WO2021254449A1 - 一种shp2抑制剂的晶型及其组合物、制备方法和用途 - Google Patents

一种shp2抑制剂的晶型及其组合物、制备方法和用途 Download PDF

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Publication number
WO2021254449A1
WO2021254449A1 PCT/CN2021/100673 CN2021100673W WO2021254449A1 WO 2021254449 A1 WO2021254449 A1 WO 2021254449A1 CN 2021100673 W CN2021100673 W CN 2021100673W WO 2021254449 A1 WO2021254449 A1 WO 2021254449A1
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crystal form
compound
diffraction pattern
ray powder
powder diffraction
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PCT/CN2021/100673
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English (en)
French (fr)
Inventor
郑乾刚
诸葛浩
赵晔
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上海奕拓医药科技有限责任公司
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Priority to JP2022577746A priority Critical patent/JP2023532217A/ja
Priority to KR1020237002092A priority patent/KR20230026458A/ko
Priority to EP21826764.9A priority patent/EP4169920A4/en
Priority to CA3183063A priority patent/CA3183063A1/en
Priority to CN202180043362.7A priority patent/CN115698007A/zh
Priority to US18/002,196 priority patent/US20230339975A1/en
Priority to AU2021290733A priority patent/AU2021290733A1/en
Publication of WO2021254449A1 publication Critical patent/WO2021254449A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • This application provides (S)-1'-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-5, New crystal forms of 7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-5-amine, hydrates and solvates thereof, and pharmaceutical compositions containing the new crystal forms .
  • This application also discloses the preparation method and application of the novel crystal form.
  • SHP2 protein tyrosine phosphatase-2 containing SH2 domain
  • SHP2 occupies an extremely important position in the process of cell signal transduction, and is a target for the development of treatment of major diseases such as diabetes, autoimmune diseases and cancer.
  • the compound may exist in one or more crystalline forms, and the crystalline forms used as pharmaceutical active ingredients may have different chemical and physical properties, such as melting point, solubility, dissolution rate, hygroscopicity, density, fluidity, stability and bioavailability These properties have a direct impact on the processing and/or manufacturing capabilities of the compound as a pharmaceutical product.
  • the difference in crystallization conditions and storage conditions may lead to changes in the crystal structure of the compound, sometimes accompanied by the production of other crystalline forms.
  • this application provides multiple novel crystal forms of Compound 1, its hydrates and solvates.
  • this application provides the crystalline form A of compound 1, characterized in that the X-ray powder diffraction pattern of the crystalline form A has one or more peaks selected from the following group: about 6.46°, about 12.64° and approximately 12.93° 2 ⁇ .
  • the present application provides the crystalline form B of the hydrate of compound 1, characterized in that the X-ray powder diffraction pattern of the crystalline form B has one or more peaks selected from the following group: about 7.36 °, about 10.82° and about 11.10°2 ⁇ .
  • this application provides the crystalline form C of the hydrate of compound 1, characterized in that the X-ray powder diffraction pattern of the crystalline form C has one or more peaks selected from the following group: about 7.33 °, about 11.08° and about 14.70°2 ⁇ .
  • the present application provides the crystalline form D of the dichloromethane solvate of compound 1, characterized in that the X-ray powder diffraction pattern of the crystalline form D has one or more peaks selected from the following group : About 8.24°, about 13.46° and about 15.32° 2 ⁇ .
  • this application provides the crystalline form E of the isopropanol solvate of compound 1, characterized in that the X-ray powder diffraction pattern of the crystalline form E has one or more peaks selected from the following group : About 9.10°, about 13.49° and about 18.24°2 ⁇ .
  • the present application provides a pharmaceutical composition comprising a novel crystal form of Compound 1.
  • the present application provides a novel crystal form of Compound 1 and a method for preparing a pharmaceutical composition containing the novel crystal form.
  • the present application provides a novel crystal form of Compound 1 and the use of a pharmaceutical composition comprising the novel crystal form.
  • Figure 1 shows the X-ray powder diffraction (XRPD) pattern of the crystal form A of compound 1.
  • Figure 2 shows the differential scanning calorimetry/thermogravimetric analysis (DSC/TGA) spectrum of the crystalline form A of compound 1.
  • Figure 3 shows the XRPD pattern of the crystalline form B of the hydrate of compound 1.
  • Figure 4 shows the DSC/TGA chart of the crystalline form B of the hydrate of compound 1.
  • Figure 5 shows the XRPD pattern of Form C of the hydrate of Compound 1.
  • Figure 6 shows the DSC/TGA spectrum of the crystalline form C of the hydrate of compound 1.
  • Figure 7 shows the XRPD pattern of Form D of the dichloromethane solvate of Compound 1.
  • Figure 8 shows the DSC/TGA pattern of the crystalline form D of the dichloromethane solvate of Compound 1.
  • Figure 9 shows the XRPD pattern of Form E of the isopropanol solvate of Compound 1.
  • Figure 10 shows the DSC/TGA pattern of Form E of the isopropanol solvate of Compound 1.
  • Figures 11A to 11E show the crystal form A of compound 1 under three stability test conditions (25°C/60%RH/1 week, 40°C/75%RH/1 week and 60°C/closed/24 hours) High performance liquid chromatography (HPLC) profile.
  • HPLC High performance liquid chromatography
  • Figure 12 shows the XRPD patterns of the crystal form A of compound 1 under three stability test conditions (25°C/60%RH/1 week, 40°C/75%RH/1 week and 60°C/closed/24 hours) .
  • Fig. 13 shows the dynamic vapor adsorption (DVS) test spectrum of the crystal form A of compound 1 in the hygroscopicity investigation test of the crystal form A of compound 1.
  • Figure 14 shows the comparison of XRPD patterns of the crystal form A before and after the DVS test in the hygroscopicity investigation test of the crystal form A of compound 1.
  • Figure 15 shows the comparison of XRPD patterns after heating to different temperatures (30°C, 92°C, 118°C, 132°C, 175°C, respectively) and cooling of the crystalline form A of compound 1 under the protection of nitrogen.
  • Figure 16 shows the 1 H NMR spectrum of the hydrate crystal form B of Compound 1.
  • Figure 17 shows the 1 H NMR spectrum of the hydrate crystal form C of Compound 1.
  • Figure 18 shows the 1 H NMR spectrum of the dichloromethane solvate form D of Compound 1.
  • Figure 19 shows the 1 H NMR spectrum of the isopropanol solvate form E of Compound 1.
  • Figure 20 shows the comparison of XRPD patterns of the hydrate crystalline form B of compound 1 after heating to different temperatures (130°C and 180°C, respectively) and cooling under the protection of nitrogen.
  • Figure 21 shows the comparison of XRPD patterns after heating to different temperatures (130°C, 160°C, respectively) and cooling of the hydrate crystal form C of compound 1 under the protection of nitrogen.
  • Figure 22 shows the comparison of XRPD patterns of the dichloromethane solvate form D of compound 1 under the protection of nitrogen and heated to different temperatures (100°C and 160°C, respectively) and cooled.
  • Figure 23 shows the comparison of XRPD patterns of isopropanol solvate form E of compound 1 after heating to different temperatures (96°C and 180°C, respectively) under nitrogen protection and cooling.
  • the compound 1 described in this application is the compound 6 of Example 6 described in the PCT Patent Application Publication No. WO2020094018, and its synthesis is described in detail in the Example 6 of the PCT Patent Application.
  • the compound 1 described in this application also covers all tautomeric forms and isotopic substitution forms of compound 1.
  • solvate refers to a complex formed by combining compound 1 with a solvent, which contains a stoichiometric or non-stoichiometric solvent. If the solvent is water, the solvate is a hydrate. Examples of solvents that can form solvates include, but are not limited to, water, isopropanol, dichloromethane, methanol, ethanol, ethyl acetate, and the like.
  • pharmaceutically acceptable refers to a compound, material, composition and/or dosage form that is suitable for use in contact with human and animal tissues within the scope of reasonable medical judgment without excessive Toxicity, irritation, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier refers to a pharmaceutically acceptable material, composition or vehicle, such as liquid or solid fillers, diluents, excipients, solvents or encapsulating materials, which Involving the carrying or transport of therapeutic agents (for example, Compound 1 and its various crystal forms) from one location, body fluid, tissue, organ (internal or external) or part of the body to another location, body fluid, tissue, organ, or body Part of it without interfering with the structure and properties of the therapeutic agent.
  • the pharmaceutically acceptable carrier can be a vehicle, diluent, excipient, or other material that can be used to contact animal tissues without excessive toxicity or side effects.
  • Certain such carriers enable therapeutic agents (for example, Compound 1 and its various crystal forms) to be formulated into, for example, tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions, and lozenges for administration The subject of administration takes it orally.
  • Certain such carriers enable therapeutic agents (for example, Compound 1 and its various crystal forms) to be formulated for injection, infusion, or topical administration.
  • Exemplary pharmaceutically acceptable carriers include sugar, starch, cellulose, malt, tragacanth, gelatin, Ringer's solution, alginic acid, isotonic saline, buffers, and the like.
  • the pharmaceutically acceptable carriers that can be used in this application include carriers generally known in the art, such as those disclosed in "Remington Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference. .
  • administration refers to the introduction of a therapeutic agent (for example, Compound 1 and its various crystalline forms) into a patient.
  • a therapeutic agent for example, Compound 1 and its various crystalline forms
  • administration refers to direct administration and/or indirect administration.
  • the direct administration can be administered to the patient by a medical professional or the patient himself.
  • the indirect administration can be a prescription for drugs the behavior of. For example, the physician instructs the patient to administer the drug himself and/or to provide the patient with a prescription for the drug to administer the drug to the patient. In any case, administration requires delivery of the drug to the patient.
  • the term "effective amount” or “therapeutically effective amount” used in this application refers to the amount of a drug that can suppress or alleviate the disease or symptom of a subject or patient, or can prevent or prevent the occurrence of a disease or symptom prophylactically.
  • the therapeutically effective amount can be the amount of the drug that relieves one or more diseases or symptoms of the subject or patient to a certain degree; it can be part of one or more physiological or biochemical parameters related to the cause of the disease or symptom Or the amount of the drug that completely returns to normal; and/or the amount of the drug that can reduce the likelihood of disease or symptoms.
  • subject or patient refers to an animal that has been or will be the object of treatment, observation, or experiment, including human and non-human animals.
  • Non-human animals include all vertebrates, such as mammals and non-mammals.
  • Subject or patient can also be livestock animals, such as cattle, pigs, sheep, poultry, and horses; or rodents, such as rats, mice; or primates, such as apes, monkeys; or Domestic animals, such as dogs and cats.
  • the subject or patient is a human.
  • a "subject in need” refers to a subject who may have or is suspected of having a disease or condition that would benefit from certain treatments.
  • the term "substantially pure" used in this application means that the composition containing the crystalline form contains less than 99%, less than 95%, less than 90%, Less than 85%, less than 80%, less than 75%, less than 70%, less than 65%, less than 60%, less than 55%, less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25 %, less than 20%, less than 15%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1% by weight
  • the other substances include other crystal forms and/or impurities.
  • the impurities may include by-products, reaction starting materials, reagents from chemical reactions, contaminants, degradation products, water or solvents, etc.
  • polymorph refers to different crystal structures (in solvated or unsolvated form) that a compound can crystallize.
  • the compound 1 in this application can be crystallized to form different crystal structures, that is, polymorphs.
  • C 1-6 alkyl refers to a straight-chain or branched alkyl group containing 1-6 carbon atoms. Specific examples include but are not limited to: methyl, ethyl, n-propyl, Isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl Base, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethyl Butyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, etc. .
  • hydroxyl used in this application refers to groups such as -OH.
  • ether solvent used in this application refers to a chain compound or cyclic compound containing an ether bond -O- and having 1 to 10 carbon atoms. Specific examples include, but are not limited to: tetrahydrofuran, ethyl ether, propylene glycol methyl Ether, methyl tert-butyl ether or 1,4-dioxane.
  • alcoholic solvent used in this application refers to a group derived from one or more "hydroxyl groups” substituting one or more hydrogen atoms on the "C 1-6 alkyl group", the "hydroxyl group” and “"C 1-6 alkyl” is as defined above, and specific examples include but are not limited to: methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol or trifluoroethanol.
  • ester solvent used in this application refers to a combination of a lower organic acid with 1 to 4 carbon atoms and a lower alcohol with 1 to 6 carbon atoms. Specific examples include but are not limited to: Ethyl acetate, isopropyl acetate or butyl acetate.
  • mixed solvent used in this application refers to a solvent formed by mixing one or more different types of organic solvents in a certain ratio, or a solvent formed by mixing an organic solvent and water in a certain ratio.
  • the mixed solvent may be a mixed solvent of alcohols and ethers.
  • the mixed solvent of alcohols and ethers may be a mixed solvent of methanol and ether.
  • X-ray powder diffraction pattern or "XRPD” as used in this application is an x-y pattern with a diffraction angle (ie °2 ⁇ ) on the x-axis and intensity on the y-axis. The peaks in this spectrum can be used to characterize the solid state of crystals. In the case of any data measurement result, there is variability in XRPD data.
  • the data is often uniquely represented by the diffraction angle of the peak, and does not include the intensity of the peak, because the intensity of the peak may be particularly sensitive to sample preparation (for example, particle size, moisture content, solvent content, and preferred orientation effects affect sensitivity) Therefore, samples of the same material prepared under different conditions may produce slightly different patterns; this variability is usually greater than the variability of the diffraction angle.
  • the variability of the diffraction angle can also be sensitive to sample preparation.
  • Other sources of variability come from the instrument parameters and the processing of the original X-ray data: different X-ray instrument operations use different parameters and these may result in slightly different XRPD patterns from the same solid form, and similarly, different software The package handles X-ray data in different ways and this also leads to variability.
  • a variability of ⁇ 0.3°2 ⁇ is usually assigned to the diffraction angle in the XRPD pattern.
  • the "about" used when referring to a 2 ⁇ angle means that there can be an error of ⁇ 0.3° on the basis of the mentioned value, for example, it can be -0.30°, -0.29°, -0.28° , -0.27°, -0.26°, -0.25°, -0.24°, -0.23°, -0.22°, -0.21°, -0.20°, -0.19°, -0.18°, -0.17°, -0.16°,- 0.15°, -0.14°, -0.13°, -0.12°, -0.11°, -0.10°, -0.09°, -0.08°, -0.07°, -0.06°, -0.05°,
  • interplanar spacing refers to the selection of three non-parallel unit vectors a, b, and c connecting two adjacent lattice points in a spatial lattice, and they divide the lattice
  • the parallelepiped units that are juxtaposed are called interplanar spacing.
  • the space lattice is divided according to the determined parallelepiped unit lines, and a set of linear grids are obtained, which are called spatial lattices or lattices.
  • Lattice and lattice use geometric points and lines to reflect the periodicity of the crystal structure. Different crystal planes have different interplanar distances.
  • the unit is Or angstroms.
  • DSC differential scanning calorimetry
  • thermogravimetric analysis refers to a method of measuring the relationship between the mass of a substance and temperature or time under program-controlled temperature. By analyzing the thermogravimetric curve, it is possible to know the composition, thermal stability, thermal decomposition, and resulting products of the sample and its possible intermediate products, which are related to quality.
  • the term “substantially similar” or “essentially like... “Shown” means that the basic feature information or main feature information (for example, main peak position, intensity, etc.) of the map is consistent with the information depicted in the mentioned map, and it is not required that all the features of the map are consistent with the mentioned map.
  • the information depicted is exactly the same.
  • the application provides a compound 1 represented by formula (I) (ie, (S)-1'-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazole And [1,2-c]pyrimidin-5-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-5-amine) crystalline form A , Compound 1 hydrate crystal form B and hydrate crystal form C, compound 1 dichloromethane solvate crystal form D, and compound 1 isopropanol solvate crystal form E.
  • formula (I) ie, (S)-1'-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazole And [1,2-c]pyrimidin-5-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-5-amine
  • the present application provides crystalline form A of compound 1.
  • the application provides substantially pure Form A of Compound 1.
  • Compound 1 has an unsolvated crystal form, for example, the crystal form A is an anhydrate crystal form of Compound 1.
  • the XRPD pattern of the crystalline form A has one or more (for example, two, three) peaks selected from the group consisting of about 6.46°, about 12.64°, and about 12.93° 2 ⁇ .
  • the XRPD pattern of the crystal form A has a peak at about 6.46° 2 ⁇ .
  • the XRPD pattern of the crystal form A has a peak at about 12.64° 2 ⁇ .
  • the XRPD pattern of the crystal form A has a peak at approximately 12.93° 2 ⁇ .
  • the XRPD pattern of the crystal form A has peaks at about 6.46°2 ⁇ and about 12.64°2 ⁇ .
  • the XRPD pattern of the crystal form A has peaks at about 6.46°2 ⁇ and about 12.93°2 ⁇ .
  • the XRPD pattern of the crystal form A has peaks at approximately 12.64°2 ⁇ and approximately 12.93°2 ⁇ .
  • the XRPD pattern of the crystalline form A has all peaks selected from the group consisting of about 6.46°, about 12.64°, and about 12.93° 2 ⁇ .
  • the XRPD pattern of the crystal form A further has one or more (for example, 2, 3, 4, 5, 6) peaks selected from the following group: about 13.50°, About 14.60°, about 16.49°, about 17.66°, about 18.27°, and about 23.04° 2 ⁇ .
  • the XRPD pattern of the crystal form A also has a peak at about 13.50° 2 ⁇ .
  • the XRPD pattern of the crystal form A also has a peak at about 14.60° 2 ⁇ .
  • the XRPD pattern of the crystal form A also has a peak at about 16.49° 2 ⁇ .
  • the XRPD pattern of the crystal form A also has a peak at about 17.66° 2 ⁇ .
  • the XRPD pattern of the crystal form A also has a peak at about 18.27° 2 ⁇ .
  • the XRPD pattern of the crystal form A also has a peak at about 23.04°2 ⁇ .
  • the XRPD pattern of the crystalline form A further has two or more (for example, 3, 4, 5, 6) peaks selected from the following group: about 13.50°, about 14.60°, about 16.49°, about 17.66°, about 18.27°, and about 23.04° 2 ⁇ .
  • the XRPD pattern of the crystalline form A also has peaks at approximately 13.50° 2 ⁇ and approximately 14.60° 2 ⁇ .
  • the XRPD pattern of the crystal form A also has peaks at about 13.50° 2 ⁇ and about 16.49° 2 ⁇ .
  • the XRPD pattern of the crystal form A also has peaks at about 13.50° 2 ⁇ and about 17.66° 2 ⁇ .
  • the XRPD pattern of the crystal form A also has peaks at about 13.50° 2 ⁇ and about 18.27° 2 ⁇ .
  • the XRPD pattern of the crystal form A also has peaks at about 13.50° 2 ⁇ and about 23.04° 2 ⁇ .
  • the XRPD pattern of the crystal form A also has peaks at approximately 14.60° 2 ⁇ and approximately 16.49° 2 ⁇ .
  • the XRPD pattern of the crystal form A also has peaks at approximately 14.60° 2 ⁇ and approximately 17.66° 2 ⁇ .
  • the XRPD pattern of the crystal form A also has peaks at approximately 14.60° 2 ⁇ and approximately 18.27° 2 ⁇ .
  • the XRPD pattern of the crystal form A also has peaks at approximately 14.60° 2 ⁇ and approximately 23.04° 2 ⁇ .
  • the XRPD pattern of the crystal form A also has peaks at about 16.49°2 ⁇ and about 17.66°2 ⁇ .
  • the XRPD pattern of the crystal form A also has peaks at about 16.49°2 ⁇ and about 18.27°2 ⁇ .
  • the XRPD pattern of the crystal form A also has peaks at about 16.49°2 ⁇ and about 23.04°2 ⁇ .
  • the XRPD pattern of the crystal form A also has peaks at about 17.66°2 ⁇ and about 18.27°2 ⁇ .
  • the XRPD pattern of the crystal form A also has peaks at about 17.66°2 ⁇ and about 23.04°2 ⁇ .
  • the XRPD pattern of the crystal form A also has peaks at about 18.27°2 ⁇ and about 23.04°2 ⁇ .
  • the XRPD pattern of the crystalline form A further has three or more (for example, 4, 5, 6) peaks selected from the following group: about 13.50°, about 14.60°, About 16.49°, about 17.66°, about 18.27°, and about 23.04° 2 ⁇ .
  • the XRPD pattern of the crystalline form A also has peaks at approximately 13.50°2 ⁇ , approximately 14.60°2 ⁇ , and approximately 16.49°2 ⁇ .
  • the XRPD pattern of the crystal form A also has peaks at about 13.50° 2 ⁇ , about 14.60° 2 ⁇ , and about 17.66° 2 ⁇ .
  • the XRPD pattern of the crystal form A also has peaks at about 13.50° 2 ⁇ , about 14.60° 2 ⁇ , and about 18.27° 2 ⁇ .
  • the XRPD pattern of the crystalline form A also has peaks at about 13.50°2 ⁇ , about 14.60°2 ⁇ , and about 23.04°2 ⁇ .
  • the XRPD pattern of the crystal form A also has peaks at about 13.50° 2 ⁇ , about 16.49° 2 ⁇ , and about 17.66° 2 ⁇ .
  • the XRPD pattern of the crystal form A also has peaks at about 13.50° 2 ⁇ , about 16.49° 2 ⁇ , and about 18.27° 2 ⁇ .
  • the XRPD pattern of the crystal form A also has peaks at about 13.50° 2 ⁇ , about 16.49° 2 ⁇ , and about 23.04° 2 ⁇ .
  • the XRPD pattern of the crystal form A also has peaks at about 13.50°2 ⁇ , about 17.66°°2 ⁇ , and about 18.27°2 ⁇ .
  • the XRPD pattern of the crystalline form A also has peaks at about 13.50°2 ⁇ , about 17.66°2 ⁇ , and about 23.04°2 ⁇ .
  • the XRPD pattern of the crystal form A also has peaks at about 13.50° 2 ⁇ , about 18.27° 2 ⁇ , and about 23.04° 2 ⁇ .
  • the XRPD pattern of the crystal form A also has peaks at about 14.60° 2 ⁇ , about 16.49° 2 ⁇ , and about 17.66° 2 ⁇ .
  • the XRPD pattern of the crystal form A also has peaks at approximately 14.60° 2 ⁇ , approximately 16.49° 2 ⁇ , and approximately 18.27° 2 ⁇ .
  • the XRPD pattern of the crystalline form A also has peaks at approximately 14.60°2 ⁇ , approximately 16.49°2 ⁇ , and approximately 23.04°2 ⁇ .
  • the XRPD pattern of the crystal form A also has peaks at about 14.60° 2 ⁇ , about 17.66° 2 ⁇ , and about 18.27° 2 ⁇ .
  • the XRPD pattern of the crystalline form A also has peaks at about 14.60°2 ⁇ , about 17.66°2 ⁇ , and about 23.04°2 ⁇ .
  • the XRPD pattern of the crystal form A also has peaks at about 14.60° 2 ⁇ , about 18.27° 2 ⁇ , and about 23.04° 2 ⁇ .
  • the XRPD pattern of the crystal form A also has peaks at about 16.49°2 ⁇ , about 17.66°2 ⁇ , and about 18.27°2 ⁇ .
  • the XRPD pattern of the crystal form A also has peaks at about 16.49°2 ⁇ , about 17.66°2 ⁇ , and about 23.04°2 ⁇ .
  • the XRPD pattern of the crystal form A also has peaks at about 17.66°2 ⁇ , about 18.27°2 ⁇ , and about 23.04°2 ⁇ .
  • the XRPD pattern of the crystalline form A also has peaks at about 16.49°2 ⁇ , about 18.27°2 ⁇ , and about 23.04°2 ⁇ .
  • the XRPD pattern of the crystal form A also has peaks at about 17.66°2 ⁇ , about 18.27°2 ⁇ , and about 23.04°2 ⁇ .
  • the XRPD pattern of the crystalline form A further has all peaks selected from the following group: about 13.50°, about 14.60°, about 16.49°, about 17.66°, about 18.27° and about 23.04° 2 ⁇ .
  • the XRPD pattern of the crystalline form A further has one or more (for example, 2, 3, 4) peaks selected from the following group: about 23.61°, about 25.42°, about 25.79 ° and about 27.83°2 ⁇ .
  • the XRPD pattern of the crystal form A also has a peak at about 23.61°2 ⁇ .
  • the XRPD pattern of the crystal form A also has a peak at about 25.42° 2 ⁇ .
  • the XRPD pattern of the crystal form A also has a peak at about 25.79° 2 ⁇ .
  • the XRPD pattern of the crystal form A also has a peak at about 27.83° 2 ⁇ .
  • the XRPD pattern of the crystalline form A further has two or more (for example, 3, 4) peaks selected from the following group: about 23.61°, about 25.42°, about 25.79° And about 27.83°2 ⁇ .
  • the XRPD pattern of the crystalline form A also has peaks at about 23.61°2 ⁇ and about 25.42°2 ⁇ .
  • the XRPD pattern of the crystal form A also has peaks at about 23.61°2 ⁇ and about 25.79°2 ⁇ .
  • the XRPD pattern of the crystal form A also has peaks at approximately 23.61°2 ⁇ and approximately 27.83°2 ⁇ .
  • the XRPD pattern of the crystal form A also has peaks at about 25.42° 2 ⁇ and about 25.79° 2 ⁇ .
  • the XRPD pattern of the crystal form A also has peaks at about 25.42°2 ⁇ and about 27.83°2 ⁇ .
  • the XRPD pattern of the crystal form A also has peaks at about 25.79°2 ⁇ and about 27.83°2 ⁇ .
  • the XRPD pattern of the crystalline form A further has three or more (for example, 4) peaks selected from the following group: about 23.61°, about 25.42°, about 25.79°, and about 27.83° 2 ⁇ .
  • the XRPD pattern of the crystalline form A also has peaks at about 23.61°2 ⁇ , about 25.42°2 ⁇ , and about 25.79°2 ⁇ .
  • the XRPD pattern of the crystal form A also has peaks at about 23.61°2 ⁇ , about 25.42°2 ⁇ , and about 27.83°2 ⁇ .
  • the XRPD pattern of the crystalline form A also has peaks at about 25.42°2 ⁇ , about 25.79°2 ⁇ , and about 27.83°2 ⁇ .
  • the XRPD pattern of the crystal form A also has peaks at about 23.61°2 ⁇ , about 25.79°2 ⁇ , and about 27.83°2 ⁇ .
  • the XRPD pattern of the crystal form A further has all peaks selected from the group consisting of about 23.61°, about 25.42°, about 25.79° and about 27.83° 2 ⁇ .
  • the XRPD pattern of the crystal form A has all peaks selected from the following group:
  • the XRPD pattern of the crystal form A is substantially similar to the XRPD pattern depicted in FIG. 1. In some embodiments, the XRPD pattern of the crystal form A is shown in FIG. 1. In some embodiments, the crystal form A has at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least XRPD patterns of 10, at least 11, at least 12, and at least 13 2 ⁇ angles.
  • the DSC spectrum of the crystalline form A includes an endothermic peak at about 262.0°C (peak temperature). In some embodiments, the DSC spectrum of the crystal form A further includes an exothermic peak at about 153.7°C (peak temperature). In some embodiments, the DSC profile of the crystal form A is substantially similar to the DSC profile depicted in FIG. 2. In some embodiments, the DSC spectrum of the crystal form A is shown in FIG. 2.
  • the TGA pattern of the crystal form A shows that when heated to about 120°C, the weight loss of the sample is about 1.5% to 2.0%, for example, about 1.5%, about 1.6%, about 1.61%, about 1.62% , About 1.63%, about 1.64%, about 1.65%, about 1.66%, about 1.67%, 1.68%, about 1.69%, about 1.70%, about 1.71%, about 1.72%, about 1.8%, about 1.9%, about 2.0 %.
  • the TGA pattern of the crystalline form A shows that when heated to 120° C., the weight loss of the sample is about 1.69%.
  • the TGA pattern of the crystal form A is substantially similar to the TGA pattern depicted in FIG. 2. In some embodiments, the TGA pattern of the crystal form A is shown in FIG. 2.
  • the crystal form A is applicable to at least one, two or three of the following (a) to (c):
  • the crystal form A has an XRPD pattern basically as shown in Figure 1;
  • the crystal form A has a TGA pattern substantially as shown in FIG. 2.
  • the crystal form A basically has the following characteristics:
  • the crystal form A has an XRPD pattern basically as shown in Figure 1;
  • the crystal form A has a TGA pattern substantially as shown in FIG. 2.
  • the crystal form A is substantially pure, for example, the purity of the crystal form A is greater than 90 wt%, greater than 91 wt%, greater than 92 wt%, greater than 93 wt%, greater than 94 wt%, greater than 95 wt% , Greater than 96 wt%, greater than 97 wt%, greater than 98 wt%, or greater than 99 wt%.
  • the purity of the crystal form A is determined by high performance liquid chromatography (HPLC).
  • compound 1 contains no more than about 5.0 area percent HPLC total organic impurities; in some embodiments, it contains no more than about 3.0 area percent HPLC total organic impurities; in some implementations In the method, it contains not more than about 1.5 area percent HPLC total organic impurities. In other embodiments, relative to the total area of the HPLC chromatogram, compound 1 contains no more than about 1.0 area percent HPLC any single impurity; no more than about 0.6 area percent HPLC any single impurity; in some embodiments, no Any single impurity that is greater than about 0.5 area percent HPLC.
  • the ratio of the HPLC purity of the crystalline form A to the initial HPLC purity of the crystalline form A after being placed at 60°C/closed conditions for 24 hours is greater than 99%, for example, greater than 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9% or higher.
