WO2022063229A1 - 含芳氨基喹唑啉的化合物的盐及其制备方法和应用 - Google Patents

含芳氨基喹唑啉的化合物的盐及其制备方法和应用 Download PDF

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WO2022063229A1
WO2022063229A1 PCT/CN2021/120328 CN2021120328W WO2022063229A1 WO 2022063229 A1 WO2022063229 A1 WO 2022063229A1 CN 2021120328 W CN2021120328 W CN 2021120328W WO 2022063229 A1 WO2022063229 A1 WO 2022063229A1
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salt
hydrate
solvate
formula
arylaminoquinazoline
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PCT/CN2021/120328
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English (en)
French (fr)
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周付刚
赫玉霞
张颜
吕健
史凯
底辉锋
杨欣欣
孙静
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石药集团中奇制药技术（石家庄）有限公司
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Priority to KR1020237014117A priority Critical patent/KR20230074785A/ko
Priority to US18/028,120 priority patent/US20230322687A1/en
Priority to CN202180065719.1A priority patent/CN116323564A/zh
Priority to EP21871598.5A priority patent/EP4219476A1/en
Priority to AU2021350982A priority patent/AU2021350982B2/en
Priority to JP2023519337A priority patent/JP2023543281A/ja
Priority to CA3196595A priority patent/CA3196595A1/en
Publication of WO2022063229A1 publication Critical patent/WO2022063229A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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

  • the application belongs to the field of medicinal chemistry, and specifically relates to salts of compounds containing arylaminoquinazoline, and preparation methods and applications thereof.
  • PTKs Protein tyrosine kinases
  • RET Heavy Rearranged during Transfection
  • EGFR is a cell growth factor that can bind to receptor tyrosine kinases, including EGFR (ErbB-1), human epidermal growth factor receptor type 2 HER2 (ErbB-2), and human epidermal growth factor receptor type 3 HER3 (ErbB -3) and type 4 human epidermal growth factor receptor HER4 (ErbB-4), among which, EGFR and HER2 are the most closely related tumor targets in the EGFR family members. Studies have shown that EGFR exhibits overexpression, gene mutation or gene fusion in various tumors such as lung cancer, gastric cancer, epidermoid cancer, renal cancer, ovarian cancer, etc.
  • FGFR mainly includes four subtypes of FGFR1/2/3/4, which are overexpressed or overactivated by gene amplification, mutation, fusion or ligand induction, and have important effects on tumor cell proliferation, invasion and migration and tumor angiogenesis. important role. Studies have found that FGFRs are overexpressed or overactivated in a variety of tumors, such as non-small cell lung cancer, gastric cancer, colorectal cancer, esophageal cancer, liver cancer, and biliary tract cancer.
  • RET resonin receptor mediated endometrial reonucleic acid
  • kidney development development of the nervous system
  • maintenance and renewal of sperm stem cells differentiation of myelomonocytic cells
  • formation of lymphoid tissue It is expressed in cells such as medullary carcinoma, thyroid C cells and melanoma.
  • medullary carcinoma thyroid C cells
  • melanoma a malignant reonuclear cell proliferation
  • papillary thyroid cancer papillary thyroid cancer
  • colorectal cancer pancreatic cancer
  • melanoma etc.
  • Compound 1 chemical name 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-[(4-N,N-dimethylamino)butoxy]quinazoline, is One with RET, VEGFR (Vascular Endothelial Growth Factor Receptor (VEGFR)), FGFR, EGFR, FLT (Fms-like tyrosine kinase or Fms Related Receptor Tyrosine Kinase) and other inhibitory activity of multi-target inhibitors.
  • VEGFR Vascular Endothelial Growth Factor Receptor
  • FGFR FGFR
  • EGFR EGFR
  • FLT Fms-like tyrosine kinase or Fms Related Receptor Tyrosine Kinase
  • WO2016023330A1 relates to arylaminoquinazoline-containing compounds as tyrosine kinase inhibitors, and describes compound 1 and its analogs, preparation methods and medical uses.
  • Compound 1 has poor water solubility and cannot meet the general requirements for drug solubility of solid oral dosage forms (should be greater than 0.1 g/L), not to mention the development of other pharmaceutical dosage forms (for example, injections, solutions), Moreover, the water solubility of the drug is also the main factor affecting the dissolution, absorption and pharmacokinetic properties of the drug. Therefore, it is necessary to modify compound 1 to optimize its physicochemical properties and improve its druggability.
  • the application provides a salt, a solvate or a hydrate of the arylaminoquinazoline-containing compound represented by formula 2:
  • HA is hydrochloric acid, sulfuric acid, oxalic acid or maleic acid
  • n is an integer or half-integer of 1/2-2;
  • n 0.5, 1.5 or 2.
  • the application provides the salt of the arylaminoquinazoline-containing compound represented by formula 2, the crystalline form of its solvate or hydrate:
  • HA is hydrochloric acid, sulfuric acid, oxalic acid or maleic acid
  • n is an integer or half-integer of 1/2-2;
  • n 0.5, 1.5 or 2.
  • the present application provides a pharmaceutical composition, which comprises a salt of the arylaminoquinazoline-containing compound shown in the aforementioned formula 2, a solvate or hydrate thereof, or the arylaminoquinazoline-containing compound shown in the formula 2. Salts of the compounds of oxazolines, crystalline forms of solvates or hydrates thereof, and containing one or more pharmaceutically acceptable carriers.
  • the present application provides the salt of the arylaminoquinazoline-containing compound shown in the aforementioned formula 2, its solvate or hydrate, the salt of the arylaminoquinazoline-containing compound shown in the formula 2, and its Use of a solvate or a crystalline form of a hydrate or a pharmaceutical composition of the foregoing for the manufacture of a medicament as a receptor tyrosine kinase inhibitor.
  • the present application also provides salts of the arylaminoquinazoline-containing compounds represented by the aforementioned formula 2, solvates or hydrates thereof, salts of the arylaminoquinazoline-containing compounds represented by formula 2, and solvates thereof Or the crystalline form of hydrate or the use of the aforementioned pharmaceutical composition in the preparation of antitumor drugs.
  • the present application also provides the salt of the arylaminoquinazoline-containing compound shown in the aforementioned formula 2, its solvate or hydrate, the salt of the arylaminoquinazoline-containing compound shown in the formula 2, Use of a solvate or crystalline form of the hydrate or the aforementioned pharmaceutical composition in the treatment of receptor tyrosine kinase-related diseases.
  • the present application also provides salts of the arylaminoquinazoline-containing compounds represented by the aforementioned formula 2, solvates or hydrates thereof, salts of the arylaminoquinazoline-containing compounds represented by formula 2, and solvates thereof Or the use of a crystalline form of a hydrate or the aforementioned pharmaceutical composition in the treatment of tumors.
  • the application also provides a method for treating a patient's receptor tyrosine kinase-related disease, comprising administering to the patient a therapeutically effective amount of the salt of the arylaminoquinazoline-containing compound represented by the aforementioned formula 2, Its solvate or hydrate, the salt of the arylaminoquinazoline-containing compound represented by formula 2, the crystalline form of its solvate or hydrate, or the aforementioned pharmaceutical composition.
  • the present application also provides a method for treating a tumor disease in a patient, comprising administering to the patient a therapeutically effective amount of the salt of the arylaminoquinazoline-containing compound represented by the aforementioned formula 2, its solvate or hydrate, the formula 2
  • the indicated salt of the arylaminoquinazoline-containing compound, the crystalline form of its solvate or hydrate, or the aforementioned pharmaceutical composition comprising administering to the patient a therapeutically effective amount of the salt of the arylaminoquinazoline-containing compound represented by the aforementioned formula 2, its solvate or hydrate, the formula 2
  • the indicated salt of the arylaminoquinazoline-containing compound, the crystalline form of its solvate or hydrate, or the aforementioned pharmaceutical composition comprising administering to the patient a therapeutically effective amount of the salt of the arylaminoquinazoline-containing compound represented by the aforementioned formula 2, its solvate or hydrate, the formula 2
  • the present application also provides a salt, a solvate or a hydrate of the arylaminoquinazoline-containing compound represented by the aforementioned formula 2, a solvate or a hydrate thereof, and a compound represented by the formula 2 for the treatment of receptor tyrosine kinase-related diseases.
  • the present application also provides a salt of the arylaminoquinazoline-containing compound shown in the aforementioned formula 2, its solvate or hydrate, and the arylaminoquinazoline-containing compound shown in formula 2 for the treatment of tumor diseases.
  • the present application provides a salt, a solvate or a hydrate of a compound containing an arylaminoquinazoline shown in formula 2, comprising compounding the arylaminoquinazoline shown in formula 1
  • the compound and acid (HA) are reacted in a suitable solvent, and the salt of the compound containing arylaminoquinazoline shown in formula 2, its solvate or hydrate is obtained by isolation:
  • HA is hydrochloric acid, sulfuric acid, oxalic acid or maleic acid
  • n is an integer or half-integer of 1/2-2;
  • n 0.5, 1.5 or 2.
  • Figure 1 XRPD spectrum of the dihydrochloride salt of Compound 1 obtained in Example 1, its solvate or the crystal form I of its hydrate.
  • Figure 2 The XRPD spectrum of the dihydrochloride salt of Compound 1 obtained in Example 2, its solvate or the crystal form II of its hydrate.
  • FIG. 7 XRPD spectrum of the oxalate salt of Compound 1 obtained in Example 9.
  • FIG. 7 XRPD spectrum of the oxalate salt of Compound 1 obtained in Example 9.
  • Figure 8 DSC-TGA diagram of the dihydrochloride salt of Compound 1 obtained in Example 1, the crystalline form I of its solvate or hydrate.
  • FIG. 9 Thermogravimetric analysis (TGA) diagram of the dihydrochloride salt of Compound 1 obtained in Example 2, its solvate or hydrate form II.
