 5.9° ⁇ 0.2°, 16.8° ⁇ 0.2°, 24.7° ⁇ 0.2°.
  • the powder X-ray diffraction pattern of the hydrochloride salt form L of the compound of formula (I) further comprises at least one characteristic peak at the following diffraction angle (2 ⁇ ): 19.5° ⁇ 0.2 °, 23.6° ⁇ 0.2°.
  • the powder X-ray diffraction pattern of the hydrochloride salt form L of the compound of formula (I) includes diffraction at 5.9° ⁇ 0.2°, 16.8° ⁇ 0.2°, 24.7° ⁇ 0.2°, 19.5° ⁇ 0.2° Characteristic peak at angle (2 ⁇ ).
  • the powder X-ray diffraction pattern of the hydrochloride salt form L of the compound of formula (I) includes positions at 5.9° ⁇ 0.2°, 16.8° ⁇ 0.2°, 24.7° ⁇ 0.2°, 19.5° ⁇ 0.2°, Characteristic peak at 23.6° ⁇ 0.2° diffraction angle (2 ⁇ ).
  • the powder X-ray diffraction pattern of the hydrochloride salt form L of the compound of formula (I) further comprises at least one characteristic peak at the following diffraction angle (2 ⁇ ): 22.1° ⁇ 0.2 °, 11.3° ⁇ 0.2°.
  • the powder X-ray diffraction pattern of the hydrochloride salt form L of the compound of formula (I) includes diffraction at 5.9° ⁇ 0.2°, 16.8° ⁇ 0.2°, 24.7° ⁇ 0.2°, 22.1° ⁇ 0.2° Characteristic peak at angle (2 ⁇ ).
  • the powder X-ray diffraction pattern of the hydrochloride salt crystal form L of the compound of formula (I) includes positions at 5.9° ⁇ 0.2°, 16.8° ⁇ 0.2°, 24.7° ⁇ 0.2°, 22.1° ⁇ 0.2°, Characteristic peak at 11.3° ⁇ 0.2° diffraction angle (2 ⁇ ).
  • the powder X-ray diffraction pattern of the hydrochloride salt form L of the compound of formula (I) includes positions at 5.9° ⁇ 0.2°, 16.8° ⁇ 0.2°, 24.7° ⁇ 0.2°, 19.5° ⁇ 0.2°, Characteristic peaks at 23.6° ⁇ 0.2°, 22.1° ⁇ 0.2° diffraction angle (2 ⁇ ).
  • the powder X-ray diffraction pattern of the hydrochloride salt form L of the compound of formula (I) includes positions at 5.9° ⁇ 0.2°, 16.8° ⁇ 0.2°, 24.7° ⁇ 0.2°, 19.5° ⁇ 0.2°, Characteristic peaks at diffraction angles (2 ⁇ ) at 23.6° ⁇ 0.2°, 22.1° ⁇ 0.2°, 11.3° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the hydrochloride salt form L of the compound of formula (I) is substantially the same as FIG. 6 .
  • the X-ray powder diffraction pattern of the hydrochloride salt form L of the compound of formula (I) is substantially the same as that in FIG. 2 or FIG. 5 .
  • the powder X-ray diffraction pattern of the hydrochloride salt form L of the compound of formula (I) comprises positions at 5.9° ⁇ 0.2°, 16.8° ⁇ 0.2°, 24.7° ⁇ 0.2°
  • the characteristic peak at the diffraction angle (2 ⁇ ) and the X-ray powder diffraction pattern of the hydrochloride salt form L of the compound of formula (I) is basically the same as that in FIG. 6 .
  • the powder X-ray diffraction pattern of the hydrochloride salt form L of the compound of formula (I) comprises positions at 5.9° ⁇ 0.2°, 16.8° ⁇ 0.2°, 24.7° ⁇ 0.2° , 19.5° ⁇ 0.2°, 23.6° ⁇ 0.2° characteristic peaks at the diffraction angle (2 ⁇ ); and the X-ray powder diffraction pattern of the hydrochloride salt crystal form L of the compound of formula (I) is substantially the same as in FIG. 6 .
  • the powder X-ray diffraction pattern of the hydrochloride salt form L of the compound of formula (I) comprises positions at 5.9° ⁇ 0.2°, 16.8° ⁇ 0.2°, 24.7° ⁇ 0.2° , 19.5° ⁇ 0.2°, 23.6° ⁇ 0.2°, 22.1° ⁇ 0.2°, 11.3° ⁇ 0.2° characteristic peaks at the diffraction angle (2 ⁇ ); and the hydrochloride salt crystal form L of the compound of formula (I)
  • the X-ray powder diffraction pattern of is basically the same as that in Figure 6.
  • the TGA profile of the hydrochloride salt form L of the compound of formula (I) is substantially the same as FIG. 3 .
  • the powder X-ray diffraction pattern of the hydrochloride salt form L of the compound of formula (I) comprises positions at 5.9° ⁇ 0.2°, 16.8° ⁇ 0.2°, 24.7° ⁇ 0.2°
  • the TGA pattern of the hydrochloride salt form L of the compound of formula (I) is basically the same as that of FIG. 3 .
  • the powder X-ray diffraction pattern of the hydrochloride salt form L of the compound of formula (I) comprises positions at 5.9° ⁇ 0.2°, 16.8° ⁇ 0.2°, 24.7° ⁇ 0.2° , 19.5° ⁇ 0.2°, 23.6° ⁇ 0.2° characteristic peaks at diffraction angles (2 ⁇ ); and the TGA diagram of the hydrochloride salt form L of the compound of formula (I) is basically the same as FIG. 3 .
  • the powder X-ray diffraction pattern of the hydrochloride salt form L of the compound of formula (I) comprises positions at 5.9° ⁇ 0.2°, 16.8° ⁇ 0.2°, 24.7° ⁇ 0.2° , 19.5° ⁇ 0.2°, 23.6° ⁇ 0.2°, 22.1° ⁇ 0.2°, 11.3° ⁇ 0.2° characteristic peaks at the diffraction angle (2 ⁇ ); and the hydrochloride salt crystal form L of the compound of formula (I)
  • the TGA plot of is basically the same as Figure 3.
  • the DSC pattern of the hydrochloride salt form L of the compound of formula (I) is substantially the same as that of FIG. 4 .
  • the powder X-ray diffraction pattern of the hydrochloride salt form L of the compound of formula (I) comprises positions at 5.9° ⁇ 0.2°, 16.8° ⁇ 0.2°, 24.7° ⁇ 0.2°
  • the DSC pattern of the hydrochloride salt form L of the compound of formula (I) is substantially the same as that of FIG. 4 .
  • the powder X-ray diffraction pattern of the hydrochloride salt form L of the compound of formula (I) comprises positions at 5.9° ⁇ 0.2°, 16.8° ⁇ 0.2°, 24.7° ⁇ 0.2° , 19.5° ⁇ 0.2°, 23.6° ⁇ 0.2° characteristic peaks at diffraction angles (2 ⁇ ); and the DSC chart of the hydrochloride salt form L of the compound of formula (I) is basically the same as FIG. 4 .
  • the powder X-ray diffraction pattern of the hydrochloride salt form L of the compound of formula (I) comprises positions at 5.9° ⁇ 0.2°, 16.8° ⁇ 0.2°, 24.7° ⁇ 0.2° , 19.5° ⁇ 0.2°, 23.6° ⁇ 0.2°, 22.1° ⁇ 0.2°, 11.3° ⁇ 0.2° characteristic peaks at the diffraction angle (2 ⁇ ); and the hydrochloride salt crystal form L of the compound of formula (I)
  • the DSC chart of is basically the same as that of Figure 4.
  • the preparation method of the hydrochloride salt crystal form L of the compound of the formula (I) is provided, and the method comprises:
  • the alcoholic solvent in the method comprises isopropanol.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the hydrochloride salt crystal form L of the compound represented by the formula (I) and one or more pharmaceutically acceptable carriers, diluents or excipients .
  • the present invention provides the hydrochloride salt crystal form L of the compound represented by the formula (I), and the pharmaceutical composition for preventing and/or treating Bcr-Abl tyrosine kinase-mediated diseases. use in medicines.
  • the Bcr-Abl tyrosine kinase mediated disease comprises chronic myeloid leukemia.
  • the present invention provides the hydrochloride salt crystal form F of the compound of formula (I), using Cu-K ⁇ radiation to obtain an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , the powder X-ray diffraction pattern comprising: Characteristic peaks located at diffraction angles (2 ⁇ ) of 16.9° ⁇ 0.2°, 9.6° ⁇ 0.2°, 10.4° ⁇ 0.2°.
  • the powder X-ray diffraction pattern of the hydrochloride salt form F of the compound of formula (I) further comprises at least one characteristic peak at the following diffraction angle (2 ⁇ ): 20.4° ⁇ 0.2 °, 16.1° ⁇ 0.2°, 23.5° ⁇ 0.2°.
  • the powder X-ray diffraction pattern of the hydrochloride salt form F of the compound of formula (I) includes diffraction at 16.9° ⁇ 0.2°, 9.6° ⁇ 0.2°, 10.4° ⁇ 0.2°, 20.4° ⁇ 0.2° Characteristic peak at angle (2 ⁇ ).
  • the powder X-ray diffraction pattern of the hydrochloride salt form F of the compound of formula (I) includes positions at 16.9° ⁇ 0.2°, 9.6° ⁇ 0.2°, 10.4° ⁇ 0.2°, 20.4° ⁇ 0.2°, Characteristic peak at 16.1° ⁇ 0.2° diffraction angle (2 ⁇ ).
  • the powder X-ray diffraction pattern of the hydrochloride salt form F of the compound of formula (I) includes positions at 16.9° ⁇ 0.2°, 9.6° ⁇ 0.2°, 10.4° ⁇ 0.2°, 20.4° ⁇ 0.2°, Characteristic peaks at diffraction angles (2 ⁇ ) of 16.1° ⁇ 0.2°, 23.5° ⁇ 0.2°.
  • the powder X-ray diffraction pattern of the hydrochloride salt form F of the compound of formula (I) further comprises at least one characteristic peak at the following diffraction angle (2 ⁇ ): 22.0° ⁇ 0.2 °, 11.0° ⁇ 0.2°, 12.7° ⁇ 0.2°.
  • the powder X-ray diffraction pattern of the hydrochloride salt form F of the compound of formula (I) includes diffraction at 16.9° ⁇ 0.2°, 9.6° ⁇ 0.2°, 10.4° ⁇ 0.2°, 22.0° ⁇ 0.2° Characteristic peak at angle (2 ⁇ ).
  • the powder X-ray diffraction pattern of the hydrochloride salt form F of the compound of formula (I) includes positions at 16.9° ⁇ 0.2°, 9.6° ⁇ 0.2°, 10.4° ⁇ 0.2°, 22.0° ⁇ 0.2°, Characteristic peak at 11.0° ⁇ 0.2° diffraction angle (2 ⁇ ).
  • the powder X-ray diffraction pattern of the hydrochloride salt form F of the compound of formula (I) includes positions at 16.9° ⁇ 0.2°, 9.6° ⁇ 0.2°, 10.4° ⁇ 0.2°, 22.0° ⁇ 0.2°, Characteristic peaks at 11.0° ⁇ 0.2°, 12.7° ⁇ 0.2° diffraction angle (2 ⁇ ).
  • the powder X-ray diffraction pattern of the hydrochloride salt form F of the compound of formula (I) includes positions at 16.9° ⁇ 0.2°, 9.6° ⁇ 0.2°, 10.4° ⁇ 0.2°, 20.4° ⁇ 0.2°, Characteristic peaks at diffraction angles (2 ⁇ ) of 16.1° ⁇ 0.2°, 23.5° ⁇ 0.2°, 22.0° ⁇ 0.2°.