  • the ratio of the HPLC purity of the crystalline form A to the initial HPLC purity of the crystalline form A after being left open for 1 week at 25°C/60%RH is greater than 99%, for example, greater than 99.1% , 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9% or higher.
  • the ratio of the HPLC purity of the crystalline form A to the initial HPLC purity of the crystalline form A after being left open at 40°C/75%RH for 1 week is greater than 99%, for example, greater than 99.1% , 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9% or higher.
  • the present application provides crystalline form B of compound 1.
  • the application provides substantially pure Form B of Compound 1.
  • the crystal form B is the hydrate crystal form of compound 1.
  • the XRPD pattern of the crystalline form B has one or more (for example, two, three) peaks selected from the following group: about 7.36°, about 10.82°, and about 11.10° 2 ⁇ .
  • the XRPD pattern of the crystalline form B has a peak at about 7.36° 2 ⁇ .
  • the XRPD pattern of the crystal form B has a peak at about 10.82° 2 ⁇ .
  • the XRPD pattern of the crystal form B has a peak at about 11.10° 2 ⁇ .
  • the XRPD pattern of the crystal form B has peaks at about 7.36°2 ⁇ and about 10.82°2 ⁇ .
  • the XRPD pattern of the crystal form B has peaks at about 7.36° 2 ⁇ and about 11.10° 2 ⁇ .
  • the XRPD pattern of the crystal form B has peaks at about 10.82° 2 ⁇ and about 11.10° 2 ⁇ .
  • the XRPD pattern of the crystalline form B has all peaks selected from the group consisting of about 7.36°, about 10.82°, and about 11.10° 2 ⁇ .
  • the XRPD pattern of the crystalline form B further has one or more (for example, 2, 3, 4) peaks selected from the following group: about 14.70°, about 15.99°, about 20.96 ° and about 23.78°2 ⁇ .
  • the XRPD pattern of the crystalline form B also has a peak at about 14.70° 2 ⁇ .
  • the XRPD pattern of the crystal form B also has a peak at about 15.99° 2 ⁇ .
  • the XRPD pattern of the crystal form B also has a peak at about 20.96° 2 ⁇ .
  • the XRPD pattern of the crystal form B also has a peak at about 23.78°2 ⁇ .
  • the XRPD pattern of the crystalline form B further has two or more (for example, 3, 4) peaks selected from the following group: about 14.70°, about 15.99°, about 20.96° And about 23.78°2 ⁇ .
  • the XRPD pattern of the crystalline form B also has peaks at approximately 14.70° 2 ⁇ and approximately 15.99° 2 ⁇ .
  • the XRPD pattern of the crystal form B also has peaks at approximately 14.70° 2 ⁇ and approximately 20.96° 2 ⁇ .
  • the XRPD pattern of the crystal form B also has peaks at approximately 14.70° 2 ⁇ and approximately 23.78° 2 ⁇ .
  • the XRPD pattern of the crystal form B also has peaks at approximately 15.99° 2 ⁇ and approximately 20.96° 2 ⁇ .
  • the XRPD pattern of the crystal form B also has peaks at approximately 15.99° 2 ⁇ and approximately 23.78° 2 ⁇ .
  • the XRPD pattern of the crystal form B also has peaks at about 20.96°2 ⁇ and about 23.78°2 ⁇ .
  • the XRPD pattern of the crystalline form B further has three or more (for example, 4) peaks selected from the group consisting of about 14.70°, about 15.99°, about 20.96°, and about 23.78° 2 ⁇ .
  • the XRPD pattern of the crystalline form B also has peaks at about 14.70°, about 15.99°, and about 20.96° 2 ⁇ .
  • the XRPD pattern of the crystal form B also has peaks at about 14.70° 2 ⁇ , about 15.99° 2 ⁇ , and about 23.78° 2 ⁇ .
  • the XRPD pattern of the crystalline form B also has peaks at approximately 14.70°2 ⁇ , approximately 20.96°2 ⁇ , and approximately 23.78°2 ⁇ .
  • the XRPD pattern of the crystalline form B also has peaks at about 15.99°2 ⁇ , about 20.96°2 ⁇ , and about 23.78°2 ⁇ .
  • the XRPD pattern of the crystalline form B further has all peaks selected from the group consisting of about 14.70°, about 15.99°, about 20.96°, and about 23.78° 2 ⁇ .
  • the XRPD pattern of the crystal form B has all peaks selected from the following group:
  • the XRPD pattern of the crystalline form B is substantially similar to the XRPD pattern depicted in FIG. 3. In some embodiments, the XRPD pattern of the crystal form B is shown in FIG. 3. In some embodiments, the crystal form B has at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least XRPD patterns of 10, at least 11, at least 12, and at least 13 2 ⁇ angles. In some embodiments, the DSC spectrum of the crystalline form B includes endothermic peaks at about 113.5°C (peak temperature) and about 266.8°C (peak temperature). In some embodiments, the DSC spectrum of the crystalline form B further includes an exothermic peak at about 161.8° C. (peak temperature). In some embodiments, the DSC profile of the crystalline form B is substantially similar to the DSC profile depicted in FIG. 4. In some embodiments, the DSC spectrum of the crystal form B is shown in FIG. 4.
  • the TGA pattern of the crystal form B shows that when heated to 120° C., the weight loss of the sample is about 10% to 14%, for example, about 10%, about 11%, about 12%, about 12.1%, About 12.2%, about 12.3%, about 12.4%, about 12.5%, about 12.6%, about 12.7%, about 12.75%, about 12.8%, about 12.9%, about 13%, about 14%.
  • the TGA pattern of the crystalline form B shows that the weight loss of the sample is about 12.75% when heated to 120°C.
  • the TGA pattern of the crystal form B is substantially similar to the TGA pattern depicted in FIG. 4. In some embodiments, the TGA pattern of the crystal form B is shown in FIG. 4.
  • the molar ratio of water molecules to compound 1 in the crystal form B is about 3.9:1, for example, 3:1, 3.1:1, 3.2:1, 3.3:1, 3.4:1, 3.5:1, 3.6:1, 3.7:1, 3.8:1, 3.9:1, 4:1, 4.1:1, 4.2:1, 4.3:1, 4.4:1, 4.5:1, 4.6:1, 4.7: 1. 4.8:1, 4.9:1, or 5:1, or any ratio between any of the above ranges.
  • the 1 H NMR spectrum of the crystal form B is substantially similar to the 1 H NMR spectrum shown in FIG. 16. In some embodiments, the 1 H NMR spectrum of the crystal form B is shown in FIG. 16.
  • the crystal form B is applicable to at least one, two, three or four of the following (a) to (d):
  • the crystal form B has an XRPD pattern substantially as shown in Figure 3;
  • the crystal form B has a DSC spectrum substantially as shown in Fig. 4;
  • the crystal form B has a TGA pattern substantially as shown in FIG. 4;
  • the crystal form B has a 1 H NMR spectrum substantially as shown in FIG. 16.
  • the crystal form B basically has the following characteristics:
  • the crystal form B has an XRPD pattern substantially as shown in Figure 3;
  • the crystal form B has a DSC spectrum substantially as shown in Figure 4.
  • the crystal form B has a TGA pattern substantially as shown in FIG. 4.
  • the crystal form B basically has the following characteristics:
  • the crystal form B has an XRPD pattern substantially as shown in Figure 3;
  • the crystal form B has a DSC spectrum substantially as shown in Fig. 4;
  • the crystal form B has a TGA pattern substantially as shown in FIG. 4;
  • the crystal form B has a 1 H NMR spectrum substantially as shown in FIG. 16.
  • the crystal form B is substantially pure, for example, the purity of the crystal form B is greater than 90 wt%, greater than 91 wt%, greater than 92 wt%, greater than 93 wt%, greater than 94 wt%, greater than 95 wt% , Greater than 96 wt%, greater than 97 wt%, greater than 98 wt%, or greater than 99 wt%.
  • the purity of the crystal form B is determined by high performance liquid chromatography (HPLC).
  • compound 1 contains no more than about 5.0 area percent HPLC total organic impurities; in some embodiments, it contains no more than about 3.0 area percent HPLC total organic impurities; in some implementations In the method, it contains not more than about 1.5 area percent HPLC total organic impurities. In other embodiments, relative to the total area of the HPLC chromatogram, compound 1 contains no more than about 1.0 area percent HPLC any single impurity; no more than about 0.6 area percent HPLC any single impurity; in some embodiments, no Any single impurity that is greater than about 0.5 area percent HPLC.
  • the application provides Form C of Compound 1. In certain embodiments, the application provides substantially pure Form C of Compound 1. In certain embodiments, the crystal form C is the hydrate crystal form of compound 1.
  • the XRPD pattern of the crystalline form C has one or more (for example, two, three) peaks selected from the following group: about 7.33°, about 11.08°, and about 14.70° 2 ⁇ .
  • the XRPD pattern of the crystal form C has a peak at about 7.33° 2 ⁇ .
  • the XRPD pattern of the crystal form C has a peak at about 11.08°2 ⁇ .
  • the XRPD pattern of the crystal form C has a peak at about 14.70° 2 ⁇ .
  • the XRPD pattern of the crystal form C has peaks at about 7.33°2 ⁇ and about 11.08°2 ⁇ .
  • the XRPD pattern of the crystal form C has peaks at about 7.33° 2 ⁇ and about 14.70° 2 ⁇ .
  • the XRPD pattern of the crystalline form C has peaks at approximately 11.08°2 ⁇ and approximately 14.70°2 ⁇ .
  • the XRPD pattern of the crystalline form C has all peaks selected from the group consisting of about 7.33°, about 11.08°, and about 14.70° 2 ⁇ .
  • the XRPD pattern of the crystalline form C further has one or more (for example, 2, 3, 4, 5) peaks selected from the following group: about 16.23°, about 18.85° , About 21.20°, about 22.03° and about 24.33°2 ⁇ .
  • the XRPD pattern of the crystal form C also has a peak at about 16.23° 2 ⁇ .
  • the XRPD pattern of the crystal form C also has a peak at about 18.85° 2 ⁇ .
  • the XRPD pattern of the crystal form C also has a peak at about 21.20° 2 ⁇ .
  • the XRPD pattern of the crystal form C also has a peak at about 22.03° 2 ⁇ .
  • the XRPD pattern of the crystal form C also has a peak at about 24.33° 2 ⁇ .
  • the XRPD pattern of the crystal form C further has two or more (for example, 3, 4, 5) peaks selected from the following group: about 16.23°, about 18.85°, About 21.20°, about 22.03° and about 24.33° 2 ⁇ .
  • the XRPD pattern of the crystal form C also has peaks at about 16.23° 2 ⁇ and about 18.85° 2 ⁇ .
  • the XRPD pattern of the crystal form C also has peaks at about 16.23° 2 ⁇ and about 21.20° 2 ⁇ .
  • the XRPD pattern of the crystal form C also has peaks at about 16.23°2 ⁇ and about 22.03°2 ⁇ .
  • the XRPD pattern of the crystal form C also has peaks at about 16.23°2 ⁇ and about 24.33°2 ⁇ .
  • the XRPD pattern of the crystal form C also has peaks at about 18.85° 2 ⁇ and about 21.20° 2 ⁇ .
  • the XRPD pattern of the crystal form C also has peaks at about 18.85° 2 ⁇ and about 22.03° 2 ⁇ .
  • the XRPD pattern of the crystal form C also has peaks at about 18.85° 2 ⁇ and about 24.33° 2 ⁇ .
  • the XRPD pattern of the crystalline form C also has peaks at about 21.20°2 ⁇ and about 22.03°2 ⁇ .
  • the XRPD pattern of the crystal form C also has peaks at about 21.20° 2 ⁇ and about 24.33° 2 ⁇ .
  • the XRPD pattern of the crystal form C also has peaks at about 22.03°2 ⁇ and about 24.33°2 ⁇ .
  • the XRPD pattern of the crystalline form C further has three or more (for example, 4, 5) peaks selected from the following group: about 16.23°, about 18.85°, about 21.20° , About 22.03° and about 24.33°2 ⁇ .
  • the XRPD pattern of the crystalline form C also has peaks at about 16.23°2 ⁇ , about 18.85°2 ⁇ , and about 21.20°2 ⁇ .
  • the XRPD pattern of the crystalline form C also has peaks at about 16.23°2 ⁇ , about 18.85°2 ⁇ , and about 22.03°2 ⁇ .
  • the XRPD pattern of the crystalline form C also has peaks at about 16.23°2 ⁇ , about 18.85°2 ⁇ , and about 24.33°2 ⁇ .
  • the XRPD pattern of the crystalline form C also has peaks at about 16.23°2 ⁇ , about 21.20°2 ⁇ , and about 22.03°2 ⁇ .
  • the XRPD pattern of the crystalline form C also has peaks at about 16.23°2 ⁇ , about 21.20°2 ⁇ , and about 24.33°2 ⁇ .
  • the XRPD pattern of the crystal form C also has peaks at about 16.23°2 ⁇ , about 22.03°2 ⁇ , and about 24.33°2 ⁇ .
  • the XRPD pattern of the crystal form C also has peaks at about 18.85° 2 ⁇ , about 21.20° 2 ⁇ , and about 22.03° 2 ⁇ .
  • the XRPD pattern of the crystal form C also has peaks at about 18.85° 2 ⁇ , about 21.20° 2 ⁇ , and about 24.33° 2 ⁇ .
  • the XRPD pattern of the crystalline form C also has peaks at about 21.20°2 ⁇ , about 22.03°2 ⁇ , and about 24.33°2 ⁇ .
  • the XRPD pattern of the crystal form C also has peaks at about 18.85°2 ⁇ , about 22.03°2 ⁇ , and about 24.33°2 ⁇ .
  • the XRPD pattern of the crystal form C further has all peaks selected from the group consisting of about 16.23°, about 18.85°, about 21.20°, about 22.03°, and about 24.33° 2 ⁇ .
  • the XRPD pattern of the crystalline form C further has one or more (for example, 2, 3, 4) peaks selected from the following group: about 15.20°, about 20.05°, about 23.70 ° and about 29.13°2 ⁇ .
  • the XRPD pattern of the crystal form C also has a peak at about 15.20° 2 ⁇ .
  • the XRPD pattern of the crystal form C also has a peak at about 20.05° 2 ⁇ .
  • the XRPD pattern of the crystal form C also has a peak at about 23.70° 2 ⁇ .
  • the XRPD pattern of the crystal form C also has a peak at about 29.13° 2 ⁇ .
  • the XRPD pattern of the crystalline form C further has two or more (for example, 3, 4) peaks selected from the following group: about 15.20°, about 20.05°, about 23.70° And about 29.13°2 ⁇ .
  • the XRPD pattern of the crystal form C also has peaks at about 15.20° 2 ⁇ and about 20.05° 2 ⁇ .
  • the XRPD pattern of the crystal form C also has peaks at approximately 15.20° 2 ⁇ and approximately 23.70° 2 ⁇ .
  • the XRPD pattern of the crystal form C also has peaks at approximately 15.20° 2 ⁇ and approximately 29.13° 2 ⁇ .
  • the XRPD pattern of the crystal form C also has peaks at about 20.05°2 ⁇ and about 23.70°2 ⁇ .
  • the XRPD pattern of the crystal form C also has peaks at about 20.05°2 ⁇ and about 29.13°2 ⁇ .
  • the XRPD pattern of the crystalline form C also has peaks at about 23.70°2 ⁇ and about 29.13°2 ⁇ .
  • the XRPD pattern of the crystalline form C further has three or more (for example, 4) peaks selected from the group consisting of: about 15.20°, about 20.05°, about 23.70°, and about 29.13° 2 ⁇ .
  • the XRPD pattern of the crystalline form C also has peaks at about 15.20°2 ⁇ , about 20.05°2 ⁇ , and about 23.70°2 ⁇ .
  • the XRPD pattern of the crystalline form C also has peaks at about 15.20°2 ⁇ , about 20.05°2 ⁇ , and about 29.13°2 ⁇ .
  • the XRPD pattern of the crystal form C also has peaks at about 20.05°2 ⁇ , about 23.70°2 ⁇ , and about 29.13°2 ⁇ .
  • the XRPD pattern of the crystal form C also has peaks at about 15.20° 2 ⁇ , about 23.70° 2 ⁇ , and about 29.13° 2 ⁇ .
  • the XRPD pattern of the crystal form C further has all peaks selected from the group consisting of about 15.20°, about 20.05°, about 23.70° and about 29.13° 2 ⁇ .
  • the XRPD pattern of the crystal form C has all peaks selected from the following group:
  • the XRPD pattern of the crystalline form C is substantially similar to the XRPD pattern depicted in FIG. 5. In some embodiments, the XRPD pattern of the crystal form C is shown in FIG. 5. In some embodiments, the crystal form C has at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least XRPD patterns of 10, at least 11, at least 12, and at least 13 2 ⁇ angles. In some embodiments, the DSC spectrum of the crystalline form C includes endothermic peaks at about 117.2°C (peak temperature) and about 265.6°C (peak temperature). In some embodiments, the DSC spectrum of the crystal form C further includes an endothermic peak at about 46.4° C. (peak temperature).
  • the DSC spectrum of the crystalline form C further includes an exothermic peak at about 147.0°C (peak temperature).
  • the DSC profile of the crystal form C is substantially similar to the DSC profile depicted in FIG. 6.
  • the DSC spectrum of the crystal form C is shown in FIG. 6.
  • the TGA pattern of the crystal form C shows that when heated to 120° C., the weight loss of the sample is about 10% to 14%, for example, about 10%, about 11%, about 11.5%, about 12%, About 12.1%, about 12.2%, about 12.3%, about 12.4%, about 12.5%, about 12.6%, about 12.7%, about 12.8%, about 12.9%, about 13%, about 13.5%, about 14%.
  • the TGA pattern of the crystalline form C shows that when heated to 120° C., the weight loss of the sample is about 12.23%.
  • the TGA pattern of the crystal form C is substantially similar to the TGA pattern depicted in FIG. 6. In some embodiments, the TGA pattern of the crystal form C is shown in FIG. 6.
  • the molar ratio of water molecules to compound 1 in the crystal form C is about 3.7:1, for example, 3:1, 3.1:1, 3.2:1, 3.3:1, 3.4:1, 3.5:1, 3.6:1, 3.7:1, 3.8:1, 3.9:1, 4:1, 4.1:1, 4.2:1, 4.3:1, 4.4:1, 4.5:1, 4.6:1, 4.7: 1, 4.8:1, 4.9:1, or 5:1.
  • the 1 H NMR spectrum of the crystal form C is substantially similar to the 1 H NMR spectrum shown in FIG. 17. In some embodiments, the 1 H NMR spectrum of the crystal form C is shown in FIG. 17.
  • the crystal form C is applicable to at least one, two, three, or four of the following (a) to (d):
  • the crystal form C has a DSC spectrum substantially as shown in FIG. 6;
  • the crystal form C has a TGA pattern substantially as shown in FIG. 6;
  • the crystal form C basically has the following characteristics:
  • the crystal form C has a DSC spectrum substantially as shown in FIG. 6;
  • the crystal form C has a TGA pattern substantially as shown in FIG. 6.
  • the crystal form C basically has the following characteristics:
  • the crystal form C has a DSC spectrum substantially as shown in FIG. 6;
  • the crystal form C has a TGA pattern substantially as shown in FIG. 6;
  • the crystal form C is substantially pure, for example, the purity of the crystal form C is greater than 90 wt%, greater than 91 wt%, greater than 92 wt%, greater than 93 wt%, greater than 94 wt%, greater than 95 wt% , Greater than 96 wt%, greater than 97 wt%, greater than 98 wt%, or greater than 99 wt%.
  • the purity of the crystal form C is determined by high performance liquid chromatography (HPLC).
  • compound 1 contains no more than about 5.0 area percent HPLC total organic impurities; in some embodiments, it contains no more than about 3.0 area percent HPLC total organic impurities; in some implementations In the method, it contains not more than about 1.5 area percent HPLC total organic impurities. In other embodiments, relative to the total area of the HPLC chromatogram, compound 1 contains no more than about 1.0 area percent HPLC any single impurity; no more than about 0.6 area percent HPLC any single impurity; in some embodiments, no Any single impurity that is greater than about 0.5 area percent HPLC.
  • the present application provides crystalline form D of compound 1.
  • the present application provides substantially pure Form D of Compound 1.
  • the crystal form D is a crystalline form of a solvate of compound 1.
  • the crystalline form D is the dichloromethane solvate crystalline form of Compound 1.
  • the XRPD pattern of the crystalline form D has one or more (for example, two, three) peaks selected from the following group: about 8.24°, about 13.46°, and about 15.32° 2 ⁇ .
  • the XRPD pattern of the crystal form D has a peak at about 8.24° 2 ⁇ .
  • the XRPD pattern of the crystal form D has a peak at about 13.46° 2 ⁇ .
  • the XRPD pattern of the crystal form D has a peak at about 15.32° 2 ⁇ .
  • the XRPD pattern of the crystalline form D has peaks at about 8.24°2 ⁇ and about 13.46°2 ⁇ .
  • the XRPD pattern of the crystal form D has peaks at about 8.24°2 ⁇ and about 15.32°2 ⁇ .
  • the XRPD pattern of the crystalline form D has peaks at about 13.46°2 ⁇ and about 15.32°2 ⁇ .
  • the XRPD pattern of the crystalline form D has all peaks selected from the group consisting of about 8.24°, about 13.46°, and about 15.32° 2 ⁇ .
  • the XRPD pattern of the crystalline form D further has one or more (for example, two, three) peaks selected from the following group: about 12.89°, about 15.90°, and about 16.84° 2 ⁇ .
  • the XRPD pattern of the crystal form D also has a peak at approximately 12.89° 2 ⁇ .
  • the XRPD pattern of the crystal form D also has a peak at about 15.90° 2 ⁇ .
  • the XRPD pattern of the crystal form D also has a peak at about 16.84° 2 ⁇ .
  • the XRPD pattern of the crystalline form D further has two or more (for example, three) peaks selected from the group consisting of about 12.89°, about 15.90°, and about 16.84° 2 ⁇ .
  • the XRPD pattern of the crystalline form D also has peaks at approximately 12.89° 2 ⁇ and approximately 15.90° 2 ⁇ .
  • the XRPD pattern of the crystal form D also has peaks at approximately 12.89°2 ⁇ and approximately 16.84°2 ⁇ .
  • the XRPD pattern of the crystal form D also has peaks at approximately 15.90° 2 ⁇ and approximately 16.84° 2 ⁇ .
  • the XRPD pattern of the crystalline form D further has all peaks selected from the group consisting of about 12.89°, about 15.90°, and about 16.84° 2 ⁇ .
  • the XRPD pattern of the crystalline form D further has one or more (for example, 2, 3, 4, 5) peaks selected from the following group: about 18.45°, about 21.83° , About 23.08°, about 23.80° and about 25.59°2 ⁇ .
  • the XRPD pattern of the crystal form D also has a peak at about 18.45° 2 ⁇ .
  • the XRPD pattern of the crystal form D also has a peak at about 21.83° 2 ⁇ .
  • the XRPD pattern of the crystal form D also has a peak at about 23.08°2 ⁇ .
  • the XRPD pattern of the crystal form D also has a peak at about 23.80° 2 ⁇ .
  • the XRPD pattern of the crystal form D also has a peak at about 25.59° 2 ⁇ .
  • the XRPD pattern of the crystalline form D further has two or more (for example, 3, 4, 5) peaks selected from the following group: about 18.45°, about 21.83°, About 23.08°, about 23.80° and about 25.59° 2 ⁇ .
  • the XRPD pattern of the crystalline form D also has peaks at about 18.45° 2 ⁇ and about 21.83° 2 ⁇ .
  • the XRPD pattern of the crystal form D also has peaks at about 18.45°2 ⁇ and about 23.08°2 ⁇ .
  • the XRPD pattern of the crystal form D also has peaks at about 18.45° 2 ⁇ and about 23.80° 2 ⁇ .
  • the XRPD pattern of the crystal form D also has peaks at about 18.45°2 ⁇ and about 25.59°2 ⁇ .
  • the XRPD pattern of the crystal form D also has peaks at about 21.83° 2 ⁇ and about 23.08° 2 ⁇ .
  • the XRPD pattern of the crystal form D also has peaks at about 21.83° 2 ⁇ and about 23.80° 2 ⁇ .
  • the XRPD pattern of the crystal form D also has peaks at about 21.83° 2 ⁇ and about 25.59° 2 ⁇ .
  • the XRPD pattern of the crystalline form D also has peaks at about 23.08°2 ⁇ and about 23.80°2 ⁇ .
  • the XRPD pattern of the crystal form D also has peaks at about 23.08°2 ⁇ and about 25.59°2 ⁇ .
  • the XRPD pattern of the crystal form D also has peaks at about 23.80°2 ⁇ and about 25.59°2 ⁇ .
  • the XRPD pattern of the crystalline form D further has three or more (for example, 4, 5) peaks selected from the following group: about 18.45°, about 21.83°, about 23.08° , About 23.80° and about 25.59°2 ⁇ .
  • the XRPD pattern of the crystalline form D also has peaks at about 18.45°2 ⁇ , about 21.83°2 ⁇ , and about 23.08°2 ⁇ .
  • the XRPD pattern of the crystalline form D also has peaks at about 18.45°2 ⁇ , about 21.83°2 ⁇ , and about 23.80°2 ⁇ .
  • the XRPD pattern of the crystal form D also has peaks at about 18.45°2 ⁇ , about 21.83°2 ⁇ , and about 25.59°2 ⁇ .
  • the XRPD pattern of the crystal form D also has peaks at about 18.45°2 ⁇ , about 23.08°2 ⁇ , and about 23.80°2 ⁇ .
  • the XRPD pattern of the crystal form D also has peaks at about 18.45°2 ⁇ , about 23.08°2 ⁇ , and about 25.59°2 ⁇ .
  • the XRPD pattern of the crystalline form D also has peaks at about 18.45°2 ⁇ , about 23.80°2 ⁇ , and about 25.59°2 ⁇ .
  • the XRPD pattern of the crystal form D also has peaks at about 21.83° 2 ⁇ , about 23.08° 2 ⁇ , and about 23.80° 2 ⁇ .
  • the XRPD pattern of the crystalline form D also has peaks at about 21.83°2 ⁇ , about 23.08°2 ⁇ , and about 25.59°2 ⁇ .
  • the XRPD pattern of the crystalline form D also has peaks at about 21.83°2 ⁇ , about 23.80°2 ⁇ , and about 25.59°2 ⁇ .
  • the XRPD pattern of the crystal form D also has peaks at about 23.08°2 ⁇ , about 23.80°2 ⁇ , and about 25.59°2 ⁇ .
  • the XRPD pattern of the crystalline form D further has four or more (for example, 5) peaks selected from the following group: about 18.45°, about 21.83°, about 23.08°, about 23.80 ° and about 25.59°2 ⁇ .
  • the XRPD pattern of the crystalline form D also has peaks at about 18.45°2 ⁇ , about 21.83°2 ⁇ , about 23.08°2 ⁇ , and about 23.80°2 ⁇ .
  • the XRPD pattern of the crystal form D also has peaks at about 18.45°2 ⁇ , about 21.83°2 ⁇ , about 23.08°2 ⁇ , and about 25.59°2 ⁇ .
  • the XRPD pattern of the crystal form D also has peaks at about 18.45°2 ⁇ , about 21.83°2 ⁇ , about 23.80°2 ⁇ , and about 25.59°2 ⁇ .
  • the XRPD pattern of the crystal form D also has peaks at about 21.83°2 ⁇ , about 23.08°2 ⁇ , about 23.80°2 ⁇ , and about 25.59°2 ⁇ .
  • the XRPD pattern of the crystalline form D further has all peaks selected from the group consisting of about 18.45°, about 21.83°, about 23.08°, about 23.80°, and about 25.59° 2 ⁇ .
  • the XRPD pattern of the crystal form D has all peaks selected from the following group:
  • the XRPD pattern of the crystalline form D is substantially similar to the XRPD pattern depicted in FIG. 7. In some embodiments, the XRPD pattern of the crystal form D is shown in FIG. 7. In some embodiments, the crystal form D has at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least XRPD patterns of 10, at least 11, at least 12, and at least 13 2 ⁇ angles. In some embodiments, the DSC spectrum of the crystalline form D includes an endothermic peak at about 124.1°C (peak temperature). In some embodiments, the DSC spectrum of the crystalline form D further includes an endothermic peak at about 59.8°C (peak temperature).
  • the DSC spectrum of the crystalline form D further includes an endothermic peak at about 129.8°C (peak temperature).
  • the DSC spectrum of the crystal form D is substantially similar to the DSC spectrum shown in FIG. 8.
  • the DSC spectrum of the crystal form D is shown in FIG. 8.
  • the TGA pattern of the crystal form D shows that when heated to 150° C., the weight loss of the sample is about 11% to 15%, for example, about 11%, 11.5%, 12%, 12.5%, 13%, 13.1%, 13.2%, 13.3%, 13.4%, 13.5%, 13.6%, 13.7%, 13.8%, 13.9%, 14%, 14.5%, 15%.
  • the TGA pattern of the crystalline form D shows that when heated to 150° C., the weight loss of the sample is about 13.08%.
  • the TGA pattern of the crystal form D is substantially similar to the TGA pattern depicted in FIG. 8. In some embodiments, the TGA pattern of the crystal form D is shown in FIG. 8.
  • the molar ratio of dichloromethane molecules to compound 1 in the crystal form D is about 0.8:1, for example, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9: 1, 1:1, 1.1:1 or 1.2:1.