  • Figure 10 XRPD spectrum of the dihydrochloride salt obtained in Example 1, its solvate or hydrate crystal form I after long-term stability test.
  • FIG. 11 XRPD spectrum of the dihydrochloride salt of Compound 1 obtained in Example 5, its solvate or the crystal form III of its hydrate.
  • Figure 13 XRPD spectrum of the dihydrochloride salt of Compound 1 obtained in Example 6, its solvate or hydrate of crystal form IV.
  • Figure 14 DSC-TGA diagram of the dihydrochloride salt of Compound 1 obtained in Example 6, the crystalline form IV of its solvate or hydrate.
  • FIG. 15 XRPD spectrum of the dihydrochloride salt of Compound 1 obtained in Example 7, its solvate or the crystal form V of its hydrate.
  • FIG. 16 DSC-TGA diagram of the dihydrochloride salt of Compound 1 obtained in Example 7, its solvate or hydrate of crystal form V.
  • FIG. 16 DSC-TGA diagram of the dihydrochloride salt of Compound 1 obtained in Example 7, its solvate or hydrate of crystal form V.
  • Figure 17 XRPD spectrum of the dihydrochloride salt of Compound 1 obtained in Example 8, its solvate or hydrate crystal form VII.
  • Figure 18 DSC-TGA diagram of the dihydrochloride salt of Compound 1, its solvate or hydrate crystal form VII obtained in Example 8.
  • Figure 19 XRPD spectrum of the dihydrochloride salt of Compound 1 obtained in Example 10, its solvate or hydrate of crystal form II.
  • the application provides a salt, a solvate or a hydrate of an arylaminoquinazoline-containing compound as shown in formula 2:
  • HA is an acid
  • n is an integer or half-integer of 1/2-2, ie n is 0.5, 1, 1.5 or 2.
  • the HA is hydrochloric acid, sulfuric acid, oxalic acid, maleic acid or malic acid. In some embodiments of the present application, the HA is hydrochloric acid, sulfuric acid, or maleic acid. In some embodiments of the present application, the HA is hydrochloric acid.
  • HA is hydrochloric acid, sulfuric acid, oxalic acid or maleic acid
  • n is an integer or half-integer of 1/2-2, ie n is 0.5, 1, 1.5 or 2; and when HA is hydrochloric acid , and n is 0.5, 1.5 or 2. In some embodiments of the present application, n is 1 or 2.
  • the salt of the arylaminoquinazoline-containing compound, its solvate or hydrate is the hydrochloride of the arylaminoquinazoline-containing compound represented by formula 3, its solvate Compound or Hydrate:
  • n 0.5, 1.5 or 2.
  • the solvate is selected from the group consisting of acetonitrile/water solvate and ethanol solvate.
  • the hydrate is selected from the group consisting of hemihydrate, monohydrate and tetrahydrate.
  • the salt of the arylaminoquinazoline-containing compound, its solvate or hydrate is the hydrochloride represented by formula 3' or its hydrate:
  • n is an integer of 1-2; m is an integer or half-integer of 0-4, that is, m is 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5 or 4; and when n is 1, m is an integer or half-integer from 1 to 4, ie m is 0.5, 1, 1.5, 2, 2.5, 3, 3.5 or 4.
  • n is 2 and m is 0, 0.5, 1, or 4.
  • n is 2 and m is 0 or 4.
  • the salt of the arylaminoquinazoline-containing compound, its solvate or hydrate is the dihydrochloride represented by formula 3" or its hydrate:
  • n is an integer or half-integer from 0 to 4, that is, m is 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5 or 4.
  • the salt of the arylaminoquinazoline-containing compound, its solvate or hydrate is the dihydrochloride represented by formula 3-1:
  • the salt of the arylaminoquinazoline-containing compound, its solvate or hydrate is the dihydrochloride tetrahydrate represented by formula 3-2:
  • the application provides salts, solvates or hydrates of the arylaminoquinazoline-containing compounds of formula 2 in crystalline forms:
  • HA is an acid
  • n is an integer or half-integer of 1/2-2, ie n is 0.5, 1, 1.5 or 2.
  • the HA is hydrochloric acid, sulfuric acid, oxalic acid, maleic acid or malic acid. In some embodiments of the present application, the HA is hydrochloric acid, sulfuric acid, or maleic acid. In some embodiments of the present application, the HA is hydrochloric acid.
  • HA is hydrochloric acid, sulfuric acid, oxalic acid or maleic acid
  • n is an integer or half-integer of 1/2-2, ie n is 0.5, 1, 1.5 or 2; and when HA is hydrochloric acid , and n is 0.5, 1.5 or 2. In some embodiments of the present application, n is 1 or 2.
  • the salt of the arylaminoquinazoline-containing compound, the crystalline form of its solvate or hydrate is the hydrochloride of the arylaminoquinazoline-containing compound represented by formula 3, Its solvate or hydrated crystalline form:
  • n 0.5, 1.5 or 2.
  • the crystalline form of the salt of the arylaminoquinazoline-containing compound, its solvate or hydrate is the dihydrochloride represented by Formula 3-1, its solvate or hydrate
  • the crystalline form of the dihydrochloride represented by Formula 3-1, its solvate or hydrate is selected from crystal form I, crystal form II, crystal form III, crystal form IV, One or more of Form V and Form VII.
  • the crystalline form I is the crystalline form of the dihydrochloride salt represented by formula 3-1:
  • the crystalline form II is the crystalline form of the dihydrochloride tetrahydrate represented by formula 3-2:
  • the dihydrochloride salt represented by Formula 3-1 is irradiated with Cu-K ⁇ at a 2 ⁇ angle (°)
  • the indicated powder X-ray diffraction pattern has characteristic diffraction peaks at the following positions: 12.4 ⁇ 0.2°, 18.8 ⁇ 0.2°, 20.3 ⁇ 0.2°, 24.6 ⁇ 0.2°;
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angles (°) has characteristic diffraction peaks at: 9.8 ⁇ 0.2°, 12.4 ⁇ 0.2°, 18.8 ⁇ 0.2°, 20.3 ⁇ 0.2°, 24.6 ⁇ 0.2°;
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angles (°) has characteristic diffraction peaks at: 8.1 ⁇ 0.2°, 9.8 ⁇ 0.2°, 12.4 ⁇ 0.2°, 18.8 ⁇ 0.2°, 20.3 ⁇ 0.2°, 24.6 ⁇ 0.2°, 29.9 ⁇ 0.2°;
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angles (°) has characteristic diffraction peaks at: 8.1 ⁇ 0.2°, 9.8 ⁇ 0.2°, 12.4 ⁇ 0.2°, 18.8 ⁇ 0.2°, 19.3 ⁇ 0.2°, 20.3 ⁇ 0.2°, 24.6 ⁇ 0.2°, 28.6 ⁇ 0.2°, 29.9 ⁇ 0.2°;
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angles (°) has characteristic diffraction peaks at: 8.1 ⁇ 0.2°, 9.8 ⁇ 0.2°, 12.4 ⁇ 0.2°, 16.1 ⁇ 0.2°, 18.8 ⁇ 0.2°, 19.3 ⁇ 0.2°, 20.3 ⁇ 0.2°, 24.6 ⁇ 0.2°, 28.6 ⁇ 0.2°, 29.9 ⁇ 0.2°, 30.9 ⁇ 0.2°;
  • the relative intensities of the above characteristic peaks are:
  • the relative intensities of the above characteristic peaks are:
  • the powder X-ray diffraction pattern in 2 theta angle (°) has diffraction peaks at:
  • the relative intensity of the above-mentioned diffraction peaks is:
  • Cu-K ⁇ radiation is used, having an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
  • the dihydrochloride represented by Formula 3-1 is measured by DSC-TGA, and its DSC chart is between 200 and 200
  • Two obvious endothermic peaks appeared in the range of 320°C the starting points of the endothermic peaks appeared at 219.1 ⁇ 3°C and 235.1 ⁇ 3°C, respectively, and the peaks appeared at 231.0 ⁇ 3°C and 284.2 ⁇ 3°C;
  • the TGA diagram of the hydrochloride shows that decomposition begins to occur at 205.6 ⁇ 3°C; alternatively, the crystal form I of the dihydrochloride represented by formula 3-1 has a DSC-TGA diagram substantially as shown in FIG. 8 .
  • the crystalline form (crystal form I) of the dihydrochloride represented by Formula 3-1, its solvate or hydrate has a DSC chart at 231.0 ⁇ 5° C. and 284.2 ⁇ 5° C. There are endothermic peaks at °C.
  • the dihydrochloride salt represented by Formula 3-1 the crystalline form of its solvate or hydrate (crystal form I), its TGA diagram begins to decompose at 205.6 ⁇ 5°C .
  • the crystalline form of the dihydrochloride salt represented by Formula 3-1, its solvate or hydrate (crystal form I) has a DSC chart substantially as shown in FIG. 8 .
  • the crystalline form of the dihydrochloride salt represented by Formula 3-1, its solvate or hydrate (crystal form I) has a TGA diagram substantially as shown in FIG. 8 .