  • the powder X-ray diffraction pattern of the hydrochloride salt form F of the compound of formula (I) includes positions at 16.9° ⁇ 0.2°, 9.6° ⁇ 0.2°, 10.4° ⁇ 0.2°, 20.4° ⁇ 0.2°, Characteristic peaks at diffraction angles (2 ⁇ ) of 16.1° ⁇ 0.2°, 23.5° ⁇ 0.2°, 22.0° ⁇ 0.2°, 11.0° ⁇ 0.2°.
  • the powder X-ray diffraction pattern of the hydrochloride salt form F of the compound of formula (I) includes positions at 16.9° ⁇ 0.2°, 9.6° ⁇ 0.2°, 10.4° ⁇ 0.2°, 20.4° ⁇ 0.2°, Characteristic peaks at diffraction angles (2 ⁇ ) at 16.1° ⁇ 0.2°, 23.5° ⁇ 0.2°, 22.0° ⁇ 0.2°, 11.0° ⁇ 0.2°, 12.7° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the hydrochloride salt form F of the compound of formula (I) is substantially the same as FIG. 7 .
  • the powder X-ray diffraction pattern of the hydrochloride salt form F of the compound of formula (I) comprises positions at 16.9° ⁇ 0.2°, 9.6° ⁇ 0.2°, 10.4° ⁇ 0.2°
  • the characteristic peak at the diffraction angle (2 ⁇ ) and the X-ray powder diffraction pattern of the hydrochloride salt form F of the compound of formula (I) is substantially the same as that in FIG. 7 .
  • the powder X-ray diffraction pattern of the hydrochloride salt form F of the compound of formula (I) comprises positions at 16.9° ⁇ 0.2°, 9.6° ⁇ 0.2°, 10.4° ⁇ 0.2° , 20.4° ⁇ 0.2°, 16.1° ⁇ 0.2°, 23.5° ⁇ 0.2° characteristic peaks at diffraction angles (2 ⁇ ); and the X-ray powder diffraction pattern of the hydrochloride salt form F of the compound of formula (I) Basically the same as in FIG. 7 .
  • the powder X-ray diffraction pattern of the hydrochloride salt form F of the compound of formula (I) comprises positions at 16.9° ⁇ 0.2°, 9.6° ⁇ 0.2°, 10.4° ⁇ 0.2° , 20.4° ⁇ 0.2°, 16.1° ⁇ 0.2°, 23.5° ⁇ 0.2°, 22.0° ⁇ 0.2°, 11.0° ⁇ 0.2°, 12.7° ⁇ 0.2° characteristic peaks at the diffraction angle (2 ⁇ ); and the The X-ray powder diffraction pattern of the hydrochloride salt form F of the compound of formula (I) is substantially the same as that in FIG. 7 .
  • the TGA profile of the hydrochloride salt form F of the compound of formula (I) is substantially the same as that of FIG. 8 .
  • the powder X-ray diffraction pattern of the hydrochloride salt form F of the compound of formula (I) comprises positions at 16.9° ⁇ 0.2°, 9.6° ⁇ 0.2°, 10.4° ⁇ 0.2°
  • the characteristic peak at the diffraction angle (2 ⁇ ); and the TGA pattern of the hydrochloride salt form F of the compound of formula (I) is basically the same as that in FIG. 8 .
  • the powder X-ray diffraction pattern of the hydrochloride salt form F of the compound of formula (I) comprises positions at 16.9° ⁇ 0.2°, 9.6° ⁇ 0.2°, 10.4° ⁇ 0.2° , 20.4° ⁇ 0.2°, 16.1° ⁇ 0.2°, 23.5° ⁇ 0.2° characteristic peaks at the diffraction angle (2 ⁇ ); and the TGA diagram of the hydrochloride salt form F of the compound of formula (I) is shown in Figure 8 Basically the same.
  • the powder X-ray diffraction pattern of the hydrochloride salt form F of the compound of formula (I) comprises positions at 16.9° ⁇ 0.2°, 9.6° ⁇ 0.2°, 10.4° ⁇ 0.2° , 20.4° ⁇ 0.2°, 16.1° ⁇ 0.2°, 23.5° ⁇ 0.2°, 22.0° ⁇ 0.2°, 11.0° ⁇ 0.2°, 12.7° ⁇ 0.2° characteristic peaks at the diffraction angle (2 ⁇ ); and the The TGA profile of the hydrochloride salt form F of the compound of formula (I) is substantially the same as that of FIG. 8 .
  • the DSC pattern of the hydrochloride salt form F of the compound of formula (I) is substantially the same as that of FIG. 9 .
  • the powder X-ray diffraction pattern of the hydrochloride salt form F of the compound of formula (I) comprises positions at 16.9° ⁇ 0.2°, 9.6° ⁇ 0.2°, 10.4° ⁇ 0.2°
  • the DSC pattern of the hydrochloride salt form F of the compound of formula (I) is substantially the same as that of FIG. 9 .
  • the powder X-ray diffraction pattern of the hydrochloride salt form F of the compound of formula (I) comprises positions at 16.9° ⁇ 0.2°, 9.6° ⁇ 0.2°, 10.4° ⁇ 0.2° , 20.4° ⁇ 0.2°, 16.1° ⁇ 0.2°, 23.5° ⁇ 0.2° characteristic peaks at diffraction angles (2 ⁇ ); and the DSC chart of the hydrochloride salt form F of the compound of formula (I) is shown in Figure 9 Basically the same.
  • the powder X-ray diffraction pattern of the hydrochloride salt form F of the compound of formula (I) comprises positions at 16.9° ⁇ 0.2°, 9.6° ⁇ 0.2°, 10.4° ⁇ 0.2° , 20.4° ⁇ 0.2°, 16.1° ⁇ 0.2°, 23.5° ⁇ 0.2°, 22.0° ⁇ 0.2°, 11.0° ⁇ 0.2°, 12.7° ⁇ 0.2° characteristic peaks at the diffraction angle (2 ⁇ ); and the The DSC pattern of the hydrochloride salt form F of the compound of formula (I) is substantially the same as that of FIG. 9 .
  • a method for preparing the hydrochloride salt form F of the compound of formula (I) comprising: using the compound of formula (I) as an amorphous sample of hydrochloride at room temperature
  • the starting material is stirred into a suspended state by adding an ether solvent, and the suspension is centrifuged and evaporated to dryness at room temperature to obtain the hydrochloride salt crystal form F.
  • the ether solvent in the method includes methyl tert-butyl ether.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the hydrochloride salt crystal form F of the compound represented by the formula (I) and one or more pharmaceutically acceptable carriers, diluents or excipients .
  • the present invention provides the hydrochloride salt crystal form F of the compound represented by the formula (I), and the pharmaceutical composition for preventing and/or treating the diseases mediated by Bcr-Abl tyrosine kinase. use in medicines.
  • the Bcr-Abl tyrosine kinase mediated disease comprises chronic myeloid leukemia.
  • the present invention provides the hydrochloride salt crystal form J of the compound of formula (I), using Cu-K ⁇ radiation to obtain an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , the powder X-ray diffraction pattern comprising: Characteristic peaks located at diffraction angles (2 ⁇ ) of 20.8° ⁇ 0.2°, 21.2° ⁇ 0.2°, 7.3° ⁇ 0.2°.
  • the powder X-ray diffraction pattern of the hydrochloride salt form J of the compound of formula (I) further comprises at least one characteristic peak at the following diffraction angle (2 ⁇ ): 19.9° ⁇ 0.2 °, 12.8° ⁇ 0.2°.
  • the powder X-ray diffraction pattern of the hydrochloride salt form J of the compound of formula (I) includes diffraction at 20.8° ⁇ 0.2°, 21.2° ⁇ 0.2°, 7.3° ⁇ 0.2°, 19.9° ⁇ 0.2° Characteristic peak at angle (2 ⁇ ).
  • the powder X-ray diffraction pattern of the hydrochloride salt form J of the compound of formula (I) includes positions at 20.8° ⁇ 0.2°, 21.2° ⁇ 0.2°, 7.3° ⁇ 0.2°, 19.9° ⁇ 0.2°, Characteristic peak at 12.8° ⁇ 0.2° diffraction angle (2 ⁇ ).
  • the powder X-ray diffraction pattern of the hydrochloride salt form J of the compound of formula (I) further comprises at least one characteristic peak at the following diffraction angle (2 ⁇ ): 8.8° ⁇ 0.2 °, 21.6° ⁇ 0.2°.
  • the powder X-ray diffraction pattern of the hydrochloride salt form J of the compound of formula (I) includes diffraction patterns at 20.8° ⁇ 0.2°, 21.2° ⁇ 0.2°, 7.3° ⁇ 0.2°, 8.8° ⁇ 0.2° Characteristic peak at angle (2 ⁇ ).
  • the powder X-ray diffraction pattern of the hydrochloride salt form J of the compound of formula (I) includes positions at 20.8° ⁇ 0.2°, 21.2° ⁇ 0.2°, 7.3° ⁇ 0.2°, 8.8° ⁇ 0.2°, Characteristic peak at 21.6° ⁇ 0.2° diffraction angle (2 ⁇ ).
  • the powder X-ray diffraction pattern of the hydrochloride salt form J of the compound of formula (I) includes positions at 20.8° ⁇ 0.2°, 21.2° ⁇ 0.2°, 7.3° ⁇ 0.2°, 19.9° ⁇ 0.2°, Characteristic peaks at 12.8° ⁇ 0.2°, 8.8° ⁇ 0.2° diffraction angle (2 ⁇ ).
  • the powder X-ray diffraction pattern of the hydrochloride salt form J of the compound of formula (I) includes positions at 20.8° ⁇ 0.2°, 21.2° ⁇ 0.2°, 7.3° ⁇ 0.2°, 19.9° ⁇ 0.2°, Characteristic peaks at diffraction angles (2 ⁇ ) of 12.8° ⁇ 0.2°, 8.8° ⁇ 0.2°, 21.6° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the hydrochloride salt form J of the compound of formula (I) is substantially the same as FIG. 10 .
  • the powder X-ray diffraction pattern of the hydrochloride salt form J of the compound of formula (I) includes positions at 20.8° ⁇ 0.2°, 21.2° ⁇ 0.2°, 7.3° ⁇ 0.2°
  • the characteristic peak at the diffraction angle (2 ⁇ ) and the X-ray powder diffraction pattern of the hydrochloride salt form J of the compound of formula (I) is basically the same as that in FIG. 10 .
  • the powder X-ray diffraction pattern of the hydrochloride salt form J of the compound of formula (I) includes positions at 20.8° ⁇ 0.2°, 21.2° ⁇ 0.2°, 7.3° ⁇ 0.2° , 19.9° ⁇ 0.2°, 12.8° ⁇ 0.2° characteristic peaks at the diffraction angle (2 ⁇ ); and the X-ray powder diffraction pattern of the hydrochloride salt form J of the compound of formula (I) is basically the same as Figure 10 .
  • the powder X-ray diffraction pattern of the hydrochloride salt form J of the compound of formula (I) includes positions at 20.8° ⁇ 0.2°, 21.2° ⁇ 0.2°, 7.3° ⁇ 0.2° , 19.9° ⁇ 0.2°, 12.8° ⁇ 0.2°, 8.8° ⁇ 0.2°, 21.6° ⁇ 0.2° characteristic peaks at the diffraction angle (2 ⁇ ); and the hydrochloride salt crystal form J of the compound of formula (I)
  • the X-ray powder diffraction pattern of is basically the same as that in Figure 10.
  • a method for preparing the hydrochloride salt form J of the compound of formula (I) is provided.
  • the sample was dissolved in a nitrogen-containing solvent, added to a ketone solvent pre-cooled at -20°C to 5°C, and the solid was precipitated to obtain the hydrochloride salt crystal form J.