  • the 1 H NMR spectrum of the crystal form D is substantially similar to the 1 H NMR spectrum depicted in FIG. 18. In some embodiments, the 1 H NMR spectrum of the crystal form D is shown in FIG. 18.
  • the crystal form D is applicable to at least one, two, three or four of the following (a) to (d):
  • the crystal form D has an XRPD pattern substantially as shown in FIG. 7;
  • the crystal form D has a DSC spectrum substantially as shown in FIG. 8;
  • the crystal form D has a TGA pattern substantially as shown in FIG. 8;
  • the crystal form D has a 1 H NMR spectrum substantially as shown in FIG. 18.
  • the crystal form D basically has the following characteristics:
  • the crystal form D has an XRPD pattern substantially as shown in FIG. 7;
  • the crystal form D has a DSC spectrum substantially as shown in FIG. 8;
  • the crystal form D has a TGA pattern substantially as shown in FIG. 8.
  • the crystal form B basically has the following characteristics:
  • the crystal form D has an XRPD pattern substantially as shown in FIG. 7;
  • the crystal form D has a DSC spectrum substantially as shown in FIG. 8;
  • the crystal form D has a TGA pattern substantially as shown in FIG. 8;
  • the crystal form D has a 1 H NMR spectrum substantially as shown in FIG. 18.
  • the crystal form D is substantially pure, for example, the purity of the crystal form D is greater than 90 wt%, greater than 91 wt%, greater than 92 wt%, greater than 93 wt%, greater than 94 wt%, greater than 95 wt% , Greater than 96 wt%, greater than 97 wt%, greater than 98 wt%, or greater than 99 wt%.
  • the purity of the crystal form D is determined by high performance liquid chromatography (HPLC).
  • compound 1 contains no more than about 5.0 area percent HPLC total organic impurities; in some embodiments, it contains no more than about 3.0 area percent HPLC total organic impurities; in some implementations In the method, it contains not more than about 1.5 area percent HPLC total organic impurities. In other embodiments, relative to the total area of the HPLC chromatogram, compound 1 contains no more than about 1.0 area percent HPLC any single impurity; no more than about 0.6 area percent HPLC any single impurity; in some embodiments, no Any single impurity that is greater than about 0.5 area percent HPLC.
  • the present application provides crystal form E of compound 1. In certain embodiments, the present application provides substantially pure Form E of Compound 1. In certain embodiments, the crystal form E is a solvate crystal form of compound 1. In certain embodiments, the crystal form E is the isopropanol solvate crystalline form of compound 1.
  • the XRPD pattern of the crystal form E has one or more (for example, two, three) peaks selected from the group consisting of about 9.10°, about 13.49°, and about 18.24° 2 ⁇ .
  • the XRPD pattern of the crystal form E has a peak at about 9.10° 2 ⁇ .
  • the XRPD pattern of the crystal form E has a peak at about 13.49° 2 ⁇ .
  • the XRPD pattern of the crystal form E has a peak at about 18.24° 2 ⁇ .
  • the XRPD pattern of the crystal form E has peaks at about 9.10°2 ⁇ and about 13.49°2 ⁇ .
  • the XRPD pattern of the crystal form E has peaks at about 9.10°2 ⁇ and about 18.24°2 ⁇ .
  • the XRPD pattern of the crystal form E has peaks at about 13.49° 2 ⁇ and about 18.24° 2 ⁇ .
  • the XRPD pattern of the crystal form E has all peaks selected from the group consisting of about 9.10°, about 13.49°, and about 18.24° 2 ⁇ .
  • the XRPD pattern of the crystal form E further has one or more (for example, 2, 3, 4, 5, 6, 7) peaks selected from the following group: about 13.03°, about 20.13°, about 22.63°, about 23.35°, about 25.06°, about 27.51°, and about 29.46° 2 ⁇ .
  • the XRPD pattern of the crystal form E also has a peak at about 13.03° 2 ⁇ .
  • the XRPD pattern of the crystal form E also has a peak at about 20.13° 2 ⁇ .
  • the XRPD pattern of the crystal form E also has a peak at about 22.63° 2 ⁇ .
  • the XRPD pattern of the crystal form E also has a peak at about 23.35° 2 ⁇ .
  • the XRPD pattern of the crystal form E also has a peak at about 25.06°2 ⁇ .
  • the XRPD pattern of the crystal form E also has a peak at about 27.51°2 ⁇ .
  • the XRPD pattern of the crystal form E also has a peak at about 29.46°2 ⁇ .
  • the XRPD pattern of the crystal form E further has two or more (for example, 3, 4, 5, 6, 7) peaks selected from the group consisting of: about 13.03 °, about 20.13°, about 22.63°, about 23.35°, about 25.06°, about 27.51°, and about 29.46° 2 ⁇ .
  • the XRPD pattern of the crystalline form E also has peaks at approximately 13.03°2 ⁇ and approximately 20.13°2 ⁇ .
  • the XRPD pattern of the crystal form E also has peaks at approximately 13.03°2 ⁇ and approximately 22.63°2 ⁇ .
  • the XRPD pattern of the crystal form E also has peaks at about 13.03°2 ⁇ and about 23.35°2 ⁇ .
  • the XRPD pattern of the crystal form E also has peaks at about 13.03°2 ⁇ and about 25.06°2 ⁇ .
  • the XRPD pattern of the crystal form E also has peaks at about 13.03°2 ⁇ and about 27.51°2 ⁇ .
  • the XRPD pattern of the crystal form E also has peaks at about 13.03° 2 ⁇ and about 29.46° 2 ⁇ .
  • the XRPD pattern of the crystal form E also has peaks at about 20.13°2 ⁇ and about 22.63°2 ⁇ .
  • the XRPD pattern of the crystal form E also has peaks at about 20.13°2 ⁇ and about 23.35°2 ⁇ .
  • the XRPD pattern of the crystal form E also has peaks at about 20.13°2 ⁇ and about 25.06°2 ⁇ .
  • the XRPD pattern of the crystal form E also has peaks at about 20.13°2 ⁇ and about 27.51°2 ⁇ .
  • the XRPD pattern of the crystal form E also has peaks at about 20.13°2 ⁇ and about 29.46°2 ⁇ .
  • the XRPD pattern of the crystal form E also has peaks at about 22.63°2 ⁇ and about 23.35°2 ⁇ .
  • the XRPD pattern of the crystal form E also has peaks at about 22.63°2 ⁇ and about 25.06°2 ⁇ .
  • the XRPD pattern of the crystal form E also has peaks at about 22.63°2 ⁇ and about 27.51°2 ⁇ .
  • the XRPD pattern of the crystal form E also has peaks at about 22.63°2 ⁇ and about 29.46°2 ⁇ .
  • the XRPD pattern of the crystal form E also has peaks at about 23.35°2 ⁇ and about 25.06°2 ⁇ .
  • the XRPD pattern of the crystal form E also has peaks at about 23.35°2 ⁇ and about 27.51°2 ⁇ .
  • the XRPD pattern of the crystal form E also has peaks at about 23.35°2 ⁇ and about 29.46°2 ⁇ .
  • the XRPD pattern of the crystal form E also has peaks at about 25.06°2 ⁇ and about 27.51°2 ⁇ .
  • the XRPD pattern of the crystal form E also has peaks at about 25.06°2 ⁇ and about 29.46°2 ⁇ .
  • the XRPD pattern of the crystal form E also has peaks at about 27.51°2 ⁇ and about 29.46°2 ⁇ .
  • the XRPD pattern of the crystalline form E further has all peaks selected from the following group: about 13.03°, about 20.13°, about 22.63°, about 23.35°, about 25.06°, about 27.51°, and about 29.46 °2 ⁇ .
  • the XRPD pattern of the crystal form E has all peaks selected from the following group:
  • the XRPD pattern of the crystal form E is substantially similar to the XRPD pattern depicted in FIG. 9. In some embodiments, the XRPD pattern of the crystal form E is shown in FIG. 9. In some embodiments, the crystal form E has at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least XRPD patterns of 10, at least 11, at least 12, and at least 13 2 ⁇ angles.
  • the DSC spectrum of the crystalline form E includes an endothermic peak at about 269.0°C (peak temperature). In some embodiments, the DSC spectrum of the crystal form E further includes an endothermic peak at about 123.6° C. (peak temperature). In some embodiments, the DSC spectrum of the crystal form E is substantially similar to the DSC spectrum depicted in FIG. 10. In some embodiments, the DSC spectrum of the crystal form E is shown in FIG. 10.
  • the TGA pattern of the crystal form E shows that the weight loss before 100°C is about 4% to 6%, for example, about 4%, about 4.5%, about 4.6%, about 4.7%, about 4.8 %, about 4.9%, about 4.96%, about 5%, about 5.5%, about 6%; the weight loss between 100°C and 150°C is about 11%-14%, for example, about 11%, about 11.5%, About 12%, about 12.1%, about 12.2%, about 12.3%, about 12.4%, about 12.5%, about 12.54%, about 12.6%, about 12.7%, about 12.8%, about 12.9%, about 13%, about 13.5% %, about 14%.
  • the TGA pattern of the crystal form E shows that the weight loss before 100°C is about 4.96%, and the weight loss between 100°C and 150°C is about 12.54%. In some embodiments, the TGA pattern of the crystal form E is substantially similar to the TGA pattern depicted in FIG. 10. In some embodiments, the TGA pattern of the crystal form E is shown in FIG. 10. In some embodiments, the molar ratio of isopropanol molecules to compound 1 in the crystal form E is about 1:1, for example, 0.7:1, 0.8:1, 0.9:1, 1:1, 1.1: 1, 1.2:1, 1.3:1.
  • the 1 H NMR spectrum of the crystal form E is substantially similar to the 1 H NMR spectrum depicted in FIG. 19. In some embodiments, the 1 H NMR spectrum of the crystal form E is shown in FIG. 19.
  • the crystal form E is applicable to at least one, two, three or four of the following (a) to (d):
  • the crystal form E has an XRPD pattern substantially as shown in Fig. 9;
  • the crystal form E has a TGA pattern substantially as shown in FIG. 10;
  • the crystal form E basically has the following characteristics:
  • the crystal form E has an XRPD pattern substantially as shown in Fig. 9;
  • the crystal form E has a DSC spectrum substantially as shown in FIG. 10;
  • the crystal form E has a TGA pattern substantially as shown in FIG. 10.
  • the crystal form E basically has the following characteristics:
  • the crystal form E has an XRPD pattern substantially as shown in Fig. 9;
  • the crystal form E has a TGA pattern substantially as shown in FIG. 10;
  • the crystal form E is substantially pure, for example, the purity of the crystal form E is greater than 90 wt%, greater than 91 wt%, greater than 92 wt%, greater than 93 wt%, greater than 94 wt%, greater than 95 wt% , Greater than 96 wt%, greater than 97 wt%, greater than 98 wt%, or greater than 99 wt%.
  • the purity of the crystal form E is determined by high performance liquid chromatography (HPLC).
  • compound 1 contains no more than about 5.0 area percent HPLC total organic impurities; in some embodiments, it contains no more than about 3.0 area percent HPLC total organic impurities; in some implementations In the method, it contains not more than about 1.5 area percent HPLC total organic impurities. In other embodiments, relative to the total area of the HPLC chromatogram, compound 1 contains no more than about 1.0 area percent HPLC any single impurity; no more than about 0.6 area percent HPLC any single impurity; in some embodiments, no Any single impurity that is greater than about 0.5 area percent HPLC.
  • this application also provides a method for preparing the crystalline form A-E of Compound 1.
  • exemplary methods include, for example, beating method (room temperature or 50°C), gas-solid diffusion method, temperature cycling method, slow volatilization method, gas-liquid diffusion method, polymer induction method, anti-solvent addition method, grinding method Wait.
  • the starting material used in the preparation method of the crystal form described in the present application can be compound 1 in any form, such as amorphous, any crystal form, and the like.
  • Compound 1 can be prepared by the method disclosed in the PCT patent application with publication number WO2020072656A1 or WO2020094018A1 (which is incorporated herein by reference in its entirety).
  • the crystalline form AD of Compound 1 can be prepared by a room temperature beating method.
  • compound 1 is dissolved in a first solvent, suspended and stirred at room temperature, and then crystallized, and the crystals are collected by filtration.
  • the first solvent may be selected from the following group: ethers (for example, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, anisole, methyl tert-butyl ether, 1,4-dioxane, etc.
  • alcohols for example, methanol, ethanol, n-propanol, isopropanol, butanol, etc.
  • esters for example, ethyl acetate, isopropyl acetate, butyl acetate, etc.
  • ketones for example, acetone , Methyl ethyl ketone, methyl ethyl ketone, methyl isobutyl ketone, N-methyl pyrrolidone, etc.
  • sulfones for example, dimethyl sulfoxide
  • alkanes for example, C 1-7 alkanes, including methane, ethane , Propane, butane, pentane, hexane, n-heptane, etc.
  • halogenated hydrocarbons for example, dichloromethane, chloroform, etc.
  • acetonitrile water, and mixed solvents formed by any combination thereof.
  • the volume ratio of at least two solvents in the mixed solvent can be any ratio, for example, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1, 95:1 or any two ratio ranges above Any ratio between.
  • the mixed solvent may be selected from the following group: isopropyl acetate/chloroform, 2-methyltetrahydrofuran/methanol, cyclopentyl methyl ether/ethanol, isopropanol/dichloromethane, anisole/butanone, ethyl acetate Ester/dimethyl sulfoxide, methyl tert-butyl ether/methanol, n-heptane/chloroform, acetone/water, acetonitrile/methanol, methanol/tetrahydrofuran, 2-butanol/acetonitrile, dichloromethane/n-hexane, 1, 4-Dioxane/ethanol, anisole/chloroform, methyl acetate/methanol, methyl isobutyl ketone/ethanol.
  • the crystalline forms A, C and amorphous forms of Compound 1 can be prepared by a 50°C beating method.
  • compound 1 is dissolved in a second solvent, suspended and stirred at room temperature, and then crystallized, and the crystals are collected by filtration.
  • the second solvent may be selected from the following group: ethers (for example, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, anisole, methyl tert-butyl ether, 1,4-dioxane, etc.
  • alcohols for example, methanol, ethanol, n-propanol, isopropanol, butanol, etc.
  • esters for example, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, etc.
  • ketones For example, acetone, methyl ethyl ketone, methyl ethyl ketone, methyl isobutyl ketone, N-methyl pyrrolidone, etc.
  • alkanes for example, C 1-7 alkanes, including methane, ethane, propane, butane, pentane Alkane, hexane, n-heptane, etc.
  • halogenated hydrocarbons for example, dichloromethane, chloroform, etc.
  • acetonitrile water, and mixed solvents formed by any combination thereof.
  • the volume ratio of at least two solvents in the mixed solvent can be any ratio, for example, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1, 95:1 or any two ratio ranges above Any ratio between.
  • the mixed solvent may be selected from the following group: methanol/tetrahydrofuran, methyl acetate/methanol, 2-butanol/acetonitrile, dichloromethane/n-hexane, methanol/toluene, 1,4-dioxane/ethanol, tetrahydrofuran /Water, anisole/chloroform, methyl isobutyl ketone/ethanol, acetonitrile/methanol or n-heptane/chloroform.
  • the crystalline form A of compound 1 can be prepared by a gas-solid diffusion method. For example, putting compound 1 in a first container, and then placing the first container open in a second container containing a third solvent, the volume of the second container is greater than the volume of the first container, Then the second container was sealed and allowed to stand at room temperature to obtain the crystal form of compound 1.
  • the third solvent may be selected from the following group: alcohols (for example, methanol, ethanol, n-propanol, isopropanol, butanol, etc.), ethers (for example, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentylmethyl) Ether, anisole, methyl tert-butyl ether, 1,4-dioxane, etc.), esters (e.g., ethyl acetate, isopropyl acetate, butyl acetate, etc.), ketones (e.g., acetone , Methyl ethyl ketone, methyl ethyl ketone, methyl isobutyl ketone, N-methylpyrrolidone, etc.), halogenated hydrocarbons (for example, dichloromethane, chloroform, etc.), acetonitrile, water.
  • alcohols for example, methanol, ethanol
  • the crystalline forms A and C of compound 1 can be prepared by a temperature cycling method.
  • compound 1 is added to the fourth solvent, and the resulting suspension is subjected to cyclic heating and suspension stirring (for example, one cycle is to heat up at 4.5°C/min to 50°C, hold the temperature for 30 minutes, and cool down to 5°C at 0.1°C/min, Constant temperature for 30 min, 3 cycles), crystallize to obtain the crystal form of compound 1.
  • the fourth solvent may be selected from the following group: alcohols (for example, methanol, ethanol, n-propanol, isopropanol, butanol, etc.), ethers (for example, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentylmethyl) Ether, anisole, methyl tert-butyl ether, 1,4-dioxane, etc.), esters (e.g., ethyl acetate, isopropyl acetate, butyl acetate, etc.), ketones (e.g., acetone , Methyl ethyl ketone, methyl ethyl ketone, methyl isobutyl ketone, N-methyl pyrrolidone, etc.), sulfones (for example, dimethyl sulfoxide), alkanes (for example, C 1-7 alkanes, including methane, ethane ,
  • the volume ratio of at least two solvents in the mixed solvent can be any ratio, for example, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1, 95:1 or any two ratio ranges above Any ratio between.
  • the mixed solvent may be selected from the following group: water/dimethylformamide, n-hexane/dimethylsulfoxide, acetonitrile/N-methylpyrrolidone.
  • the crystalline forms A-E and amorphous forms of Compound 1 can be prepared by a slow volatilization method.
  • compound 1 is added to the fifth solvent to obtain a clear solution, which is slowly volatilized to obtain the crystal form of compound 1.
  • the fifth solvent may be selected from the following group: alcohols (for example, methanol, ethanol, n-propanol, isopropanol, butanol, etc.), ethers (for example, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentylmethyl) Ether, anisole, methyl tert-butyl ether, 1,4-dioxane, etc.), esters (e.g., ethyl acetate, isopropyl acetate, butyl acetate, etc.), ketones (e.g., acetone , Methyl ethyl ketone, methyl ethyl ketone, methyl isobutyl ketone, N-methyl pyrrolidone, etc.), halogenated hydrocarbons (for example, dichloromethane, chloroform, etc.), acetonitrile, water, and mixed solvents formed by any mixture thereof .
  • the volume ratio of at least two solvents in the mixed solvent can be any ratio, for example, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1, 95:1 or any two ratio ranges above Any ratio between.
  • the mixed solvent may be selected from the following group: water/ethanol, ethyl acetate/methanol, acetonitrile/methanol, methyl tert-butyl ether/methanol, acetone/dichloromethane, isopropanol/chloroform.
  • the crystalline forms A and C of compound 1 can also be prepared by a gas-liquid diffusion method. For example, put compound 1 in a third container and dissolve it with a sixth solvent, then filter, place the filtrate in the fourth container, and then place the fourth container open in the first container where the anti-solvent of the sixth solvent is placed.
  • the volume of the fifth container is greater than the volume of the fourth container, and then the fifth container is sealed and allowed to stand at room temperature to obtain the crystal form of compound 1.
  • the sixth solvent may be selected from the following group: alcohols (for example, methanol, ethanol, n-propanol, isopropanol, butanol, etc.), ketones (for example, acetone, butanone, methyl ethyl ketone, methyl ethyl ketone, etc.) Isobutyl ketone, N-methylpyrrolidone, etc.), dimethylformamide.
  • alcohols for example, methanol, ethanol, n-propanol, isopropanol, butanol, etc.
  • ketones for example, acetone, butanone, methyl ethyl ketone, methyl ethyl ketone, etc.
  • Isobutyl ketone N-methylpyrrolidone, etc.
  • dimethylformamide dimethylformamide
  • the anti-solvent of the sixth solvent may be selected from the following group: acetonitrile, esters (e.g., ethyl acetate, isopropyl acetate, butyl acetate, etc.), alkanes (e.g., C 1-7 alkanes, including methane, ethane, etc.) Alkane, propane, butane, pentane, hexane (e.g., cyclohexane, n-heptane, etc.).
  • esters e.g., ethyl acetate, isopropyl acetate, butyl acetate, etc.
  • alkanes e.g., C 1-7 alkanes, including methane, ethane, etc.
  • Alkane propane, butane, pentane, hexane (e.g., cyclohexane, n-heptane, etc.).
  • the anti-solvent system in the method can be selected from the following group: ethanol/acetonitrile, ethanol/n-heptane, ethanol/ethyl acetate, N-methylpyrrolidone/isopropyl acetate, dimethyl Formamide/acetonitrile, dimethylformamide/cyclohexane.
  • the crystalline forms A, D and amorphous forms of Compound 1 can be prepared by a polymer induction method.
  • the compound 1 is dissolved in the seventh solvent to obtain a clear solution, and then the mixed polymer is added to the solution and placed at room temperature to evaporate slowly to obtain the crystal form of compound 1.
  • the seventh solvent may be selected from the group consisting of alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, butanol, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, etc.), and acetonitrile.
  • the mixed polymer can be selected from the following: polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, hydroxypropyl methylcellulose and methylcellulose, or a mixture of equal masses, or polycaproic acid Equal quality mixture of ester, polyethylene glycol, polymethyl methacrylate, sodium alginate and hydroxyethyl cellulose.
  • the crystalline forms A-C and amorphous forms of Compound 1 can be prepared by an anti-solvent addition method.
  • the compound 1 is dissolved in the eighth solvent, and then the anti-solvent of the eighth solvent is added dropwise with stirring, and the crystal form of the compound 1 is obtained by crystallization.
  • the eighth solvent may be selected from the following group: alcohols (for example, methanol, ethanol, n-propanol, isopropanol, butanol, etc.), halogenated hydrocarbons (for example, dichloromethane, chloroform, etc.), ketones ( For example, acetone, methyl ethyl ketone, methyl ethyl ketone, methyl isobutyl ketone, N-methylpyrrolidone, etc.), sulfones (for example, dimethyl sulfoxide).
  • alcohols for example, methanol, ethanol, n-propanol, isopropanol, butanol, etc.
  • halogenated hydrocarbons for example, dichloromethane, chloroform, etc.
  • ketones For example, acetone, methyl ethyl ketone, methyl ethyl ketone, methyl isobutyl ketone, N-methylpyrroli
  • the anti-solvent of the eighth solvent can be selected from the following group: toluene, ethers (for example, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, anisole, methyl tert-butyl ether, 1,4- Dioxane, etc.), alcohols (for example, methanol, ethanol, n-propanol, isopropanol, butanol, etc.), esters (for example, ethyl acetate, isopropyl acetate, butyl acetate, etc.), ketones (For example, acetone, methyl ethyl ketone, methyl isobutyl ketone, N-methylpyrrolidone, etc.), water.
  • ethers for example, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, anisole, methyl tert-butyl
  • the anti-solvent system may be selected from the group consisting of chloroform/toluene, chloroform/ethyl acetate, chloroform/cyclopentyl methyl ether, methanol/water, methanol/tetrahydrofuran, methanol/acetone, dimethyl sulfoxide /Isopropanol, dimethyl sulfoxide/water.
  • the crystalline forms A and B of compound 1 can be prepared by grinding methods. For example, compound 1 is placed in a mortar and optionally water is added for grinding to obtain a crystal form of compound 1.
  • the preparation method of the crystal form in this application further includes steps such as filtration, washing or drying.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising compound 1 and a pharmaceutically acceptable carrier, said compound 1 having one or more crystal forms selected from the group consisting of crystal form A, hydrate Form B, hydrate form C, dichloromethane solvate form D, and isopropanol solvate form E.
  • the crystalline form A, hydrate crystalline form B, hydrate crystalline form C, dichloromethane solvate crystalline form D and isopropanol solvate crystalline form E or pharmaceutical composition of compound 1 of the present application can be formulated as required.
  • Required forms such as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injections and concentrated solutions for injections), suppositories, inhalants or sprays Agent.
  • the crystalline form A, hydrate crystalline form B, hydrate crystalline form C, dichloromethane solvate crystalline form D and isopropanol solvate crystalline form E or pharmaceutical composition of compound 1 of the present application can be administered in any suitable way
  • the method is administered to patients or subjects in need, such as oral, parenteral, rectal, pulmonary or topical administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the crystalline form A, hydrate crystalline form B, hydrate crystalline form C, dichloromethane solvate crystalline form D or isopropanol solvate crystalline form E of compound 1 of the present application are combined with at least one conventional Inert excipients or carriers are mixed, such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) fillers or compatibilizers, for example, microcrystalline cellulose, starch, lactose, sucrose, glucose, mannitol and Silicic acid; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, such as glycerin; (d) disintegrants , For example, agar, calcium carbonate, potato starch or tapioca starch, alg
  • Solid dosage forms can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of active ingredients in such compositions may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active ingredient can also be formed into a microcapsule form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain inert diluents (such as water or other solvents), solubilizers and emulsifiers (for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils (especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil), sweeteners (for example, glycerin, propylene glycol, sorbitol, natural Aspartame or sucrose), preservatives, flavor enhancers, colorants, or mixtures of these substances.
  • inert diluents such as water or other solvents
  • solubilizers and emulsifiers for example, ethanol, isopropanol, ethyl
  • compositions for parenteral injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, Ringer's solution of polyols, isotonic sodium chloride solution or mixtures of these substances.
  • composition for rectal administration may include suppositories and the like.
  • composition for pulmonary administration may include inhalants, sprays, and the like.
  • compositions for topical administration may include ointments, powders, patches, propellants, and inhalants.
  • the active ingredient is combined with a pharmaceutically acceptable carrier (e.g., animal oil, vegetable oil, wax, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, Zinc oxide, etc.) and any preservatives, buffers, or propellants that may be required if necessary are mixed together.
  • a pharmaceutically acceptable carrier e.g., animal oil, vegetable oil, wax, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, Zinc oxide, etc.
  • pharmaceutically acceptable carriers known in the art can also be included in this application.
  • Such carriers are described in, for example, “Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991), in “Remington: The Science and Practice of Pharmacy”, Ed. University of the Sciences in Philadelphia, 21 st Edition, LWW (2005), which is incorporated herein by reference in its entirety.
  • the crystalline form A, hydrate crystalline form B, hydrate crystalline form C, dichloromethane solvate crystalline form D, and isopropanol solvate crystalline form E of compound 1 of the present application are used to treat and/ Or a preventive effective amount is present in the pharmaceutical composition or medicine.
  • the pharmaceutical composition of the application can be formulated as a unit dosage form.
  • the content mentioned in this application refers to the equivalent of compound 1 in the free base form, excluding the additional weight generated by the contained solvent (if present in the crystal form).
  • the dosage of Form E can be about 0.01 to about 100 mg/kg body weight/day, about 0.05 to about 100 mg/kg body weight/day, about 0.1 to about 100 mg/kg body weight/day, about 0.5 to about 100 mg/kg body weight/day, About 1 to about 100 mg/kg body weight/day, about 1 to about 90 mg/kg body weight/day, about 1 to about 80 mg/kg body weight/day, about 1 to about 70 mg/kg body weight/day, about 1 to about 60 mg/ kg body weight/day, about 1 to about 50 mg/kg body weight/day, about 1 to about 45 mg/kg body weight/day, about 1 to about 40 mg/kg body weight/day, about 1 to about 35 mg/kg body weight/day, or About 1 to about 30 mg/kg body weight/day
  • the unit dosage form (eg, tablet, capsule) may contain, for example, about 1-1000 mg, about 1-900 mg, about 1-800 mg, about 1-700 mg, about 1-600 mg, about 1-500 mg, about 1- 400 mg, about 1-300 mg, about 1-200 mg, or about 1-100 mg of the crystal form A, hydrate crystal form B, hydrate crystal form C, dichloromethane solvate crystal form D or isoforms of compound 1 of the present application Propanol Solvate Form E.
  • the content of crystal form A, hydrate crystal form B, hydrate crystal form C, dichloromethane solvate crystal form D, and isopropanol solvate crystal form E of compound 1 of the present application in the pharmaceutical composition may depend on a variety of Factors are different, such as potency, biological half-life, disease type and severity, subjects to be treated (such as age and weight), specific administration methods, etc., and those skilled in the art can routinely determine the required content according to needs.
  • time and administration time (the time period between doses, the time point of the dose (e.g. before meal, after meal, during meal)) also depend on the subject to be treated, the specific crystal form and its properties (e.g. pharmacokinetics) The nature), the type of disease and its severity, the specific composition and method used are different, and those skilled in the art can determine it routinely according to needs.
  • the compound 1 has crystalline form A.
  • the compound 1 has crystalline form B.
  • the compound 1 of has crystalline form C.
  • the compound 1 has crystalline form D.
  • the compound 1 of has the crystalline form E.
  • the pharmaceutical composition described in the present application further includes other therapeutic agents.
  • the other therapeutic agents include anti-cancer drugs, for example, abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol ), altretamine, amifostine, anastrozole, arsenic trioxide, asparaginase, azacitidine, BCG Live, bevacuzimab, fluorouracil , Bexarotene, bleomycin, bortezomib, busulfan, calusterone, capecitabine, camptothecin, Carboplatin, carmustine, celecoxib, cetuximab, chlorambucil, cladribine, clofarabine, cyclophosphate Amide, Cytarabine, Actinomycin D, Darbepoetin Alfa, Daunorubicin, Denileukin, Dexrazoxane, Docetaxel, Small Cran
  • this application also provides a method for preparing a pharmaceutical composition, which comprises combining the crystal form A, hydrate crystal form B, hydrate crystal form C, dichloromethane solvate crystal form D, and isoforms of compound 1
  • the propanol solvate crystal form E or the crystal form AE of compound 1 prepared by the foregoing method is mixed with a pharmaceutically acceptable carrier.