  • the dihydrochloride represented by Formula 3-1 is irradiated with Cu-K ⁇ at a 2 ⁇ angle (°)
  • the indicated powder X-ray diffraction pattern has characteristic diffraction peaks at the following positions: 6.0 ⁇ 0.2°, 6.8 ⁇ 0.2°, 12.4 ⁇ 0.2°, 26.0 ⁇ 0.2°;
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angles (°) has characteristic diffraction peaks at: 6.0 ⁇ 0.2°, 6.8 ⁇ 0.2°, 12.4 ⁇ 0.2°, 15.5 ⁇ 0.2°, 26.0 ⁇ 0.2°;
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angles (°) has characteristic diffraction peaks at: 6.0 ⁇ 0.2°, 6.8 ⁇ 0.2°, 12.4 ⁇ 0.2°, 15.5 ⁇ 0.2°, 25.4 ⁇ 0.2°, 26.0 ⁇ 0.2°;
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angles (°) has characteristic diffraction peaks at: 6.0 ⁇ 0.2°, 6.8 ⁇ 0.2°, 12.4 ⁇ 0.2°, 15.5 ⁇ 0.2°, 18.0 ⁇ 0.2°, 24.4 ⁇ 0.2°, 25.4 ⁇ 0.2°, 26.0 ⁇ 0.2°;
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angles (°) has characteristic diffraction peaks at: 6.0 ⁇ 0.2°, 6.8 ⁇ 0.2°, 12.4 ⁇ 0.2°, 15.5 ⁇ 0.2°, 18.0 ⁇ 0.2°, 22.7 ⁇ 0.2°, 24.4 ⁇ 0.2°, 25.4 ⁇ 0.2°, 26.0 ⁇ 0.2°;
  • the relative intensity of the characteristic peak is:
  • the relative intensity of the characteristic peak is:
  • the relative intensity of the characteristic peak is:
  • the relative intensity of the characteristic peak is:
  • the diffraction pattern has characteristic diffraction peaks at the following positions: 6.0 ⁇ 0.2°, 6.8 ⁇ 0.2°, 12.4 ⁇ 0.2°, 15.5 ⁇ 0.2°, 18.0 ⁇ 0.2°, 20.5 ⁇ 0.2°, 22.7 ⁇ 0.2°, 24.4 ⁇ 0.2°, 25.4 ⁇ 0.2°, 26.0 ⁇ 0.2°, 27.5 ⁇ 0.2°;
  • the diffraction pattern has diffraction peaks at the following positions:
  • the relative peak intensity of the above-mentioned diffraction peaks is:
  • the relative peak intensity of the above-mentioned diffraction peaks is:
  • the dihydrochloride of Formula 3-1 a crystalline form of its solvate or hydrate (Form II), using Cu-K ⁇ radiation, has substantially as shown in FIG. 2 or FIG. 19 .
  • X-ray powder diffraction pattern a crystalline form of its solvate or hydrate (Form II), using Cu-K ⁇ radiation.
  • the crystalline form (crystal form II) of the dihydrochloride represented by Formula 3-1, its solvate or hydrate is determined by TGA, and its TGA graph is in the range of 50-140°C Weight loss 12.24 ⁇ 0.20%.
  • the crystalline form (crystal form II) of the dihydrochloride salt represented by Formula 3-1, a solvate or a hydrate thereof has a TGA diagram substantially as shown in FIG. 9 .
  • the dihydrochloride salt represented by Formula 3-1 is irradiated with Cu-K ⁇ at a 2 ⁇ angle (°)
  • the indicated powder X-ray diffraction pattern has characteristic diffraction peaks at the following positions: 12.7 ⁇ 0.2°, 13.3 ⁇ 0.2°, 23.3 ⁇ 0.2°, 29.3 ⁇ 0.2°;
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angles (°) has characteristic diffraction peaks at: 12.7 ⁇ 0.2°, 13.3 ⁇ 0.2°, 17.2 ⁇ 0.2°, 23.3 ⁇ 0.2°, 29.3 ⁇ 0.2°;
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angles (°) has characteristic diffraction peaks at the following positions: 11.5 ⁇ 0.2°, 11.9 ⁇ 0.2°, 12.7 ⁇ 0.2°, 13.3 ⁇ 0.2°, 17.2 ⁇ 0.2°, 23.3 ⁇ 0.2°, 29.3 ⁇ 0.2°;
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angles (°) has characteristic diffraction peaks at the following positions: 11.5 ⁇ 0.2°, 11.9 ⁇ 0.2°, 12.2 ⁇ 0.2°, 12.7 ⁇ 0.2°, 13.3 ⁇ 0.2°, 17.2 ⁇ 0.2°, 23.3 ⁇ 0.2°, 29.3 ⁇ 0.2°;
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angles (°) has characteristic diffraction peaks at the following positions: 11.5 ⁇ 0.2°, 11.9 ⁇ 0.2°, 12.2 ⁇ 0.2°, 12.7 ⁇ 0.2°, 13.3 ⁇ 0.2°, 17.2 ⁇ 0.2°, 17.6 ⁇ 0.2°, 23.0 ⁇ 0.2°, 23.3 ⁇ 0.2°, 29.3 ⁇ 0.2°;
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angles (°) has characteristic diffraction peaks at: 8.4 ⁇ 0.2°, 11.5 ⁇ 0.2°, 11.9 ⁇ 0.2°, 12.2 ⁇ 0.2°, 12.7 ⁇ 0.2°, 13.3 ⁇ 0.2°, 17.2 ⁇ 0.2°, 17.6 ⁇ 0.2°, 23.0 ⁇ 0.2°, 23.3 ⁇ 0.2°, 24.6 ⁇ 0.2°, 29.3 ⁇ 0.2°;
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angles (°) has characteristic diffraction peaks at: 8.4 ⁇ 0.2°, 11.5 ⁇ 0.2°, 11.9 ⁇ 0.2°, 12.2 ⁇ 0.2°, 12.7 ⁇ 0.2°, 13.3 ⁇ 0.2°, 17.2 ⁇ 0.2°, 17.6 ⁇ 0.2°, 23.0 ⁇ 0.2°, 23.3 ⁇ 0.2°, 24.6 ⁇ 0.2°, 28.8 ⁇ 0.2°, 29.3 ⁇ 0.2°;
  • the powder X-ray diffraction pattern in 2 theta angle (°) has diffraction peaks at:
  • Cu-K ⁇ radiation is used, with an X-ray powder diffraction pattern substantially as shown in FIG. 11 .
  • the crystalline form of the dihydrochloride represented by Formula 3-1, its solvate or hydrate (crystal form III) is measured by DSC, and its DSC chart is at 101.52 ⁇ 5°C There are endothermic peaks at 183.70 ⁇ 5°C, respectively.
  • the dihydrochloride salt represented by Formula 3-1, its solvate or the crystalline form of hydrate (crystal form III) is measured by TGA, and its TGA diagram is at room temperature ⁇ 120°C The range weight loss is 6.3 ⁇ 0.20%.
  • the dihydrochloride salt represented by Formula 3-1 is irradiated with Cu-K ⁇ at a 2 ⁇ angle (°)
  • the indicated powder X-ray diffraction pattern has characteristic diffraction peaks at the following positions: 5.4 ⁇ 0.2°, 8.2 ⁇ 0.2°, 13.0 ⁇ 0.2°, 16.5 ⁇ 0.2°;
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angles (°) has characteristic diffraction peaks at: 5.4 ⁇ 0.2°, 8.2 ⁇ 0.2°, 12.0 ⁇ 0.2°, 13.0 ⁇ 0.2°, 16.5 ⁇ 0.2°, 22.8 ⁇ 0.2°;
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angles (°) has characteristic diffraction peaks at: 5.4 ⁇ 0.2°, 8.2 ⁇ 0.2°, 12.0 ⁇ 0.2°, 13.0 ⁇ 0.2°, 16.5 ⁇ 0.2°, 17.8 ⁇ 0.2°, 22.8 ⁇ 0.2°, 29.0 ⁇ 0.2°;
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angles (°) has characteristic diffraction peaks at: 5.4 ⁇ 0.2°, 8.2 ⁇ 0.2°, 11.3 ⁇ 0.2°, 12.0 ⁇ 0.2°, 13.0 ⁇ 0.2°, 16.5 ⁇ 0.2°, 17.8 ⁇ 0.2°, 19.4 ⁇ 0.2°, 22.8 ⁇ 0.2°, 29.0 ⁇ 0.2°;
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angles (°) has characteristic diffraction peaks at the following positions: 5.4 ⁇ 0.2°, 6.4 ⁇ 0.2°, 7.4 ⁇ 0.2°, 8.2 ⁇ 0.2°, 11.3 ⁇ 0.2°, 12.0 ⁇ 0.2°, 13.0 ⁇ 0.2°, 16.5 ⁇ 0.2°, 17.8 ⁇ 0.2°, 19.4 ⁇ 0.2°, 22.8 ⁇ 0.2°, 29.0 ⁇ 0.2°;
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angles (°) has characteristic diffraction peaks at the following positions: 5.4 ⁇ 0.2°, 6.4 ⁇ 0.2°, 7.4 ⁇ 0.2°, 8.2 ⁇ 0.2°, 10.8 ⁇ 0.2°, 11.3 ⁇ 0.2°, 12.0 ⁇ 0.2°, 13.0 ⁇ 0.2°, 14.6 ⁇ 0.2°, 16.5 ⁇ 0.2°, 17.8 ⁇ 0.2°, 19.4 ⁇ 0.2°, 22.8 ⁇ 0.2°, 29.0 ⁇ 0.2°;
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angles (°) has characteristic diffraction peaks at the following positions: 5.4 ⁇ 0.2°, 6.4 ⁇ 0.2°, 7.4 ⁇ 0.2°, 8.2 ⁇ 0.2°, 10.8 ⁇ 0.2°, 11.3 ⁇ 0.2°, 12.0 ⁇ 0.2°, 13.0 ⁇ 0.2°, 14.2 ⁇ 0.2°, 14.6 ⁇ 0.2°, 16.5 ⁇ 0.2°, 16.9 ⁇ 0.2°, 17.8 ⁇ 0.2°, 19.4 ⁇ 0.2°, 22.8 ⁇ 0.2°, 29.0 ⁇ 0.2°;
  • the powder X-ray diffraction pattern in 2 theta angle (°) has diffraction peaks at:
  • Cu-K ⁇ radiation is used, with an X-ray powder diffraction pattern substantially as shown in FIG. 13 .