  • the nitrogen-based solvent in the method includes N,N-dimethylacetamide
  • the ketone-based solvent includes methyl isobutyl ketone
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the hydrochloride salt crystal form J of the compound represented by the formula (I) and one or more pharmaceutically acceptable carriers, diluents or excipients .
  • the present invention provides the hydrochloride salt crystal form J of the compound represented by the formula (I), and the pharmaceutical composition prepared for preventing and/or treating Bcr-Abl tyrosine kinase-mediated diseases use in medicines.
  • the Bcr-Abl tyrosine kinase mediated disease comprises chronic myeloid leukemia.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a plurality of the hydrochloride salt crystal form L, the hydrochloride salt crystal form F, the hydrochloride salt crystal form J, and a one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the X-ray powder diffraction pattern of the present invention was collected on a Bruker D2 PHASER X-ray powder diffractometer.
  • the method parameters of X-ray powder diffraction of the present invention are as follows:
  • the infrared spectrum conditions of the present invention are as follows:
  • Spectral range 7800-350cm -1 , spectral resolution: better than 0.4cm -1 , signal-to-noise ratio: peak-to-peak noise value: less than 9.65x10-6Abs, wavenumber accuracy: better than 0.005cm-1, diamond ATR accessory, 100,000 infrared high-resolution spectral library.
  • DSC Differential Scanning Calorimetry
  • thermogravimetric analysis (TGA) plots described in the present invention were collected on a TA Q500.
  • the method parameters of thermogravimetric analysis (TGA) of the present invention are as follows:
  • the data of ultra-high performance liquid chromatography are collected from Waters H-Clas, and the detector used is a diode array detector (PDA).
  • the UPLC method parameter of test solubility of the present invention is as follows:
  • the elution gradient is as follows:
  • the asnib starting material used in the following examples can be prepared according to the prior art, for example, according to the method described in WO2013171639A1, but the starting crystal form is not a limitation for preparing the crystal form of the present invention.
  • Example 1 After placing the solid obtained in Example 1 at room temperature and humidity for about one month, the solid is collected to obtain the hydrochloride salt crystal form L.
  • hydrochloride crystal form A of the compound of formula (I) prepared in Example 1 Take ⁇ 5 mg of the hydrochloride crystal form A of the compound of formula (I) prepared in Example 1, heat it to 150 ° C with a differential scanning calorimeter (DSC), and equilibrate at 150 ° C for several minutes, the temperature drops to 150 ° C.
  • the hydrochloride salt form L can be obtained at room temperature.
  • hydrochloride salt crystal form A of the compound of formula (I) prepared in Example 1 heat it to 150 ° C with a differential scanning calorimeter (DSC), and equilibrate at 150 ° C for several minutes, and the temperature is reduced to room temperature.
  • the hydrochloride salt form L can be obtained.
  • hydrochloride crystal form L, the hydrochloride crystal form F and the hydrochloride Form A disclosed in WO2020230099A1 of the present invention were added to pure water, respectively, and prepared into a suspension. After equilibration for 1 hour, the solution was filtered to obtain a saturated solution. The content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC). The test results are shown in Table 7, and the solubility curve is shown in Figure 11. The test results show that the solubility of hydrochloride crystal form L and hydrochloride crystal form F of the present invention in pure water is higher than that of hydrochloride Form A disclosed in WO2020230099A1.
  • hydrochloride crystal form L initial purity 99.6%
  • hydrochloride crystal form F initial purity 98.3%
  • Table 10 The test results show that the hydrochloride salt crystal form L and hydrochloride salt crystal form F of the present invention have high stability under the condition of 40°C/75%RH.
  • Example 11 Comparative study on wettability
  • hydrochloride crystal form L and hydrochloride crystal form F of the present invention were weighed for dynamic moisture adsorption (DVS) test.
  • the hydrochloride salt crystal form L and the hydrochloride salt crystal form F of the present invention have lower hygroscopicity.
  • Moisture gain is less than 15% but not less than 2%
  • wet weight gain is less than 2% but not less than 0.2%
  • wet weight gain is less than 0.2%
  • test results show that the particle size of the hydrochloride Form A is bimodal distribution, and the particle size of the hydrochloride crystal form L is unimodal distribution, indicating that the hydrochloride crystal form L of the present invention has a more uniform distribution than the hydrochloride Form A. Particle size distribution.

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Abstract

提供一种 (R)-N-(4-(氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-5-(1H-吡唑-5-基)烟酰胺的盐酸盐新晶型及其制备方法、包含该化合物的药物组合物和在制备药物中的用途。该化合物是一种选择性的Abl1变构抑制剂，可用于预防和/或治疗Bcr-Abl酪氨酸激酶介导的疾病。

Description

一种吡唑取代的烟酰胺类化合物的盐酸盐新晶型及其制备方法 技术领域
本发明涉及(R)-N-(4-(氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-5-(1H-吡唑-5-基)烟酰胺的盐酸盐新晶型及其制备方法，其在制备预防和/或治疗Bcr-Abl酪氨酸激酶介导的疾病的药物中的用途。
背景技术
Bcr-Abl酪氨酸激酶是由bcr-abl致癌基因所表达的一种蛋白激酶，Bcr-Abl酪氨酸激酶的持续活性是导致慢性粒细胞白血病(chronic myeloid leukaemia，CML)的原因之一。增强的激酶活性承担细胞内的磷酸化和多种信号分子的激活，这些功能加速了细胞的增殖同时抑制了细胞的凋亡。因此，对Bcr-Abl酪氨酸激酶活性的抑制是靶向治疗CML的有效途径。
(R)-N-(4-(氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-5-(1H-吡唑-5-基)烟酰胺是一种选择性的Abl1变构抑制剂，与通常靶向Abl1的分子不同，该化合物靶向激酶的非活性位点而不是活性位点，其作用机制效仿蛋白调控的自然机理。由于其独特的作用机理，与传统疗法相比对T315I突变的肿瘤具有更显著的活性。临床前研究数据表明，该化合物与ATP竞争性TKI联合应用可产生协同作用和克服耐药性的能力。其分子结构如下所示：