  • the application also provides the use of the crystalline forms A-E of compound 1 and the pharmaceutical composition described in the application in the following:
  • the "SHP2-mediated disease or disorder” refers to a disease or disorder related to abnormal SHP2 activity/level, which may be due to abnormal activation or destruction of SHP2 in the subject's body, which causes an abnormal increase in SHP2 activity/level Or lower.
  • the SHP2-mediated disease or condition is associated with an abnormal increase in SHP2 activity/level.
  • the SHP2-mediated disease or disorder is cancer.
  • the cancer is selected from the group consisting of Noonan syndrome, leopard skin syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer , Lung cancer, colon cancer, head cancer, head and neck squamous cell carcinoma, gastric cancer, anaplastic large cell lymphoma, glioblastoma, hepatocellular carcinoma (HCC), acute lymphoblastic leukemia, adrenal cortical cancer, anal cancer, Appendix cancer, astrocytoma, atypical malformation/tumor-like, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumor, brain And spinal cord tumors, bronchial tumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic gran
  • the present application also provides a method for treating or preventing SHP2-mediated diseases or conditions, including administering to a subject in need the crystal form A and hydrate crystal form of compound 1 described in this application B, hydrate crystal form C, dichloromethane solvate crystal form D, isopropanol solvate crystal form E, or the pharmaceutical composition described in this application.
  • the present application also provides crystal form A, hydrate crystal form B, hydrate crystal form C, dichloromethane solvate crystal form of compound 1 for the treatment or prevention of SHP2-mediated diseases or conditions D.
  • the present application also provides a method for inhibiting the activity of SHP2, which includes the following steps: administering an effective amount of the crystalline form AE of compound 1 described in the present application to a subject in need thereof, or The subject in need thereof administers an effective amount of the pharmaceutical composition described in this application.
  • Humidity change 0-95-0-95-0%RH, the step is 10%, the judgment standard is that the mass change is less than 0.01% within 10000min
  • Example 1.1 With reference to the method of Example 1.1, the methanol in Example 1.1 was replaced with a different solvent (specifically as shown in Table 1), and the obtained solid was determined to be the crystal form A of compound 1 by XRPD detection.
  • Example 1.16 Referring to the preparation method of Example 1.16, the chloroform/toluene anti-solvent system in Example 1.16 (specifically shown in Table 2) was replaced with a different anti-solvent system, and the obtained solids were determined to be the crystal form A of compound 1 through XRPD detection.
  • Example number Anti-solvent system selected Example 1.17 CHCl 3 /EtOAc Example 1.18 CHCl 3 /CPME Example 1.19 DMSO/IPA
  • Example 1.20 With reference to the preparation method of Example 1.20, the isopropanol in Example 1.20 was replaced with a different solvent (specifically as shown in Table 3), and the obtained solid was determined to be the crystal form A of compound 1 by XRPD detection.
  • Example 1.37 Referring to the preparation method of Example 1.37, the methanol in Example 1.37 (specifically shown in Table 4) was replaced with a different solvent, and the obtained solid was determined to be the crystal form A of compound 1 by XRPD detection.
  • Example number Selected solvent (v:v) Example 1.38 EtOH Example 1.39 CHCl 3 Example 1.40 EtOAc/MeOH, 9:1 Example 1.41 ACN/MeOH, 9:1
  • Example 1.42 With reference to the preparation method of Example 1.42, the ethanol in Example 1.42 (specifically shown in Table 5) was replaced with a different solvent, and the obtained solid was determined to be the crystal form A of compound 1 by XRPD detection.
  • Example 1.52 With reference to the preparation method of Example 1.52, the water in Example 1.52 (specifically shown in Table 6) was replaced with a different solvent, and the obtained solid was determined to be the crystal form A of Compound 1 by XRPD detection.
  • Example number Choose solvent Example 1.53 DCM Example 1.54 EtOH Example 1.55 Acetone Example 1.56 EtOAc Example 1.57 ACN Example 1.58 MTBE Example 1.59 THF
  • Example 1.60 With reference to the preparation method of Example 1.60, the ethanol/acetonitrile anti-solvent system in Example 1.60 was replaced with a different anti-solvent system (specifically as shown in Table 7), and XRPD detection confirmed that the obtained solids were all crystal form A of compound 1. .
  • Example number Anti-solvent system selected Example 1.61 NMP/IPAc Example 1.62 DMF/ACN Example 1.63 DMF/Cyclohexane
  • the composition of the mixed polymer A is: polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, hydroxypropyl methyl cellulose and methyl cellulose (mixed with equal mass).
  • the obtained solid was collected and subjected to XRPD test, and it was determined that the obtained solid was the crystalline form A of compound 1.
  • the DSC spectrum and TGA spectrum of the crystalline form A of Compound 1 are shown in FIG. 2.
  • the DSC spectrum shows that the crystalline form A of compound 1 has a very shallow exothermic peak at 153.7°C (peak temperature), followed by a sharp endothermic peak at about 262.0°C (peak temperature), the sharp endothermic peak Corresponds to the melting of crystal form A.
  • the TGA chart showed that the weight loss of the crystal form A of compound 1 was 1.69% before 120° C., indicating that the crystal form A of compound 1 was an anhydrate crystal form.
  • the hygroscopicity of the crystal form A of compound 1 was evaluated by DVS test.
  • the DVS map is shown in Figure 13.
  • DVS test results show that the crystalline form A of compound 1 has a moisture absorption weight gain of 1.88% at a relative humidity of 80.0%, indicating that it has a slight hygroscopicity.
  • the XRPD patterns of the crystal form A of compound 1 before and after the DVS test are shown in FIG. 14, which shows that the crystal form of the crystal form A is consistent before and after the DVS test.
  • the HPLC test results are shown in Figures 11A to 11E. From the HPLC test results, it can be seen that the crystal form A of compound 1 has not undergone significant changes in purity after being placed under the above three stability test conditions, maintaining extremely high purity (about 98%), and exhibiting good chemical stability. sex.
  • the XRPD test results are shown in Figure 12. After the crystal form A of compound 1 was placed at 60°C/closed for 24 hours and at 25°C/60%RH for 1 week, there was no crystalline transformation. After being left open for 1 week at 40°C/75%RH, only part of the crystal form A was converted to the hydrate crystal form B.
  • the crystalline form A of compound 1 was heated to different temperatures (30°C, 92°C, 118°C, 132°C, and 175°C, respectively) under the protection of nitrogen, and the temperature was lowered to perform the XRPD test.
  • the temperature-variable XRPD spectrum is shown in Fig. 15 and the results show that the crystal form A of compound 1 did not undergo a crystalline transformation during the heating process (the small shift observed at high temperature is caused by the lattice stretching at high temperature).
  • Example 2.1 With reference to the preparation method of Example 2.1, the methanol/water anti-solvent system in Example 2.1 was replaced with a dimethyl sulfoxide/water anti-solvent system, and the obtained solid was determined to be the crystal form B of compound 1 by XRPD detection.
  • the 1 H NMR spectrum of the crystalline form B of compound 1 is shown in FIG. 16. It can be seen from the 1 H NMR spectrum that the crystalline form B of compound 1 did not decompose during the preparation process, and a clear water signal was observed.
  • the XRPD pattern of the crystalline form B of compound 1 is shown in FIG. 3, and the peaks in the XRPD pattern and their related intensities and interplanar spacing data are shown in Table 10.
  • the DSC spectrum and TGA spectrum of the crystalline form B of compound 1 are shown in FIG. 4.
  • the DSC spectrum showed that the crystalline form B of compound 1 had two sharp endothermic peaks at 113.5°C and 266.8°C (peak temperature), and an exothermic peak at 161.8°C (peak temperature).
  • the TGA chart showed that the crystal form B of compound 1 had a weight loss of 12.75% before 120°C.
  • the crystalline form B of compound 1 was heated to different temperatures (130°C and 180°C, respectively) under the protection of nitrogen, and cooled to room temperature, and then the XRPD test was performed.
  • the variable temperature XRPD spectrum is shown in Figure 20. The results show that when the crystalline form B is heated to 130°C and cooled to room temperature, the crystalline form B transforms into an amorphous form; when the crystalline form B is heated to 180°C and cooled to room temperature, The crystal form B is transformed into the crystal form A.
  • thermal analysis data, 1 H NMR test and variable temperature XRPD test results of the crystal form B of compound 1, it is speculated that the crystal form B is a hydrate, and the molar ratio of water molecules to compound 1 is about 3.9:1.
  • it is first dehydrated and transformed into an amorphous form, and then transformed into crystal form A through high-temperature recrystallization.
  • Example 3.1 Refer to the preparation method of Example 3.1, replace the acetone/water in Example 3.1 with 1,4-dioxane/water (4:1, v:v), and XRPD detection confirms that the obtained solid is the crystal form of compound 1.
  • Example 3.5 Referring to the preparation method of Example 3.5, the ethanol/n-heptane anti-solvent system in Example 3.5 was replaced with an ethanol/ethyl acetate anti-solvent system, and the obtained solid was determined to be the hydrate crystal form C of compound 1 by XRPD detection.
  • the 1 H NMR spectrum of the crystalline form C of compound 1 is shown in FIG. 17. It can be seen from the 1 H NMR spectrum that the crystalline form C of compound 1 did not decompose during the preparation process, and a clear water signal was observed.
  • the XRPD pattern of the crystalline form C of Compound 1 is shown in FIG. 5, and the peaks in the XRPD pattern and their related intensities and interplanar spacing data are shown in Table 11.
  • the DSC spectrum and TGA spectrum of the crystalline form C of compound 1 are shown in FIG. 6.
  • the DSC spectrum showed that the crystalline form C of compound 1 had a very shallow endothermic peak at 46.4°C (peak temperature), followed by two sharp endothermic peaks at 117.2°C and 265.6°C (peak temperature). There is an exothermic peak at 147.0°C (peak temperature).
  • the TGA chart showed that the weight loss of Form C of Compound 1 was 12.23% before 120°C.
  • the crystalline form C of compound 1 was heated to different temperatures (130°C and 160°C, respectively) under the protection of nitrogen, and cooled to room temperature, and then the XRPD test was performed.
  • the variable temperature XRPD spectrum is shown in Figure 21. The results show that when the crystal form C is heated to 130°C and cooled to room temperature, the crystal form C is transformed into an amorphous form; when the crystal form C is heated to 160°C and cooled to room temperature, The crystal form C is transformed into the crystal form A.
  • the crystal form C is a hydrate, in which the molar ratio of water molecules to compound 1 is about 3.7:1, which is In the process of high-temperature heating, it is first dehydrated and transformed into an amorphous form, and then transformed into crystal form A through high-temperature recrystallization.
  • the 1 H NMR spectrum of the crystalline form D of compound 1 is shown in FIG. 18. It can be seen from the 1 H NMR spectrum that the crystalline form D of compound 1 did not decompose during the preparation process, and a clear dichloromethane signal was observed.
  • the DSC spectrum and TGA spectrum of the crystalline form D of compound 1 are shown in FIG. 8.
  • the DSC spectrum shows that the crystalline form D of compound 1 has three endothermic peaks at 59.8°C, 124.1°C and 129.8°C (peak temperature).
  • the TGA chart showed that the weight loss of the crystal form D of compound 1 was 13.08% before 150°C.
  • the crystalline form D of compound 1 was heated to different temperatures (100°C and 160°C, respectively) under the protection of nitrogen, and cooled to room temperature, and then the XRPD test was performed.
  • the variable temperature XRPD spectrum is shown in Figure 22. The results show that when the crystal form D is heated to 100°C and cooled to room temperature, the crystallinity decreases significantly; when the crystal form D is heated to 160°C and cooled to room temperature, crystals are observed Diffraction signal of type A.
  • the 1 H NMR spectrum of the crystalline form E of compound 1 is shown in FIG. 19. It can be seen from the 1 H NMR spectrum that the crystal form E of compound 1 did not decompose during the preparation process, and a clear isopropanol signal was observed.
  • the DSC spectrum and TGA spectrum of the crystalline form E of compound 1 are shown in FIG. 10.
  • the DSC spectrum shows that the crystalline form E of compound 1 has two endothermic peaks at 123.6°C and 269.0°C (peak temperature).
  • the TGA chart shows that the weight loss of the crystal form E of compound 1 before 100°C is 4.96%, and the weight loss between 100 and 150°C is 12.54%.
  • the crystalline form E of compound 1 was heated to different temperatures (96°C and 180°C, respectively) under the protection of nitrogen, and cooled to room temperature, and then the XRPD test was performed.
  • the temperature-variable XRPD spectrum is shown in Figure 23. The results show that when the crystal form E is heated to 96°C and cooled to room temperature, a small amount of diffraction signal of the crystal form A is observed; when the crystal form E is heated to 180°C and cooled to room temperature Later, the crystal form E was completely transformed into the crystal form A.