  • the dihydrochloride salt represented by Formula 3-1, its solvate or the crystalline form of its hydrate (crystal form IV) is measured by DSC, and its DSC chart is at 68.81 ⁇ 5°C There are endothermic peaks at 177.55 ⁇ 5°C, respectively.
  • the dihydrochloride represented by Formula 3-1, its solvate or the crystalline form of hydrate (crystal form IV) is measured by TGA, and its TGA diagram is between room temperature and 150° C. Range weight loss 3.9 ⁇ 0.20%.
  • the crystalline form of the dihydrochloride salt represented by Formula 3-1, its solvate or hydrate (crystal form IV), has a DSC-TGA diagram substantially as shown in FIG. 14 .
  • the dihydrochloride represented by Formula 3-1 is irradiated with Cu-K ⁇ at a 2 ⁇ angle (°)
  • the indicated powder X-ray diffraction pattern has characteristic diffraction peaks at the following positions: 8.4 ⁇ 0.2°, 9.6 ⁇ 0.2°, 19.8 ⁇ 0.2°, 29.2 ⁇ 0.2°;
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angles (°) has characteristic diffraction peaks at: 8.4 ⁇ 0.2°, 9.6 ⁇ 0.2°, 10.5 ⁇ 0.2°, 19.3 ⁇ 0.2°, 19.8 ⁇ 0.2°, 29.2 ⁇ 0.2°;
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angles (°) has characteristic diffraction peaks at: 4.2 ⁇ 0.2°, 6.4 ⁇ 0.2°, 8.4 ⁇ 0.2°, 9.6 ⁇ 0.2°, 10.5 ⁇ 0.2°, 19.3 ⁇ 0.2°, 19.8 ⁇ 0.2°, 29.2 ⁇ 0.2°;
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angles (°) has characteristic diffraction peaks at: 4.2 ⁇ 0.2°, 6.4 ⁇ 0.2°, 8.4 ⁇ 0.2°, 9.6 ⁇ 0.2°, 10.5 ⁇ 0.2°, 15.1 ⁇ 0.2°, 19.3 ⁇ 0.2°, 19.8 ⁇ 0.2°, 21.2 ⁇ 0.2°, 29.2 ⁇ 0.2°;
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angles (°) has characteristic diffraction peaks at: 4.2 ⁇ 0.2°, 6.4 ⁇ 0.2°, 8.4 ⁇ 0.2°, 9.6 ⁇ 0.2°, 10.5 ⁇ 0.2°, 15.1 ⁇ 0.2°, 16.9 ⁇ 0.2°, 19.3 ⁇ 0.2°, 19.8 ⁇ 0.2°, 21.2 ⁇ 0.2°, 24.6 ⁇ 0.2°, 29.2 ⁇ 0.2°;
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angles (°) has characteristic diffraction peaks at: 4.2 ⁇ 0.2°, 6.4 ⁇ 0.2°, 8.4 ⁇ 0.2°, 9.6 ⁇ 0.2°, 10.5 ⁇ 0.2°, 15.1 ⁇ 0.2°, 16.9 ⁇ 0.2°, 19.3 ⁇ 0.2°, 19.8 ⁇ 0.2°, 21.2 ⁇ 0.2°, 24.6 ⁇ 0.2°, 28.9 ⁇ 0.2°, 29.2 ⁇ 0.2°, 29.5 ⁇ 0.2°;
  • Cu-K ⁇ radiation is used, with an X-ray powder diffraction pattern substantially as shown in FIG. 15 .
  • the dihydrochloride salt represented by Formula 3-1, its solvate or the crystalline form of hydrate (crystal form V) is measured by DSC, and its DSC chart is at 48.29 ⁇ 5°C , 153.99 ⁇ 5°C and 190.59 ⁇ 5°C have endothermic peaks respectively.
  • the dihydrochloride salt represented by Formula 3-1, its solvate or the crystalline form of hydrate (crystal form V) is measured by TGA, and its TGA diagram is at room temperature ⁇ 200°C The range weight loss was 7.3 ⁇ 0.20%.
  • the crystalline form of the dihydrochloride salt represented by Formula 3-1, its solvate or hydrate (crystal form V), has a DSC-TGA diagram substantially as shown in FIG. 16 .
  • the dihydrochloride salt represented by Formula 3-1 is irradiated with Cu-K ⁇ at a 2 ⁇ angle (°)
  • the indicated powder X-ray diffraction pattern has characteristic diffraction peaks at the following positions: 8.3 ⁇ 0.2°, 11.9 ⁇ 0.2°, 12.9 ⁇ 0.2°, 14.6 ⁇ 0.2°;
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angles (°) has characteristic diffraction peaks at: 6.5 ⁇ 0.2°, 8.3 ⁇ 0.2°, 11.9 ⁇ 0.2°, 12.9 ⁇ 0.2°, 14.6 ⁇ 0.2°, 16.5 ⁇ 0.2°;
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angles (°) has characteristic diffraction peaks at: 6.5 ⁇ 0.2°, 8.3 ⁇ 0.2°, 11.9 ⁇ 0.2°, 12.9 ⁇ 0.2°, 14.6 ⁇ 0.2°, 16.5 ⁇ 0.2°, 17.6 ⁇ 0.2°, 24.4 ⁇ 0.2°;
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angles (°) has characteristic diffraction peaks at: 6.5 ⁇ 0.2°, 8.3 ⁇ 0.2°, 11.9 ⁇ 0.2°, 12.9 ⁇ 0.2°, 14.6 ⁇ 0.2°, 16.5 ⁇ 0.2°, 17.6 ⁇ 0.2°, 24.4 ⁇ 0.2°, 24.8 ⁇ 0.2°, 29.6 ⁇ 0.2°;
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angles (°) has characteristic diffraction peaks at: 6.5 ⁇ 0.2°, 8.3 ⁇ 0.2°, 11.9 ⁇ 0.2°, 12.9 ⁇ 0.2°, 14.6 ⁇ 0.2°, 16.5 ⁇ 0.2°, 17.6 ⁇ 0.2°, 18.8 ⁇ 0.2°, 20.4 ⁇ 0.2°, 24.4 ⁇ 0.2°, 24.8 ⁇ 0.2°, 29.6 ⁇ 0.2°;
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angles (°) has characteristic diffraction peaks at: 6.5 ⁇ 0.2°, 8.3 ⁇ 0.2°, 11.9 ⁇ 0.2°, 12.9 ⁇ 0.2°, 14.6 ⁇ 0.2°, 16.5 ⁇ 0.2°, 17.6 ⁇ 0.2°, 18.8 ⁇ 0.2°, 20.4 ⁇ 0.2°, 22.2 ⁇ 0.2°, 23.6 ⁇ 0.2°, 24.4 ⁇ 0.2°, 24.8 ⁇ 0.2°, 29.6 ⁇ 0.2°;
  • Cu-K ⁇ radiation is used, with an X-ray powder diffraction pattern substantially as shown in FIG. 17 .
  • the dihydrochloride represented by Formula 3-1 is measured by DSC, and its DSC chart is at 87.64 ⁇ 5°C There are endothermic peaks at 182.15 ⁇ 5°C, respectively.
  • the dihydrochloride salt represented by Formula 3-1, its solvate or hydrated crystalline form (crystal form VII) is measured by TGA, and its TGA diagram is at room temperature ⁇ 120°C Range weight loss 1.4 ⁇ 0.20%.
  • the crystalline form of the dihydrochloride salt represented by Formula 3-1, its solvate or hydrate (crystal form VII), has a DSC-TGA diagram substantially as shown in FIG. 18 .
  • the salt of the arylaminoquinazoline-containing compound, its solvate or hydrate is the sulfate shown in formula 4:
  • n is an integer or half-integer from 1 to 2, ie n is 1, 1.5 or 2.
  • the salt of the arylaminoquinazoline-containing compound is the sulfate shown in formula 4-1:
  • the crystalline form of the salt, solvate or hydrate of the arylaminoquinazoline-containing compound is the crystal form of the sulfate, solvate or hydrate represented by Formula 4 form:
  • n is an integer or half-integer from 1 to 2, ie n is 1, 1.5 or 2.
  • the crystalline form of the salt of the arylaminoquinazoline compound, its solvate or hydrate is the crystal form of the sulfate, its solvate or hydrate represented by Formula 4-1 form:
  • the crystalline form of the sulfate represented by Formula 4-1, its solvate or hydrate is its crystal form I.
  • the crystalline form (crystal form I) of the sulfate represented by formula 4-1, its solvate or hydrate, using Cu-K ⁇ radiation, X-ray represented by 2 ⁇ angle Powder diffraction has characteristic peaks at the following positions: 12.4 ⁇ 0.2°, 15.5 ⁇ 0.2°, 24.8 ⁇ 0.2°, 25.9 ⁇ 0.2°;
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angles (°) has characteristic diffraction peaks at: 6.8 ⁇ 0.2°, 8.5 ⁇ 0.2°, 12.4 ⁇ 0.2°, 15.5 ⁇ 0.2°, 24.8 ⁇ 0.2°, 25.9 ⁇ 0.2°;
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angles (°) has characteristic diffraction peaks at: 6.8 ⁇ 0.2°, 8.5 ⁇ 0.2°, 12.4 ⁇ 0.2°, 13.6 ⁇ 0.2°, 15.5 ⁇ 0.2°, 24.8 ⁇ 0.2°, 25.9 ⁇ 0.2°;
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angles (°) has characteristic diffraction peaks at: 6.8 ⁇ 0.2°, 8.5 ⁇ 0.2°, 12.4 ⁇ 0.2°, 13.6 ⁇ 0.2°, 15.5 ⁇ 0.2°, 17.9 ⁇ 0.2°, 19.6 ⁇ 0.2°, 24.8 ⁇ 0.2°, 25.9 ⁇ 0.2°;
  • the relative intensity of the characteristic peak is:
  • the relative peak intensity of the above-mentioned diffraction peaks is:
  • Cu-K ⁇ radiation is used, having an X-ray powder diffraction pattern substantially as shown in FIG. 3 .