Figure PCTCN2022084708-appb-000001
专利US20130310395A1公开了化合物(I)及其制备方法，公开的式(I)中化合物的合成方法，需通过色谱柱提纯或减压蒸发获得终产物，色谱法耗时长，消耗溶剂量大，工业放大难度大，成本高，减压蒸发虽可相对减少溶剂消耗，但无法达到对终产物提纯的效果。WO2020230099A1中公开了化合物(I)的游离碱晶型以及盐酸盐晶型。其中，游离碱晶型与盐酸盐相比，溶解度低，在水以及其他介质中的固有溶出速率均低于盐酸盐。盐酸盐形式A在制备过程复杂，需要经过多步升降温，熟化，溶剂添加，方可制得，较难满足工业生产的要求。此外，盐酸盐形式A在水中不稳定，易转化为游离碱形式A和HA。盐酸盐形式B稳定性差，在环境条件下会发生转晶。因此，有必要寻找出化合物(I)的其他晶体形态，以满 足工业生产以及临床应用的需求。
发明内容
药物多晶型是固体药物中普遍存在的现象，不同晶型药物的理化性质会有所差异，这些性质可以直接影响药物的生产和储存，进而可能会影响药物在人体内的作用效果。因此，为选择最适合开发的晶型，有必要对式(I)化合物进行全面系统的晶型筛选。以下所述晶型，皆为(I)化合物的盐酸盐晶型。
根据发明的一个方面，提供了式(I)化合物的盐酸盐晶型L，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其粉末X-射线衍射图谱包括位于5.9°±0.2°，16.8°±0.2°，24.7°±0.2°衍射角(2θ)处的特征峰。
Figure PCTCN2022084708-appb-000002
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型L的粉末X-射线衍射图谱还包括至少一个以下衍射角(2θ)处的特征峰：19.5°±0.2°，23.6°±0.2°。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型L的粉末X-射线衍射图谱还包括至少一个以下衍射角(2θ)处的特征峰：22.1°±0.2°，11.3°±0.2°。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型L的X射线粉末衍射图谱与图6基本上相同。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型L的X射线粉末衍射图谱与图2或图5基本上相同。
根据发明的一个方面，提供了所述的式(I)化合物的盐酸盐晶型L的制备方法，所述方法包括：
a)将式(I)化合物和等当量的盐酸加入至醇类溶剂中，室温条件下搅拌过夜，得到的固体置于室温下放置1个月后，得到盐酸盐晶型L；或
b)将式(I)化合物和等当量的盐酸加入至醇类溶剂中，室温条件下搅拌过夜，得到的固体加热至120-160℃，冷却后得到盐酸盐晶型L。
在本发明的一些实施方案中，所述方法中的醇类溶剂包括异丙醇。
根据发明的一个方面，提供了药物组合物，其包含所述的式(I)所示化合物的盐酸盐晶型L以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
根据发明的一个方面，提供了所述的式(I)所示化合物的盐酸盐晶型L、所述的药物组合物在制备预防和/或治疗Bcr-Abl酪氨酸激酶介导的疾病的药物中的用途。
根据发明的一个方面，提供了一种预防和/或治疗Bcr-Abl酪氨酸激酶介导的疾病的方法，其包括向所述患者施用治疗有效量的所述的式(I)所示化合物的盐酸盐晶型L或所述的药物组合物。
根据发明的一个方面，提供了一种用于预防和/或治疗Bcr-Abl酪氨酸激酶介导的疾病的药物，其包含治疗有效量的所述的式(I)所示化合物的盐酸盐晶型L或所述的药物组合物。
在本发明的一些实施方案中，所述的Bcr-Abl酪氨酸激酶介导的疾病包括慢性粒细胞白血病。
根据发明的一个方面，提供了式(I)化合物的盐酸盐晶型F，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其粉末X-射线衍射图谱包括位于16.9°±0.2°，9.6°±0.2°，10.4°±0.2°衍射角(2θ)处的特征峰。
Figure PCTCN2022084708-appb-000003
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型F的粉末X-射线衍射图谱还包括至少一个以下衍射角(2θ)处的特征峰：20.4°±0.2°，16.1°±0.2°，23.5°±0.2°。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型F的粉末X-射线衍射图谱还包括至少一个以下衍射角(2θ)处的特征峰：22.0°±0.2°，11.0°±0.2°，12.7°±0.2°。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型F的X射线粉末衍射图谱与图7基本上相同。
根据发明的一个方面，提供了所述的式(I)化合物的盐酸盐晶型F的制备方法，所述方法包括：将式(I)化合物在室温下，以盐酸盐无定形样品为起始物，在加入醚类溶剂中搅拌至呈混悬状态，将混悬液离心后室温条件下自然挥干，得到盐酸盐晶型F。
在本发明的一些实施方案中，所述方法中的醚类溶剂包括甲基叔丁基醚。
根据发明的一个方面，提供了药物组合物，其包含所述的式(I)所示化合物的盐酸盐晶型F以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
根据发明的一个方面，提供了所述的式(I)所示化合物的盐酸盐晶型F、所述的药物组合物在制备预防和/或治疗Bcr-Abl酪氨酸激酶介导的疾病的药物中的用途。
根据发明的一个方面，提供了一种预防和/或治疗Bcr-Abl酪氨酸激酶介导的疾病的方法，其包括向所述患者施用治疗有效量的所述的式(I)所示化合物的盐酸盐晶型F或所述的药物组合物。
根据发明的一个方面，提供了一种用于预防和/或治疗Bcr-Abl酪氨酸激酶介导的疾病的药物，其包含治疗有效量的所述的式(I)所示化合物的盐酸盐晶型F或所述的药物组合物。
在本发明的一些实施方案中，所述的Bcr-Abl酪氨酸激酶介导的疾病包括慢性粒细胞白血病。
根据发明的一个方面，提供了式(I)化合物的盐酸盐晶型J，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其粉末X-射线衍射图谱包括位于20.8°±0.2°，21.2°±0.2°，7.3°±0.2°衍射角(2θ)处的特征峰。
Figure PCTCN2022084708-appb-000004
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型J的粉末X-射线衍射图谱还包括至少一个以下衍射角(2θ)处的特征峰：19.9°±0.2°，12.8°±0.2°。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型J的粉末X-射线衍射图谱还包括至少一个以下衍射角(2θ)处的特征峰：8.8°±0.2°，21.6°±0.2°。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型J的X射线粉末衍射图谱与图10基本上相同。
根据发明的一个方面，提供了所述的式(I)化合物的盐酸盐晶型J的制备方法，所述方法包括：将式(I)化合物在30℃到50℃下，将盐酸盐样品在杂氮类溶剂中溶清，将其加入至-20℃到5℃预冷的酮类溶剂中，固体析出，得到盐酸盐晶型J。
在本发明的一些实施方案中，所述方法中的杂氮类溶剂包括N,N-二甲基乙酰胺，酮类溶剂包括甲基异丁酮。
根据发明的一个方面，提供了药物组合物，其包含所述的式(I)所示化合物的盐酸盐晶型J以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
根据发明的一个方面，提供了所述的式(I)所示化合物的盐酸盐晶型J、所述的药物组合物在制备预防和/或治疗Bcr-Abl酪氨酸激酶介导的疾病的药物中的用途。
根据发明的一个方面，提供了一种预防和/或治疗Bcr-Abl酪氨酸激酶介导的疾病的方法，其包括向所述患者施用治疗有效量的所述的式(I)所示化合物的盐酸盐晶型J或所述的药物组合物。
根据发明的一个方面，提供了一种用于预防和/或治疗Bcr-Abl酪氨酸激酶介导的疾病的药物，其包含治疗有效量的所述的式(I)所示化合物的盐酸盐晶型J或所述的药物组合物。
在本发明的一些实施方案中，所述的Bcr-Abl酪氨酸激酶介导的疾病包括慢性粒细胞白血病。
根据发明的一个方面，提供了药物组合物，其包含所述的盐酸盐晶型L、所述的盐酸盐晶型F、所述的盐酸盐晶型J中的多种，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
根据发明的一个方面，提供了一种预防和/或治疗Bcr-Abl酪氨酸激酶介导的疾病的方法，其包括向所述患者施用治疗有效量的所述的盐酸盐晶型L、所述的盐酸盐晶型F、所述的盐酸盐晶型J中的多种或所述的药物组合物。
根据发明的一个方面，提供了一种用于预防和/或治疗Bcr-Abl酪氨酸激酶介导的疾病的药物，其包含治疗有效量的所述的盐酸盐晶型L、所述的盐酸盐晶型F、所述的盐酸盐晶型J中的多种或所述的药物组合物。
在本发明的一些实施方案中，所述的Bcr-Abl酪氨酸激酶介导的疾病包括慢性粒细胞白血病。
本领域技术人员能够从下文的详细描述中容易地洞察到本申请的其它方面和优势。下文的详细描述中仅显示和描述了本申请的示例性实施方式。如本领域技术人员将认识到的，本申请的内容使得本领域技术人员能够对所公开的具体实施方式进行改动而不脱离本申请所涉及发明的精神和范围。相应地，本申请的附图和说明书中的描述仅仅是示例性的，而非为限制性的。
附图说明
本申请所涉及的发明的具体特征如所附权利要求书所显示。通过参考下文中详细描述的示例性实施方式和附图能够更好地理解本申请所涉及发明的特点和优势。对附图简要说明书如下：
图1显示的是本申请所述盐酸盐晶型A的XRPD图；
图2显示的是本申请所述实施例2盐酸盐晶型L的XRPD图；
图3显示的是本申请所述实施例2盐酸盐晶型L的TGA曲线；
图4显示的是本申请所述实施例2盐酸盐晶型L的DSC曲线；
图5显示的是本申请所述实施例3盐酸盐晶型L的XRPD图；
图6显示的是本申请所述实施例4盐酸盐晶型L的XRPD图；
图7显示的是本申请所述盐酸盐晶型F的XRPD图；
图8显示的是本申请所述盐酸盐晶型F的TGA曲线；
图9显示的是本申请所述盐酸盐晶型F的DSC曲线；
图10显示的是本申请所述盐酸盐晶型J的XRPD图；
图11显示的是本申请所述不同晶型在纯水中的溶解度对比曲线；
图12显示的是本申请所述盐酸盐晶型L的PLM图；
图13显示的是本申请所述盐酸盐Form A的粒径分布图
图14显示的是本申请所述盐酸盐晶型L的粒径分布图
图15显示的是本申请所述盐酸盐晶型L在25℃/60％相对湿度下稳定性测试XRPD对比图
具体实施方式
以下由特定的具体实施例说明本申请发明的实施方式，熟悉此技术的人士可由本说明书所公开的内容容易地了解本申请发明的其他优点及效果。
术语定义
本发明所使用的术语“无定形”或者“无定形形式”意在表示所讨论的物质、组分或产物，缺少特征性的晶体形状或结晶结构，例如通过XRPD测定时基本上不是晶体或者所讨论的物质、组分或产物，例如当使用偏振光显微镜观看时不是双折射的，或者X射线粉末衍射图不具尖峰。在某些实施方案中，包含物质的无定形形式的样品可基本上不含其它无定形形 式和/或结晶形式。
本发明所使用的术语“多晶型的”或“多晶型现象”被定义为对于相同的化学分子有至少两种不同的结晶排列的可能性。
本发明所使用的术语“多晶型”、“多晶型物(polymorphs)”、“晶体变化形式(crystal modification)”、“晶型(crystal form)”、“结晶变化形式(crystalline modification)”、“多晶型形式”和“结晶形式(crystalline form)”被理解为是同义的，在本发明中是指化合物或复合物的固体晶体形式，包括，但不限于，单组分或者多组分晶体，和/或化合物的多晶型物、溶剂化物、水合物、包合物、共晶、盐、盐的溶剂化物、盐的水合物。
可用本领域技术人员所熟知的技术检测、鉴定、分类和定性多晶型物，这些技术例如但不限于：差示扫描量热法(DSC)、热重分析法(TGA)、X-射线粉末衍射法(XRPD)、单晶X射线衍射法、振动光谱法、溶液量热法、固态核磁共振(SSNMR)、傅立叶变换-红外光谱(FT-IRspectrum)法、拉曼光谱(Ramanspectrum)法、热载台光学显微术、扫描电镜术(SEM)、电子晶体学、以及定量分析、粒度分析(PSA)、表面区域分析、溶解度和溶出速度。可以将晶型(Polymorphism)描绘成具体的化合物以不同晶体变化形式结晶同时维持相同化学结构式的能力。给定物质的多晶型物为化学等同的，其含有以相同方式互相键合的相同原子，但它们的晶体变化形式不同，这会影响一种或多种物理性质，诸如溶出速率(dissolution rate)、熔点、堆积密度(bulk density)、稳定性、流动性质等等。这类数据的图形表示可发生小的变化(例如峰相对强度和峰位置)，原因是诸如仪器响应变化和样品浓度及纯度变化的因素，这对于本领域技术人员是公知的。尽管如此，本领域技术人员能够比较本发明图中的图形数据和对未知晶型产生的图形数据，并可确认两组图形数据是否表征相同的晶型。