  • the crystal form E is an isopropanol solvate, in which the molar ratio of isopropanol molecules to compound 1 is about 1. :1, which is transformed into crystal form A through recrystallization in the process of high temperature heating.

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Abstract

涉及一种式(I)所示的化合物1((S)-1'-(8-((2-氨基-3-氯吡啶-4-基)硫代)咪唑并[1,2-c]嘧啶-5-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-胺)、其水合物或溶剂化物的新型晶型以及包含所述新型晶型的药物组合物，还涉及所述新型晶型的制备方法及其用途。

Description

一种SHP2抑制剂的晶型及其组合物、制备方法和用途 技术领域
本申请提供了(S)-1’-(8-((2-氨基-3-氯吡啶-4-基)硫代)咪唑并[1,2-c]嘧啶-5-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4’-哌啶]-5-胺、其水合物和溶剂化物的新型晶型以及包含所述新型晶型的药物组合物。本申请也公开了所述新型晶型的制备方法及其用途。
背景技术
SHP2(含SH2结构域的蛋白酪氨酸磷酸酶-2)在细胞信号传导过程中占据及其重要的位置，是开发治疗糖尿病、自身免疫疾病和癌症等重大疾病的靶点。
如公开号为WO2020094018的PCT专利申请中所述，(S)-1’-(8-((2-氨基-3-氯吡啶-4-基)硫代)咪唑并[1,2-c]嘧啶-5-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4’-哌啶]-5-胺(下文称为“化合物1”)为一种有效的SHP2抑制剂，可用于预防或治疗与SHP2相关的疾病和病症，该PCT专利申请在此以全文引用的方式并入本文。化合物1的结构如下式(I)所示：
Figure PCTCN2021100673-appb-000001
化合物可能以一种或多种晶型存在，作为药用活性成分的晶型可具有不同的化学和物理性质，例如熔点、溶解度、溶出率、吸湿性、密度、流动性、稳定性和生物利用度等，这些性质对作为药物产品的化合物加工和/或制造能力具有直接影响。此外，结晶条件及储存条件的不同有可能导致化合物晶体结构的变化，有时还会伴随着产生其他形态的晶型。为了确保药物产品的质量、安全和效能，重要的是选择稳定、可再生产地制造和具有有利物理化学性质的晶型。
因此，仍然需要具有有利的化学和物理性质的化合物1的稳定形式。
发明内容
在一方面，本申请提供了化合物1、其水合物和溶剂化物的多种新型晶型。
在一个实施方案中，本申请提供了化合物1的晶型A，其特征在于，所述晶型A的X-射线粉末衍射图谱具有一个或多个选自下组的峰：约6.46°、约12.64°和约12.93°2θ。
在一个实施方案中，本申请提供了化合物1的水合物的晶型B，其特征在于，所述晶型B的X-射线粉末衍射图谱具有一个或多个选自下组的峰：约7.36°、约10.82°和约11.10°2θ。
在一个实施方案中，本申请提供了化合物1的水合物的晶型C，其特征在于，所述晶型C的X-射线粉末衍射图谱具有一个或多个选自下组的峰：约7.33°、约11.08°和约14.70°2θ。
在一个实施方案中，本申请提供了化合物1的二氯甲烷溶剂化物的晶型D，其特征在于，所述晶型D的X-射线粉末衍射图谱具有一个或多个选自下组的峰：约8.24°、约13.46°和约15.32°2θ。
在一个实施方案中，本申请提供了化合物1的异丙醇溶剂化物的晶型E，其特征在于，所述晶型E的X-射线粉末衍射图谱具有一个或多个选自下组的峰：约9.10°、约13.49°和约18.24°2θ。
在另一方面，本申请提供了包含化合物1的新型晶型的药物组合物。
在又一方面，本申请提供了化合物1的新型晶型和包含所述新型晶型的药物组合物的制备方法。
在另一方面，本申请提供了化合物1的新型晶型和包含所述新型晶型的药物组合物的用途。
附图简述
图1显示了化合物1的晶型A的X-射线粉末衍射(XRPD)图谱。
图2显示了化合物1的晶型A的差示扫描量热/热重分析(DSC/TGA)图谱。
图3显示了化合物1的水合物的晶型B的XRPD图谱。
图4显示了化合物1的水合物的晶型B的DSC/TGA图谱。
图5显示了化合物1的水合物的晶型C的XRPD图谱。
图6显示了化合物1的水合物的晶型C的DSC/TGA图谱。
图7显示了化合物1的二氯甲烷溶剂化物的晶型D的XRPD图谱。
图8显示了化合物1的二氯甲烷溶剂化物的晶型D的DSC/TGA图谱。
图9显示了化合物1的异丙醇溶剂化物的晶型E的XRPD图谱。
图10显示了化合物1的异丙醇溶剂化物的晶型E的DSC/TGA图谱。
图11A～11E显示了化合物1的晶型A在三种稳定性试验条件(25℃/60％RH/1周、40℃/75％RH/1周及60℃/闭口/24小时)下的高效液相色谱(HPLC)图谱。
图12显示了化合物1的晶型A在三种稳定性试验条件(25℃/60％RH/1周、40℃/75％RH/1周及60℃/闭口/24小时)下的XRPD图谱。
图13显示了在化合物1的晶型A的引湿性考察试验中，晶型A的动态蒸汽吸附(DVS)测试图谱。
图14显示了在化合物1的晶型A的引湿性考察试验中，晶型A在DVS测试之前和之后的XRPD图谱对比。
图15显示了分别将化合物1的晶型A置于氮气保护下加热至不同温度(分别为30℃、92℃、118℃、132℃、175℃)并降温后的XRPD图谱对比。
图16显示了化合物1的水合物晶型B的 1H NMR图谱。
图17显示了化合物1的水合物晶型C的 1H NMR图谱。
图18显示了化合物1的二氯甲烷溶剂化物晶型D的 1H NMR图谱。
图19显示了化合物1的异丙醇溶剂化物晶型E的 1H NMR图谱。
图20显示了分别将化合物1的水合物晶型B置于氮气保护下加热至不同温度(分别为130℃、180℃)并降温后的XRPD图谱对比。
图21显示了分别将化合物1的水合物晶型C置于氮气保护下加热至不同温度(分别为130℃、160℃)并降温后的XRPD图谱对比。
图22显示了分别将化合物1的二氯甲烷溶剂化物晶型D置于氮气保护下加热至不同温度(分别为100℃、160℃)并降温后的XRPD图谱对比。
图23显示了分别将化合物1的异丙醇溶剂化物晶型E置于氮气保护下加热至不同温度(分别为96℃、180℃)并降温后的XRPD图谱对比。
发明详述
本申请中所述的化合物1为公开号为WO2020094018的PCT专利申请中记载的实施例六化合物6，其合成详细描述于该PCT专利申请的实施例六中。在本申请中所述的化合物1也涵盖化合物1的所有互变异构形式和同位素取代形式。
在本申请的说明书和权利要求书中，除非另有说明，否则本申请中使用的科学和技术名词具有本领域技术人员所通常理解的含义。然而，为了更好地理解本发明，下面提供了部分相关术语的定义和解释。另外，当本申请所提供的术语的定义和解释与本领域技术人员所通常理解的含义不一致时，以本申请所提供的术语的定义和解释为准。
定义
除非上下文另有说明，否则在整个说明书和权利要求书中，术语“包含”或“包括”应以开放的含义来理解，即“包括但不限于”。
本申请所用的术语“溶剂化物”是指由化合物1与溶剂组合所形成的复合物，其包含化学计量的或非化学计量的溶剂。如果溶剂为水，则所述溶剂化物为水合物。可形成溶剂化物的溶剂的例子包括但不限于水、异丙醇、二氯甲烷、甲醇、乙醇、乙酸乙酯等。
本申请中使用的术语“药学上可接受的”是指这样的化合物、材料、组合物和/或剂型：其在合理的医学判断范围内适合用于与人和动物的组织接触而无过多毒性、刺激性、过敏反应或其他问题或并发症，与合理的利益/风险比相称。
本申请中使用的术语“药学上可接受的载体”是指药学上可接受的材料、组合物或媒介物，例如液体或固体填充剂、稀释剂、赋形剂、溶剂或包封材料，其涉及将治疗剂(例如，化合物1及其各种晶型)从一个位置、体液、组织、器官(内部或外部)或身体的一部分携带或运输至另一个位置、体液、组织、器官或身体的一部分，而不干扰治疗剂的结构和性质。药学上可接受的载体可以是媒介物、稀释剂、赋形剂或可用于接触动物的组织而无过多毒性或副作用的其他材料。某些此类载体能使治疗剂(例如，化合物1及其各种晶型)配制成例如片剂、丸剂、胶囊、液体、凝胶剂、糖浆剂、浆液、混悬液和锭剂以给给药对象口服摄入。某些此类载体能使治疗剂(例如，化合物1及其各种晶型)配制成注射、输注或局部给药。示例性的药学上可接受的载体包括糖、淀粉、纤维素、麦芽、黄蓍胶、明胶、林格氏溶液、海藻酸、等渗盐水、缓冲剂等。可用于本申请的药学上可接受的载体包括本领域通常已知的载体，例如在“Remington Pharmaceutical Sciences”Mack Pub.Co.,New Jersey(1991)中公开的载体，该文章通过引入并入本文。
本申请中使用的术语“施用”是指将治疗剂(例如，化合物1及其各种晶型)引入患者体内。当术语“施用”与化合物或药物组合物联用时，是指直接施用和/或间接施用，所述直接施用可以通过医疗专业人员给患者施用或患者自己施用，所述间接施用可以是开药物处方的行为。例如，医师指示患者自己施用药物和/或给患者提供药物的处方为给患者施用所述药物。在任何情况下，施用需要将药物递送给患者。
本申请中使用的术语“有效量”或“治疗有效量”是指可以实现抑制或缓解受试者或患者的疾病或症状，或者可以预防性地抑制或防止疾病或症状发生的药物的量。治疗有效量可以是将受试者或患者的一种或多种疾病或症状缓解到一定程度的药物的量；可以将那些跟疾病或症状成因相关的一种或多种生理或生物化学参数部分或完全恢复到正常的药物的量；和/或可以降低疾病或症状发生的可能性的药物的量。
本申请中使用的术语“受试者”或“患者”是指已经是或将要是治疗、观察或实验对象的动物，包括人类和非人类的动物。非人类的动物包括所有的脊椎动物，例如哺乳动物和非哺乳动物。“受试者”或“患者”也可以是家畜动物，例如牛、猪、羊、家禽和马；或啮齿类动物，例如大鼠、小鼠；或灵长类动物，例如猿、猴子；或家养动物，例如狗和猫。在一些实施方案中，所述受试者或患者是人。“有此需要的受试者”是指可能患有或怀疑患有将受益于某些治疗的疾病或病症的受试者。
就化合物的特定晶型而言，在某些实施方式中，本申请中使用的术语“基本上纯的”是指包含该晶型的组合物含有小于99％、小于95％、小于90％、小于85％、小于80％、小于75％、小于70％、小于65％、小于60％、小于55％、小于50％、小于45％、小于40％、小于35％、小于30％、小于25％、小于20％、小于15％、小于10％、小于9％、小于8％、小于7％、小于6％、小于5％、小于4％、小于3％、小于2％、小于1％重量的其他物质，所述其他物质包括其他晶型和/或杂质，例如，杂质可能包括副产物、反应起始物质、来自化学反应的试剂、污染物、降解产物、水或溶剂等。
本申请中使用的术语“多晶型物”是指化合物可以结晶的(溶剂化或非溶剂化形式的)不同晶体结构。例如，本申请中的化合物1可以结晶形成不同晶体结构，即为多晶型物。
本申请中使用的术语“C 1-6烷基”是指直链或支链的含有1-6个碳原子的烷基，具体实例包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1,2-二甲基丙基等。
本申请中使用的术语“羟基”是指-OH等基团。
本申请中使用的术语“醚类溶剂”是指含有醚键-O-且碳原子数为1至10个的链状化合物或环状化合物，具体实例包括但不限于：四氢呋喃、乙醚、丙二醇甲醚、甲基叔丁基醚或1,4-二氧六环。
本申请中使用的术语“醇类溶剂”是指一个或多个“羟基”取代“C 1-6烷基”上的一个或多个氢原子所衍生的基团，所述“羟基”和“C 1-6烷基”如前文所定义，具体实例包括但不限于：甲醇、乙醇、异丙醇、正丙醇、异戊醇或三氟乙醇。
本申请中使用的术语“酯类溶剂”是指含碳原子数为1至4个的低级有机酸与含碳原子数为1至6个的低级醇的结合物，具体实例包括但不限于：乙酸乙酯、乙酸异丙酯或乙酸丁酯。
本申请中使用的术语“混合溶剂”是指一种或多种不同种类的有机溶剂按照一定比例混合而成的溶剂，或有机溶剂与水按照一定比例混合而成的溶剂。所述混合溶剂可以为醇类与醚类的混合溶剂。所述醇类与醚类的混合溶剂可以为甲醇与乙醚的混合溶剂。
本申请中使用的术语“X-射线粉末衍射图谱”或“XRPD”为在x-轴上具有衍射角(即°2θ)并在y-轴上具有强度的x-y图。这种图谱中的峰可以用于表征晶体固态形态。在任何数据测量结果的情况下，XRPD数据存在可变性。数据经常唯一地由峰的衍射角来表示，而不包括峰的强度，因为峰的强度可能对样品的制备特别敏感(例如，粒径、水分含量、溶剂含量和优选的取向效果影响敏感性)，因此在不同条件下制备的相同材料的样品可能产生略微不同的图谱；这一可变性通常大于衍射角的可变性。衍射角的可变性也可以对样品的制备敏感。其他可变性的来源来自仪器参数和对原始X-射线数据的处理：不同的X-射线仪器操作使用不同的参数并且这些可能导致与相同的固体形态略微不同的XRPD图谱，并且类似地，不同软件包以不同方式处理X-射线数据并且这也导致可变性。可变性的这些和其他的来源对药学领域中的技术人员来说是已知的。由于该可变性的来源，通常对XRPD图谱中的衍射角分配±0.3°2θ的可变性。例如，在本申请中，当提及2θ角度时使用的“约”是指在提及的数值基础上可以有±0.3°的误差，例如，可以为-0.30°、-0.29°、-0.28°、-0.27°、-0.26°、-0.25°、-0.24°、-0.23°、-0.22°、-0.21°、-0.20°、-0.19°、-0.18°、-0.17°、-0.16°、-0.15°、-0.14°、-0.13°、-0.12°、-0.11°、-0.10°、-0.09°、-0.08°、-0.07°、-0.06°、-0.05°、-0.04°、-0.03°、-0.02°、-0.01°、0.00°、0.01°、0.02°、0.03°、0.04°、0.05°、0.06°、0.07°、0.08°、0.09°、0.10°、0.11°、0.12°、0.13°、0.14°、0.15°、0.16°、0.17°、0.18°、0.19°、0.20°、 0.21°、0.22°、0.23°、0.24°、0.25°、0.26°、0.27°、0.28°、0.29°、0.30°，优选为±0.2°。
本申请中使用的术语“晶面间距”或“d值”是指空间点阵选择3个不相平行的连结相邻两个点阵点的单位矢量a，b，c，它们将点阵划分成并置的平行六面体单位，称为晶面间距。空间点阵按照确定的平行六面体单位连线划分，获得一套直线网格，称为空间格子或晶格。点阵和晶格是分别用几何的点和线反映晶体结构的周期性，不同的晶面，其面间距各不相同，单位为
Figure PCTCN2021100673-appb-000002
或埃。
本申请中使用的术语“差示扫描量热”或“DSC”是指在样品升温或恒温过程中，测量样品与参考物之间的温度差、热流差，以表征所有与热效应有关的物理变化和化学变化，得到样品的相变信息。
本申请中使用的术语“热重分析”或“TGA”是指在程序控制温度下，测量物质的质量与温度或时间的关系的方法。通过分析热重曲线，可以知道样品及其可能产生的中间产物的组成、热稳定性、热分解情况及生成的产物等与质量相联系的信息。
在本申请中，当提及图谱(例如，XRPD图谱、DSC图谱、TGA图谱、HPLC图谱、 1H NMR图谱、DVS图谱等)时，使用的术语“实质上类似于”或者“基本上如…所示”是指图谱的基本特征信息或主要特征信息(例如，主峰位置、强度等)与所提及的图谱所描绘的信息一致，而不要求图谱的所有特征均与所提及的图谱所描绘的信息完全一致。
发明内容
在一个方面，本申请提供一种式(I)所示的化合物1(即，(S)-1’-(8-((2-氨基-3-氯吡啶-4-基)硫代)咪唑并[1,2-c]嘧啶-5-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4’-哌啶]-5-胺)的晶型A、化合物1的水合物晶型B和水合物晶型C、化合物1的二氯甲烷溶剂化物晶型D以及化合物1的异丙醇溶剂化物晶型E。
Figure PCTCN2021100673-appb-000003
晶型A
在一个方面，本申请提供化合物1的晶型A。在某些实施方式中，本申请提供了基本上纯的化合物1的晶型A。在某些实施方式中，化合物1具有非溶剂化晶体形式，例如，所述晶型A是化合物1的无水合物晶型。
在某些实施方式中，所述晶型A的XRPD图谱具有一个或多个(例如，两个、三个)选自下组的峰：约6.46°、约12.64°和约12.93°2θ。例如，所述晶型A的XRPD图谱在约6.46°2θ处具有峰。又例如，所述晶型A的XRPD图谱在约12.64°2θ处具有峰。又例如，所述晶型A的XRPD图谱在约12.93°2θ处具有峰。又例如，所述晶型A的XRPD图谱在约6.46°2θ和约12.64°2θ处具有峰。又例如，所述晶型A的XRPD图谱在约6.46°2θ和约12.93°2θ处具有峰。又例如，所述晶型A的XRPD图谱在约12.64°2θ和约12.93°2θ处具有峰。在某些实施方式中，所述晶型A的XRPD图谱具有所有选自下组的峰：约6.46°、约12.64°和约12.93°2θ。
在某些实施方式中，所述晶型A的XRPD图谱还具有一个或多个(例如，2个、3个、4个、5个、6个)选自下组的峰：约13.50°、约14.60°、约16.49°、约17.66°、约18.27°和约23.04°2θ。例如，所述晶型A的XRPD图谱还在约13.50°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约14.60°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约16.49°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约17.66°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约18.27°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约23.04°2θ处具有峰。
在某些实施方式中，所述晶型A的XRPD图谱还具有两个或更多个(例如，3个、4个、5个、6个)选自下组的峰：约13.50°、约14.60°、约16.49°、约17.66°、约18.27°和约23.04°2θ。例如，所述晶型A的XRPD图谱还在约13.50° 2θ和约14.60°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约13.50°2θ和约16.49°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约13.50°2θ和约17.66°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约13.50°2θ和约18.27°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约13.50°2θ和约23.04°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约14.60°2θ和约16.49°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约14.60°2θ和约17.66°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约14.60°2θ和约18.27°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约14.60°2θ和约23.04°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约16.49°2θ和约17.66°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约16.49°2θ和约18.27°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约16.49°2θ和约23.04°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约17.66°2θ和约18.27°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约17.66°2θ和约23.04°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约18.27°2θ和约23.04°2θ处具有峰。
在某些实施方式中，所述晶型A的XRPD图谱还具有三个或更多个(例如，4个、5个、6个)选自下组的峰：约13.50°、约14.60°、约16.49°、约17.66°、约18.27°和约23.04°2θ。例如，所述晶型A的XRPD图谱还在约13.50°2θ、约14.60°2θ和约16.49°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约13.50°2θ、约14.60°2θ和约17.66°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约13.50°2θ、约14.60°2θ和约18.27°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约13.50°2θ、约14.60°2θ和约23.04°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约13.50°2θ、约16.49°2θ和约17.66°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约13.50°2θ、约16.49°2θ和约18.27°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约13.50°2θ、约16.49°2θ和约23.04°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约13.50°2θ、约17.66°°2θ和约18.27°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约13.50°2θ、约17.66°2θ和约23.04°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约13.50°2θ、约18.27°2θ和约23.04°2θ处具有峰。又例 如，所述晶型A的XRPD图谱还在约14.60°2θ、约16.49°2θ和约17.66°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约14.60°2θ、约16.49°2θ和约18.27°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约14.60°2θ、约16.49°2θ和约23.04°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约14.60°2θ、约17.66°2θ和约18.27°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约14.60°2θ、约17.66°2θ和约23.04°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约14.60°2θ、约18.27°2θ和约23.04°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约16.49°2θ、约17.66°2θ和约18.27°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约16.49°2θ、约17.66°2θ和约23.04°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约17.66°2θ、约18.27°2θ和约23.04°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约16.49°2θ、约18.27°2θ和约23.04°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约17.66°2θ、约18.27°2θ和约23.04°2θ处具有峰。
在某些实施方式中，所述晶型A的XRPD图谱还具有所有选自下组的峰：约13.50°、约14.60°、约16.49°、约17.66°、约18.27°和约23.04°2θ。
在某些实施方式中，所述晶型A的XRPD图谱还具有一个或多个(例如，2个、3个、4个)选自下组的峰：约23.61°、约25.42°、约25.79°和约27.83°2θ。例如，所述晶型A的XRPD图谱还在约23.61°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约25.42°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约25.79°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约27.83°2θ处具有峰。
在某些实施方式中，所述晶型A的XRPD图谱还具有两个或更多个(例如，3个、4个)选自下组的峰：约23.61°、约25.42°、约25.79°和约27.83°2θ。例如，所述晶型A的XRPD图谱还在约23.61°2θ和约25.42°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约23.61°2θ和约25.79°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约23.61°2θ和约27.83°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约25.42°2θ和约25.79°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约25.42°2θ和约27.83°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约25.79°2θ和约27.83°2θ处具有峰。
在某些实施方式中，所述晶型A的XRPD图谱还具有三个或更多个(例如，4个)选自下组的峰：约23.61°、约25.42°、约25.79°和约27.83°2θ。例如，所述晶型A的XRPD图谱还在约23.61°2θ、约25.42°2θ和约25.79°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约23.61°2θ、约25.42°2θ和约27.83°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约25.42°2θ、约25.79°2θ和约27.83°2θ处具有峰。又例如，所述晶型A的XRPD图谱还在约23.61°2θ、约25.79°2θ和约27.83°2θ处具有峰。
在某些实施方式中，所述晶型A的XRPD图谱还具有所有选自下组的峰：约23.61°、约25.42°、约25.79°和约27.83°2θ。
在某些实施方式中，所述晶型A的XRPD图谱具有所有选自下组的峰：
Figure PCTCN2021100673-appb-000004
在某些实施方式中，所述晶型A的XRPD图谱实质上类似于图1中所描绘的XRPD图谱。在某些实施方式中，所述晶型A的XRPD图谱如图1所示。在某些实施方式中，所述晶型A具有以最大强度显示至少2个、至少3个、至少4个、至少5个、至少6个、至少7个、至少8个、至少9个、至少10个、至少11个、至少12个、至少13个2θ角度的XRPD图谱。
在某些实施方式中，所述晶型A的DSC图谱包括于约262.0℃(峰值温度)处的吸热峰。在某些实施方式中，所述晶型A的DSC图谱还包括于约153.7℃(峰值温度)处的放热峰。在某些实施方式中，所述晶型A的DSC图谱实质上类似于图2所描绘的DSC图谱。在某些实施方式中，所述晶型A的DSC图谱如图2所示。
在某些实施方式中，所述晶型A的TGA图谱显示，加热至约120℃，样品失重为约1.5％～2.0％，例如，约1.5％、约1.6％、约1.61％、约1.62％、约1.63％、约1.64％、约1.65％、约1.66％、约1.67％、1.68％、约1.69％、约1.70％、约1.71％、约1.72％、约1.8％、约1.9％、约2.0％。在某些实施方式中，所述晶型A的TGA图谱显示，加热至120℃，样品失重为约1.69％。在某些实施方式中，所述晶型A的TGA图谱实质上类似于图2所描绘的TGA图谱。在某些实施方式中，所述晶型A的TGA图谱如图2所示。
在某些实施方式中，所述晶型A适用以下(a)～(c)中的至少一项、两项或三项：
(a)所述晶型A具有基本上如图1所示的XRPD图谱；
(b)所述晶型A具有基本上如图2所示的DSC图谱；
(c)所述晶型A具有基本上如图2所示的TGA图谱。
在某些实施方式中，所述晶型A基本上具有以下特征：
(a)所述晶型A具有基本上如图1所示的XRPD图谱；
(b)所述晶型A具有基本上如图2所示的DSC图谱；和
(c)所述晶型A具有基本上如图2所示的TGA图谱。
在某些实施方式中，所述晶型A是基本上纯的，例如，所述晶型A的纯度大于90wt％、大于91wt％、大于92wt％、大于93wt％、大于94wt％、大于95wt％、大于96wt％、大于97wt％、大于98wt％或大于99wt％。在某些实施方式中，所述晶型A的纯度通过高效液相色谱法(HPLC)测定。例如，相对于HPLC色谱图的总面积，化合物1含有不大于约5.0面积百分比HPLC的总有机杂质；在某些实施方式中，含有不大于约3.0面积百分比HPLC的总有机杂质；在某些实施方式中，含有不大于约1.5面积百分比HPLC的总有机杂质。在其它实施方式中，相对于HPLC色谱图的总面积，化合物1含有不大于约1.0面积百分比HPLC的任何单一杂质；不大于约0.6面积百分比HPLC的任何单一杂质；在某些实施方式中，不大于约0.5面积百分比HPLC的任何单一杂质。
在某些实施方式中，所述晶型A在60℃/闭口条件下放置24小时后的HPLC纯度相对于晶型A的起始HPLC纯度的比例大于99％，例如大于99.1％、99.2％、99.3％、99.4％、99.5％、99.6％、99.7％、99.8％、99.9％或者更高。
在某些实施方式中，所述晶型A在25℃/60％RH条件下敞口放置1周后的HPLC纯度相对于晶型A的起始HPLC纯度的比例大于99％，例如大于99.1％、99.2％、99.3％、99.4％、99.5％、99.6％、99.7％、99.8％、99.9％或者更高。
在某些实施方式中，所述晶型A在40℃/75％RH条件下敞口放置1周后的HPLC纯度相对于晶型A的起始HPLC纯度的比例大于99％，例如大于99.1％、99.2％、99.3％、99.4％、99.5％、99.6％、99.7％、99.8％、99.9％或者更高。
晶型B
在一个方面，本申请提供化合物1的晶型B。在某些实施方式中，本申请提供了基本上纯的化合物1的晶型B。在某些实施方式中，所述晶型B是化合物1的水合物结晶形式。
在某些实施方式中，所述晶型B的XRPD图谱具有一个或多个(例如，两个、三个)选自下组的峰：约7.36°、约10.82°和约11.10°2θ。例如，所述晶型B的XRPD图谱在约7.36°2θ处具有峰。又例如，所述晶型B的XRPD图谱在约10.82°2θ处具有峰。又例如，所述晶型B的XRPD图谱在约11.10°2θ处具有峰。又例如，所述晶型B的XRPD图谱在约7.36°2θ和约10.82°2θ处具有峰。又例如，所述晶型B的XRPD图谱在约7.36°2θ和约11.10°2θ处具有峰。又例如，所述晶型B的XRPD图谱在约10.82°2θ和约11.10°2θ处具有峰。在某些实施方式中，所述晶型B的XRPD图谱具有所有选自下组的峰：约7.36°、约10.82°和约11.10°2θ。
在某些实施方式中，所述晶型B的XRPD图谱还具有一个或多个(例如，2个、3个、4个)选自下组的峰：约14.70°、约15.99°、约20.96°和约23.78°2θ。例如，所述晶型B的XRPD图谱还在约14.70°2θ处具有峰。又例如，所述晶型B的XRPD图谱还在约15.99°2θ处具有峰。又例如，所述晶型B的XRPD图谱还在约20.96°2θ处具有峰。又例如，所述晶型B的XRPD图谱还在约23.78°2θ处具有峰。