  • the salt of the arylaminoquinazoline-containing compound, its solvate or hydrate is the maleate represented by formula 5:
  • n is an integer or half-integer from 1 to 2, ie n is 1, 1.5 or 2.
  • the salt of the arylaminoquinazoline-containing compound is the maleate represented by formula 5-1:
  • the crystalline form of the salt of the arylaminoquinazoline-containing compound, its solvate or hydrate is the maleate represented by Formula 5, its solvate or hydrate Crystalline form:
  • n is an integer or half-integer from 1 to 2, ie n is 1, 1.5 or 2.
  • the crystalline form of the salt of the arylaminoquinazoline-containing compound, its solvate or hydrate is the maleate represented by Formula 5-1, its solvate or hydrate
  • the crystalline form of the maleate salt represented by Formula 5-1, its solvate or hydrate is its crystal form I.
  • the maleate salt represented by Formula 5-1 the crystalline form of its solvate or hydrate (crystal form I), using Cu-K ⁇ radiation
  • X represented by a 2 ⁇ angle -ray powder diffraction has characteristic peaks at the following positions: 4.9 ⁇ 0.2°, 7.6 ⁇ 0.2°, 16.7 ⁇ 0.2°, 24.9 ⁇ 0.2°;
  • X-ray powder diffraction in 2 ⁇ angles has characteristic peaks at: 4.4 ⁇ 0.2°, 4.9 ⁇ 0.2°, 7.6 ⁇ 0.2°, 16.7 ⁇ 0.2°, 20.6 ⁇ 0.2°, 24.9 ⁇ 0.2°;
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angles (°) has characteristic diffraction peaks at: 4.4 ⁇ 0.2°, 4.9 ⁇ 0.2°, 7.6 ⁇ 0.2°, 13.3 ⁇ 0.2°, 16.7 ⁇ 0.2°, 19.6 ⁇ 0.2°, 20.6 ⁇ 0.2°, 24.9 ⁇ 0.2°;
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angles (°) has characteristic diffraction peaks at: 4.4 ⁇ 0.2°, 4.9 ⁇ 0.2°, 7.6 ⁇ 0.2°, 13.3 ⁇ 0.2°, 16.7 ⁇ 0.2°, 18.9 ⁇ 0.2°, 19.6 ⁇ 0.2°, 20.6 ⁇ 0.2°, 24.9 ⁇ 0.2°, 26.3 ⁇ 0.2°;
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angles (°) has characteristic diffraction peaks at: 4.4 ⁇ 0.2°, 4.9 ⁇ 0.2°, 7.6 ⁇ 0.2°, 11.4 ⁇ 0.2°, 13.3 ⁇ 0.2°, 14.2 ⁇ 0.2°, 16.7 ⁇ 0.2°, 18.9 ⁇ 0.2°, 19.6 ⁇ 0.2°, 20.6 ⁇ 0.2°, 24.9 ⁇ 0.2°, 26.3 ⁇ 0.2°;
  • the relative intensity of the characteristic peak is:
  • the relative peak intensity of the above-mentioned diffraction peaks is:
  • Cu-K ⁇ radiation is used, having an X-ray powder diffraction pattern substantially as shown in FIG. 4 .
  • the salt of the arylaminoquinazoline-containing compound, its solvate or hydrate is the oxalate represented by formula 6:
  • n is an integer or half-integer from 0.5 to 2, ie n is 0.5, 1, 1.5 or 2.
  • the salt of the arylaminoquinazoline-containing compound is the oxalate represented by formula 6-1:
  • the crystalline form of the salt of the arylaminoquinazoline-containing compound, its solvate or hydrate is the crystal of the oxalate represented by Formula 6, its solvate or hydrate form:
  • n is an integer or half-integer from 0.5 to 2, ie n is 0.5, 1, 1.5 or 2.
  • the crystalline form of the salt of the arylaminoquinazoline-containing compound, its solvate or hydrate is the oxalate represented by Formula 6-1, its solvate or hydrate
  • the crystalline form of the oxalate represented by Formula 6-1, its solvate or hydrate is its crystal form I.
  • the oxalate represented by Formula 6-1 its solvate or hydrated crystalline form (crystal form I), using Cu-K ⁇ radiation, X- Ray powder diffraction has characteristic peaks at the following positions: 5.9 ⁇ 0.2°, 9.9 ⁇ 0.2°, 17.5 ⁇ 0.2°, 21.5 ⁇ 0.2°, 19.8 ⁇ 0.2°;
  • X-ray powder diffraction in 2 ⁇ angles has characteristic peaks at: 5.9 ⁇ 0.2°, 9.9 ⁇ 0.2°, 17.5 ⁇ 0.2°, 21.5 ⁇ 0.2°, 19.8 ⁇ 0.2°, 23.0 ⁇ 0.2°, 25.5 ⁇ 0.2°;
  • X-ray powder diffraction in 2 ⁇ angles has characteristic peaks at: 5.9 ⁇ 0.2°, 9.9 ⁇ 0.2°, 17.5 ⁇ 0.2°, 18.4 ⁇ 0.2°, 21.5 ⁇ 0.2°, 19.8 ⁇ 0.2°, 23.0 ⁇ 0.2°, 24.4 ⁇ 0.2°, 25.5 ⁇ 0.2°;
  • X-ray powder diffraction in 2 ⁇ angles has characteristic peaks at: 5.9 ⁇ 0.2°, 9.9 ⁇ 0.2°, 17.5 ⁇ 0.2°, 18.4 ⁇ 0.2°, 21.5 ⁇ 0.2°, 19.8 ⁇ 0.2°, 23.0 ⁇ 0.2°, 23.5 ⁇ 0.2°, 24.4 ⁇ 0.2°, 25.5 ⁇ 0.2°, 26.6 ⁇ 0.2°;
  • X-ray powder diffraction in 2 ⁇ angles has characteristic peaks at: 5.9 ⁇ 0.2°, 9.9 ⁇ 0.2°, 10.7 ⁇ 0.2°, 17.5 ⁇ 0.2°, 18.4 ⁇ 0.2°, 21.5 ⁇ 0.2°, 19.8 ⁇ 0.2°, 23.0 ⁇ 0.2°, 23.5 ⁇ 0.2°, 24.4 ⁇ 0.2°, 25.5 ⁇ 0.2°, 26.6 ⁇ 0.2°, 27.3 ⁇ 0.2°;
  • X-ray powder diffraction in 2 ⁇ angles has characteristic peaks at: 5.9 ⁇ 0.2°, 9.9 ⁇ 0.2°, 10.7 ⁇ 0.2°, 17.5 ⁇ 0.2°, 18.4 ⁇ 0.2°, 21.5 ⁇ 0.2°, 19.8 ⁇ 0.2°, 20.3 ⁇ 0.2°, 23.0 ⁇ 0.2°, 23.5 ⁇ 0.2°, 24.4 ⁇ 0.2°, 25.5 ⁇ 0.2°, 26.6 ⁇ 0.2°, 27.3 ⁇ 0.2°, 27.9 ⁇ 0.2°;
  • Cu-K ⁇ radiation is used, having an X-ray powder diffraction pattern substantially as shown in FIG. 7 .
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising the salt of the arylaminoquinazoline-containing compound represented by the aforementioned formula 2, a solvate or a hydrate thereof.
  • the pharmaceutical composition comprises a salt of the arylaminoquinazoline-containing compound represented by the aforementioned formula 2, a crystalline form of a solvate or a hydrate thereof.
  • the pharmaceutical composition comprises the crystalline form of the dihydrochloride, solvate or hydrate of the arylaminoquinazoline-containing compound represented by the aforementioned formula 3-1.
  • the pharmaceutical composition comprises the dihydrochloride salt of the arylaminoquinazoline-containing compound represented by the aforementioned formula 3-1, the crystalline form I of its solvate or hydrate, One or more of Form II, Form III, Form IV, Form V or Form VII.
  • the pharmaceutical composition comprises a salt, a solvate or a hydrate of the arylaminoquinazoline-containing compound represented by the aforementioned formula 2, and one or more pharmaceutically acceptable carriers .
  • the pharmaceutical composition comprises the salt of the arylaminoquinazoline-containing compound represented by the aforementioned formula 2, the crystalline form of its solvate or hydrate, and one or more a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises the dihydrochloride salt of the arylaminoquinazoline-containing compound represented by the aforementioned formula 3-1, the crystalline form of its solvate or hydrate, and One or more pharmaceutically acceptable carriers are included.
  • the pharmaceutical composition comprises the dihydrochloride salt of the arylaminoquinazoline-containing compound represented by the aforementioned formula 3-1, the crystalline form I of its solvate or hydrate, One or more of Form II, Form III, Form IV, Form V or Form VII, and one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition comprises a therapeutically effective amount of the salt, solvate or hydrate of the arylaminoquinazoline-containing compound represented by the aforementioned formula 2, and contains one or more Pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present application can be prepared by conventional methods in the art. Prepared by mixing with carrier.
  • the present application provides the salt of the arylaminoquinazoline-containing compound shown in the aforementioned formula 2, its solvate or hydrate, the salt of the arylaminoquinazoline-containing compound shown in the aforementioned formula 2, Use of a crystalline form of a solvate or hydrate thereof or a pharmaceutical composition of the foregoing for the preparation of a medicament as a receptor tyrosine kinase inhibitor.
  • the receptor tyrosine kinase is one or more of VEGFR, FLT, FGFR, RET, EGFR and mutants thereof.