除非另有说明，当文中提及光谱或以图形形式出现的数据(例如，XRPD、FT-IR、拉曼和NMR谱)时，术语“峰”是指本领域的普通技术人员可识别的非背景噪音造成的峰或其它特殊特征。
正如在X射线粉末衍射(XRPD)领域中所熟知的，对任何指定的晶型而言，获得X-射线粉末衍射图时所用装置、湿度、温度、粉末晶体的取向以及其它参数均可能引起衍射图中峰的外观、强度和位置的一些变异性。例如，参见The United States Pharmacopeia#23，National Formulary#18，1843-1844页，1995。在目前的情况中，±0.2°2θ峰位的变异性考虑到了这些可能的变化，而不会妨碍所示晶型的明确鉴定。晶型的鉴别可以基于任意独特的差别峰(以°2θ单位计)或其组合，典型地是更显著的峰。因此，在一些实施方案中，本发明的结晶化合物的特征在于具有某些峰位置的XRPD图，具有与本发明附图中提供的XRPD图实质上相同的特 征。根据本申请所用仪器状况，衍射峰位置可存在±0.2°的误差容限。例如，与本发明提供的图3、7或8“基本一致”的X-射线粉末衍射图可与附图中的XRPD图相同，或更可能其可稍微不同。这样的XRPD图可不必要显示本发明所呈现的衍射图中的每个峰，和/或可显示由于在获得数据时涉及的条件差异而导致的所述峰的外观、强度或位移的轻微变化。本领域技术人员通过比较它们的XRPD图，能够确定结晶化合物的样品是否具有与本发明公开的晶型相同的晶型或不同的晶型。类似地，本领域技术人员能够确定给出的得自XRPD图的衍射峰位置(以°2θ表示)是否在与本发明呈现的数值大致相同的位置。在本发明的上下文中，X-射线粉末衍射图中的2θ值均以度(°)为单位。
同样，正如差示扫描量热(DSC)领域中所熟知的，DSC曲线的熔融峰高取决于样品的制备和测试仪器条件等许多有关的因素，而峰位置对实验细节相对不敏感。因此，在一些实施方案中，本发明的结晶化合物的特征在于具有特征峰位置的DSC图，具有与本发明附图中提供的DSC图实质上相同的性质。根据本试验所用仪器状况，熔融温度存在±3℃，±4℃或±5℃的误差容限。
正如傅立叶变换-红外光谱领域中所熟知的，红外光谱的吸收峰的位置和形状取决于样品分子中共价键运动能级的跃迁。因此，在一些实施方案中，本发明的结晶化合物的特征在于具有特征峰位置和形状的傅立叶变换-红外光谱图，具有与本发明附图中提供的傅立叶变换-红外光谱图实质上相同的性质。根据《中国药典》(2010版)附录IV C-红外分光光度法，以及本试验所用仪器状况，吸收峰在3000cm -1附近存在±5cm -1的误差容限，在1000cm -1附近存在±2cm -1的误差容限。
X-射线粉末衍射图、DSC曲线图、拉曼光谱图和傅立叶变换-红外光谱图“实质上相同”或“基本上相同”是指X-射线粉末衍射图、DSC曲线图、拉曼光谱图和傅立叶变换-红外光谱图中至少有50％，或至少60％，或至少70％，或至少80％，或至少90％，或至少95％，或至少99％的峰显示在图中。
例如，本发明中的X-射线粉末衍射图“基本上相同”意指考虑典型的X射线衍射峰位置和强度可变性。本领域技术人员将理解，峰位置(2θ)将由于XRPD仪器不同，而造成测量值有所变化，有时这种变化达有时多达0.2°。此外，本领域技术人员将理解，XRPD样品制样方法，XRPD仪器，样品结晶度，样品用量以及晶体择优取向等因素将导致样品XRPD衍射图中相对峰强度的改变。
本发明所述的(R)-N-(4-(氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-5-(1H-吡唑-5-基)烟酰胺的新晶型包括盐酸盐晶型L、盐酸盐晶型F、盐酸盐晶型J它们均以基本 上纯净的结晶形态存在。
术语“基本上纯净的”是指化学纯度和晶型纯度，更具体地讲，一种晶型基本上不含另外一种或多种晶型，即晶型的纯度至少60％，或至少70％，或至少80％，或至少85％，或至少90％，或至少93％，或至少95％，或至少98％，或至少99％，或至少99.5％，或至少99.6％，或至少99.7％，或至少99.8％，或至少99.9％，或晶型中含有其它晶型，所述其它晶型在晶型的总体积或总重量中的百分比少于30％，或少于20％，或少于10％，或少于5％，或少于3％，或少于1％，或少于0.5％，或少于0.1％，或少于0.01％。
本发明的晶体的纯度可以通过，例如已知方法诸如X-射线粉末衍射学、热分析等来测定。本发明的晶体或混合晶体的纯度不需要是100％，并且可以不低于70％，或不低于80％，或不低于90％，或不低于95％，或不低于98％。且在该范围内的纯度可以保证质量。
本发明所用的术语“约”和“大约”通常是指在给定的值或范围的±10％以内，适当地在±5％以内，特别是在±1％以内。或者，对于本领域普通技术人员而言，术语“约”和“大约”表示在平均值的可接受的标准误差范围内。
本发明所使用的术语“溶液”是指含有至少一种溶剂以及至少一种化合物的一个混合物，该化合物在该溶剂中至少部分地溶解。
本发明所使用的术语“溶剂化物”意思是在表面、在晶格中或者在表面上和在晶格中具有溶剂，所述溶剂例如是水、乙酸、丙酮、乙腈、苯、氯仿、四氯化碳、二氯甲烷、二甲基亚砜、1，4-二氧六环、乙醇、乙酸乙酯、丁醇、叔丁醇、N，N-二甲基乙酰胺、N，N-二甲基甲酰胺、甲酰胺、蚁酸、庚烷、己烷、异丙醇、甲醇、甲基乙基酮、l-甲基-2-吡咯烷酮、硝基甲烷、聚乙二醇、丙醇、2-丙酮、吡啶、四氢呋喃、甲苯、二甲苯、它们的混合物等等。溶剂化物的一个具体例子是水合物，其中在表面上、在晶格中或者在表面上和在晶格中的溶剂是水。在物质的表面上、在晶格中或者在表面上和在晶格中，水合物可以具有或者不具有除了水的其它溶剂。
本发明所使用的术语“正溶剂”是指本发明的式(I)所示化合物在该溶剂中溶解性较好，例如，甲醇、乙醇、N，N-二甲基甲酰胺、N-甲基吡咯烷酮、二甲亚砜中一种或多种；“反溶剂”是指本发明的式(I)所示化合物在该溶剂中溶解性较差，例如正庚烷、环戊基甲醚、四氢呋喃、乙醚、丙二醇甲醚、甲基叔丁基醚、丙酮、苯乙酮、甲基异丁酮、乙酸乙酯、乙腈、二氯甲烷中一种或多种。
引湿性是原料药物的重要物理性能，它直接影响到药物的储存稳定性，可加工性和工艺制备过程。采用动态水吸附仪(DVS)对样品在25℃的温度下，考察其在0～95％相对湿度对 水份的吸附与解吸实验，以确定各种不同晶型的引湿性能。下表是中国药典2015版对于药物在25℃，80％RH平衡后，引湿性的定义和范围。
潮解 吸收足够水分形成液体
极具引湿性 引湿增重不小于15％
有引湿性 引湿增重小于15％但不小于2％
略有引湿性 引湿增重小于2％但不小于0.2％
无或几乎无引湿性 引湿增重小于0.2％
术语“药物组合物”表示一种或多种本发明所述化合物或者其生理学上/药学上可以接受的盐或前体药物与其他化学组分的混合物，其他组分例如生理学上/药学上可以接受的载体、赋形剂、稀释剂、辅剂、媒介物，以及附加治疗剂。药物组合物的目的是促进化合物对生物体的给药。
像本发明所描述的，本发明药学上可接受的组合物进一步包含药学上可接受的辅料，这些辅料，例如像本发明所应用的，包括任何溶剂，固体赋形剂，稀释剂，粘合剂，崩解剂，或其他液体赋形剂，分散剂，矫味剂或悬浮剂，表面活性剂，等渗剂，增稠剂，乳化剂，防腐剂，固体粘合剂或润滑剂，等等，适合于特有的目标剂型。如以下文献所描述的：I n Remington:The Science and Practice ofPharmacy，21st edition，2005，ed.D.B.Troy，Lippincott Williams&Wilkins，Philadelphia，and Encyclopedia of Pharmaceutical Technology，eds.J.Swarbrick and J.C.Boylan，1988-1999，Marcel Dekker，New York，综合此处文献的内容，表明不同的辅料可应用于药学上可接受的组合物的制剂和它们公知的制备方法。除了任何常规的辅料与本发明的化合物不相容的范围，例如所产生的任何不良的生物效应或与药学上可接受的组合物的任何其他组分以有害的方式产生的相互作用，它们的用途也是本发明所考虑的范围。
可作为药学上可接受辅料的物质包括，但并不限于，离子交换剂；铝；硬脂酸铝；卵磷脂；血清蛋白，如人血清蛋白；缓冲物质，如磷酸盐；甘氨酸；山梨酸；山梨酸钾；饱和植物脂肪酸的部分甘油酯混合物；水；盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐；胶体硅；三硅酸镁；聚乙烯吡咯烷酮；聚丙烯酸脂；蜡；聚乙烯-聚氧丙烯-阻断聚合体；羊毛脂；糖，如乳糖，葡萄糖和蔗糖；淀粉如玉米淀粉和土豆淀粉；纤维素和它的衍生物如羧甲基纤维素钠，乙基纤维素和乙酸纤维素；树胶粉；麦芽；明胶；滑石粉；辅料如可可豆脂和栓剂蜡状物；油如花生油，棉子油，红花油，麻油，橄榄油，玉米油和豆油；二醇类化合物，如丙二醇和聚乙二醇；酯类如乙基油酸酯和乙基月桂酸酯；琼脂；缓冲 剂如氢氧化镁和氢氧化铝；海藻酸；无热原的水；等渗盐；林格(氏)溶液；乙醇；磷酸缓冲溶液；和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁；着色剂；释放剂；包衣衣料；甜味剂；调味剂；香料；防腐剂和抗氧化剂。
本发明的组合物可以是口服给药，注射给药，局部给药，含服给药，或通过植入性药盒给药。此处所使用的术语“注射给药”包括皮下的，静脉的，肌内的，关节内的，滑膜(腔)内的，胸骨内的，膜内的，眼内的，肝内的，病灶内的，和颅内的注射或输注技术。本发明药学上可接受的组合物可以是以任何可接受的口服剂型进行口服给药，其中包括，但并不限于，胶囊，片剂，水制悬浮液或溶液。本发明的组合物无菌的注射方式可以是水的或油脂性的悬浮液。这些悬浮液可以根据公知技术采用合适的分散剂、湿润剂和悬浮剂按配方制造。
本发明的晶型化合物或药学上可接受的药物组合物的“有效量”、“有效治疗量”或“有效剂量”是指处理或减轻一个或多个本发明所提到病症的严重度的有效量。本发明的晶型化合物或药学上可接受的药物组合物在相当宽的剂量范围内是有效的。例如，每天服用的剂量约在0.1mg-1000mg/人范围内，分为一次或数次给药。根据本发明的方法、晶型化合物和药物组合物可以是任何给药量和任何给药途径来有效地用于处理或减轻疾病的严重程度。必需的准确的量将根据患者的情况而改变，这取决于种族，年龄，患者的一般条件，感染的严重程度，特殊的因素，给药方式等。本发明的化合物或药物组合物可以和一个或多个其他治疗剂联合给药，如本发明所讨论的。
本发明所使用的术语“治疗”任何疾病或病症，在其中一些实施方案中指改善疾病或病症(即减缓或阻止或减轻疾病或其至少一种临床症状的发展)。在另一些实施方案中，“治疗”指缓和/或改善至少一种身体参数，包括可能不为患者所察觉的身体参数。在另一些实施方案中，“治疗”指从身体上(例如稳定可察觉的症状)生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。在另一些实施方案中，“治疗”指预防或延迟疾病或病症的发作、发生或恶化。
本发明的晶型化合物除了对人类治疗有益以外，还可应用于兽医治疗宠物、引进品种的动物和农场的动物，包括哺乳动物，啮齿类动物等等。另外一些动物的实例包括马、狗和猫。在此，本发明的化合物包括其药学上可接受的衍生物。
发明详述
一方面，本发明提供了式(I)化合物的盐酸盐晶型L，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其粉末X-射线衍射图谱包括位于5.9°±0.2°，16.8°±0.2°，24.7°±0.2°衍射角(2θ)处的特征峰。
Figure PCTCN2022084708-appb-000005
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型L的粉末X-射线衍射图谱还包括至少一个以下衍射角(2θ)处的特征峰：19.5°±0.2°，23.6°±0.2°。
例如，所述的式(I)化合物的盐酸盐晶型L的粉末X-射线衍射图谱包括位于5.9°±0.2°，16.8°±0.2°，24.7°±0.2°，19.5°±0.2°衍射角(2θ)处的特征峰。
例如，所述的式(I)化合物的盐酸盐晶型L的粉末X-射线衍射图谱包括位于5.9°±0.2°，16.8°±0.2°，24.7°±0.2°，19.5°±0.2°，23.6°±0.2°衍射角(2θ)处的特征峰。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型L的粉末X-射线衍射图谱还包括至少一个以下衍射角(2θ)处的特征峰：22.1°±0.2°，11.3°±0.2°。
例如，所述的式(I)化合物的盐酸盐晶型L的粉末X-射线衍射图谱包括位于5.9°±0.2°，16.8°±0.2°，24.7°±0.2°，22.1°±0.2°衍射角(2θ)处的特征峰。
例如，所述的式(I)化合物的盐酸盐晶型L的粉末X-射线衍射图谱包括位于5.9°±0.2°，16.8°±0.2°，24.7°±0.2°，22.1°±0.2°，11.3°±0.2°衍射角(2θ)处的特征峰。
例如，所述的式(I)化合物的盐酸盐晶型L的粉末X-射线衍射图谱包括位于5.9°±0.2°，16.8°±0.2°，24.7°±0.2°，19.5°±0.2°，23.6°±0.2°，22.1°±0.2°衍射角(2θ)处的特征峰。