在某些实施方式中，所述晶型B的XRPD图谱还具有两个或更多个(例如，3个、4个)选自下组的峰：约14.70°、约15.99°、约20.96°和约23.78°2θ。例如，所述晶型B的XRPD图谱还在约14.70°2θ和约15.99°2θ处具有峰。又例如，所述晶型B的XRPD图谱还在约14.70°2θ和约20.96°2θ处具有峰。又例如，所述晶型B的XRPD图谱还在约14.70°2θ和约23.78°2θ处具有峰。又例如，所述晶型B的XRPD图谱还在约15.99°2θ和约20.96°2θ处具有峰。又例如，所述晶型B的XRPD图谱还在约15.99°2θ和约23.78°2θ处具有峰。又例如，所述晶型B的XRPD图谱还在约20.96°2θ和约23.78°2θ处具有峰。
在某些实施方式中，所述晶型B的XRPD图谱还具有三个或更多个(例如，4个)选自下组的峰：约14.70°、约15.99°、约20.96°和约23.78°2θ。例如，所述晶型B的XRPD图谱还在约14.70°、约15.99°和约20.96°2θ处具有峰。又例如，所述晶型B的XRPD图谱还在约14.70°2θ、约15.99°2θ和约23.78°2θ处具有峰。又例如，所述晶型B的XRPD图谱还在约14.70°2θ、约20.96°2θ和约23.78°2θ处具有峰。又例如，所述晶型B的XRPD图谱还在约15.99°2θ、约20.96°2θ和约23.78°2θ处具有峰。
在某些实施方式中，所述晶型B的XRPD图谱还具有所有选自下组的峰：约14.70°、约15.99°、约20.96°和约23.78°2θ。
在某些实施方式中，所述晶型B的XRPD图谱具有所有选自下组的峰：
Figure PCTCN2021100673-appb-000005
在某些实施方式中，所述晶型B的XRPD图谱实质上类似于图3中所描绘的XRPD图谱。在某些实施方式中，所述晶型B的XRPD图谱如图3所示。在某些实施方式中，所述晶型B具有以最大强度显示至少2个、至少3个、至少4个、至少5个、至少6个、至少7个、至少8个、至少9个、至少10个、至少 11个、至少12个、至少13个2θ角度的XRPD图谱。在某些实施方式中，所述晶型B的DSC图谱包括于约113.5℃(峰值温度)和约266.8℃(峰值温度)处的吸热峰。在某些实施方式中，所述晶型B的DSC图谱还包括于约161.8℃(峰值温度)处的放热峰。在某些实施方式中，所述晶型B的DSC图谱实质上类似于图4所描绘的DSC图谱。在某些实施方式中，所述晶型B的DSC图谱如图4所示。
在某些实施方式中，所述晶型B的TGA图谱显示，加热至120℃，样品失重为约10％～14％，例如，约10％、约11％、约12％、约12.1％、约12.2％、约12.3％、约12.4％、约12.5％、约12.6％、约12.7％、约12.75％、约12.8％、约12.9％、约13％、约14％。在某些实施方式中，所述晶型B的TGA图谱显示，加热至120℃，样品失重为约12.75％。在某些实施方式中，所述晶型B的TGA图谱实质上类似于图4所描绘的TGA图谱。在某些实施方式中，所述晶型B的TGA图谱如图4所示。在某些实施方式中，在所述晶型B中水分子与化合物1的摩尔比为约3.9:1，例如，3:1、3.1:1、3.2:1、3.3:1、3.4:1、3.5:1、3.6:1、3.7:1、3.8:1、3.9:1、4:1、4.1:1、4.2:1、4.3:1、4.4:1、4.5:1、4.6:1、4.7:1、4.8:1、4.9:1、或5:1，或者以上任意比例范围之间的任意比例。
在某些实施方式中，所述晶型B的 1H NMR图谱基本上类似于图16所示的 1H NMR图谱。在某些实施方式中，所述晶型B的 1H NMR图谱如图16所示。
在某些实施方式中，所述晶型B适用以下(a)～(d)中的至少一项、两项、三项或四项：
(a)所述晶型B具有基本上如图3所示的XRPD图谱；
(b)所述晶型B具有基本上如图4所示的DSC图谱；
(c)所述晶型B具有基本上如图4所示的TGA图谱；
(d)所述晶型B具有基本上如图16所示的 1H NMR图谱。
在某些实施方式中，所述晶型B基本上具有以下特征：
(a)所述晶型B具有基本上如图3所示的XRPD图谱；
(b)所述晶型B具有基本上如图4所示的DSC图谱；和
(c)所述晶型B具有基本上如图4所示的TGA图谱。
在某些实施方式中，所述晶型B基本上具有以下特征：
(a)所述晶型B具有基本上如图3所示的XRPD图谱；
(b)所述晶型B具有基本上如图4所示的DSC图谱；
(c)所述晶型B具有基本上如图4所示的TGA图谱；和
(d)所述晶型B具有基本上如图16所示的 1H NMR图谱。
在某些实施方式中，所述晶型B是基本上纯的，例如，所述晶型B的纯度大于90wt％、大于91wt％、大于92wt％、大于93wt％、大于94wt％、大于95wt％、大于96wt％、大于97wt％、大于98wt％或大于99wt％。在某些实施方式中，所述晶型B的纯度通过高效液相色谱法(HPLC)测定。例如，相对于HPLC色谱图的总面积，化合物1含有不大于约5.0面积百分比HPLC的总有机杂质；在某些实施方式中，含有不大于约3.0面积百分比HPLC的总有机杂质；在某些实施方式中，含有不大于约1.5面积百分比HPLC的总有机杂质。在其它实施方式中，相对于HPLC色谱图的总面积，化合物1含有不大于约1.0面积百分比HPLC的任何单一杂质；不大于约0.6面积百分比HPLC的任何单一杂质；在某些实施方式中，不大于约0.5面积百分比HPLC的任何单一杂质。
晶型C
在一个方面，本申请提供化合物1的晶型C。在某些实施方式中，本申请提供了基本上纯的化合物1的晶型C。在某些实施方式中，所述晶型C是化合物1的水合物结晶形式。
在某些实施方式中，所述晶型C的XRPD图谱具有一个或多个(例如，两个、三个)选自下组的峰：约7.33°、约11.08°和约14.70°2θ。例如，所述晶型C的XRPD图谱在约7.33°2θ处具有峰。又例如，所述晶型C的XRPD图谱在约11.08°2θ处具有峰。又例如，所述晶型C的XRPD图谱在约14.70°2θ处具有峰。又例如，所述晶型C的XRPD图谱在约7.33°2θ和约11.08°2θ处具有峰。 又例如，所述晶型C的XRPD图谱在约7.33°2θ和约14.70°2θ处具有峰。又例如，所述晶型C的XRPD图谱在约11.08°2θ和约14.70°2θ处具有峰。在某些实施方式中，所述晶型C的XRPD图谱具有所有选自下组的峰：约7.33°、约11.08°和约14.70°2θ。
在某些实施方式中，所述晶型C的XRPD图谱还具有一个或多个(例如，2个、3个、4个、5个)选自下组的峰：约16.23°、约18.85°、约21.20°、约22.03°和约24.33°2θ。例如，所述晶型C的XRPD图谱还在约16.23°2θ处具有峰。又例如，所述晶型C的XRPD图谱还在约18.85°2θ处具有峰。又例如，所述晶型C的XRPD图谱还在约21.20°2θ处具有峰。又例如，所述晶型C的XRPD图谱还在约22.03°2θ处具有峰。又例如，所述晶型C的XRPD图谱还在约24.33°2θ处具有峰。
在某些实施方式中，所述晶型C的XRPD图谱还具有两个或更多个(例如，3个、4个、5个)选自下组的峰：约16.23°、约18.85°、约21.20°、约22.03°和约24.33°2θ。例如，所述晶型C的XRPD图谱还在约16.23°2θ和约18.85°2θ处具有峰。又例如，所述晶型C的XRPD图谱还在约16.23°2θ和约21.20°2θ处具有峰。又例如，所述晶型C的XRPD图谱还在约16.23°2θ和约22.03°2θ处具有峰。又例如，所述晶型C的XRPD图谱还在约16.23°2θ和约24.33°2θ处具有峰。又例如，所述晶型C的XRPD图谱还在约18.85°2θ和约21.20°2θ处具有峰。又例如，所述晶型C的XRPD图谱还在约18.85°2θ和约22.03°2θ处具有峰。又例如，所述晶型C的XRPD图谱还在约18.85°2θ和约24.33°2θ处具有峰。又例如，所述晶型C的XRPD图谱还在约21.20°2θ和约22.03°2θ处具有峰。又例如，所述晶型C的XRPD图谱还在约21.20°2θ和约24.33°2θ处具有峰。又例如，所述晶型C的XRPD图谱还在约22.03°2θ和约24.33°2θ处具有峰。
在某些实施方式中，所述晶型C的XRPD图谱还具有三个或更多个(例如，4个、5个)选自下组的峰：约16.23°、约18.85°、约21.20°、约22.03°和约24.33°2θ。例如，所述晶型C的XRPD图谱还在约16.23°2θ、约18.85°2θ和约21.20°2θ处具有峰。又例如，所述晶型C的XRPD图谱还在约16.23°2θ、约18.85°2θ和约22.03°2θ处具有峰。又例如，所述晶型C的XRPD图谱还在约16.23°2θ、 约18.85°2θ和约24.33°2θ处具有峰。又例如，所述晶型C的XRPD图谱还在约16.23°2θ、约21.20°2θ和约22.03°2θ处具有峰。又例如，所述晶型C的XRPD图谱还在约16.23°2θ、约21.20°2θ和约24.33°2θ处具有峰。又例如，所述晶型C的XRPD图谱还在约16.23°2θ、约22.03°2θ和约24.33°2θ处具有峰。又例如，所述晶型C的XRPD图谱还在约18.85°2θ、约21.20°2θ和约22.03°2θ处具有峰。又例如，所述晶型C的XRPD图谱还在约18.85°2θ、约21.20°2θ和约24.33°2θ处具有峰。又例如，所述晶型C的XRPD图谱还在约21.20°2θ、约22.03°2θ和约24.33°2θ处具有峰。又例如，所述晶型C的XRPD图谱还在约18.85°2θ、约22.03°2θ和约24.33°2θ处具有峰。
在某些实施方式中，所述晶型C的XRPD图谱还具有所有选自下组的峰：约16.23°、约18.85°、约21.20°、约22.03°和约24.33°2θ。
在某些实施方式中，所述晶型C的XRPD图谱还具有一个或多个(例如，2个、3个、4个)选自下组的峰：约15.20°、约20.05°、约23.70°和约29.13°2θ。例如，所述晶型C的XRPD图谱还在约15.20°2θ处具有峰。又例如，所述晶型C的XRPD图谱还在约20.05°2θ处具有峰。又例如，所述晶型C的XRPD图谱还在约23.70°2θ处具有峰。又例如，所述晶型C的XRPD图谱还在约29.13°2θ处具有峰。
在某些实施方式中，所述晶型C的XRPD图谱还具有两个或更多个(例如，3个、4个)选自下组的峰：约15.20°、约20.05°、约23.70°和约29.13°2θ。例如，所述晶型C的XRPD图谱还在约15.20°2θ和约20.05°2θ处具有峰。又例如，所述晶型C的XRPD图谱还在约15.20°2θ和约23.70°2θ处具有峰。又例如，所述晶型C的XRPD图谱还在约15.20°2θ和约29.13°2θ处具有峰。又例如，所述晶型C的XRPD图谱还在约20.05°2θ和约23.70°2θ处具有峰。又例如，所述晶型C的XRPD图谱还在约20.05°2θ和约29.13°2θ处具有峰。又例如，所述晶型C的XRPD图谱还在约23.70°2θ和约29.13°2θ处具有峰。
在某些实施方式中，所述晶型C的XRPD图谱还具有三个或更多个(例如，4个)选自下组的峰：约15.20°、约20.05°、约23.70°和约29.13°2θ。例如，所述晶型C的XRPD图谱还在约15.20°2θ、约20.05°2θ和约23.70°2θ处具有峰。 又例如，所述晶型C的XRPD图谱还在约15.20°2θ、约20.05°2θ和约29.13°2θ处具有峰。又例如，所述晶型C的XRPD图谱还在约20.05°2θ、约23.70°2θ和约29.13°2θ处具有峰。又例如，所述晶型C的XRPD图谱还在约15.20°2θ、约23.70°2θ和约29.13°2θ处具有峰。
在某些实施方式中，所述晶型C的XRPD图谱还具有所有选自下组的峰：约15.20°、约20.05°、约23.70°和约29.13°2θ。
在某些实施方式中，所述晶型C的XRPD图谱具有所有选自下组的峰：
Figure PCTCN2021100673-appb-000006
在某些实施方式中，所述晶型C的XRPD图谱实质上类似于图5中所描绘的XRPD图谱。在某些实施方式中，所述晶型C的XRPD图谱如图5所示。在某些实施方式中，所述晶型C具有以最大强度显示至少2个、至少3个、至少4个、至少5个、至少6个、至少7个、至少8个、至少9个、至少10个、至少11个、至少12个、至少13个2θ角度的XRPD图谱。在某些实施方式中，所述晶型C的DSC图谱包括于约117.2℃(峰值温度)和约265.6℃(峰值温度)处的吸热峰。在某些实施方式中，所述晶型C的DSC图谱还包括于约46.4℃(峰值温度)处的吸热峰。在某些实施方式中，所述晶型C的DSC图谱还包括于约147.0℃(峰值温度)处的放热峰。在某些实施方式中，所述晶型C的DSC图谱实质上类似于图6所描绘的DSC图谱。在某些实施方式中，所述晶型C的DSC图谱如图6所示。
在某些实施方式中，所述晶型C的TGA图谱显示，加热至120℃，样品失重为约10％～14％，例如，约10％、约11％、约11.5％、约12％、约12.1％、约 12.2％、约12.3％、约12.4％、约12.5％、约12.6％、约12.7％、约12.8％、约12.9％、约13％、约13.5％、约14％。在某些实施方式中，所述晶型C的TGA图谱显示，加热至120℃，样品失重为约12.23％。在某些实施方式中，所述晶型C的TGA图谱实质上类似于图6所描绘的TGA图谱。在某些实施方式中，所述晶型C的TGA图谱如图6所示。在某些实施方式中，在所述晶型C中水分子与化合物1的摩尔比为约3.7:1，例如，3:1、3.1:1、3.2:1、3.3:1、3.4:1、3.5:1、3.6:1、3.7:1、3.8:1、3.9:1、4:1、4.1:1、4.2:1、4.3:1、4.4:1、4.5:1、4.6:1、4.7:1、4.8:1、4.9:1、或5:1。
在某些实施方式中，所述晶型C的 1H NMR图谱实质上类似于图17所示的 1H NMR图谱。在某些实施方式中，所述晶型C的 1H NMR图谱如图17所示。
在某些实施方式中，所述晶型C适用以下(a)～(d)中的至少一项、两项、三项或四项：
(a)所述晶型C具有基本上如图5所示的XRPD图谱；
(b)所述晶型C具有基本上如图6所示的DSC图谱；
(c)所述晶型C具有基本上如图6所示的TGA图谱；
(d)所述晶型C具有基本上如图17所示的 1H NMR图谱。
在某些实施方式中，所述晶型C基本上具有以下特征：
(a)所述晶型C具有基本上如图5所示的XRPD图谱；
(b)所述晶型C具有基本上如图6所示的DSC图谱；和
(c)所述晶型C具有基本上如图6所示的TGA图谱。
在某些实施方式中，所述晶型C基本上具有以下特征：
(a)所述晶型C具有基本上如图5所示的XRPD图谱；
(b)所述晶型C具有基本上如图6所示的DSC图谱；
(c)所述晶型C具有基本上如图6所示的TGA图谱；和
(d)所述晶型C具有基本上如图17所示的 1H NMR图谱。
在某些实施方式中，所述晶型C是基本上纯的，例如，所述晶型C的纯度大于90wt％、大于91wt％、大于92wt％、大于93wt％、大于94wt％、大于95wt％、大于96wt％、大于97wt％、大于98wt％或大于99wt％。在某些实施方式中，所述晶型C的纯度通过高效液相色谱法(HPLC)测定。例如，相对于HPLC色谱图的总面积，化合物1含有不大于约5.0面积百分比HPLC的总有机杂质；在某些实施方式中，含有不大于约3.0面积百分比HPLC的总有机杂质；在某些实施方式中，含有不大于约1.5面积百分比HPLC的总有机杂质。在其它实施方式中，相对于HPLC色谱图的总面积，化合物1含有不大于约1.0面积百分比HPLC的任何单一杂质；不大于约0.6面积百分比HPLC的任何单一杂质；在某些实施方式中，不大于约0.5面积百分比HPLC的任何单一杂质。
晶型D
在一个方面，本申请提供化合物1的晶型D。在某些实施方式中，本申请提供了基本上纯的化合物1的晶型D。在某些实施方式中，所述晶型D是化合物1的溶剂化物结晶形式。在某些实施方式中，所述晶型D是化合物1的二氯甲烷溶剂化物结晶形式。
在某些实施方式中，所述晶型D的XRPD图谱具有一个或多个(例如，两个、三个)选自下组的峰：约8.24°、约13.46°和约15.32°2θ。例如，所述晶型D的XRPD图谱在约8.24°2θ处具有峰。又例如，所述晶型D的XRPD图谱在约13.46°2θ处具有峰。又例如，所述晶型D的XRPD图谱在约15.32°2θ处具有峰。又例如，所述晶型D的XRPD图谱在约8.24°2θ和约13.46°2θ处具有峰。又例如，所述晶型D的XRPD图谱在约8.24°2θ和约15.32°2θ处具有峰。又例如，所述晶型D的XRPD图谱在约13.46°2θ和约15.32°2θ处具有峰。在某些实施方式中，所述晶型D的XRPD图谱具有所有选自下组的峰：约8.24°、约13.46°和约15.32°2θ。
在某些实施方式中，所述晶型D的XRPD图谱还具有一个或多个(例如，两个、三个)选自下组的峰：约12.89°、约15.90°和约16.84°2θ。例如，所述晶型D的XRPD图谱还在约12.89°2θ处具有峰。又例如，所述晶型D的XRPD图 谱还在约15.90°2θ处具有峰。又例如，所述晶型D的XRPD图谱还在约16.84°2θ处具有峰。
在某些实施方式中，所述晶型D的XRPD图谱还具有两个或更多个(例如，三个)选自下组的峰：约12.89°、约15.90°和约16.84°2θ。例如，所述晶型D的XRPD图谱还在约12.89°2θ和约15.90°2θ处具有峰。又例如，所述晶型D的XRPD图谱还在约12.89°2θ和约16.84°2θ处具有峰。又例如，所述晶型D的XRPD图谱还在约15.90°2θ和约16.84°2θ处具有峰。在某些实施方式中，所述晶型D的XRPD图谱还具有所有选自下组的峰：约12.89°、约15.90°和约16.84°2θ。
在某些实施方式中，所述晶型D的XRPD图谱还具有一个或多个(例如，2个、3个、4个、5个)选自下组的峰：约18.45°、约21.83°、约23.08°、约23.80°和约25.59°2θ。例如，所述晶型D的XRPD图谱还在约18.45°2θ处具有峰。又例如，所述晶型D的XRPD图谱还在约21.83°2θ处具有峰。又例如，所述晶型D的XRPD图谱还在约23.08°2θ处具有峰。又例如，所述晶型D的XRPD图谱还在约23.80°2θ处具有峰。又例如，所述晶型D的XRPD图谱还在约25.59°2θ处具有峰。
在某些实施方式中，所述晶型D的XRPD图谱还具有两个或更多个(例如，3个、4个、5个)选自下组的峰：约18.45°、约21.83°、约23.08°、约23.80°和约25.59°2θ。例如，所述晶型D的XRPD图谱还在约18.45°2θ和约21.83°2θ处具有峰。又例如，所述晶型D的XRPD图谱还在约18.45°2θ和约23.08°2θ处具有峰。又例如，所述晶型D的XRPD图谱还在约18.45°2θ和约23.80°2θ处具有峰。又例如，所述晶型D的XRPD图谱还在约18.45°2θ和约25.59°2θ处具有峰。又例如，所述晶型D的XRPD图谱还在约21.83°2θ和约23.08°2θ处具有峰。又例如，所述晶型D的XRPD图谱还在约21.83°2θ和约23.80°2θ处具有峰。又例如，所述晶型D的XRPD图谱还在约21.83°2θ和约25.59°2θ处具有峰。又例如，所述晶型D的XRPD图谱还在约23.08°2θ和约23.80°2θ处具有峰。又例如，所述晶型D的XRPD图谱还在约23.08°2θ和约25.59°2θ处具有峰。又例如，所述晶型D的XRPD图谱还在约23.80°2θ和约25.59°2θ处具有峰。
在某些实施方式中，所述晶型D的XRPD图谱还具有三个或更多个(例如，4个、5个)选自下组的峰：约18.45°、约21.83°、约23.08°、约23.80°和约25.59°2θ。例如，所述晶型D的XRPD图谱还在约18.45°2θ、约21.83°2θ和约23.08°2θ处具有峰。又例如，所述晶型D的XRPD图谱还在约18.45°2θ、约21.83°2θ和约23.80°2θ处具有峰。又例如，所述晶型D的XRPD图谱还在约18.45°2θ、约21.83°2θ和约25.59°2θ处具有峰。又例如，所述晶型D的XRPD图谱还在约18.45°2θ、约23.08°2θ和约23.80°2θ处具有峰。又例如，所述晶型D的XRPD图谱还在约18.45°2θ、约23.08°2θ和约25.59°2θ处具有峰。又例如，所述晶型D的XRPD图谱还在约18.45°2θ、约23.80°2θ和约25.59°2θ处具有峰。又例如，所述晶型D的XRPD图谱还在约21.83°2θ、约23.08°2θ和约23.80°2θ处具有峰。又例如，所述晶型D的XRPD图谱还在约21.83°2θ、约23.08°2θ和约25.59°2θ处具有峰。又例如，所述晶型D的XRPD图谱还在约21.83°2θ、约23.80°2θ和约25.59°2θ处具有峰。又例如，所述晶型D的XRPD图谱还在约23.08°2θ、约23.80°2θ和约25.59°2θ处具有峰。
在某些实施方式中，所述晶型D的XRPD图谱还具有四个或更多个(例如，5个)选自下组的峰：约18.45°、约21.83°、约23.08°、约23.80°和约25.59°2θ。例如，所述晶型D的XRPD图谱还在约18.45°2θ、约21.83°2θ、约23.08°2θ和约23.80°2θ处具有峰。又例如，所述晶型D的XRPD图谱还在约18.45°2θ、约21.83°2θ、约23.08°2θ和约25.59°2θ处具有峰。又例如，所述晶型D的XRPD图谱还在约18.45°2θ、约21.83°2θ、约23.80°2θ和约25.59°2θ处具有峰。又例如，所述晶型D的XRPD图谱还在约21.83°2θ、约23.08°2θ、约23.80°2θ和约25.59°2θ处具有峰。
在某些实施方式中，所述晶型D的XRPD图谱还具有所有选自下组的峰：约18.45°、约21.83°、约23.08°、约23.80°和约25.59°2θ。
在某些实施方式中，所述晶型D的XRPD图谱具有所有选自下组的峰：
Figure PCTCN2021100673-appb-000007
Figure PCTCN2021100673-appb-000008
在某些实施方式中，所述晶型D的XRPD图谱实质上类似于图7中所描绘的XRPD图谱。在某些实施方式中，所述晶型D的XRPD图谱如图7所示。在某些实施方式中，所述晶型D具有以最大强度显示至少2个、至少3个、至少4个、至少5个、至少6个、至少7个、至少8个、至少9个、至少10个、至少11个、至少12个、至少13个2θ角度的XRPD图谱。在某些实施方式中，所述晶型D的DSC图谱包括于约124.1℃(峰值温度)处的吸热峰。在某些实施方式中，所述晶型D的DSC图谱还包括于约59.8℃(峰值温度)处的吸热峰。在某些实施方式中，所述晶型D的DSC图谱还包括于约129.8℃(峰值温度)处的吸热峰。在某些实施方式中，所述晶型D的DSC图谱实质上类似于图8所示的DSC图谱。在某些实施方式中，所述晶型D的DSC图谱如图8所示。
在某些实施方式中，所述晶型D的TGA图谱显示，加热至150℃，样品失重为约11％～15％，例如，约11％、11.5％、12％、12.5％、13％、13.1％、13.2％、13.3％、13.4％、13.5％、13.6％、13.7％、13.8％、13.9％、14％、14.5％、15％。在某些实施方式中，所述晶型D的TGA图谱显示，加热至150℃，样品失重为约13.08％。在某些实施方式中，所述晶型D的TGA图谱实质上类似于图8所描绘的TGA图谱。在某些实施方式中，所述晶型D的TGA图谱如图8所示。在某些实施方式中，在所述晶型D中二氯甲烷分子与化合物1的摩尔比为约0.8:1，例如，0.5:1、0.6:1、0.7:1、0.8:1、0.9:1、1:1、1.1:1或1.2:1。
在某些实施方式中，所述晶型D的 1H NMR图谱实质上类似于图18所描绘的 1H NMR图谱。在某些实施方式中，所述晶型D的 1H NMR图谱如图18所示。
在某些实施方式中，所述晶型D适用以下(a)～(d)中的至少一项、两项、三项或四项：
(a)所述晶型D具有基本上如图7所示的XRPD图谱；
(b)所述晶型D具有基本上如图8所示的DSC图谱；
(c)所述晶型D具有基本上如图8所示的TGA图谱；
(d)所述晶型D具有基本上如图18所示的 1H NMR图谱。
在某些实施方式中，所述晶型D基本上具有以下特征：
(a)所述晶型D具有基本上如图7所示的XRPD图谱；
(b)所述晶型D具有基本上如图8所示的DSC图谱；和
(c)所述晶型D具有基本上如图8所示的TGA图谱。
在某些实施方式中，所述晶型B基本上具有以下特征：
(a)所述晶型D具有基本上如图7所示的XRPD图谱；
(b)所述晶型D具有基本上如图8所示的DSC图谱；
(c)所述晶型D具有基本上如图8所示的TGA图谱；和
(d)所述晶型D具有基本上如图18所示的 1H NMR图谱。
在某些实施方式中，所述晶型D是基本上纯的，例如，所述晶型D的纯度大于90wt％、大于91wt％、大于92wt％、大于93wt％、大于94wt％、大于95wt％、大于96wt％、大于97wt％、大于98wt％或大于99wt％。在某些实施方式中，所述晶型D的纯度通过高效液相色谱法(HPLC)测定。例如，相对于HPLC色谱图的总面积，化合物1含有不大于约5.0面积百分比HPLC的总有机杂质；在某些实施方式中，含有不大于约3.0面积百分比HPLC的总有机杂质；在某些实施方式中，含有不大于约1.5面积百分比HPLC的总有机杂质。在其它实施方式中，相对于HPLC色谱图的总面积，化合物1含有不大于约1.0面积百分比HPLC的任何单一杂质；不大于约0.6面积百分比HPLC的任何单一杂质；在某些实施方式中，不大于约0.5面积百分比HPLC的任何单一杂质。
晶型E
在一个方面，本申请提供化合物1的晶型E。在某些实施方式中，本申请提供了基本上纯的化合物1的晶型E。在某些实施方式中，所述晶型E是化合物1的溶剂化物结晶形式。在某些实施方式中，所述晶型E是化合物1的异丙醇溶剂化物结晶形式。
在某些实施方式中，所述晶型E的XRPD图谱具有一个或多个(例如，两个、三个)选自下组的峰：约9.10°、约13.49°和约18.24°2θ。例如，所述晶型E的XRPD图谱在约9.10°2θ处具有峰。又例如，所述晶型E的XRPD图谱在约13.49°2θ处具有峰。又例如，所述晶型E的XRPD图谱在约18.24°2θ处具有峰。又例如，所述晶型E的XRPD图谱在约9.10°2θ和约13.49°2θ处具有峰。又例如，所述晶型E的XRPD图谱在约9.10°2θ和约18.24°2θ处具有峰。又例如，所述晶型E的XRPD图谱在约13.49°2θ和约18.24°2θ处具有峰。在某些实施方式中，所述晶型E的XRPD图谱具有所有选自下组的峰：约9.10°、约13.49°和约18.24°2θ。
在某些实施方式中，所述晶型E的XRPD图谱还具有一个或多个(例如，2个、3个、4个、5个、6个、7个)选自下组的峰：约13.03°、约20.13°、约22.63°、约23.35°、约25.06°、约27.51°和约29.46°2θ。例如，所述晶型E的XRPD图谱还在约13.03°2θ处具有峰。又例如，所述晶型E的XRPD图谱还在约20.13°2θ处具有峰。又例如，所述晶型E的XRPD图谱还在约22.63°2θ处具有峰。又例如，所述晶型E的XRPD图谱还在约23.35°2θ处具有峰。又例如，所述晶型E的XRPD图谱还在约25.06°2θ处具有峰。又例如，所述晶型E的XRPD图谱还在约27.51°2θ处具有峰。又例如，所述晶型E的XRPD图谱还在约29.46°2θ处具有峰。
在某些实施方式中，所述晶型E的XRPD图谱还具有两个或更多个(例如，3个、4个、5个、6个、7个)选自下组的峰：约13.03°、约20.13°、约22.63°、约23.35°、约25.06°、约27.51°和约29.46°2θ。例如，所述晶型E的XRPD图谱还在约13.03°2θ和约20.13°2θ处具有峰。又例如，所述晶型E的XRPD图谱还在约13.03°2θ和约22.63°2θ处具有峰。又例如，所述晶型E的XRPD图谱还在 约13.03°2θ和约23.35°2θ处具有峰。又例如，所述晶型E的XRPD图谱还在约13.03°2θ和约25.06°2θ处具有峰。又例如，所述晶型E的XRPD图谱还在约13.03°2θ和约27.51°2θ处具有峰。又例如，所述晶型E的XRPD图谱还在约13.03°2θ和约29.46°2θ处具有峰。又例如，所述晶型E的XRPD图谱还在约20.13°2θ和约22.63°2θ处具有峰。又例如，所述晶型E的XRPD图谱还在约20.13°2θ和约23.35°2θ处具有峰。又例如，所述晶型E的XRPD图谱还在约20.13°2θ和约25.06°2θ处具有峰。又例如，所述晶型E的XRPD图谱还在约20.13°2θ和约27.51°2θ处具有峰。又例如，所述晶型E的XRPD图谱还在约20.13°2θ和约29.46°2θ处具有峰。又例如，所述晶型E的XRPD图谱还在约22.63°2θ和约23.35°2θ处具有峰。又例如，所述晶型E的XRPD图谱还在约22.63°2θ和约25.06°2θ处具有峰。又例如，所述晶型E的XRPD图谱还在约22.63°2θ和约27.51°2θ处具有峰。又例如，所述晶型E的XRPD图谱还在约22.63°2θ和约29.46°2θ处具有峰。又例如，所述晶型E的XRPD图谱还在约23.35°2θ和约25.06°2θ处具有峰。又例如，所述晶型E的XRPD图谱还在约23.35°2θ和约27.51°2θ处具有峰。又例如，所述晶型E的XRPD图谱还在约23.35°2θ和约29.46°2θ处具有峰。又例如，所述晶型E的XRPD图谱还在约25.06°2θ和约27.51°2θ处具有峰。又例如，所述晶型E的XRPD图谱还在约25.06°2θ和约29.46°2θ处具有峰。又例如，所述晶型E的XRPD图谱还在约27.51°2θ和约29.46°2θ处具有峰。
在某些实施方式中，所述晶型E的XRPD图谱还具有所有选自下组的峰：约13.03°、约20.13°、约22.63°、约23.35°、约25.06°、约27.51°和约29.46°2θ。
在某些实施方式中，所述晶型E的XRPD图谱具有所有选自下组的峰：
Figure PCTCN2021100673-appb-000009
Figure PCTCN2021100673-appb-000010
在某些实施方式中，所述晶型E的XRPD图谱实质上类似于图9中所描绘的XRPD图谱。在某些实施方式中，所述晶型E的XRPD图谱如图9所示。在某些实施方式中，所述晶型E具有以最大强度显示至少2个、至少3个、至少4个、至少5个、至少6个、至少7个、至少8个、至少9个、至少10个、至少11个、至少12个、至少13个2θ角度的XRPD图谱。在某些实施方式中，所述晶型E的DSC图谱包括于约269.0℃(峰值温度)处的吸热峰。在某些实施方式中，所述晶型E的DSC图谱还包括于约123.6℃(峰值温度)处的吸热峰。在某些实施方式中，所述晶型E的DSC图谱实质上类似于图10所描绘的DSC图谱。在某些实施方式中，所述晶型E的DSC图谱如图10所示。
在某些实施方式中，所述晶型E的TGA图谱显示，在100℃之前失重为约4％～6％，例如为约4％、约4.5％、约4.6％、约4.7％、约4.8％、约4.9％、约4.96％、约5％、约5.5％、约6％；在100℃至150℃之间失重为约11％～14％，例如，为约11％、约11.5％、约12％、约12.1％、约12.2％、约12.3％、约12.4％、约12.5％、约12.54％、约12.6％、约12.7％、约12.8％、约12.9％、约13％、约13.5％、约14％。在某些实施方式中，所述晶型E的TGA图谱显示，在100℃之前失重为约4.96％，在100℃至150℃之间失重为约12.54％。在某些实施方式中，所述晶型E的TGA图谱实质上类似于图10所描绘的TGA图谱。在某些实施方式中，所述晶型E的TGA图谱如图10所示。在某些实施方式中，在所述晶型E中异丙醇分子与化合物1的摩尔比为约1:1，例如，0.7:1、0.8:1、0.9:1、1:1、1.1:1、1.2:1、1.3:1。
在某些实施方式中，所述晶型E的 1H NMR图谱实质上类似于图19所描绘的 1H NMR图谱。在某些实施方式中，所述晶型E的 1H NMR图谱如图19所示。
在某些实施方式中，所述晶型E适用以下(a)～(d)中的至少一项、两项、三项或四项：
(a)所述晶型E具有基本上如图9所示的XRPD图谱；
(b)所述晶型E具有基本上如图10所示的DSC图谱；
(c)所述晶型E具有基本上如图10所示的TGA图谱；
(d)所述晶型E具有基本上如图19所示的 1H NMR图谱。
在某些实施方式中，所述晶型E基本上具有以下特征：
(a)所述晶型E具有基本上如图9所示的XRPD图谱；
(b)所述晶型E具有基本上如图10所示的DSC图谱；和
(c)所述晶型E具有基本上如图10所示的TGA图谱。
在某些实施方式中，所述晶型E基本上具有以下特征：
(a)所述晶型E具有基本上如图9所示的XRPD图谱；
(b)所述晶型E具有基本上如图10所示的DSC图谱；
(c)所述晶型E具有基本上如图10所示的TGA图谱；和
(d)所述晶型E具有基本上如图19所示的 1H NMR图谱。