  • the present application also provides a salt of the arylaminoquinazoline-containing compound shown in the aforementioned formula 2, a solvate or hydrate thereof, and a salt of the arylaminoquinazoline-containing compound shown in the aforementioned formula 2 , the use of a crystalline form of a solvate or a hydrate thereof or a pharmaceutical composition of the foregoing in the treatment of a receptor tyrosine kinase-related disease.
  • the present application also provides a method for treating a patient's receptor tyrosine kinase-related disease, comprising administering to the patient a therapeutically effective amount of the salt of the arylaminoquinazoline-containing compound represented by the aforementioned formula 2, The solvate or hydrate thereof, the salt of the arylaminoquinazoline-containing compound represented by the aforementioned formula 2, the crystalline form of the solvate or hydrate thereof, or the aforementioned pharmaceutical composition.
  • the present application also provides a salt of the arylaminoquinazoline-containing compound represented by the aforementioned formula 2, its solvate or hydrate, the aforementioned formula 2 for the treatment of receptor tyrosine kinase-related diseases.
  • the receptor tyrosine kinase-related diseases described in the above aspects are diseases caused by one or more of VEGFR, FLT, FGFR, RET, EGFR and their mutants.
  • the disease is a cell proliferative disease.
  • the disease involves dysregulation of the expression, level or activity of one or more of VEGFR, FLT, FGFR, RET and EGFR.
  • the cell proliferative disease is a tumor or cancer.
  • the tumor comprises thyroid cancer, biliary tract cancer, epidermoid cancer, melanoma, colorectal cancer, gastric cancer, esophageal cancer, pancreatic cancer, kidney cancer, liver cancer, lung cancer, or ovarian cancer.
  • the thyroid cancer is medullary thyroid cancer and the lung cancer is non-small cell lung cancer.
  • the non-small cell lung cancer is RET fusion non-small cell lung cancer.
  • the present application also provides a salt of the arylaminoquinazoline-containing compound shown in the aforementioned formula 2, a solvate or hydrate thereof, and a salt of the arylaminoquinazoline-containing compound shown in the aforementioned formula 2 , the crystalline form of its solvate or hydrate or the use of the aforementioned pharmaceutical composition in the preparation of an antitumor drug.
  • the present application also provides a salt of the arylaminoquinazoline-containing compound shown in the aforementioned formula 2, a solvate or hydrate thereof, and a salt of the arylaminoquinazoline-containing compound shown in the aforementioned formula 2 , the crystalline form of its solvate or hydrate or the use of the aforementioned pharmaceutical composition in the treatment of tumors.
  • the application also provides a method for treating a tumor disease in a patient, comprising administering to the patient a therapeutically effective amount of a salt, a solvate or a hydrate of the arylaminoquinazoline-containing compound represented by the aforementioned formula 2 compound, the salt of the arylaminoquinazoline-containing compound represented by the aforementioned formula 2, the crystalline form of its solvate or hydrate, or the aforementioned pharmaceutical composition.
  • the present application also provides a salt of the arylaminoquinazoline-containing compound shown in the aforementioned formula 2, its solvate or hydrate, and the arylaminoquinazoline-containing compound shown in the aforementioned formula 2 for the treatment of tumor diseases.
  • the tumors or tumor diseases described in the above aspects include thyroid cancer, biliary tract cancer, epidermoid cancer, melanoma, colorectal cancer, gastric cancer, esophageal cancer, pancreatic cancer, kidney cancer, liver cancer, lung cancer or ovarian cancer.
  • the thyroid cancer is medullary thyroid cancer and the lung cancer is non-small cell lung cancer.
  • the non-small cell lung cancer is RET fusion non-small cell lung cancer.
  • the tumor or tumor disease is a tumor or tumor disease caused by one or more of VEGFR, FLT, FGFR, RET, EGFR and their mutants.
  • the tumor or tumor disease involves dysregulation of the expression, level or activity of one or more of VEGFR, FLT, FGFR, RET and EGFR.
  • the above-mentioned "patient” includes all members of the animal kingdom, including, but not limited to, mammals (eg, mice, rats, cats, monkeys, dogs, pigs, etc.) and humans.
  • mammals eg, mice, rats, cats, monkeys, dogs, pigs, etc.
  • the present application provides a salt, a solvate or a hydrate of a compound containing an arylaminoquinazoline shown in formula 2, comprising compounding the arylaminoquinazoline shown in formula 1
  • the compound and acid (HA) are reacted in a suitable solvent, and the salt of the compound containing arylaminoquinazoline shown in formula 2, its solvate or hydrate is obtained by isolation:
  • HA is acid
  • n is an integer or half integer of 1/2-2.
  • the HA is hydrochloric acid, sulfuric acid, oxalic acid, maleic acid or malic acid.
  • the molar ratio of the arylaminoquinazoline-containing compound represented by Formula 1 to the acid is 1:1-2.5, preferably 1:1-2.
  • the reaction temperature is 10-90°C, preferably 40-70°C.
  • the reaction solvent is selected from one or a combination of alcohols, ketones, nitriles, water or heterocycloalkane solvents; preferably ethyl acetate, methanol, ethanol, water, One or a combination of acetonitrile, acetone, tetrahydrofuran, DMF, NMP, isopropanol, n-propanol, DMA, and dioxane; more preferably, ethyl acetate, methanol or water.
  • the reaction solvent is a combination of methanol and ethyl acetate. In some embodiments of the present application, the reaction solvent is water. In some embodiments of the present application, the reaction solvent is a combination of methanol and acetonitrile. In some embodiments of the present application, the reaction solvent is a combination of water and acetonitrile. In some embodiments of the present application, the reaction solvent is ethanol.
  • reaction solvents when the above-mentioned reaction solvents are two kinds of combinations, they can be added separately, that is, the good solvent is added first, and the poor solvent is added later.
  • the salt of the arylaminoquinazoline-containing compound represented by formula 2, its solvate or hydrate is isolated and obtained in crystalline form.
  • the temperature for cooling and crystallization is -5 to 35°C, preferably 0 to 25°C, stirring for crystallization for 0.5 to 24 hours, separation of the solid, and drying to obtain the compound shown in formula 2.
  • Salts of arylaminoquinazoline compounds Preferably, the temperature for collecting the salt is 10° C., and the crystallization time is 0.5-12 h.
  • the separating step includes separating the obtained salt of the arylaminoquinazoline compound represented by formula 2 from the crystallizing solution by using suitable methods such as filtration and centrifugation.
  • the drying method can adopt any suitable known method, preferably drying.
  • the specific drying conditions are, for example, using a vacuum drying oven, the temperature is preferably 30-65°C, more preferably 40-55°C; the drying time is preferably 1-50h, more preferably 1-16h, further preferably 3-6h. No matter what drying method is used, it is advisable that the residual amount of solvent in the obtained product meets the quality standard.
  • the arylaminoquinazoline-containing compound represented by formula 1 can be prepared by referring to methods disclosed in the prior art, such as the method described in WO2016023330A1, the contents of the above documents are incorporated herein by reference.
  • solvate refers to an association formed by one or more solvent molecules and the compound represented by formula 2 of the present application, including those containing both water molecules and one or more other solvent molecules. associates.
  • hydrate refers to an association of one or more water molecules with a compound of formula 2 of the present application.
  • the hydrate in the present application includes the dihydrochloride tetrahydrate of the compound represented by formula 3-2.
  • the “2 ⁇ ”, “2 ⁇ angle” or “2 ⁇ angle” mentioned in this application refers to the diffraction angle, the unit is ° or degree, and the error range of 2 ⁇ can be ⁇ 0.5, ⁇ 0.4, ⁇ 0.3, ⁇ 0.2 or ⁇ 0.1°.
  • the "heating temperature”, “cooling temperature” or “crystallization temperature” described in this application is in °C or °C, and the error range can be ⁇ 10, ⁇ 5, ⁇ 4, ⁇ 3, ⁇ 2 or ⁇ 1°C.
  • substantially as shown means at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least in an X-ray powder diffraction pattern or a DSC pattern or a TGA pattern 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99% of the peaks are shown in their graph. Further, when the content of a certain crystal form in the product is gradually reduced, some diffraction peaks in the powder X-ray diffraction pattern that belong to the crystal form may be reduced due to the detection sensitivity of the instrument.
  • characteristic diffraction peak refers to a diffraction peak in an X-ray powder diffraction pattern that can be used to represent the crystal form, which is related to the peak position, peak shape and relative peak intensity of the diffraction peak, for example, small angle peaks, peaks
  • the shape is sharp, and the relative peak intensity is at least 3% or more, or at least 5% or more, or at least 10% or more, or at least 20% or more, or at least 30% or more, or at least 40% or more, or at least 50% or more, or at least 60% or more, or at least 70% or more, or at least 75% or more of the diffraction peaks.
  • cell proliferative disease refers to a disorder in which a population of cells grows at a rate lower or higher than that expected under a given physiological state and condition.
  • tumor includes benign tumors, malignant tumors, and borderline tumors, wherein malignant tumors are also collectively referred to as cancers.
  • treating generally refers to obtaining a desired pharmacological and/or physiological effect, including partial or complete stabilization or cure of a disease and/or effects resulting from a disease.
  • Treatment encompasses any treatment of a disease in a patient, including: (a) inhibiting the symptoms of the disease, ie, preventing its progression; or (b) alleviating the symptoms of the disease, ie, causing regression of the disease or symptoms.
  • an effective amount or "therapeutically effective amount” means an amount of a compound of the present application that (i) treats a particular disease, or (ii) reduces, ameliorates, or eliminates one or more symptoms of a particular disease.
  • therapeutically effective amount means an amount of a compound sufficient to effect treatment of a disease when administered to a patient for the treatment of the disease.