例如，所述的式(I)化合物的盐酸盐晶型L的粉末X-射线衍射图谱包括位于5.9°±0.2°，16.8°±0.2°，24.7°±0.2°，19.5°±0.2°，23.6°±0.2°，22.1°±0.2°，11.3°±0.2°衍射角(2θ)处的特征峰。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型L的X射线粉末衍射图谱与图6基本上相同。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型L的X射线粉末衍射图谱与图2或图5基本上相同。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型L的粉末X-射线衍射图谱包括位于5.9°±0.2°，16.8°±0.2°，24.7°±0.2°衍射角(2θ)处的特征峰；且所述的式(I)化合物的盐酸盐晶型L的X射线粉末衍射图谱与图6基本上相同。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型L的粉末X-射线衍射图谱包括位于5.9°±0.2°，16.8°±0.2°，24.7°±0.2°，19.5°±0.2°，23.6°±0.2°衍射角(2θ)处的特征峰；且所述的式(I)化合物的盐酸盐晶型L的X射线粉末衍射图谱与图6基本上相同。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型L的粉末X-射线衍射图谱包括位于5.9°±0.2°，16.8°±0.2°，24.7°±0.2°，19.5°±0.2°，23.6°±0.2°，22.1°±0.2°，11.3°±0.2°衍射角(2θ)处的特征峰；且所述的式(I)化合物的盐酸盐晶型L的X射线粉末衍射图谱与图6基本上相同。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型L的TGA图与图3基本上相同。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型L的粉末X-射线衍射图谱包括位于5.9°±0.2°，16.8°±0.2°，24.7°±0.2°衍射角(2θ)处的特征峰；且所述的式(I)化合物的盐酸盐晶型L的TGA图与图3基本上相同。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型L的粉末X-射线衍射图谱包括位于5.9°±0.2°，16.8°±0.2°，24.7°±0.2°，19.5°±0.2°，23.6°±0.2°衍射角(2θ)处的特征峰；且所述的式(I)化合物的盐酸盐晶型L的TGA图与图3基本上相同。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型L的粉末X-射线衍射图谱包括位于5.9°±0.2°，16.8°±0.2°，24.7°±0.2°，19.5°±0.2°，23.6°±0.2°，22.1°±0.2°，11.3°±0.2°衍射角(2θ)处的特征峰；且所述的式(I)化合物的盐酸盐晶型L的TGA图与图3基本上相同。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型L的DSC图与图4基本上相同。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型L的粉末X-射线衍射图谱包括位于5.9°±0.2°，16.8°±0.2°，24.7°±0.2°衍射角(2θ)处的特征峰；且所述的式(I)化合物的盐酸盐晶型L的DSC图与图4基本上相同。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型L的粉末X-射线衍射图谱包括位于5.9°±0.2°，16.8°±0.2°，24.7°±0.2°，19.5°±0.2°，23.6°±0.2°衍射角(2θ)处的特征峰；且所述的式(I)化合物的盐酸盐晶型L的DSC图与图4基本上相同。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型L的粉末X-射线衍射图谱包括位于5.9°±0.2°，16.8°±0.2°，24.7°±0.2°，19.5°±0.2°，23.6°±0.2°，22.1°±0.2°，11.3°±0.2°衍射角(2θ)处的特征峰；且所述的式(I)化合物的盐酸盐晶型L的DSC图与图4基本上相同。
根据发明的一个方面，提供了所述的式(I)化合物的盐酸盐晶型L的制备方法，所述方 法包括：
a)将式(I)化合物和等当量的盐酸加入至醇类溶剂中，室温条件下搅拌过夜，得到的固体置于室温下放置1个月后，得到盐酸盐晶型L；或
b)将式(I)化合物和等当量的盐酸加入至醇类溶剂中，室温条件下搅拌过夜，得到的固体加热至120-160℃，冷却后得到盐酸盐晶型L。
在本发明的一些实施方案中，所述方法中的醇类溶剂包括异丙醇。
另一方面，本发明提供了药物组合物，其包含所述的式(I)所示化合物的盐酸盐晶型L以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
另一方面，本发明提供了所述的式(I)所示化合物的盐酸盐晶型L、所述的药物组合物在制备预防和/或治疗Bcr-Abl酪氨酸激酶介导的疾病的药物中的用途。
在本发明的一些实施方案中，所述的Bcr-Abl酪氨酸激酶介导的疾病包括慢性粒细胞白血病。
另一方面，本发明提供了式(I)化合物的盐酸盐晶型F，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其粉末X-射线衍射图谱包括位于16.9°±0.2°，9.6°±0.2°，10.4°±0.2°衍射角(2θ)处的特征峰。
Figure PCTCN2022084708-appb-000006
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型F的粉末X-射线衍射图谱还包括至少一个以下衍射角(2θ)处的特征峰：20.4°±0.2°，16.1°±0.2°，23.5°±0.2°。
例如，所述的式(I)化合物的盐酸盐晶型F的粉末X-射线衍射图谱包括位于16.9°±0.2°，9.6°±0.2°，10.4°±0.2°，20.4°±0.2°衍射角(2θ)处的特征峰。
例如，所述的式(I)化合物的盐酸盐晶型F的粉末X-射线衍射图谱包括位于16.9°±0.2°，9.6°±0.2°，10.4°±0.2°，20.4°±0.2°，16.1°±0.2°衍射角(2θ)处的特征峰。
例如，所述的式(I)化合物的盐酸盐晶型F的粉末X-射线衍射图谱包括位于16.9°±0.2°，9.6°±0.2°，10.4°±0.2°，20.4°±0.2°，16.1°±0.2°，23.5°±0.2°衍射角(2θ)处的特征峰。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型F的粉末X-射线衍射 图谱还包括至少一个以下衍射角(2θ)处的特征峰：22.0°±0.2°，11.0°±0.2°，12.7°±0.2°。
例如，所述的式(I)化合物的盐酸盐晶型F的粉末X-射线衍射图谱包括位于16.9°±0.2°，9.6°±0.2°，10.4°±0.2°，22.0°±0.2°衍射角(2θ)处的特征峰。
例如，所述的式(I)化合物的盐酸盐晶型F的粉末X-射线衍射图谱包括位于16.9°±0.2°，9.6°±0.2°，10.4°±0.2°，22.0°±0.2°，11.0°±0.2°衍射角(2θ)处的特征峰。
例如，所述的式(I)化合物的盐酸盐晶型F的粉末X-射线衍射图谱包括位于16.9°±0.2°，9.6°±0.2°，10.4°±0.2°，22.0°±0.2°，11.0°±0.2°，12.7°±0.2°衍射角(2θ)处的特征峰。
例如，所述的式(I)化合物的盐酸盐晶型F的粉末X-射线衍射图谱包括位于16.9°±0.2°，9.6°±0.2°，10.4°±0.2°，20.4°±0.2°，16.1°±0.2°，23.5°±0.2°，22.0°±0.2°衍射角(2θ)处的特征峰。
例如，所述的式(I)化合物的盐酸盐晶型F的粉末X-射线衍射图谱包括位于16.9°±0.2°，9.6°±0.2°，10.4°±0.2°，20.4°±0.2°，16.1°±0.2°，23.5°±0.2°，22.0°±0.2°，11.0°±0.2°衍射角(2θ)处的特征峰。
例如，所述的式(I)化合物的盐酸盐晶型F的粉末X-射线衍射图谱包括位于16.9°±0.2°，9.6°±0.2°，10.4°±0.2°，20.4°±0.2°，16.1°±0.2°，23.5°±0.2°，22.0°±0.2°，11.0°±0.2°，12.7°±0.2°衍射角(2θ)处的特征峰。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型F的X射线粉末衍射图谱与图7基本上相同。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型F的粉末X-射线衍射图谱包括位于16.9°±0.2°，9.6°±0.2°，10.4°±0.2°衍射角(2θ)处的特征峰；且所述的式(I)化合物的盐酸盐晶型F的X射线粉末衍射图谱与图7基本上相同。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型F的粉末X-射线衍射图谱包括位于16.9°±0.2°，9.6°±0.2°，10.4°±0.2°，20.4°±0.2°，16.1°±0.2°，23.5°±0.2°衍射角(2θ)处的特征峰；且所述的式(I)化合物的盐酸盐晶型F的X射线粉末衍射图谱与图7基本上相同。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型F的粉末X-射线衍射图谱包括位于16.9°±0.2°，9.6°±0.2°，10.4°±0.2°，20.4°±0.2°，16.1°±0.2°，23.5°±0.2°，22.0°±0.2°，11.0°±0.2°，12.7°±0.2°衍射角(2θ)处的特征峰；且所述的式(I)化合物的盐酸盐晶型F的X射线粉末衍射图谱与图7基本上相同。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型F的TGA图与图8基本上相同。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型F的粉末X-射线衍射图谱包括位于16.9°±0.2°，9.6°±0.2°，10.4°±0.2°衍射角(2θ)处的特征峰；且所述的式(I)化合物的盐酸盐晶型F的TGA图与图8基本上相同。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型F的粉末X-射线衍射图谱包括位于16.9°±0.2°，9.6°±0.2°，10.4°±0.2°，20.4°±0.2°，16.1°±0.2°，23.5°±0.2°衍射角(2θ)处的特征峰；且所述的式(I)化合物的盐酸盐晶型F的TGA图与图8基本上相同。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型F的粉末X-射线衍射图谱包括位于16.9°±0.2°，9.6°±0.2°，10.4°±0.2°，20.4°±0.2°，16.1°±0.2°，23.5°±0.2°，22.0°±0.2°，11.0°±0.2°，12.7°±0.2°衍射角(2θ)处的特征峰；且所述的式(I)化合物的盐酸盐晶型F的TGA图与图8基本上相同。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型F的DSC图与图9基本上相同。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型F的粉末X-射线衍射图谱包括位于16.9°±0.2°，9.6°±0.2°，10.4°±0.2°衍射角(2θ)处的特征峰；且所述的式(I)化合物的盐酸盐晶型F的DSC图与图9基本上相同。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型F的粉末X-射线衍射图谱包括位于16.9°±0.2°，9.6°±0.2°，10.4°±0.2°，20.4°±0.2°，16.1°±0.2°，23.5°±0.2°衍射角(2θ)处的特征峰；且所述的式(I)化合物的盐酸盐晶型F的DSC图与图9基本上相同。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型F的粉末X-射线衍射图谱包括位于16.9°±0.2°，9.6°±0.2°，10.4°±0.2°，20.4°±0.2°，16.1°±0.2°，23.5°±0.2°，22.0°±0.2°，11.0°±0.2°，12.7°±0.2°衍射角(2θ)处的特征峰；且所述的式(I)化合物的盐酸盐晶型F的DSC图与图9基本上相同。
根据发明的一个方面，提供了所述的式(I)化合物的盐酸盐晶型F的制备方法，所述方法包括：将式(I)化合物在室温下，以盐酸盐无定形样品为起始物，在加入醚类溶剂中搅拌至呈混悬状态，将混悬液离心后室温条件下自然挥干，得到盐酸盐晶型F。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型F的制备方法，所述方法中的醚类溶剂包括甲基叔丁基醚。
另一方面，本发明提供了药物组合物，其包含所述的式(I)所示化合物的盐酸盐晶型F以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
另一方面，本发明提供了所述的式(I)所示化合物的盐酸盐晶型F、所述的药物组合物 在制备预防和/或治疗Bcr-Abl酪氨酸激酶介导的疾病的药物中的用途。
在本发明的一些实施方案中，所述的Bcr-Abl酪氨酸激酶介导的疾病包括慢性粒细胞白血病。