在某些实施方式中，所述晶型E是基本上纯的，例如，所述晶型E的纯度大于90wt％、大于91wt％、大于92wt％、大于93wt％、大于94wt％、大于95wt％、大于96wt％、大于97wt％、大于98wt％或大于99wt％。在某些实施方式中，所述晶型E的纯度通过高效液相色谱法(HPLC)测定。例如，相对于HPLC色谱图的总面积，化合物1含有不大于约5.0面积百分比HPLC的总有机杂质；在某些实施方式中，含有不大于约3.0面积百分比HPLC的总有机杂质；在某些实施方式中，含有不大于约1.5面积百分比HPLC的总有机杂质。在其它实施方式中，相对于HPLC色谱图的总面积，化合物1含有不大于约1.0面积百分比HPLC的任何单一杂质；不大于约0.6面积百分比HPLC的任何单一杂质；在某些实施方式中，不大于约0.5面积百分比HPLC的任何单一杂质。
晶型A～E的制备方法
在另一个方面，本申请还提供了化合物1的晶型A-E的制备方法。示例性的方法包括，例如，打浆法(室温或者50℃)、气-固扩散法、温度循环法、缓慢挥发法、气-液扩散法、高聚物诱导法、反溶剂添加法、研磨法等。
本申请所述的晶型制备方法中所用的起始原料可以是任意形式的化合物1，例如无定形、任意晶型等。化合物1可通过公开号为WO2020072656A1或WO2020094018A1的PCT专利申请(其通过全文引用的方式并入本文)中公开的方法制得。
在某些实施方式中，化合物1的晶型A-D可通过室温打浆法制得。例如，将化合物1溶解于第一溶剂中并在室温下悬浮搅拌，随后结晶、过滤收集晶体。所述第一溶剂可以选自下组：醚类(例如，四氢呋喃、2-甲基四氢呋喃、环戊基甲醚、苯甲醚、甲基叔丁基醚、1,4-二氧六环等)、醇类(例如，甲醇、乙醇、正丙醇、异丙醇、丁醇等)、酯类(例如，乙酸乙酯、乙酸异丙酯、乙酸丁酯等)、酮类(例如，丙酮、丁酮、甲基乙基酮、甲基异丁酮、N-甲基吡咯烷酮等)、砜类(例如，二甲亚砜)、烷烃(例如，C 1-7烷烃，包括甲烷、乙烷、丙烷、丁烷、戊烷、己烷、正庚烷等)、卤代烃(例如，二氯甲烷、氯仿等)、乙腈、水，及其任意组合形成的混合溶剂。所述混合溶剂中的至少两种溶剂体积比可以是任意比例，例如1:1、2:1、3:1、4:1、5:1、6:1、7:1、8:1、9:1、10:1、20:1、30:1、40:1、50:1、60:1、70:1、80:1、90:1、95:1或以上任意两个比例范围之间的任意比例。所述混合溶剂可以选自下组：乙酸异丙酯/氯仿、2-甲基四氢呋喃/甲醇、环戊基甲醚/乙醇、异丙醇/二氯甲烷、苯甲醚/丁酮、乙酸乙酯/二甲亚砜、甲基叔丁基醚/甲醇、正庚烷/氯仿、丙酮/水、乙腈/甲醇、甲醇/四氢呋喃、2-丁醇/乙腈、二氯甲烷/正己烷、1,4-二氧六环/乙醇、苯甲醚/氯仿、乙酸甲酯/甲醇、甲基异丁酮/乙醇。
在某些实施方式中，化合物1的晶型A、C和无定形形式可通过50℃打浆法制得。例如，将化合物1溶解于第二溶剂中并在室温下悬浮搅拌，随后结晶、过滤收集晶体。所述第二溶剂可以选自下组：醚类(例如，四氢呋喃、2-甲基四氢呋喃、环戊基甲醚、苯甲醚、甲基叔丁基醚、1,4-二氧六环等)、醇类(例如，甲醇、乙醇、正丙醇、异丙醇、丁醇等)、酯类(例如，乙酸甲酯、乙酸乙酯、乙酸异丙酯、乙酸丁酯等)、酮类(例如，丙酮、丁酮、甲基乙基酮、甲基异丁 酮、N-甲基吡咯烷酮等)、烷烃(例如，C 1-7烷烃，包括甲烷、乙烷、丙烷、丁烷、戊烷、己烷、正庚烷等)、卤代烃(例如，二氯甲烷、氯仿等)、乙腈、水，及其任意组合形成的混合溶剂。所述混合溶剂中的至少两种溶剂体积比可以是任意比例，例如1:1、2:1、3:1、4:1、5:1、6:1、7:1、8:1、9:1、10:1、20:1、30:1、40:1、50:1、60:1、70:1、80:1、90:1、95:1或以上任意两个比例范围之间的任意比例。所述混合溶剂可以选自下组：甲醇/四氢呋喃、乙酸甲酯/甲醇、2-丁醇/乙腈、二氯甲烷/正己烷、甲醇/甲苯、1,4-二氧六环/乙醇、四氢呋喃/水、苯甲醚/氯仿、甲基异丁酮/乙醇、乙腈/甲醇或正庚烷/氯仿。
在某些实施方式中，化合物1的晶型A可通过气-固扩散法制得。例如，将化合物1放入第一容器中，然后将所述第一容器敞口置于放有第三溶剂的第二容器中，所述第二容器的体积大于所述第一容器的体积，然后将所述第二容器密封，室温下静置，得到化合物1的晶型。所述第三溶剂可以选自下组：醇类(例如，甲醇、乙醇、正丙醇、异丙醇、丁醇等)、醚类(例如，四氢呋喃、2-甲基四氢呋喃、环戊基甲醚、苯甲醚、甲基叔丁基醚、1,4-二氧六环等)、酯类(例如，乙酸乙酯、乙酸异丙酯、乙酸丁酯等)、酮类(例如，丙酮、丁酮、甲基乙基酮、甲基异丁酮、N-甲基吡咯烷酮等)、卤代烃(例如，二氯甲烷、氯仿等)、乙腈、水。
在某些实施方式中，化合物1的晶型A和C可通过温度循环法制得。例如，将化合物1加入至第四溶剂中，所得悬浮液进行循环升降温悬浮搅拌(例如，一个循环为以4.5℃/min升温至50℃，恒温30min，以0.1℃/min降温至5℃，恒温30min，进行3个循环)，析晶得到化合物1的晶型。所述第四溶剂可以选自下组：醇类(例如，甲醇、乙醇、正丙醇、异丙醇、丁醇等)、醚类(例如，四氢呋喃、2-甲基四氢呋喃、环戊基甲醚、苯甲醚、甲基叔丁基醚、1,4-二氧六环等)、酯类(例如，乙酸乙酯、乙酸异丙酯、乙酸丁酯等)、酮类(例如，丙酮、丁酮、甲基乙基酮、甲基异丁酮、N-甲基吡咯烷酮等)、砜类(例如，二甲亚砜)、烷烃(例如，C 1-7烷烃，包括甲烷、乙烷、丙烷、丁烷、戊烷、己烷、正庚烷等)、甲苯、乙腈、二甲基甲酰胺，及其任意混合形成的混合溶剂。所述混合溶剂中的至少两种溶剂体积比可以是任意比例，例如1:1、2:1、3:1、4:1、5:1、6:1、7:1、8:1、9:1、10:1、20:1、30:1、40:1、50:1、60:1、70:1、80:1、90:1、95:1或以上 任意两个比例范围之间的任意比例。所述混合溶剂可以选自下组：水/二甲基甲酰胺、正己烷/二甲亚砜、乙腈/N-甲基吡咯烷酮。
在某些实施方式中，化合物1的晶型A-E和无定形形式可通过缓慢挥发法制得。例如，将化合物1加入第五溶剂中，得到澄清溶液，缓慢挥发得到化合物1的晶型。所述第五溶剂可以选自下组：醇类(例如，甲醇、乙醇、正丙醇、异丙醇、丁醇等)、醚类(例如，四氢呋喃、2-甲基四氢呋喃、环戊基甲醚、苯甲醚、甲基叔丁基醚、1,4-二氧六环等)、酯类(例如，乙酸乙酯、乙酸异丙酯、乙酸丁酯等)、酮类(例如，丙酮、丁酮、甲基乙基酮、甲基异丁酮、N-甲基吡咯烷酮等)、卤代烃(例如，二氯甲烷、氯仿等)、乙腈、水，及其任意混合形成的混合溶剂。所述混合溶剂中的至少两种溶剂体积比可以是任意比例，例如1:1、2:1、3:1、4:1、5:1、6:1、7:1、8:1、9:1、10:1、20:1、30:1、40:1、50:1、60:1、70:1、80:1、90:1、95:1或以上任意两个比例范围之间的任意比例。所述混合溶剂可以选自下组：水/乙醇、乙酸乙酯/甲醇、乙腈/甲醇、甲基叔丁基醚/甲醇、丙酮/二氯甲烷、异丙醇/氯仿。
在某些实施方式中，化合物1的晶型A和C还可通过气-液扩散法制得。例如，将化合物1放入第三容器中，并用第六溶剂溶解，然后过滤，将滤液至于第四容器中，然后将所述第四容器敞口置于放有第六溶剂的反溶剂的第五容器中，所述第五容器的体积大于所述第四容器的体积，然后将所述第五容器密封，室温下静置，得到化合物1的晶型。所述第六溶剂可以选自下组：醇类(例如，甲醇、乙醇、正丙醇、异丙醇、丁醇等)、酮类(例如，丙酮、丁酮、甲基乙基酮、甲基异丁酮、N-甲基吡咯烷酮等)、二甲基甲酰胺。所述第六溶剂的反溶剂可以选自下组：乙腈、酯类(例如，乙酸乙酯、乙酸异丙酯、乙酸丁酯等)、烷烃(例如，C 1-7烷烃，包括甲烷、乙烷、丙烷、丁烷、戊烷、己烷(例如，环己烷)、正庚烷等)。在某些实施方式中，该方法中的反溶剂体系可以选自下组：乙醇/乙腈、乙醇/正庚烷、乙醇/乙酸乙酯、N-甲基吡咯烷酮/乙酸异丙酯、二甲基甲酰胺/乙腈、二甲基甲酰胺/环己烷。
在某些实施方式中，化合物1的晶型A、D和无定形形式可通过高聚物诱导法制得。例如，将化合物1溶解于第七溶剂中，得到澄清溶液，然后向溶液中加入混合高聚物，放置在室温下缓慢挥发，得到化合物1的晶型。所述第七溶剂可 以选自下组：醇类(例如，甲醇、乙醇、正丙醇、异丙醇、丁醇等)、卤代烃(例如，二氯甲烷、氯仿等)、乙腈。所述混合高聚物可选自如下：聚乙烯吡咯烷酮、聚乙烯醇、聚氯乙烯、聚醋酸乙烯酯、羟丙基甲基纤维素和甲基纤维素的等质量混合物，或者聚己酸内酯、聚乙二醇、聚甲基丙烯酸甲酯、海藻酸钠和羟乙基纤维素的等质量混合物。
在某些实施方式中，化合物1的晶型A-C和无定形形式可通过反溶剂添加法制得。例如，将化合物1溶解于第八溶剂中，随后在搅拌下逐滴加入所述第八溶剂的反溶剂，析晶得到化合物1的晶型。所述第八溶剂可以选自下组：醇类(例如，甲醇、乙醇、正丙醇、异丙醇、丁醇等)、卤代烃(例如，二氯甲烷、氯仿等)、酮类(例如，丙酮、丁酮、甲基乙基酮、甲基异丁酮、N-甲基吡咯烷酮等)、砜类(例如，二甲亚砜)。所述第八溶剂的反溶剂可以选自下组：甲苯、醚类(例如，四氢呋喃、2-甲基四氢呋喃、环戊基甲醚、苯甲醚、甲基叔丁基醚、1,4-二氧六环等)、醇类(例如，甲醇、乙醇、正丙醇、异丙醇、丁醇等)、酯类(例如，乙酸乙酯、乙酸异丙酯、乙酸丁酯等)、酮类(例如，丙酮、丁酮、甲基异丁酮、N-甲基吡咯烷酮等)、水。在某些实施方式中，反溶剂体系可以选自下组：氯仿/甲苯、氯仿/乙酸乙酯、氯仿/环戊基甲醚、甲醇/水、甲醇/四氢呋喃、甲醇/丙酮、二甲亚砜/异丙醇、二甲亚砜/水。
在某些实施方式中，化合物1的晶型A和B可通过研磨法制得。例如，将化合物1置于研钵中，任选加入水进行研磨，得到化合物1的晶型。
在某些实施方式中，本申请中晶型的制备方法还包括过滤、洗涤或干燥等步骤。
药物组合物
在另一方面，本申请提供了一种药物组合物，其包含化合物1和药学上可接受的载体，所述化合物1具有选自如下的一种或多种晶型：晶型A、水合物晶型B、水合物晶型C、二氯甲烷溶剂化物晶型D以及异丙醇溶剂化物晶型E。
本申请的化合物1的晶型A、水合物晶型B、水合物晶型C、二氯甲烷溶剂化物晶型D以及异丙醇溶剂化物晶型E或药物组合物可以根据需要而配制为所 需的形式，例如片剂、胶囊剂、丸剂、颗粒剂、溶液剂、混悬剂、糖浆剂、注射剂(包括注射液、注射用无菌粉末与注射用浓溶液)、栓剂、吸入剂或喷雾剂。
本申请的化合物1的晶型A、水合物晶型B、水合物晶型C、二氯甲烷溶剂化物晶型D以及异丙醇溶剂化物晶型E或药物组合物可以以任何合适的给药方式施用于需要有需要的患者或受试者，例如口服、肠胃外、直肠、经肺或局部给药等方式。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，本申请的化合物1的晶型A、水合物晶型B、水合物晶型C、二氯甲烷溶剂化物晶型D或异丙醇溶剂化物晶型E与至少一种常规惰性赋形剂或载体混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，微晶纤维素、淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、碳酸钠、交联聚维酮、交联羧甲基纤维素钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型(如片剂、糖丸、胶囊剂、丸剂和颗粒剂)可采用包衣和壳材制备，如肠衣和其他本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性成分的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性成分也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型可包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性成分外，液体剂型可包含本领域中常规采用的惰性稀释剂(如水或其他溶剂)、增溶剂和乳化剂(例如，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油(特别是棉籽油、花生油、玉米胚油、 橄榄油、蓖麻油和芝麻油))、甜味剂(例如，甘油、丙二醇、山梨醇、天冬甜素或蔗糖)、防腐剂、增味剂、着色剂或这些物质的混合物等。
用于肠胃外注射的组合物可包括生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂，包括水、乙醇、多元醇林格氏溶液、等渗氯化钠溶液或这些物质的混合物。
用于直肠给药的组合物可包括栓剂等。
用于经肺给药的组合物可包括吸入剂和喷雾剂等。
用于局部给药的组合物可包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与药学上可接受的载体(例如，动物油、植物油、蜡、石蜡、淀粉、黄芪胶、纤维素衍生物、聚乙二醇、硅酮、膨润土、硅酸、滑石、氧化锌等)及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
除了上述代表性的剂型之外，本领域已知的药学上可接受的载体也可包括在本申请中。这样的载体描述于，例如，“Remingtons Pharmaceutical Sciences”Mack Pub.Co.,New Jersey(1991),in“Remington:The Science and Practice of Pharmacy”,Ed.University of the Sciences in Philadelphia,21 st Edition,LWW(2005)，其以全文引用的方式并入本文。
在某些实施方式中，本申请的化合物1的晶型A、水合物晶型B、水合物晶型C、二氯甲烷溶剂化物晶型D以及异丙醇溶剂化物晶型E以治疗和/或预防有效量存在于药物组合物或药物中。在某些实施方案中，本申请的药物组合物可配制为单位剂型。为了清楚起见，本申请提及的含量是指游离碱形式的化合物1的当量，不包括所含的溶剂(如果晶型中存在的话)所产生的额外重量。
例如，在单次或多次给药的情况下，本申请化合物1的晶型A、水合物晶型B、水合物晶型C、二氯甲烷溶剂化物晶型D以及异丙醇溶剂化物晶型E的剂量可为约0.01至约100mg/kg体重/天，约0.05至约100mg/kg体重/天，约0.1至约100mg/kg体重/天，约0.5至约100mg/kg体重/天，约1至约100mg/kg体重/天，约1至约90mg/kg体重/天，约1至约80mg/kg体重/天，约1至约70mg/kg 体重/天，约1至约60mg/kg体重/天，约1至约50mg/kg体重/天，约1至约45mg/kg体重/天，约1至约40mg/kg体重/天，约1至约35mg/kg体重/天，或约1至约30mg/kg体重/天。在一些情况中，低于上述范围的下限的剂量水平可能也是足够的，而在其他情况中，也可使用高于上述范围的上限的剂量水平而无任何副作用。在一些情况中，单位剂型(如片剂、胶囊)可含有例如约1-1000mg，约1-900mg，约1-800mg，约1-700mg，约1-600mg，约1-500mg，约1-400mg，约1-300mg，约1-200mg，或约1-100mg的本申请的化合物1的晶型A、水合物晶型B、水合物晶型C、二氯甲烷溶剂化物晶型D或异丙醇溶剂化物晶型E。
本申请化合物1的晶型A、水合物晶型B、水合物晶型C、二氯甲烷溶剂化物晶型D以及异丙醇溶剂化物晶型E在药物组合物中的含量可取决于多种因素而不同，例如效力、生物半衰期、疾病类型及其严重程度、待治疗的受试者(如年龄和体重)、特定的施用方式等，本领域技术人员能够根据需要而常规确定所需含量。
同样，本申请化合物1的晶型A、水合物晶型B、水合物晶型C、二氯甲烷溶剂化物晶型D以及异丙醇溶剂化物晶型E以及包含其的药物组合物的治疗持续时间和给药时间(剂量之间的时间段、剂量时间点(如饭前、饭后、饭中))也取决于待治疗的受试者、特定晶型及其性质(例如药代动力学性质)、疾病类型及其严重程度、所用的特定组合物和方法而不同，本领域技术人员能够根据需要而常规确定。
在某些实施方式中，本申请所述的药物组合物中至少约85％、至少约90％、至少约95％、至少约99％、至少约99.5％、至少约99.9％或至少约99.99％的化合物1具有晶型A。
在某些实施方式中，本申请所述的药物组合物中至少约85％、至少约90％、至少约95％、至少约99％、至少约99.5％、至少约99.9％或至少约99.99％的化合物1具有晶型B。
在某些实施方式中，本申请所述的药物组合物中至少约85％、至少约90％、至少约95％、至少约99％、至少约99.5％、至少约99.9％或至少约99.99％的化合物1具有晶型C。
在某些实施方式中，本申请所述的药物组合物中至少约85％、至少约90％、至少约95％、至少约99％、至少约99.5％、至少约99.9％或至少约99.99％的化合物1具有晶型D。
在某些实施方式中，本申请所述的药物组合物中至少约85％、至少约90％、至少约95％、至少约99％、至少约99.5％、至少约99.9％或至少约99.99％的化合物1具有晶型E。
在某些实施方式中，本申请所述的药物组合物进一步包括其他治疗剂。所述其他治疗剂包括抗癌药物，例如，阿巴瑞克(abarelix)、阿地白介素(aldesleukin)、阿伦单抗(alemtuzumab)、亚利崔托宁(alitretinoin)、安乐普利诺(allopurinol)、六甲蜜胺(altretamine)、胺磷汀(amifostine)、阿那曲唑(anastrozole)、三氧化二砷、天冬酰胺酶、阿扎胞苷(azacitidine)、BCG Live、贝伐单抗(bevacuzimab)、氟尿嘧啶、贝瑟罗汀(bexarotene)、博莱霉素(bleomycin)、硼替佐米(bortezomib)、白消安(busulfan)、卡普睾酮(calusterone)、卡培他滨(capecitabine)、喜树碱、卡铂、卡莫司汀(carmustine)、塞内昔布(celecoxib)、西妥昔单抗(cetuximab)、苯丁酸氮芥、克拉屈滨(cladribine)、氯法拉滨(clofarabine)、环磷酰胺、阿糖胞苷(cytarabine)、放线菌素D、达贝泊汀α(darbepoetin alfa)、道诺霉素、地尼白介素(denileukin)、右雷佐生(dexrazoxane)、多烯紫杉醇、小红莓(中性)、盐酸小红莓、丙酸屈他雄酮(dromostanolone propionate)、表柔比星(epirubicin)、依伯汀α(epoetin alfa)、埃罗替尼、雌莫司汀(estramustine)、磷酸依托泊苷、依托泊苷、依西美坦(exemestane)、非格司亭(filgrastim)、氟尿苷氟达拉滨(floxuridine fludarabine)、氟维司群(fulvestrant)、吉非替尼、吉西他滨(gemcitabine)、吉妥珠单抗(gemtuzumab)、乙酸戈舍瑞林(goserelin acetate)、乙酸组胺瑞林(histrelin acetate)、羟基脲(hydroxyurea)、替伊莫单抗(ibritumomab)、艾达霉素(idarubicin)、异环磷酰胺、甲磺酸伊马替尼(imatinib mesylate)、干扰素α-2a、干扰素α-2b、伊立替康(irinotecan)、来那度胺(lenalidomide)、来曲唑(letrozole)、甲酰四氢叶酸(leucovorin)、乙酸亮丙立德(leuprolide acetate)、左旋咪唑(levamisole)、洛莫司汀(lomustine)、乙酸甲地孕酮 (megestrol acetate)、美法仑(melphalan)、巯嘌呤(mercaptopurine)、6-MP、美司钠(mesna)、甲氨蝶呤、甲氧沙林(methoxsalen)、丝裂霉素C(mitomycin C)、米托坦(mitotane)、米托蒽醌(mitoxantrone)、诺龙(nandrolone)、奈拉滨(nelarabine)、诺非单抗(nofetumomab)、奥普瑞白介素(oprelvekin)、奥沙利铂(oxaliplatin)、太平洋紫杉醇、帕利夫明(palifermin)、帕米膦酸盐(pamidronate)、培加酶(pegademase)、培门冬酶(pegaspargase)、聚乙二醇化非格司亭(pegfilgrastim)、培美曲塞二钠(pemetrexed disodium)、喷司他汀(pentostatin)、哌泊溴烷(pipobroman)、普卡霉素(plicamycin)、卟吩姆钠(porfimer sodium)、丙卡巴肼(procarbazine)、奎纳克林(quinacrine)、拉布立酶(rasburicase)、利妥昔单抗(rituximab)、沙格司亭(sargramostim)、索拉非尼(sorafenib)、链佐星(streptozocin)、顺丁烯二酸舒尼替尼(sunitinib maleate)、滑石、他莫昔芬(tamoxifen)、替莫唑胺(temozolomide)、替尼泊苷、VM-26、睾内酯(testolactone)、硫鸟嘌呤(thioguanine)、6-TG、噻替派(thiotepa)、拓朴替康、托瑞米芬(toremifene)、托西莫单抗(tositumomab)、曲妥珠单抗(trastuzumab)、维甲酸(tretinoin)、ATRA、尿嘧啶氮芥(uracil mustard)、伐柔比星(valrubicin)、长春碱、长春新碱、长春瑞滨(vinorelbine)、唑来膦酸盐(zoledronate)或唑来膦酸。
在另一方面，本申请还提供了一种药物组合物的制备方法，包括将化合物1的晶型A、水合物晶型B、水合物晶型C、二氯甲烷溶剂化物晶型D、异丙醇溶剂化物晶型E或由前述方法制备获得的化合物1的晶型A-E与药学上可接受的载体混合。
用途
在另一方面，本申请还提供了本申请所述的化合物1的晶型A-E以及药物组合物在以下中的用途：
(a)制备预防或治疗与SHP2活性/水平异常相关的疾病或病症的药物；
(b)制备预防或治疗SHP2-介导的疾病或病症的药物；
(c)制备抑制SHP2活性/水平的抑制剂药物；
(d)体外非治疗性地抑制SHP2活性/水平；
(e)体外非治疗性地抑制肿瘤细胞增殖；或
(f)治疗与SHP2活性/水平异常相关的疾病或病症。
所述“SHP2-介导的疾病或病症”是指与SHP2活性/水平异常相关的疾病或病症，可能是由于受试者体内的SHP2异常活化或破坏而引起的SHP2活性/水平的异常升高或降低。在某些实施方式中，所述SHP2-介导的疾病或病症与SHP2活性/水平的异常升高相关。在某些实施方式中，所述SHP2-介导的疾病或病症为癌症。在某些实施方式中，所述癌症选自下组：努南综合征、豹皮综合征、青少年髓单核细胞白血病、成神经细胞瘤、黑色素瘤、急性髓性白血病、乳腺癌、食道癌、肺癌、结肠癌、头癌、头颈的鳞状细胞癌、胃癌、间变性大细胞淋巴瘤、成胶质细胞瘤、肝细胞癌(HCC)、急性淋巴细胞白血病、肾上腺皮质癌、肛门癌、阑尾癌、星形细胞瘤、非典型类畸形/类瘤、基底细胞癌、胆管癌、膀胱癌、骨癌(骨肉瘤和恶性纤维组织细胞瘤)、脑干神经胶质瘤、脑肿瘤、脑和脊髓肿瘤、支气管肿瘤、伯基特(Burkitt)淋巴瘤、子宫颈癌、慢性淋巴细胞性白血病、慢性粒细胞性白血病、结肠直肠癌、颅咽管瘤、胚胎肿瘤、子宫内膜癌、上皮细胞瘤、室管膜瘤、尤因肉瘤家族肿瘤、眼癌、视网膜母细胞瘤、胆囊癌、胃肠道类癌、胃肠道间质瘤(GIST)、胃肠道间质细胞瘤、生殖细胞瘤、神经胶质瘤、毛细胞白血病、头颈癌、霍奇金淋巴瘤、下咽癌、胰岛细胞瘤(内分泌胰腺)、卡波济肉瘤、肾癌、朗格汉斯细胞组织细胞增生症、喉癌、白血病、毛细胞白血病、肝癌、非小细胞肺癌、小细胞肺癌、淋巴瘤、髓母细胞瘤、髓上皮瘤、间皮瘤、口腔癌、多发性骨髓瘤、鼻咽癌、神经母细胞瘤、非霍奇金淋巴瘤、口咽癌、骨肉瘤、恶性骨纤维组织细胞瘤、卵巢癌、卵巢上皮癌、卵巢生殖细胞瘤、卵巢低恶性潜能肿瘤、胰腺癌、乳头状瘤病、甲状旁腺癌、阴茎癌、咽癌、松果体中间分化肿瘤、成骨细胞瘤和幕上原始神经外胚层肿瘤、垂体瘤、浆细胞肿瘤/多发性骨髓瘤、胸膜肺母细胞瘤、原发性中枢神经系统淋巴瘤、前列腺癌、直肠癌、肾细胞(肾)癌、视网膜母细胞瘤、横纹肌肉瘤、唾液腺癌、肉瘤、尤因肉瘤家族肿瘤、肉瘤、卡波西氏病、Sezary综合征、皮肤癌、小肠癌、软组织肉瘤、鳞状细胞癌、幕上原始神经外胚层肿瘤、T细胞淋巴瘤、睾丸癌、喉癌、胸腺瘤和胸腺癌、甲状腺癌、尿道癌、子宫癌、子宫肉瘤、阴道癌、外阴癌、Waldenstrom巨球蛋白血症和Wilms肿瘤。
在另一方面，本申请还提供了一种治疗或预防SHP2-介导的疾病或病症的方法，包括给予有需要的受试者本申请所述的化合物1的晶型A、水合物晶型B、水合物晶型C、二氯甲烷溶剂化物晶型D、异丙醇溶剂化物晶型E，或者本申请所述的药物组合物。
在另一方面，本申请还提供了用于治疗或预防SHP2-介导的疾病或病症的化合物1的晶型A、水合物晶型B、水合物晶型C、二氯甲烷溶剂化物晶型D、异丙醇溶剂化物晶型E，或者包含所述晶型中任意一种或多种的药物组合物。
在另一方面，本申请还提供了一种抑制SHP2活性的方法，其包括以下步骤：对有此需要的受试者施用有效量的本申请所述的化合物1的晶型A-E，或对有此需要的受试者施用有效量的本申请所述的药物组合物。
具体实施方式
以下将结合实施例更详细地解释本发明，本申请的实施例仅用于说明本发明的技术方案，并非限定本发明的实质和范围。
在如下实施例的描述中使用的缩写为：
缩写 含义 缩写 含义
MeOH 甲醇 DCM 二氯甲烷
EtOH 乙醇 Anisole 苯甲醚
THF 四氢呋喃 MEK 甲乙酮
ACN 乙腈 IPAc 乙酸异丙酯
2-MeTHF 2-甲基四氢呋喃 CHCl 3 氯仿
CPME 环戊基甲醚 EtOAc 乙酸乙酯
IPA 异丙醇 DMSO 二甲基亚砜
MTBE 甲基叔丁基醚 n-Heptane 正庚烷
Acetone 丙酮 1,4-Dioxane 1,4-二氧六环
Methyl acetate 乙酸甲酯 2-Butanol 2-丁醇
n-Hexane 正己烷 Toluene 甲苯
NMP N-甲基吡咯烷酮 Cyclohexane 环己烷
实施例中使用的仪器以及实验条件
1、差示扫描量热仪(Differential Scanning Calorimeter，DSC)
仪器型号：Mettler Toledo DSC3+Stare e System
吹扫气：氮气(50mL/min)
升温速率：10.0℃/min
温度范围：20-250℃
2、X-射线粉末衍射谱(X-ray Powder Diffraction，XRPD)
仪器型号：Rigaku UltimaIV X-射线粉末衍射仪
射线：单色Cu-Kα射线
Figure PCTCN2021100673-appb-000011
扫描方式：θ/2θ，扫描范围：3-45°
电压：40kV，电流：40mA
3、热重分析仪(Thermogravimetric Analysis，TGA)
仪器型号：Mettler Toledo TGA2STAR eSystem
吹扫气：氮气
升温速率：10.0℃/min
温度范围：20-250℃
4、动态蒸汽吸附(Dynamic Vapour Sorption，DVS)
仪器型号：TAQ5000VSA
温度：25℃
溶剂：水
湿度变化：0-95-0-95-0％RH，步进为10％，判断标准为10000min之内质量变化小于0.01％
4、HPLC方法
仪器型号：Agilent 1100，具有VWD检测器
色谱柱：poroshell 120 EC C18，3.0mm/50mm/2.7μm
流动相：A:0.03％NH 4OH(25％～28％)在水中
B:0.03％NH 4OH(25％～28％)在乙腈中
洗脱梯度：
Figure PCTCN2021100673-appb-000012
流动相流速：1.0mL/min
运行时间：10.0min
进样体积：2μL
检测波长：UV，254nm
柱温：25℃
进样器温度：RT
稀释剂：乙腈:水＝1:1(v:v)
实施例1：化合物1的晶型A的制备、表征与稳定性考察
(i).化合物1的晶型A的制备(室温打浆法)
实施例1.1
将化合物1(20mg)放置在玻璃小瓶中，加入0.5mL甲醇，得到的浑浊液置于室温下磁力悬浮搅拌(1000rpm)约4天后，离心(10000rpm，2min)收集固体。对所收集的固体进行XRPD表征，确定所得固体为化合物1的晶型A。
实施例1.2～1.15
参照实施例1.1的方法，用不同的溶剂替换实施例1.1中的甲醇(具体如表1所示)，经XRPD检测确定所得固体均为化合物1的晶型A。
表1：选用不同溶剂制备化合物1的晶型
实施例编号 选用的溶剂(v:v) 实施例编号 选用的溶剂(v:v)
实施例1.2 EtOH 实施例1.9 IPAc/CHCl 3，9:1
实施例1.3 THF 实施例1.10 EtOAc/DMSO，9:1
实施例1.4 ACN 实施例1.11 MTBE/MeOH，9:1
实施例1.5 2-MeTHF/MeOH，9:1 实施例1.12 n-Heptane/CHCl 3，9:1
实施例1.6 CPME/EtOH，4:1 实施例1.13 Acetone
实施例1.7 IPA/DCM，9:1 实施例1.14 Acetone/H 2O，986:14
实施例1.8 Anisole/MEK，9:1 实施例1.15 Acetone/H 2O，95:5
(ii).化合物1的晶型A的制备(反溶剂添加法)
实施例1.16
称取20mg化合物1加入到20mL的小瓶内，用氯仿溶解，并使用0.45μm的PTFE滤头过滤至另一20mL瓶中。向该澄清溶液中边搅拌(～750rpm)边逐步滴加反溶剂甲苯，直至有固体析出。当反溶剂总体积加至5mL后，停止滴加反溶剂。分离析出的固体并进行XRPD测试。经XRPD检测确定所得固体为化合物1的晶型A。
实施例1.17～1.19
参照实施例1.16的制备方法，用不同的反溶剂体系替换实施例1.16中的氯仿/甲苯反溶剂体系(具体如表2所示)，经XRPD检测确定所得固体均为化合物1的晶型A。
表2：选用不同溶剂制备化合物1的晶型
实施例编号 选用的反溶剂体系
实施例1.17 CHCl 3/EtOAc
实施例1.18 CHCl 3/CPME
实施例1.19 DMSO/IPA
(iii).化合物1的晶型A的制备(50℃打浆法)
实施例1.20
将20mg化合物1放置在玻璃小瓶中，加入0.5mL异丙醇，得到的浑浊液置于50℃下磁力悬浮搅拌(750rpm)约1周，离心(10000rpm，2min)收集固体，经XRPD检测确定所得固体为化合物1的晶型A。
实施例1.21～1.31
参照实施例1.20的制备方法，将实施例1.20中的异丙醇用不同的溶剂替换(具体如表3所示)，经XRPD检测确定所得固体均为化合物1的晶型A。
表3：选用不同溶剂制备化合物1的晶型
Figure PCTCN2021100673-appb-000013
(iv).化合物1的晶型A的制备(缓慢挥发法)
实施例1.37
将20mg化合物1放置在3mL小瓶中，加入0.2～3.0mL甲醇溶解，并使用0.45μm的PTFE滤头过滤至另一3mL小瓶中，用封口膜封住小瓶，并在上面扎1个针孔，放置在室温下缓慢挥发。收集所得固体并进行XRPD测试，确定为化合物1的晶型A。
实施例1.38～1.41
参照实施例1.37的制备方法，用不同的溶剂替换实施例1.37中的甲醇(具体如表4所示)，经XRPD检测确定所得固体均为化合物1的晶型A。
表4：选用不同溶剂制备化合物1的晶型
实施例编号 选用的溶剂(v:v)
实施例1.38 EtOH
实施例1.39 CHCl 3
实施例1.40 EtOAc/MeOH，9:1
实施例1.41 ACN/MeOH,9:1
(v).化合物1的晶型A的制备(温度循环法)
实施例1.42
称取20mg化合物1放置在玻璃小瓶中，加入0.5mL乙醇，得到的悬浮液进行温度循环后(50℃～5℃，0.1℃/min，4个循环)，离心(10000rpm，2min)收集固体并进行XRPD测试，所得固体确定为化合物1的晶型A。
实施例1.43～1.51
参照实施例1.42的制备方法，用不同的溶剂替换实施例1.42中的乙醇(具体如表5所示)，经XRPD检测确定所得固体均为化合物1的晶型A。
表5：选用不同溶剂制备化合物1的晶型
实施例编号 选用的溶剂(v:v)
实施例1.43 1,4-Dioxane
实施例1.44 Anisole
实施例1.45 IPA
实施例1.46 MIBK
实施例1.47 IPAc
实施例1.48 MTBE
实施例1.49 Toluene
实施例1.50 n-Hexane/DMSO，4:1
实施例1.51 ACN/NMP，9:1
(vi).化合物1的晶型A的制备(气-固扩散法)
实施例1.52
称取20mg化合物1放置在3mL小瓶中，另在20mL小瓶中加入约4mL水，将3mL小瓶敞口置于20mL小瓶中后，将20mL小瓶密封。室温下静置约两周后收集固体并进行XRPD测试，确定所得固体为化合物1的晶型A。
实施例1.53～1.59
参照实施例1.52的制备方法，用不同的溶剂替换实施例1.52中的水(具体如表6所示)，经XRPD检测确定所得固体均为化合物1的晶型A。
表6：选用不同溶剂制备化合物1的晶型
实施例编号 选用溶剂
实施例1.53 DCM
实施例1.54 EtOH
实施例1.55 Acetone
实施例1.56 EtOAc
实施例1.57 ACN
实施例1.58 MTBE
实施例1.59 THF
(vii).化合物1的晶型A的制备(气-液扩散法)