  • the amount of a compound of the present application that constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art according to its own knowledge and the present disclosure.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable adjuvant” refers to those carriers which are not significantly irritating to the organism and which do not impair the biological activity and properties of the active compound.
  • DMF N,N-dimethylformamide
  • NMP N-methylpyrrolidone
  • DMA N,N-dimethylaniline
  • the present application provides salts of the arylaminoquinazoline-containing compound represented by formula 2, solvates or hydrates thereof, and salts of the arylaminoquinazoline-containing compound represented by formula 2, solvates or hydrates thereof crystalline forms that have one or more of the following beneficial effects:
  • the salt of the arylaminoquinazoline-containing compound shown in formula 2, its solvate or hydrate have good solid properties, further, good crystalline properties, especially dihydrochloride, sulfate, maleate, The crystal properties of monohydrochloride, oxalate, malate, and their solvates or hydrates are good.
  • the salt and its crystalline form eg, dihydrochloride, dihydrochloride tetrahydrate, sulfate, maleate and its crystalline form
  • the salt and its crystalline form have excellent storage stability, chemical stability, thermal stability and/or mechanical stability.
  • Salts, solvates or hydrates of the arylaminoquinazoline-containing compounds represented by formula 2 of the present application especially dihydrochlorides, sulfates, maleates, oxalates, and solvates thereof
  • hydrates, more particularly dihydrochloride and its solvates or hydrates have better druggability, are suitable for storage as raw materials, and can be developed into different pharmaceutical dosage forms according to clinical needs.
  • Test conditions wavelength 252nm; column temperature 45°C;
  • Detection medium purified water, pH2.0 phosphoric acid-disodium hydrogen phosphate buffer
  • Preparation of reference substance solution take an appropriate amount of the reference substance of the compound of formula 1, accurately weigh it, add solvent to make it completely dissolved, and dilute to make a solution of 100 ⁇ g/mL, accurately measure 10uL, and use HPLC to determine the content of compound 1 in the reference substance solution .
  • Light tube type Cu target, ceramic X-ray tube
  • Light tube type Cu target, ceramic X-ray tube
  • Sample dosage 5-10 mg (Example 5-8).
  • Test method Weigh 5mg of the sample (Example 1-4), place it in a TGA platinum pot for testing, and heat the sample from 40°C to 300°C at a heating rate of 5K/min under the condition of 40mL/min dry nitrogen. .
  • Test method about 2-5 mg of the sample (Example 5-8) was placed in a peeled open aluminum pan, and the instrument automatically weighed and recorded the weight. The sample was then heated from room temperature to final temperature in a heating furnace at a heating rate of 10°C/min. The gas flow was N2 and the flow rates were 40 mL/min (sample chamber) and 25 mL/min (equilibration chamber), respectively.
  • Test method Weigh the sample (about 3mg) and place it in an aluminum oxide crucible for testing. Under the condition of 20mL/min dry nitrogen (protective gas), at a heating rate of 10K/min, heat the sample from 20°C to 340°C.
  • Test method Weigh 2-5 mg of the sample (Examples 5-8) and place it in an airtight aluminum pan with a hole, and accurately record the amount of the sample. The sample was then heated from 25°C to the final temperature at a ramp rate of 10°C/min. The gas flow was N2 and the flow rate was 50 mL/min.
  • Detection instrument Dionex ICS-900 ion chromatograph
  • test solution take an appropriate amount of the test product, accurately weigh it, dissolve it with the eluent (12.5mmol/L sodium hydroxide solution) and quantitatively dilute it into a solution containing about 0.5mg of the test product per 1mL, shake well , as the test solution.
  • Preparation of reference solution take an appropriate amount of sodium chloride (equivalent to 18 mg of chloride ion), accurately weigh it, put it in a 250 mL volumetric flask, dissolve it with eluent and make up to volume, shake well, and use it as a reference solution.
  • sodium chloride equivalent to 18 mg of chloride ion
  • Determination method Precisely measure 10 ⁇ L of the reference solution and the test solution, respectively, inject them into the ion chromatograph, record the chromatogram, and calculate the chloride ion content by the peak area according to the external standard method.
  • Test method Add the sample to be tested into a biological solvent medium, and prepare a solution or suspension with a target concentration of 10 mg/mL. The resulting solution or suspension was shaken continuously at 200 rpm at 37°C. The suspension was filtered at 0.5 hours and the compound concentration in the filtrate was determined using HPLC.
  • the chloride ion content was determined by ion chromatography, and the stoichiometric ratio of the hydrochloride was calculated (see table below), and it can be deduced that the base/acid ratio of the hydrochloride was 1:2.
  • the obtained hydrochloride sample was taken for X-ray powder diffraction, which showed good crystallinity, and was named as the crystal form I of the dihydrochloride.
  • endothermic peak 1 there is an endothermic peak starting point at 219.1 °C, and the peak is reached around 231.0 °C
  • endothermic peak 2 there is an endothermic peak starting at 235.1 °C
  • the starting point reaches a peak around 284.2°C, and decomposition occurs at about 205°C (see Fig. 8 ).
  • the PLM image shows that the crystalline particles are regular morphology.
  • Example 2 hydrochloride hydrate The crystallization water content of Example 2 hydrochloride hydrate was further detected by TGA, and the weight loss was 12.24%. It can be inferred that the alkali/crystal water ratio of the hydrochloride hydrate is 1:4, and its TGA test chart is shown in Figure 9.
  • the obtained dihydrochloride tetrahydrate sample was subjected to X-ray powder diffraction, and the obtained solid showed good crystallinity and was named as crystal form II.
  • the obtained sulfate sample was taken and subjected to X-ray powder diffraction.
  • the obtained sulfate showed good crystallinity and was named as the crystal form I of the sulfate.
  • Its XRPD characterization spectrum is shown in Figure 3, and the main diffraction peak data are shown in Table 3.
  • the obtained maleate sample was taken and subjected to X-ray powder diffraction.
  • the obtained maleate showed good crystallinity and was named as the crystal form I of the maleate.
  • Its XRPD characterization spectrum is shown in Figure 4, and the main diffraction peaks The data are shown in Table 4.
  • Example 2 Weigh a sample (about 7 mg) of Example 1, dissolve it in methanol (0.2 mL), filter and collect the filtrate, then add acetonitrile (1 mL) to the filtrate, stir overnight, and filter with suction to obtain a white solid. The obtained solid was taken and subjected to X-ray powder diffraction, which was in crystalline form, named as crystal form III of dihydrochloride, its XRPD characterization spectrum is shown in Figure 11, and the main diffraction peak data is shown in Table 5.
  • endothermic peak 1 there is an endothermic peak starting point at 72.28 °C, reaching a peak near 101.52 °C
  • endothermic peak 2 there is an endothermic peak starting at 172.06 °C
  • the peak value was reached around 183.70°C
  • the weight loss was 6.2684% between room temperature and 120°C, and the decomposition occurred at about 225°C (see Figure 12).
  • Example 2 Weigh a sample (about 7 mg) of Example 1, dissolve it in water (0.2 mL), filter and collect the filtrate, then add acetonitrile (7 mL) to the filtrate, stir for 24 h, and filter with suction to obtain a white solid. The obtained solid was taken and subjected to X-ray powder diffraction, and it was in a crystalline form, named as the crystal form IV of the dihydrochloride, its XRPD characterization spectrum is shown in Figure 13, and the main diffraction peak data are shown in Table 6.
  • endothermic peak 1 there is an endothermic peak starting point at 49.50 °C, reaching a peak near 68.81 °C
  • endothermic peak 2 there is an endothermic peak starting at 164.55 °C
  • the peak value was reached around 177.55°C
  • the weight loss was 3.9478% between room temperature and 150°C, and the decomposition occurred at about 215°C (see FIG. 14 ).
  • Example 1 A sample of Example 1 (about 30 mg) was weighed, dissolved in ethanol (1 mL), stirred at 50° C. for 30 min, filtered while hot, and the filtrate was cooled to room temperature, continued to stir for 3 days, and suction filtered to obtain a white solid. The obtained solid was subjected to X-ray powder diffraction, which was in crystalline form and named as Form V (ethanol solvate, 1:1).
  • endothermic peak 1 there is an endothermic peak onset at 28.37 °C, reaching a peak near 48.29 °C
  • endothermic peak 2 there is an endothermic peak onset at 114.96 °C , reaching a peak value around 153.99°C
  • endothermic peak 3 an endothermic peak onset at 179.32°C and a peak at 190.59°C
  • weight loss between room temperature and 200°C was 7.2663% (see Figure 16).
  • Example 5 The crystal form III obtained in Example 5 was taken, heated to 130° C. and a sample was collected to obtain a white solid. The obtained solid was taken and subjected to X-ray powder diffraction, which was in crystalline form, named as crystal form VII of dihydrochloride, its XRPD characterization spectrum is shown in Figure 17, and the main diffraction peak data is shown in Table 8.
  • endothermic peak 1 there is an endothermic peak starting point at 66.54 °C, reaching a peak near 87.64 °C
  • endothermic peak 2 there is an endothermic peak starting at 169.59 °C
  • the starting point peaked at around 182.15°C; the weight loss was 1.3751% between room temperature and 120°C (see Figure 18).
  • Example 1 A sample of Example 1 (about 369 mg) was weighed, added to water/acetone (1:1, v/v, total amount 5 mL), and stirred overnight at room temperature. The white solid was collected by filtration and dried under vacuum at 50°C overnight. After testing, it was found to be dihydrochloride tetrahydrate, and the obtained solid was subjected to X-ray powder diffraction. It was in a crystalline form, and its XRPD characterization spectrum was shown in Figure 19 .