另一方面，本发明提供了式(I)化合物的盐酸盐晶型J，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其粉末X-射线衍射图谱包括位于20.8°±0.2°，21.2°±0.2°，7.3°±0.2°衍射角(2θ)处的特征峰。
Figure PCTCN2022084708-appb-000007
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型J的粉末X-射线衍射图谱还包括至少一个以下衍射角(2θ)处的特征峰：19.9°±0.2°，12.8°±0.2°。
例如，所述的式(I)化合物的盐酸盐晶型J的粉末X-射线衍射图谱包括位于20.8°±0.2°，21.2°±0.2°，7.3°±0.2°，19.9°±0.2°衍射角(2θ)处的特征峰。
例如，所述的式(I)化合物的盐酸盐晶型J的粉末X-射线衍射图谱包括位于20.8°±0.2°，21.2°±0.2°，7.3°±0.2°，19.9°±0.2°，12.8°±0.2°衍射角(2θ)处的特征峰。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型J的粉末X-射线衍射图谱还包括至少一个以下衍射角(2θ)处的特征峰：8.8°±0.2°，21.6°±0.2°。
例如，所述的式(I)化合物的盐酸盐晶型J的粉末X-射线衍射图谱包括位于20.8°±0.2°，21.2°±0.2°，7.3°±0.2°，8.8°±0.2°衍射角(2θ)处的特征峰。
例如，所述的式(I)化合物的盐酸盐晶型J的粉末X-射线衍射图谱包括位于20.8°±0.2°，21.2°±0.2°，7.3°±0.2°，8.8°±0.2°，21.6°±0.2°衍射角(2θ)处的特征峰。
例如，所述的式(I)化合物的盐酸盐晶型J的粉末X-射线衍射图谱包括位于20.8°±0.2°，21.2°±0.2°，7.3°±0.2°，19.9°±0.2°，12.8°±0.2°，8.8°±0.2°衍射角(2θ)处的特征峰。
例如，所述的式(I)化合物的盐酸盐晶型J的粉末X-射线衍射图谱包括位于20.8°±0.2°，21.2°±0.2°，7.3°±0.2°，19.9°±0.2°，12.8°±0.2°，8.8°±0.2°，21.6°±0.2°衍射角(2θ)处的特征峰。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型J的X射线粉末衍射图谱与图10基本上相同。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型J的粉末X-射线衍射图谱包括位于20.8°±0.2°，21.2°±0.2°，7.3°±0.2°衍射角(2θ)处的特征峰；且所述的式(I)化合物的盐酸盐晶型J的X射线粉末衍射图谱与图10基本上相同。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型J的粉末X-射线衍射图谱包括位于20.8°±0.2°，21.2°±0.2°，7.3°±0.2°，19.9°±0.2°，12.8°±0.2°衍射角(2θ)处的特征峰；且所述的式(I)化合物的盐酸盐晶型J的X射线粉末衍射图谱与图10基本上相同。
在本发明的一些实施方案中，所述的式(I)化合物的盐酸盐晶型J的粉末X-射线衍射图谱包括位于20.8°±0.2°，21.2°±0.2°，7.3°±0.2°，19.9°±0.2°，12.8°±0.2°，8.8°±0.2°，21.6°±0.2°衍射角(2θ)处的特征峰；且所述的式(I)化合物的盐酸盐晶型J的X射线粉末衍射图谱与图10基本上相同。
根据发明的一个方面，提供了所述的式(I)化合物的盐酸盐晶型J的制备方法，所述方法包括：将式(I)化合物在30℃到50℃下，将盐酸盐样品在杂氮类溶剂中溶清，将其加入至-20℃到5℃预冷的酮类溶剂中，固体析出，得到盐酸盐晶型J。
在本发明的一些实施方案中，所述方法中的杂氮类溶剂包括N,N-二甲基乙酰胺，酮类溶剂包括甲基异丁酮。
另一方面，本发明提供了药物组合物，其包含所述的式(I)所示化合物的盐酸盐晶型J以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
另一方面，本发明提供了所述的式(I)所示化合物的盐酸盐晶型J、所述的药物组合物在制备预防和/或治疗Bcr-Abl酪氨酸激酶介导的疾病的药物中的用途。
在本发明的一些实施方案中，所述的Bcr-Abl酪氨酸激酶介导的疾病包括慢性粒细胞白血病。
另一方面，本发明提供了药物组合物，其包含所述的盐酸盐晶型L、所述的盐酸盐晶型F、所述的盐酸盐晶型J中的多种，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
本发明进一步通过以下实施例说明，这些实施例不应解释为将本发明公开的范围限于其中所述的具体步骤。
为了进一步理解本发明，下面结合实施例对本发明进行详细说明。
实施例
以下将通过具体实施例进一步阐述本发明，但并不用于限制本发明的保护范围。本领域技术人员可在权利要求范围内对制备方法和使用仪器作出改进，这些改进也应视为本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射
DSC：差示扫描量热分析
TGA：热重分析
DVS：动态水分吸附
HPLC：高效液相色谱
RH：相对湿度
本发明所述的X射线粉末衍射图在Bruker D2 PHASER X射线粉末衍射仪上采集。本发明所述的X射线粉末衍射的方法参数如下：
X射线光源：Cu，Kα
Kα1
Figure PCTCN2022084708-appb-000008
1.54060；Kα2
Figure PCTCN2022084708-appb-000009
1.54439
Kα2/Kα1强度比例：0.50
电压：30仟伏特(kV)
电流：10毫安培(mA)
扫描范围：自3.0至40.0度
本发明所述的红外光谱条件如下：
红外光谱仪
厂家:Thermofisher(美国)
型号:Nicolet iS 10
主要参数：
光谱范围:7800-350cm -1，光谱分辨率:优于0.4cm -1，信噪比:峰-峰噪声值:小于9.65x10-6Abs，波数精度：优于0.005cm-1，金刚石ATR附件，10万张红外高分辨谱库。
本发明所述的差示扫描量热分析(DSC)图在TA Q2000上采集。本发明所述的差示扫描量热分析(DSC)的方法参数如下：
扫描速率：10℃/min
保护气体：N 2
本发明所述的热重分析(TGA)图在TA Q500上采集。本发明所述的热重分析(TGA)的方法参数如下：
扫描速率：10℃/min
保护气体：N2
本发明中超高效液相色谱(UPLC)数据采自于Waters H-Clas，所用检测器为二极管阵列检测器(PDA)。本发明所述的测试溶解度的UPLC方法参数如下：
1、色谱柱：HSS T3，2.1mm/5mm/1.8um
2、流动相：A：0.1％H3PO4水溶液
B：乙腈溶液
洗脱梯度如下：
Figure PCTCN2022084708-appb-000010
3、流速：0.5mL/min
4、进样量：3μl
5、检测波长：254nm
6、柱温：40℃
7、稀释剂：ACN/H2O 1:1
下述实施例中所使用的阿思尼布起始物可根据现有技术制备得到，例如根据WO2013171639A1中所记载的方法制备获得，但起始晶型并非制备本发明晶型的限定条件。
实施例1：盐酸盐晶型A的制备
称取500.6毫克式(I)化合物游离碱样品，加入5毫升异丙醇，一边用磁力搅拌器搅拌，一边加入95微升浓盐酸(36％-38％)，25℃下搅拌1天后，将分离得到的固体放置于室温条件下真空干燥约1天后，收集固体可得盐酸盐晶型A。
经XRPD检测，盐酸盐晶型A的X射线粉末衍射数据如表1所示，其衍射图如图1所示。盐酸盐晶型A在约16.8°±0.2°，5.0°±0.2°，21.9°±0.2°，21.0°±0.2°，22.3°±0.2°，4.1°±0.2°，10.4°±0.2°，15.1°±0.2°，15.8°±0.2°处有特征峰。
表1:实施例1中式(I)化合物盐酸盐晶型A的X射线粉末衍射数据
衍射角2θ(±0.2°) d值 强度％
5.04 17.52 94.82
9.98 8.87 14.94
10.43 8.48 24.94
12.66 6.99 8.85
13.28 6.67 6.55
15.12 5.86 22.03
15.84 5.59 16.60
16.78 5.28 100.00
19.31 4.60 9.96
20.96 4.24 41.17
21.85 4.07 48.27
22.31 3.98 37.48
24.11 3.69 37.36
25.70 3.47 7.89
26.90 3.31 4.49
34.97 2.57 4.38
实施例2：盐酸盐晶型L的制备
将实施例1得到的固体放置于室温室湿条件下约1月后，收集固体可得盐酸盐晶型L。
经XRPD检测，盐酸盐晶型L的X射线粉末衍射数据如表2所示，其衍射图如图2所示。盐酸盐晶型L的TGA如图3所示，DSC如图4所示。
表2:实施例2中式(I)化合物盐酸盐晶型L的X射线粉末衍射数据
衍射角2θ(±0.2°) d值 强度％
5.90 14.98 100.00
11.30 7.83 9.88
12.69 6.98 5.31
15.22 5.82 8.95
衍射角2θ(±0.2°) d值 强度％
16.77 5.29 43.41
19.46 4.56 27.89
21.40 4.15 13.76
22.11 4.02 13.27
23.57 3.77 17.49
24.70 3.61 31.74
27.38 3.26 5.05
30.01 2.98 6.52
31.86 2.81 6.34
实施例3：盐酸盐晶型L的制备
取～5毫克实施例1中制备得到的式(I)化合物的盐酸盐晶型A，用差示扫描量热仪(DSC)加热至150℃，并于150℃平衡数分钟，温度降至室温即可得到盐酸盐晶型L。
经XRPD检测，盐酸盐晶型L的X射线粉末衍射数据如表3所示，其衍射图如图5所示。
表3:实施例3中式(I)化合物盐酸盐晶型L的X射线粉末衍射数据
衍射角2θ(±0.2°) d值 强度％
5.86 15.07 100.00
8.48 10.42 1.61
11.30 7.83 20.48
12.69 6.98 44.35
15.21 5.83 4.12
15.79 5.61 4.26
16.64 5.33 31.22
16.77 5.29 24.72
18.86 4.71 10.12
19.41 4.57 38.10
20.15 4.41 15.46
衍射角2θ(±0.2°) d值 强度％
20.93 4.24 52.75
21.12 4.21 54.52
22.10 4.02 9.95
23.55 3.78 29.57
24.67 3.61 22.63
25.55 3.49 11.70
29.70 3.01 8.53
实施例4：盐酸盐晶型L的制备
取适量施例1中制备得到的式(I)化合物的盐酸盐晶型A，用差示扫描量热仪(DSC)加热至150℃，并于150℃平衡数分钟，温度降至室温即可得到盐酸盐晶型L。
经XRPD检测，盐酸盐晶型L的X射线粉末衍射数据如表4所示，其衍射图如图6所示。
表4:实施例4中式(I)化合物盐酸盐晶型L的X射线粉末衍射数据
衍射角2θ(±0.2°) d值 强度％
5.90 14.98 100.00
11.31 7.82 9.91
11.80 7.50 9.34
12.70 6.97 6.16
15.23 5.82 4.76
15.82 5.60 3.98
16.66 5.32 24.53
16.86 5.26 20.27
17.75 5.00 2.27
19.44 4.57 34.09
20.22 4.39 4.75
21.27 4.18 7.77
22.05 4.03 8.55
衍射角2θ(±0.2°) d值 强度％
23.58 3.77 20.83
24.68 3.61 37.65
25.31 3.52 8.46
25.56 3.48 8.95
26.66 3.34 2.04
27.29 3.27 5.68
27.60 3.23 4.58
29.80 3.00 9.46
30.29 2.95 9.28
30.95 2.89 4.00
31.79 2.82 2.65
33.02 2.71 3.23
34.37 2.61 2.91
35.46 2.53 2.37
36.07 2.49 1.43
38.92 2.31 2.89
实施例5：盐酸盐晶型F的制备
称取9.0毫克式(I)化合物盐酸盐无定形样品，加入0.5毫升甲基叔丁基醚，室温条件下打浆2天后，离心分离固体，置于室温室湿条件下挥干，得到盐酸盐晶型F。
经XRPD检测，盐酸盐晶型F的X射线粉末衍射数据如表5所示，其衍射图如图7所示。盐酸盐晶型F的TGA如图8所示，DSC如图9所示。
表5:实施例5中式(I)化合物盐酸盐晶型F的X射线粉末衍射数据
衍射角2θ(±0.2°) d值 强度％
4.85 18.21 31.28
9.61 9.20 23.43
10.44 8.47 35.37
11.01 8.04 20.14
衍射角2θ(±0.2°) d值 强度％
12.27 7.21 13.92
12.74 6.95 16.58
15.29 5.79 14.48
15.55 5.70 16.10
16.05 5.52 39.20
16.88 5.25 100.00
18.12 4.90 5.87
18.93 4.69 10.02
20.44 4.35 51.05