实施例1.60
称取20mg化合物1放置在3mL小瓶中，加入0.2～3.0mL乙醇溶解，并使用0.45μm的PTFE滤头过滤至另一3mL小瓶中，另取20mL的小瓶向其中加入约3mL的反溶剂乙腈，将装有清液的3mL小瓶敞口置于20mL小瓶后，密封20mL的小瓶并于室温下静置。收集得到的固体并进行XRPD测试，确定所得固体为化合物1的晶型A。
实施例1.61～1.63
参照实施例1.60的制备方法，将实施例1.60中的乙醇/乙腈反溶剂体系用不同的反溶剂体系替换(具体如表7所示)，经XRPD检测确定所得固体均为化合物1的晶型A。
表7：选用不同的反溶剂体系制备化合物1的晶型
实施例编号 选用的反溶剂体系
实施例1.61 NMP/IPAc
实施例1.62 DMF/ACN
实施例1.63 DMF/Cyclohexane
(viii).化合物1的晶型A的制备(高聚物诱导法)
实施例1.64
称取20mg化合物1于3mL小瓶中，加入0.2～5.0mL乙醇溶解，并使用0.45μm的PTFE滤头过滤至另一3mL小瓶中，加入～2mg混合高聚物A，用封口膜封住小瓶，并在上面扎1个针孔，放置在室温下缓慢挥发。混合高聚物A的组成为：聚乙烯吡咯烷酮、聚乙烯醇、聚氯乙烯、聚醋酸乙烯酯、羟丙基甲基纤维素和甲基纤维素(等质量混合)。收集得到的固体并进行XRPD测试，确定所得固体为化合物1的晶型A。
实施例1.65
称取20mg化合物1于3mL小瓶中，加入0.2～5.0mL氯仿溶解，并使用0.45μm的PTFE滤头过滤至另一3mL小瓶中，加入～2mg混合高聚物B，用封口膜封住小瓶，并在上面扎1个针孔，放置在室温下缓慢挥发。混合高聚物B的组成 为：聚己酸内酯、聚乙二醇、聚甲基丙烯酸甲酯、海藻酸钠和羟乙基纤维素(等质量混合)。收集得到的固体并进行XRPD测试，确定所得固体为化合物1的晶型A。
(ix).化合物1的晶型A的制备(研磨法)
实施例1.66
称取20mg化合物1置于研钵中，研磨15分钟后收集固体并进行XRPD测试，确定所得固体为化合物1的晶型A。
(x).化合物1的晶型A的表征数据
XRPD数据
化合物1的晶型A的XRPD图谱如图1所示，在XRPD图谱中的峰及其相关强度以及晶面间距数据如表8所示。
表8：化合物1的晶型A的XRPD图谱中的峰
Figure PCTCN2021100673-appb-000014
Figure PCTCN2021100673-appb-000015
DSC和TGA数据
化合物1的晶型A的DSC图谱和TGA图谱如图2所示。DSC图谱显示化合物1的晶型A在153.7℃(峰值温度)处有一个非常浅的放热峰，随后在约262.0℃(峰值温度)处具有一个急剧的吸热峰，该急剧的吸热峰对应于晶型A的熔化。TGA图谱显示化合物1的晶型A在120℃之前失重为1.69％，表明化合物1的晶型A为无水合物晶型。
DVS引湿性数据
通过DVS测试对化合物1的晶型A进行了引湿性评估。DVS图谱如图13所示。DVS测试结果显示，化合物1的晶型A在相对湿度80.0％下吸湿增重为1.88％，表明其略有引湿性。化合物1的晶型A在DVS测试前后的XRPD图谱如图14所示，其中显示晶型A在DVS测试前后晶型一致。
(xi).化合物1的晶型A的稳定性考察
实施例1.67
将化合物1的晶型A分别在60℃/闭口条件下放置24小时、25℃/60％RH和40℃/75％RH条件下敞口放置1周后，通过XRPD和HPLC检测样品的物理和化学稳定性，结果汇总于如下表9。
HPLC测试结果如图11A～11E所示。由HPLC测试结果可以看出，化合物1的晶型A在上述三种稳定性试验条件下放置后均未发生明显的纯度变化，保持极高的纯度(约98％)，表现出良好的化学稳定性。XRPD测试结果如图12所示，化合物1的晶型A在60℃/闭口条件下放置24小时以及在25℃/60％RH条件下敞口放置1周后，均未出现晶型转变，在40℃/75％RH条件下敞口放置1周后，仅有部分晶型A转为水合物晶型B。
表9：晶型A样品稳定性的试验结果汇总(HPLC纯度)
Figure PCTCN2021100673-appb-000016
实施例1.68
将化合物1的晶型A置于氮气保护下加热至不同温度(分别为30℃、92℃、118℃、132℃和175℃)并降温后进行XRPD测试。变温XRPD图谱如图15所示，结果表明，化合物1的晶型A在加热过程中未发生晶型转变(在高温下观察到的微小偏移由高温下晶格伸缩引起)。
由以上稳定性考察可以看出，化合物1的晶型A具有极好的稳定性。
实施例2：化合物1的晶型B的制备、表征与稳定性考察
(i).化合物1的晶型B的制备(反溶剂添加法)
实施例2.1
将称取29.8mg化合物1加入到20mL瓶中，加入4.0mL甲醇将其溶解，并使用0.45μm的PTFE滤头过滤至另一20mL瓶中，后加入8.0mL水至析出沉淀，继续加入2.0mL水至无更多沉淀析出。室温下搅拌1h后，离心分离固体(10000rpm，2min)并测试其XRPD。经XRPD检测确定所得固体为化合物1的晶型B。
实施例2.2
参照实施例2.1的制备方法，用二甲亚砜/水反溶剂体系替换实施例2.1中的甲醇/水反溶剂体系，经XRPD检测确定所得固体为化合物1的晶型B。
(ii).化合物1的晶型B的制备(缓慢挥发法)
将20mg化合物1放置在玻璃小瓶中，加入0.2～3.0mL甲基叔丁基醚/甲醇(9:1，v:v)溶解，并使用0.45μm的PTFE滤头过滤至另一3mL小瓶中，用封口膜封住小瓶，并在上面扎1个针孔，放置在室温下缓慢挥发。收集所得固体并进行XRPD测试，确定为化合物1的晶型B。
(iii).化合物1的晶型B的表征数据
1H NMR数据
化合物1的晶型B的 1H NMR图谱如图16所示。由 1H NMR图谱可知，化合物1的晶型B在制备过程中未发生分解，且观察到明显的水信号。
XRPD数据
化合物1的晶型B的XRPD图谱如图3所示，在XRPD图谱中的峰及其相关强度以及晶面间距数据如表10所示。
表10：化合物1的晶型B的XRPD图谱中的峰
Figure PCTCN2021100673-appb-000017
Figure PCTCN2021100673-appb-000018
DSC和TGA数据
化合物1的晶型B的DSC图谱和TGA图谱如图4所示。DSC图谱显示化合物1的晶型B在113.5℃和266.8℃(峰值温度)处共有两个急剧的吸热峰，另外在161.8℃(峰值温度)有一个放热峰。TGA图谱显示化合物1的晶型B在120℃前失重为12.75％。
(iv).化合物1的晶型B的稳定性考察
实施例2.2
将化合物1的晶型B置于氮气保护下加热至不同温度(分别为130℃和180℃)并冷却至室温后进行XRPD测试。变温XRPD图谱如图20所示，结果表明，当将晶型B加热至130℃并冷却至室温后，晶型B转化无定形形式；当将晶型B加热至180℃并冷却至室温后，晶型B转化为晶型A。
根据化合物1的晶型B的制备方法、热分析数据、 1H NMR测试和变温XRPD测试结果，推测晶型B为水合物，其中水分子与化合物1的摩尔比为约3.9:1， 其在高温加热过程中首先脱水转化为无定形形式，随后经过高温重结晶转化为晶型A。
实施例3：化合物1的晶型C的制备、表征与稳定性考察
(i).化合物1的晶型C的制备(室温打浆法)
实施例3.1
将化合物1(20mg)放置在玻璃小瓶中，加入0.5mL丙酮/水(6:4，v:v)配成悬浊液，于室温下以～750rpm转速悬浮搅拌约48小时后，离心(10000rpm，2min)收集固体。对所收集的固体进行XRPD表征，确定所得固体为化合物1的晶型C。
实施例3.2
参照实施例3.1的制备方法，用1,4-二氧六环/水(4:1，v:v)替换实施例3.1中的丙酮/水，经XRPD检测确定所得固体为化合物1的晶型C。
(ii).化合物1的晶型C的制备(缓慢挥发法)
实施例3.3
称取20mg的化合物1至3mL小瓶中，加入3.0mL水/乙醇(4:1，v:v)溶解，并使用0.45μm的PTFE滤头过滤至另一3mL小瓶中，用封口膜封住小瓶，并在上面扎1个针孔，放置在室温下缓慢挥发。收集所得固体并进行XRPD测试，确定所得固体为化合物1的晶型C。
(iii).化合物1的晶型C的制备(温度循环法)
实施例3.4
称取20mg化合物1放置在玻璃小瓶中，加入0.5mL水，得到的悬浮液进行温度循环后(50℃～5℃，0.1℃/min，4个循环)，离心(10000rpm，2min)收集固体并进行XRPD测试，确定所得固体为化合物1的晶型C。
(iv).化合物1的晶型C的制备(气-液扩散法)
实施例3.5
称取20mg化合物1放置在3mL小瓶中，加入0.2～3.0mL乙醇溶解，并使用0.45μm的PTFE滤头过滤至另一3mL小瓶中，另取20mL的小瓶向其中加入约3mL的反溶剂正庚烷，将装有清液的3mL小瓶敞口置于20mL小瓶后，密封20mL的小瓶并于室温下静置。收集得到的固体并进行XRPD测试，确定所得固体为化合物1的晶型C。
实施例3.6
参照实施例3.5的制备方法，用乙醇/乙酸乙酯反溶剂体系替换实施例3.5中的乙醇/正庚烷反溶剂体系，经XRPD检测确定所得固体均为化合物1的水合物晶型C。
(v).化合物1的晶型C的表征数据
1H NMR数据
化合物1的晶型C的 1H NMR图谱如图17所示。由 1H NMR图谱可知，化合物1的晶型C在制备过程中未发生分解，且观察到明显的水信号。
XRPD数据
化合物1的晶型C的XRPD图谱如图5所示，在XRPD图谱中的峰及其相关强度以及晶面间距数据如表11所示。
表11：化合物1的晶型C的XRPD图谱中的峰
Figure PCTCN2021100673-appb-000019
Figure PCTCN2021100673-appb-000020
DSC和TGA数据
化合物1的晶型C的DSC图谱和TGA图谱如图6所示。DSC图谱显示化合物1的晶型C在46.4℃(峰值温度)处有一个非常浅的吸热峰，随后在117.2℃、265.6℃(峰值温度)处有两个急剧的吸热峰，另外还在147.0℃(峰值温度)处有一个放热峰。TGA图谱显示化合物1的晶型C在120℃之前失重为12.23％。
(vi).化合物1的晶型C的稳定性考察
实施例3.7
将化合物1的晶型C置于氮气保护下加热至不同温度(分别为130℃和160℃)并冷却至室温后进行XRPD测试。变温XRPD图谱如图21所示，结果表明，当将晶型C加热至130℃并冷却至室温后，晶型C转化为无定形形式；当晶型C加热至160℃并冷却至室温后，晶型C转化为晶型A。
根据化合物1的晶型C的制备方法、热分析数据、 1H NMR测试和变温XRPD测试结果，推测晶型C为水合物，其中水分子与化合物1的摩尔比为约3.7:1， 其在高温加热过程中首先脱水转化为无定形形式，随后经过高温重结晶转化为晶型A。
实施例4：化合物1的晶型D的制备、表征与稳定性考察
(i).化合物1的晶型D的制备(室温打浆法)
实施例4.1
将化合物1(20mg)放置在玻璃小瓶中，加入0.5mL二氯甲烷配成悬浊液，于室温下以～750rpm转速悬浮搅拌约一周后，离心(10000rpm，2min)收集固体。对所收集的固体进行XRPD表征，确定所得固体为化合物1的晶型D。
(ii).化合物1的晶型D的制备(缓慢挥发法)
实施例4.2
称取20mg的化合物1至3mL小瓶中，加入3.0mL二氯甲烷溶解，并使用0.45μm的PTFE滤头过滤至另一3mL小瓶中，用封口膜封住小瓶，并在上面扎1个针孔，放置在室温下缓慢挥发。收集所得固体并进行XRPD测试，确定所得固体为化合物1的晶型D。
(iii).化合物1的晶型D的表征数据
1H NMR数据
化合物1的晶型D的 1H NMR图谱如图18所示。由 1H NMR图谱可知，化合物1的晶型D在制备过程中未发生分解，且观察到明显的二氯甲烷信号。
XRPD数据
化合物1的晶型D的XRPD图谱如图7所示，在XRPD图谱中的峰及其相关强度以及晶面间距数据如表12所示。
表12：化合物1的晶型D的XRPD图谱中的峰
Figure PCTCN2021100673-appb-000021
Figure PCTCN2021100673-appb-000022
DSC和TGA数据
化合物1的晶型D的DSC图谱和TGA图谱如图8所示。DSC图谱显示化合物1的晶型D在59.8℃、124.1℃和129.8℃(峰值温度)处共有三个吸热峰。TGA图谱显示化合物1的晶型D在150℃前失重为13.08％。
(iv).化合物1的晶型D的稳定性考察
将化合物1的晶型D置于氮气保护下加热至不同温度(分别为100℃和160℃)并冷却至室温后进行XRPD测试。变温XRPD图谱如图22所示，结果表明，当将晶型D加热至100℃并冷却至室温后，结晶度明显下降；当将晶型D加热至160℃并冷却至室温后，观察到晶型A的衍射信号。
根据化合物1的晶型D的制备方法、热分析数据、 1H NMR测试和变温XRPD测试结果，推测晶型D为二氯甲烷溶剂化物，其中二氯甲烷与化合物1的摩尔比为约0.8:1，其在高温加热过程中脱溶剂并经过高温重结晶转化为晶型A。
实施例5：化合物1的晶型E的制备、表征与稳定性考察
(i).化合物1的晶型E的制备(缓慢挥发法)
实施例5.1
称取20mg的化合物1至3mL小瓶中，加入3.0mL异丙醇/氯仿(9:1，v:v)溶解，并使用0.45μm的PTFE滤头过滤至另一3mL小瓶中，用封口膜封住小 瓶，并在上面扎1个针孔，放置在室温下缓慢挥发。收集所得固体并进行XRPD测试，确定所得固体为化合物1的晶型E。
(ii).化合物1的晶型E的表征数据
1H NMR数据
化合物1的晶型E的 1H NMR图谱如图19所示。由 1H NMR图谱可知，化合物1的晶型E在制备过程中未发生分解，且观察到明显的异丙醇信号。
XRPD数据
化合物1的晶型E的XRPD图谱如图9所示，在XRPD图谱中的峰及其相关强度以及晶面间距数据如表13所示。
表13：化合物1的晶型E的XRPD图谱中的峰
Figure PCTCN2021100673-appb-000023
Figure PCTCN2021100673-appb-000024
DSC和TGA数据
化合物1的晶型E的DSC图谱和TGA图谱如图10所示。DSC图谱显示化合物1的晶型E在123.6℃和269.0℃(峰值温度)处共有两个吸热峰。TGA图谱显示化合物1的晶型E在100℃之前失重为4.96％，在100至150℃之间失重为12.54％。
(iii).化合物1的晶型E的稳定性考察
实施例5.2
将化合物1的晶型E置于氮气保护下加热至不同温度(分别为96℃和180℃)并冷却至室温后进行XRPD测试。变温XRPD图谱如图23所示，结果表明，当将晶型E加热至96℃并冷却至室温后，观察到少量晶型A的衍射信号；当将晶型E加热至180℃并冷却至室温后，晶型E完全转化为晶型A。
根据化合物1的晶型E的制备方法、热分析数据、 1H NMR测试和变温XRPD测试结果，推测晶型E为异丙醇溶剂化物，其中异丙醇分子与化合物1的摩尔比为约1:1，其在高温加热过程中经过重结晶转化为晶型A。

Claims (77)

  1. 一种式(I)所示的化合物1的晶型A，其特征在于，所述晶型A的X-射线粉末衍射图谱具有一个或多个选自下组的峰：约6.46°、约12.64°和约12.93°2θ
    Figure PCTCN2021100673-appb-100001
  2. 如权利要求1所述的晶型A，其特征在于，所述晶型A的X-射线粉末衍射图谱具有所有选自下组的峰：约6.46°、约12.64°和约12.93°2θ。
  3. 如权利要求1所述的晶型A，其特征在于，所述晶型A的X-射线粉末衍射图谱还具有一个或多个选自下组的峰：约13.50°、约14.60°、约16.49°、约17.66°、约18.27°和约23.04°2θ。
  4. 如权利要求3所述的晶型A，其特征在于，所述晶型A的X-射线粉末衍射图谱还具有两个或更多个选自下组的峰：约13.50°、约14.60°、约16.49°、约17.66°、约18.27°和约23.04°2θ。
  5. 如权利要求3所述的晶型A，其特征在于，所述晶型A的X-射线粉末衍射图谱还具有三个或更多个选自下组的峰：约13.50°、约14.60°、约16.49°、约17.66°、约18.27°和约23.04°2θ。
  6. 如权利要求3所述的晶型A，其特征在于，所述晶型A的X-射线粉末衍射图谱还具有所有选自下组的峰：约13.50°、约14.60°、约16.49°、约17.66°、约18.27°和约23.04°2θ。
  7. 如前述权利要求中任一项所述的晶型A，其特征在于，所述晶型A的X-射线粉末衍射图谱还具有一个或多个选自下组的峰：约23.61°、约25.42°、约25.79°和约27.83°2θ。
  8. 如前述权利要求中任一项所述的晶型A，其特征在于，所述晶型A的X-射线粉末衍射图谱还具有两个或更多个选自下组的峰：约23.61°、约25.42°、约25.79°和约27.83°2θ。
  9. 如前述权利要求中任一项所述的晶型A，其特征在于，所述晶型A的X-射线粉末衍射图谱还具有三个或更多个选自下组的峰：约23.61°、约25.42°、约25.79°和约27.83°2θ。
  10. 如前述权利要求中任一项所述的晶型A，其特征在于，所述晶型A的X-射线粉末衍射图谱还具有所有选自下组的峰：约23.61°、约25.42°、约25.79°和约27.83°2θ。
  11. 如前述权利要求中任一项所述的晶型A，其特征在于，所述晶型A的X-射线粉末衍射图谱具有所有选自下组的峰：
    Figure PCTCN2021100673-appb-100002
  12. 如前述权利要求中任一项所述的晶型A，其特征在于，所述晶型A的X-射线粉末衍射图谱如图1所示。
  13. 如前述权利要求中任一项所述的晶型A，其特征在于，所述晶型A的差示扫描量热(DSC)图谱包括于约262.0℃处的吸热峰。
  14. 如权利要求13所述的晶型A，其特征在于，所述晶型A的差示扫描量热(DSC)图谱如图2所示。
  15. 一种式(I)所示的化合物1的水合物的晶型B，其特征在于，所述晶型 B的X-射线粉末衍射图谱具有一个或多个选自下组的峰：约7.36°、约10.82°和约11.10°2θ
    Figure PCTCN2021100673-appb-100003
  16. 如权利要求15所述的晶型B，其特征在于，所述晶型B的X-射线粉末衍射图谱具有所有选自下组的峰：约7.36°、约10.82°和约11.10°2θ。
  17. 如权利要求15所述的晶型B，其特征在于，所述晶型B的X-射线粉末衍射图谱还具有一个或多个选自下组的峰：约14.70°、约15.99°、约20.96°和约23.78°2θ。
  18. 如权利要求15所述的晶型B，其特征在于，所述晶型B的X-射线粉末衍射图谱还具有两个或更多个选自下组的峰：约14.70°、约15.99°、约20.96°和约23.78°2θ。
  19. 如权利要求15所述的晶型B，其特征在于，所述晶型B的X-射线粉末衍射图谱还具有三个或更多个选自下组的峰：约14.70°、约15.99°、约20.96°和约23.78°2θ。
  20. 如权利要求15所述的晶型B，其特征在于，所述晶型B的X-射线粉末衍射图谱还具有所有选自下组的峰：约14.70°、约15.99°、约20.96°和约23.78°2θ。
  21. 如权利要求15所述的晶型B，其特征在于，所述晶型B的X-射线粉末衍射图谱具有所有选自下组的峰：
    Figure PCTCN2021100673-appb-100004
  22. 如权利要求15-21中任一项所述的晶型B，其特征在于，所述晶型B的X-射线粉末衍射图谱如图3所示。
  23. 如权利要求15-22中任一项所述的晶型B，其特征在于，所述晶型B的差示扫描量热(DSC)图谱包括于约113.5℃和约266.8℃处的吸热峰。
  24. 如权利要求23所述的晶型B，其特征在于，所述晶型B的差示扫描量热(DSC)图谱如图4所示。
  25. 如权利要求15-24中任一项所述的晶型B，其特征在于，在所述晶型B中水分子与所述化合物1的摩尔比为约3.9:1。
  26. 一种式(I)所示的化合物1的水合物的晶型C，其特征在于，所述晶型C的X-射线粉末衍射图谱具有一个或多个选自下组的峰：约7.33°、约11.08°和约14.70°2θ
    Figure PCTCN2021100673-appb-100005
  27. 如权利要求26所述的晶型C，其特征在于，所述晶型C的X-射线粉末衍射图谱具有所有选自下组的峰：约7.33°、约11.08°和约14.70°2θ。
  28. 如权利要求26所述的晶型C，其特征在于，所述晶型C的X-射线粉末衍射图谱还具有一个或多个选自下组的峰：约16.23°、约18.85°、约21.20°、约22.03°和约24.33°2θ。
  29. 如权利要求26所述的晶型C，其特征在于，所述晶型C的X-射线粉末衍射图谱还具有两个或更多个选自下组的峰：约16.23°、约18.85°、约21.20°、约22.03°和约24.33°2θ。
  30. 如权利要求26所述的晶型C，其特征在于，所述晶型C的X-射线粉末衍射图谱还具有三个或更多个选自下组的峰：约16.23°、约18.85°、约21.20°、 约22.03°和约24.33°2θ。
  31. 如权利要求26所述的晶型C，其特征在于，所述晶型C的X-射线粉末衍射图谱还具有所有选自下组的峰：约16.23°、约18.85°、约21.20°、约22.03°和约24.33°2θ。
  32. 如权利要求26-31中任一项所述的晶型C，其特征在于，所述晶型C的X-射线粉末衍射图谱还具有一个或多个选自下组的峰：约15.20°、约20.05°、约23.70°和约29.13°2θ。
  33. 如权利要求26-32中任一项所述的晶型C，其特征在于，所述晶型C的X-射线粉末衍射图谱还具有两个或更多个选自下组的峰：约15.20°、约20.05°、约23.70°和约29.13°2θ。
  34. 如权利要求26-33中任一项所述的晶型C，其特征在于，所述晶型C的X-射线粉末衍射图谱还具有三个或更多个选自下组的峰：约15.20°、约20.05°、约23.70°和约29.13°2θ。
  35. 如权利要求26-34中任一项所述的晶型C，其特征在于，所述晶型C的X-射线粉末衍射图谱还具有所有选自下组的峰：约15.20°、约20.05°、约23.70°和约29.13°2θ。
  36. 如权利要求26-35中任一项所述的晶型C，其特征在于，所述晶型C的X-射线粉末衍射图谱具有所有选自下组的峰：
    Figure PCTCN2021100673-appb-100006
  37. 如权利要求26-36中任一项所述的晶型C，其特征在于，所述晶型C的 X-射线粉末衍射图谱如图5所示。
  38. 如权利要求26-37中任一项所述的晶型C，其特征在于，所述晶型C的差示扫描量热(DSC)图谱包括于约117.2℃和约265.6℃处的吸热峰。
  39. 如权利要求38所述的晶型C，其特征在于，所述晶型C的差示扫描量热(DSC)图谱如图6所示。
  40. 如权利要求26-39中任一项所述的晶型C，其特征在于，在所述晶型C中水分子与所述化合物1的摩尔比为约3.7:1。
  41. 一种式(I)所示的化合物1的二氯甲烷溶剂化物的晶型D，其特征在于，所述晶型D的X-射线粉末衍射图谱具有一个或多个选自下组的峰：约8.24°、约13.46°和约15.32°2θ
    Figure PCTCN2021100673-appb-100007
  42. 如权利要求41所述的晶型D，其特征在于，所述晶型D的X-射线粉末衍射图谱具有所有选自下组的峰：约8.24°、约13.46°和约15.32°2θ。
  43. 如权利要求41所述的晶型D，其特征在于，所述晶型D的X-射线粉末衍射图谱还具有一个或多个选自下组的峰：约12.89°、约15.90°和约16.84°2θ。
  44. 如权利要求41所述的晶型D，其特征在于，所述晶型D的X-射线粉末衍射图谱还具有两个或更多个选自下组的峰：约12.89°、约15.90°和约16.84°2θ。
  45. 如权利要求41所述的晶型D，其特征在于，所述晶型D的X-射线粉末衍射图谱还具有所有选自下组的峰：约12.89°、约15.90°和约16.84°2θ。
  46. 如权利要求41-45中任一项所述的晶型D，其特征在于，所述晶型D的X-射线粉末衍射图谱还具有一个或多个选自下组的峰：约18.45°、约 21.83°、约23.08°、约23.80°和约25.59°2θ。
  47. 如权利要求41-46中任一项所述的晶型D，其特征在于，所述晶型D的X-射线粉末衍射图谱还具有两个或更多个选自下组的峰：约18.45°、约21.83°、约23.08°、约23.80°和约25.59°2θ。
  48. 如权利要求41-47中任一项所述的晶型D，其特征在于，所述晶型D的X-射线粉末衍射图谱还具有三个或更多个选自下组的峰：约18.45°、约21.83°、约23.08°、约23.80°和约25.59°2θ。
  49. 如权利要求41-48中任一项所述的晶型D，其特征在于，所述晶型D的X-射线粉末衍射图谱还具有所有选自下组的峰：约18.45°、约21.83°、约23.08°、约23.80°和约25.59°2θ。
  50. 如权利要求41-49中任一项所述的晶型D，其特征在于，所述晶型D的X-射线粉末衍射图谱具有所有选自下组的峰：
    Figure PCTCN2021100673-appb-100008
  51. 如权利要求41-50中任一项所述的晶型D，其特征在于，所述晶型D的X-射线粉末衍射图谱如图7所示。
  52. 如权利要求41-52中任一项所述的晶型D，其特征在于，所述晶型D的差示扫描量热(DSC)图谱包括于约124.1℃处的吸热峰。
  53. 如权利要求41-53中任一项所述的晶型D，其特征在于，所述晶型D的差示扫描量热(DSC)图谱如图8所示。
  54. 如权利要求41-53中任一项所述的晶型D，其特征在于，在所述晶型D中二氯甲烷分子与所述化合物1的摩尔比为约0.8:1。
  55. 一种式(I)所示的化合物1的异丙醇溶剂化物的晶型E，其特征在于，所述晶型E的X-射线粉末衍射图谱具有一个或多个选自下组的峰：约9.10°、约13.49°和约18.24°2θ
    Figure PCTCN2021100673-appb-100009
  56. 如权利要求55所述的晶型E，其特征在于，所述晶型E的X-射线粉末衍射图谱具有所有选自下组的峰：约9.10°、约13.49°和约18.24°2θ。
  57. 如权利要求55所述的晶型E，其特征在于，所述晶型E的X-射线粉末衍射图谱还具有一个或多个选自下组的峰：约13.03°、约20.13°、约22.63°、约23.35°、约25.06°、约27.51°和约29.46°2θ。
  58. 如权利要求55所述的晶型E，其特征在于，所述晶型E的X-射线粉末衍射图谱还具有两个或更多个选自下组的峰：约13.03°、约20.13°、约22.63°、约23.35°、约25.06°、约27.51°和约29.46°2θ。
  59. 如权利要求55所述的晶型E，其特征在于，所述晶型E的X-射线粉末衍射图谱还具有三个或更多个选自下组的峰：约13.03°、约20.13°、约22.63°、约23.35°、约25.06°、约27.51°和约29.46°2θ。
  60. 如权利要求55所述的晶型E，其特征在于，所述晶型E的X-射线粉末衍射图谱还具有所有选自下组的峰：约13.03°、约20.13°、约22.63°、约23.35°、约25.06°、约27.51°和约29.46°2θ。
  61. 如权利要求55-60中任一项所述的晶型E，其特征在于，所述晶型E的X-射线粉末衍射图谱具有所有选自下组的峰：
    Figure PCTCN2021100673-appb-100010
    Figure PCTCN2021100673-appb-100011
  62. 如权利要求55-62中任一项所述的晶型E，其特征在于，所述晶型E的X-射线粉末衍射图谱如图9所示。
  63. 如权利要求55-62中任一项所述的晶型E，其特征在于，所述晶型E的差示扫描量热(DSC)图谱包括于约123.6℃和约269.0℃处的吸热峰。
  64. 如权利要求55-63中任一项所述的晶型E，其特征在于，所述晶型E的差示扫描量热(DSC)图谱如图10所示。
  65. 如权利要求55-64中任一项所述的晶型E，其特征在于，在所述晶型E中异丙醇分子与所述化合物1的摩尔比为约1:1。
  66. 如权利要求1-65中任一项所述的晶型，其特征在于，所述晶型是基本上纯的晶型，其中所述基本上纯是指具有大于90wt％的纯度。
  67. 一种药物组合物，其包含式(I)所示的化合物1和药学上可接受的载体，所述化合物1具有选自如下的晶型：如权利要求1-14中任一项所述的晶型A、如权利要求15-25中任一项所述的晶型B、如权利要求26-40中任一项所述的晶型C、如权利要求41-54中任一项所述的晶型D以及如权利要求55-65中任一项所述的晶型E。
  68. 如权利要求67所述的药物组合物，其中至少约85％、至少约90％、至少约95％、至少约99％、至少约99.5％、至少约99.9％或至少约99.99％的化合物1具有晶型A。
  69. 如权利要求67所述的药物组合物，其中至少约85％、至少约90％、至少约95％、至少约99％、至少约99.5％、至少约99.9％或至少约99.99％的化合物1具有晶型B。
  70. 如权利要求67所述的药物组合物，其中至少约85％、至少约90％、至少约95％、至少约99％、至少约99.5％、至少约99.9％或至少约99.99％的 化合物1具有晶型C。
  71. 如权利要求67所述的药物组合物，其中至少约85％、至少约90％、至少约95％、至少约99％、至少约99.5％、至少约99.9％或至少约99.99％的化合物1具有晶型D。
  72. 如权利要求67所述的药物组合物，其中至少约85％、至少约90％、至少约95％、至少约99％、至少约99.5％、至少约99.9％或至少约99.99％的化合物1具有晶型E。
  73. 如权利要求67所述的药物组合物，其进一步包括其他治疗剂。
  74. 一种药物组合物的制备方法，其包括将如权利要求1-66中任一项所述的晶型和药学上可接受的载体进行混合。
  75. 如权利要求1-66中任一项所述的晶型或如权利要求67-73中任一项所述的药物组合物在以下中的用途：
    (a)制备预防或治疗与SHP2活性/水平异常相关的疾病或病症的药物；
    (b)制备预防或治疗SHP2-介导的疾病或病症的药物；
    (c)制备抑制SHP2活性/水平的抑制剂药物；
    (d)体外非治疗性地抑制SHP2活性/水平；
    (e)体外非治疗性地抑制肿瘤细胞增殖；或
    (f)治疗与SHP2活性/水平异常相关的疾病或病症。
  76. 根据权利要求75所述的用途，其中，所述与SHP2活性/水平异常相关的疾病或病症或者SHP2-介导的疾病或病症为癌症，所述癌症选自下组：努南综合征、豹皮综合征、青少年髓单核细胞白血病、成神经细胞瘤、黑色素瘤、急性髓性白血病、乳腺癌、食道癌、肺癌、结肠癌、头癌、头颈的鳞状细胞癌、胃癌、间变性大细胞淋巴瘤、成胶质细胞瘤、肝细胞癌(HCC)、急性淋巴细胞白血病、肾上腺皮质癌、肛门癌、阑尾癌、星形细胞瘤、非典型类畸形/类瘤、基底细胞癌、胆管癌、膀胱癌、骨癌(骨肉瘤和恶性纤 维组织细胞瘤)、脑干神经胶质瘤、脑肿瘤、脑和脊髓肿瘤、支气管肿瘤、伯基特(Burkitt)淋巴瘤、子宫颈癌、慢性淋巴细胞性白血病、慢性粒细胞性白血病、结肠直肠癌、颅咽管瘤、胚胎肿瘤、子宫内膜癌、上皮细胞瘤、室管膜瘤、尤因肉瘤家族肿瘤、眼癌、视网膜母细胞瘤、胆囊癌、胃肠道类癌、胃肠道间质瘤(GIST)、胃肠道间质细胞瘤、生殖细胞瘤、神经胶质瘤、毛细胞白血病、头颈癌、霍奇金淋巴瘤、下咽癌、胰岛细胞瘤(内分泌胰腺)、卡波济肉瘤、肾癌、朗格汉斯细胞组织细胞增生症、喉癌、白血病、毛细胞白血病、肝癌、非小细胞肺癌、小细胞肺癌、淋巴瘤、髓母细胞瘤、髓上皮瘤、间皮瘤、口腔癌、多发性骨髓瘤、鼻咽癌、神经母细胞瘤、非霍奇金淋巴瘤、口咽癌、骨肉瘤、恶性骨纤维组织细胞瘤、卵巢癌、卵巢上皮癌、卵巢生殖细胞瘤、卵巢低恶性潜能肿瘤、胰腺癌、乳头状瘤病、甲状旁腺癌、阴茎癌、咽癌、松果体中间分化肿瘤、成骨细胞瘤和幕上原始神经外胚层肿瘤、垂体瘤、浆细胞肿瘤/多发性骨髓瘤、胸膜肺母细胞瘤、原发性中枢神经系统淋巴瘤、前列腺癌、直肠癌、肾细胞(肾)癌、视网膜母细胞瘤、横纹肌肉瘤、唾液腺癌、肉瘤、尤因肉瘤家族肿瘤、肉瘤、卡波西氏病、Sezary综合征、皮肤癌、小肠癌、软组织肉瘤、鳞状细胞癌、幕上原始神经外胚层肿瘤、T细胞淋巴瘤、睾丸癌、喉癌、胸腺瘤和胸腺癌、甲状腺癌、尿道癌、子宫癌、子宫肉瘤、阴道癌、外阴癌、Waldenstrom巨球蛋白血症和Wilms肿瘤。
  77. 一种抑制SHP2活性的方法，其包括以下步骤：对有此需要的受试者施用有效量的如权利要求1-66中任一项所述的晶型，或对有此需要的受试者施用有效量的如权利要求67-73中任一项所述的药物组合物。
PCT/CN2021/100673 2020-06-18 2021-06-17 一种shp2抑制剂的晶型及其组合物、制备方法和用途 WO2021254449A1 (zh)

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