21.17 4.20 12.85
21.81 4.07 47.60
21.97 4.05 61.72
23.49 3.79 36.96
23.91 3.72 20.05
25.46 3.50 9.44
26.48 3.37 10.84
27.42 3.25 3.90
28.02 3.18 7.31
31.22 2.87 5.71
34.87 2.57 5.72
实施例6：盐酸盐晶型J的制备
称取15.1毫克式(I)化合物盐酸盐样品，加入0.2毫升N,N-二甲基乙酰胺在50℃溶清后，加入至4毫升-20℃预冷处理的甲基异丁酮中，沉淀析出，收集固体可得盐酸盐晶型J。
经XRPD检测，盐酸盐晶型J的X射线粉末衍射数据如表6所示，其衍射图如图10所示。
表6:实施例6中式(I)化合物盐酸盐晶型J的X射线粉末衍射数据
衍射角2θ(±0.2°) d值 强度％
7.26 12.18 54.28
8.76 10.10 21.90
12.77 6.93 33.28
19.94 4.45 47.17
20.77 4.28 100.00
21.15 4.20 73.93
21.61 4.11 18.71
26.77 3.33 3.53
实施例7：晶型的溶解度
将本发明盐酸盐晶型L、盐酸盐晶型F和WO2020230099A1中公开的盐酸盐Form A分别加入至纯水中，配制成悬浊液，在1小时、2小时、4小时和24小时平衡后过滤，得到饱和溶液。通过高效液相色谱法(HPLC)测定饱和溶液中样品的含量。试验结果如表7所示，溶解度曲线如图11所示。试验结果显示，本发明盐酸盐晶型L、盐酸盐晶型F在纯水中的溶解度高于WO2020230099A1中公开的盐酸盐Form A。
表7不同晶型在纯水中的溶解度数据
Figure PCTCN2022084708-appb-000011
实施例8：晶型的可压性
采用手动压片机进行压片，压片时，选择可以压制成圆柱体片剂的圆形平冲，加入一定量的本发明盐酸盐晶型F，采用10kN压力压制成圆形片剂，采用片剂硬度测定仪测试其径向破碎力(硬度，H)。采用游标卡尺测量片剂的直径(D)和厚度(L)，利用公式T＝2H/πDL计算出不同硬度下粉体的抗张强度，试验结果如表8所示。在一定的压力下，抗张强度越大的，表示其可压性越好。试验结果显示，本发明盐酸盐晶型F具有较大的抗张强度，说明具有较 优的可压性。
表8盐酸盐晶型F的可压性评估
晶型 直径(毫米) 厚度(毫米) 径向破碎力(牛) 抗张强度(兆帕)
盐酸盐晶型F 6.08 2.66 45.70 1.800
实施例9：晶型的固有溶出速率
称取本发明盐酸盐晶型L、盐酸盐晶型F和WO2020230099A1中公开固体各约100mg，倒入固有溶出模具，在5kN压力下持续1min，制成表面积0.5cm 2的薄片，取完整压片转移至溶出仪测试固有溶出速率，根据10～30min之间的测定点计算斜率，以mg/mL表示，根据斜率进一步计算固有溶出速率(Intrinsic dissolution rate,IDR)，以mg/min/cm 2表示。本发明盐酸盐晶型L、盐酸盐晶型F的溶出速率较现有技术晶型更快。
实施例10：稳定性对比研究
称取本发明盐酸盐晶型L(起始纯度99.6％)约15mg，敞口放置于25℃/60％RH条件的稳定箱中，在7天、17天和28天后取样测HPLC，试验结果如表9所示，稳定性的XRPD对比图如图15所示。试验结果显示，本发明盐酸盐晶型L在25℃/60％RH条件下具有较高的稳定性。
称取本发明盐酸盐晶型L(起始纯度99.6％)和盐酸盐晶型F(起始纯度98.3％)各约15mg，敞口放置于40℃/75％RH条件的稳定箱中，在7天、17天和28天后取样测HPLC，试验结果如表10所示。试验结果显示，本发明盐酸盐晶型L和盐酸盐晶型F在40℃/75％RH条件下具有较高的稳定性。
表9盐酸盐晶型L在25℃/60％RH条件下的稳定性
Figure PCTCN2022084708-appb-000012
表10盐酸盐晶型L和盐酸盐晶型F在40℃/75％RH条件下的稳定性
Figure PCTCN2022084708-appb-000013
Figure PCTCN2022084708-appb-000014
实施例11：引湿性对比研究
称取本发明盐酸盐晶型L和盐酸盐晶型F各约10mg进行动态水分吸附(DVS)测试。本发明盐酸盐晶型L和盐酸盐晶型F具有较低的引湿性。
关于引湿性特征描述与引湿性增重的界定(中国药典2020年版四部药物引湿性试验指导原则)：
潮解：吸收足量水分形成液体
极具引湿性：引湿增重不小于15％
有引湿性：引湿增重小于15％但不小于2％
略有引湿性：引湿增重小于2％但不小于0.2％
无或几乎无引湿性：引湿增重小于0.2％
实施例12：晶习对比研究
称取本发明盐酸盐晶型L约10mg，分别置于载玻片上，滴加少许真空硅油分散样品，然后盖上盖玻片，置于偏光显微镜下观察，盐酸盐晶型L的PLM如图12所示。试验结果显示，本发明盐酸盐晶型L具有较优的晶习。
实施例13：粒径分布对比研究
称取本发明盐酸盐晶型L和WO2020230099A1中公开的盐酸盐Form A各约10-30mg，然后加入约5mL Isopar G(含有0.2％卵磷脂)，将待测样品充分混合均匀后加入SDC进样系统中，使遮光度达到合适范围，超声30秒后进行粒径分布的测试，试验结果如表11所示，盐酸盐Form A的粒径分布如图13所示，盐酸盐晶型L的粒径分布图如图14所示。试验结果显示，盐酸盐Form A的粒径呈双峰分布，盐酸盐晶型L的粒径呈单峰分布，说明本发明盐酸盐晶型L比盐酸盐Form A具有更均匀的粒径分布。
表11不同晶型的粒径分布
晶型 平均粒径(微米) D10(微米) D50(微米) D90(微米)
盐酸盐Form A 10.86 1.520 4.48 23.53
盐酸盐晶型L 30.76 8.03 24.08 60.74
实施例14：黏附性对比研究
称取本发明盐酸盐晶型F和WO2020230099A1中公开的盐酸盐Form A各约100mg，然后加入到6mm圆形平冲中，采用10kN的压力进行压片处理，压片后停留约半分钟，记录最后制成片剂的质量，计算压制过程中粘附在圆形冲头的黏附量，试验结果如表12所示。试验结果显示，本发明盐酸盐晶型F比盐酸盐Form A更不易黏附。
表12盐酸盐晶型F的黏附性
晶型 压片前质量(毫克) 压片后质量(毫克) 黏附量(毫克)
盐酸盐晶型F 100.0 98.1 1.9
盐酸盐Form A 100.1 97.9 2.2
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (22)

  1. 式(I)化合物的盐酸盐晶型L，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其粉末X-射线衍射图谱包括位于5.9°±0.2°，16.8°±0.2°，24.7°±0.2°衍射角(2θ)处的特征峰。
    Figure PCTCN2022084708-appb-100001
  2. 根据权利要求1所述的式(I)化合物的盐酸盐晶型L，其粉末X-射线衍射图谱还包括至少一个以下衍射角(2θ)处的特征峰：19.5°±0.2°，23.6°±0.2°。
  3. 权利要求1-2中任一项所述的式(I)化合物的盐酸盐晶型L的制备方法，所述方法包括：
    a)将式(I)化合物和等当量的盐酸加入至醇类溶剂中，室温条件下搅拌过夜，得到的固体置于室温下放置1个月后，得到盐酸盐晶型L；或
    b)将式(I)化合物和等当量的盐酸加入至醇类溶剂中，室温条件下搅拌过夜，得到的固体加热至120-160℃，冷却后得到盐酸盐晶型L。
  4. 根据权利要求3所述的式(I)化合物的盐酸盐晶型L的制备方法，所述方法中的醇类溶剂包括异丙醇。
  5. 药物组合物，其包含权利要求1-2中任一项所述的式(I)所示化合物的盐酸盐晶型L以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  6. 权利要求1-2中任一项所述的式(I)所示化合物的盐酸盐晶型L、权利要求5所述的药物组合物在制备预防和/或治疗Bcr-Abl酪氨酸激酶介导的疾病的药物中的用途。
  7. 根据权利要求6所述的用途，所述的Bcr-Abl酪氨酸激酶介导的疾病包括慢性粒细胞白血病。
  8. 式(I)化合物的盐酸盐晶型F，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其粉末X-射线衍射图谱包括位于16.9°±0.2°，9.6°±0.2°，10.4°±0.2°衍射角(2θ)处的特征峰。
    Figure PCTCN2022084708-appb-100002
  9. 根据权利要求8所述的式(I)化合物的盐酸盐晶型F，其粉末X-射线衍射图谱还包括至少一个以下衍射角(2θ)处的特征峰：20.4°±0.2°，16.1°±0.2°，23.5°±0.2°。
  10. 权利要求8-9中任一项所述的式(I)化合物的盐酸盐晶型F的制备方法，所述方法包括：将式(I)化合物在室温下，以盐酸盐无定形样品为起始物，在加入醚类溶剂中搅拌至呈混悬状态，将混悬液离心后室温条件下自然挥干，得到盐酸盐晶型F。
  11. 根据权利要求10所述的式(I)化合物的盐酸盐晶型F的制备方法，所述方法中的醚类溶剂包括甲基叔丁基醚。
  12. 药物组合物，其包含权利要求8-9中任一项所述的式(I)所示化合物的盐酸盐晶型F以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  13. 权利要求8-9中任一项所述的式(I)所示化合物的盐酸盐晶型F、权利要求12所述的药物组合物在制备预防和/或治疗Bcr-Abl酪氨酸激酶介导的疾病的药物中的用途。
  14. 根据权利要求13所述的用途，所述的Bcr-Abl酪氨酸激酶介导的疾病包括慢性粒细胞白血病。
  15. 式(I)化合物的盐酸盐晶型J，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其粉末X-射线衍射图谱包括位于20.8°±0.2°，21.2°±0.2°，7.3°±0.2°衍射角(2θ)处的特征峰。
    Figure PCTCN2022084708-appb-100003
  16. 根据权利要求15所述的式(I)化合物的盐酸盐晶型J，其粉末X-射线衍射图谱还包括至少一个以下衍射角(2θ)处的特征峰：19.9°±0.2°，12.8°±0.2°。
  17. 权利要求15-16中任一项所述的式(I)化合物的盐酸盐晶型J的制备方法，所述方法包括：将式(I)化合物在30℃到50℃下，将盐酸盐样品在杂氮类溶剂中溶清，将其加入至-20℃到5℃预冷的酮类溶剂中，固体析出，得到盐酸盐晶型J。
  18. 根据权利要求17所述的式(I)化合物的盐酸盐晶型J的制备方法，所述方法中的杂氮类溶剂包括N,N-二甲基乙酰胺，酮类溶剂包括甲基异丁酮。
  19. 药物组合物，其包含权利要求15-16中任一项所述的式(I)所示化合物的盐酸盐晶型J以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  20. 权利要求15-16中任一项所述的式(I)所示化合物的盐酸盐晶型J、权利要求19所述的药物组合物在制备预防和/或治疗Bcr-Abl酪氨酸激酶介导的疾病的药物中的用途。
  21. 根据权利要求20所述的用途，所述的Bcr-Abl酪氨酸激酶介导的疾病包括慢性粒细胞白血病。
  22. 药物组合物，其包含权利要求1-2中任一项所述的盐酸盐晶型L、权利要求8-9中任一项所述的盐酸盐晶型F、权利要求15-16中任一项所述的盐酸盐晶型J权利要求中的多种，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104302638A (zh) * 2012-05-15 2015-01-21 诺华股份有限公司 用于抑制abl1、abl2和bcr-abl1的活性的苯甲酰胺衍生物
WO2020230100A1 (en) * 2019-05-16 2020-11-19 Novartis Ag Chemical process
WO2020230099A1 (en) * 2019-05-16 2020-11-19 Novartis Ag Crystalline forms of n-[4-(chlorodifluoromethoxy)phenyl]-6-[(3r)-3-hydroxypyrrolidin-1-yl]-5-(1h-pyrazol-5-yl)pyridine-3-carboxamide

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104302638A (zh) * 2012-05-15 2015-01-21 诺华股份有限公司 用于抑制abl1、abl2和bcr-abl1的活性的苯甲酰胺衍生物
WO2020230100A1 (en) * 2019-05-16 2020-11-19 Novartis Ag Chemical process
WO2020230099A1 (en) * 2019-05-16 2020-11-19 Novartis Ag Crystalline forms of n-[4-(chlorodifluoromethoxy)phenyl]-6-[(3r)-3-hydroxypyrrolidin-1-yl]-5-(1h-pyrazol-5-yl)pyridine-3-carboxamide

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