  • solid oral dosage forms require that the solubility of the drug in water be greater than 0.1 g/L, and solution preparations such as injection or oral liquid require the solubility of the drug to be above 10 g/L. More importantly, The solubility of the drug should meet the clinically required dose concentration. Based on the solubility results in Table 10, Examples 1-4 and Example 9 can be considered to prepare solid oral dosage forms, and Examples 1-4 can also be considered to prepare solution preparations such as injections or oral liquids.
  • Example 1 The samples of Example 1 and Example 10 (20 mg each) were weighed, and different biological solvents (2 mL) were added for solubility testing. The results are shown in Table 11.
  • Example 1 and Example 10 were maintained good solubility in biological solvents with different pH, and the dissolution rate was fast.
  • Figure 10 shows the XRPD spectrum of the crystal form I of the dihydrochloride salt of Compound 1 obtained in Example 1 after the long-term stability test.
  • Example 1 Take the sample ( ⁇ 15mg) of Example 1 and add it to 0.5mL of the different solvents listed in Table 15, and make a slurry at room temperature and 50°C. Take the filtered sample for X-ray powder diffraction. 1 The obtained dihydrochloride salts are all the same.
  • Preparation Example 1 had good solubility in various conventional organic solvents (all >10 mg/mL), while the dihydrochloride of Example 1 only showed good solubility in methanol, and had good solubility in the other 7 common organic solvents. Very little, therefore, adopt suitable conventional organic solvent, all can realize the preparation of dihydrochloride, and can realize the complete separation of (unreacted) free base and dihydrochloride, and can be with higher yield ( Low mass loss due to dissolution in organic solvents) and high purity to obtain dihydrochloride.
  • the well-grown human melanoma A375 cell suspension was inoculated into the subcutaneous tissue of the forelimb axilla of nu/nu female nude mice in a volume of 0.1 mL, containing about 1 ⁇ 10 7 tumor cells.
  • mice with good tumor growth are selected, and the animals are equally divided into 5 groups according to the tumor volume: blank control group, vandetanib 12.5mg/kg group, vandetanib 25mg/kg group, Example 1 sample 12.5 mg/kg group and Example 1 sample 25 mg/kg, 6 animals in each group.
  • the blank control group was orally administered with distilled water, and the other groups were orally administered with the corresponding test drugs, and the administration volume was 20 mL/kg, once a day, continuously until the 20th day. After administration, the animals were raised normally, and the anti-tumor effect of the test drug was dynamically observed by the method of measuring tumor diameter.
  • Example 1 Compared with the blank control group, the sample of Example 1 could significantly inhibit the growth of tumor in a dose-dependent manner, and compared with the control drug vandetanib, it had a better tumor-inhibiting effect.
  • the effective dose in the mouse model is converted into the equivalent dose for adults, and the effective dose in the mouse model is 12.5mg/
  • the equivalent doses of kg and 25mg/kg for adults (70kg) are 1.37mg/kg and 2.74mg/kg, respectively, and the oral doses for adults (70kg) are 95.9mg and 191.8mg.
  • the solubility of the drug needs to reach 11.51mg/mL and 23.02mg/mL respectively (the absolute bioavailability of dogs and monkeys in animal pharmacokinetic experiments is about 60%, so , where the oral availability of humans is calculated as 60%), and so on, to make liquid preparations with smaller specifications (less than 5 mL), the solubility of the drug is required to be higher.
  • the solubility test results in Table 10 based on the specification of 5mL liquid preparation, if the dosage is 1.37mg/kg, Example 1, Example 2 and Example 4 can meet the solubility requirements; if the dosage is 2.74mg/kg kg, Example 1 and Example 2 can meet the solubility requirements.
  • dihydrochloride has the best performance, can meet the solubility requirements of small-scale liquid preparations and has good anti-tumor effect in vivo, and has the potential to be developed into drugs of various dosage forms and different specifications.

Abstract

提供了一种式2所示的含芳氨基喹唑啉化合物的盐、其溶剂合物或水合物、及制备方法和应用。所制备的盐结晶性好，相对于游离形式化合物，水中溶解度有了显著改善，优选盐型及晶型能够稳定存在，因此，相对于游离形式的化合物或其它盐具有更好的成药性。

Description

含芳氨基喹唑啉的化合物的盐及其制备方法和应用
相关申请的交叉引用
本申请要求于2020年09月25日向中国国家知识产权局提交的第202011022290.1号中国专利申请的优先权和权益，所述申请公开的内容通过引用整体并入本文中。
技术领域
本申请属于药物化学领域，具体涉及含芳氨基喹唑啉的化合物的盐及其制备方法和应用。
背景技术
蛋白酪氨酸激酶(Protein tyrosine kinases,PTKs)是蛋白激酶家族中非常重要的一员，PTKs将三磷酸腺苷上的γ-磷酸基转移到底物的蛋白酪氨酸残基上，通过将酚羟基磷酸化来完成细胞间的信息传递，在细胞发育、调节和肿瘤细胞的分化、迁移、凋亡等过程中起着至关重要的作用。若PTKs在调节过程中失控将会影响其下游信号通路的正确激活，进而引起细胞增殖调节功能紊乱而引发许多疾病，如酪氨酸激酶活性过高使受体磷酸化进而激活下游信号，导致细胞过度转化、增殖、对抗细胞凋亡、促进细胞生存进而形成恶性肿瘤。因此，将酪氨酸激酶作为新型靶点研制该类激酶抑制剂来抑制酪氨酸激酶的过度表达，恢复其生理平衡，已经成为分子靶向抗肿瘤领域的研究热点，极具发展前景。
表皮生长因子受体(Epidermal Growth Factor Recepto,EGFR)、成纤维生长因子受体(Fibroblast Growth Factor Receptors,FGFRs)、血小板源生长因子受体(Platelet-derived Growth Factor Receptor,PDGFR)、转染期间重排(Rearranged during Transfection，RET)原癌基因编码的RET蛋白等就是PTKs的重要成员，是肿瘤治疗的重要靶标。
EGFR是能与受体酪氨酸激酶结合的细胞生长因子，包括EGFR(ErbB-1)、2型人表皮生长因子受体HER2(ErbB-2)、3型人表皮生长因子受体HER3(ErbB-3)及4型人表皮生长因子受体HER4(ErbB-4)，其中，EGFR和HER2是EGFR家族成员中与肿瘤关系最为密切的靶点。研究表明，EGFR在多种肿瘤如肺癌、胃癌、表皮样癌、肾癌、卵巢癌等中表现出过度表达、基因突变或基因融合。
FGFR主要包括FGFR1/2/3/4四种亚型，它们通过基因扩增、突变、融合或配体诱导等方式过度表达或过度激活，对肿瘤细胞增殖、侵袭和迁移及肿瘤血管的生成具有重要作用。研究发现，FGFRs在多种肿瘤如非小细胞肺癌、胃癌、结直肠癌、食管癌、肝癌、胆道癌等中均表现出过度表达或过度激活。
RET的正常生理功能包含肾发育、神经***的发育、***干细胞的维持更新、髓单核细胞分化、淋巴组织的形成等，在人肠神经节细胞、神经母细胞瘤、嗜铬细胞瘤、甲状腺髓样癌、甲状腺C细胞和黑色素瘤等细胞中表达。近年来，通过对RET深入研究，发现在肿瘤中RET的过度激活对多种肿瘤的增殖、存活、侵袭、转移及肿瘤炎症等均有显著促进作用，RET在甲状腺癌(例如，甲状腺髓样癌、***状甲状腺癌)、结直肠癌、胰腺癌、黑色素瘤等中均表现出过度表达。
化合物1，化学名为4-(4-溴-2-氟苯胺基)-6-甲氧基-7-[(4-N,N-二甲基氨基)丁氧基]喹唑啉，是一种具有RET、VEGFR(血管内皮生长因子受体(Vascular endothelial growth factor receptor，VEGFR))、FGFR、EGFR、FLT(FMS样酪氨酸激酶(Fms-like tyrosine kinase或Fms Related Receptor Tyrosine Kinase))等抑制活性的多靶点抑制剂。
Figure PCTCN2021120328-appb-000001
WO2016023330A1中涉及作为酪氨酸激酶抑制剂的含芳氨基喹唑啉的化合物，记载了化合物1及其类似物、制备方法和医药用途。
发明概述
本申请发明人发现，化合物1水溶性很差，不能满足固体口服剂型对药物溶解度的一般要求(应大于0.1g/L)，更不用说其他药物剂型(例如，注射剂、溶液剂)的开发，而且，药物的水溶性也是影响药物溶出、吸收及药代性质的主要因素，因此，有必要对化合物1进行修饰，以优化其理化性质，提高其成药性。
一方面，本申请提供了式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物：
Figure PCTCN2021120328-appb-000002
其中，
HA是盐酸、硫酸、草酸或马来酸；
n为1/2-2的整数或半整数；以及
当HA为盐酸时，n为0.5、1.5或2。
另一方面，本申请提供了式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物的结晶形式：
Figure PCTCN2021120328-appb-000003
其中，
HA是盐酸、硫酸、草酸或马来酸；
n为1/2-2的整数或半整数；以及
当HA为盐酸时，n为0.5、1.5或2。
另一方面，本申请提供了一种药物组合物，其包含前述式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物或式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物的结晶形式，以及含有一种或多种可药用载体。
又一方面，本申请提供了前述式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物、式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物的结晶形式或前述药物组合物用于制备作为受体酪氨酸激酶抑制剂的药物中的用途。
本申请还提供了前述式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物、式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物的结晶形式或前述药物组合物在制备抗肿瘤药物中的用途。
又一方面，本申请还提供了前述式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物、式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物的结晶形式或前述药物组合物在治疗受体酪氨酸激酶相关疾病中的用途。
本申请还提供了前述式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物、式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物的结晶形式或前述药物组合物在***中的用途。
又一方面，本申请还提供了一种治疗患者的受体酪氨酸激酶相关疾病的方法，包括向患者施用治疗有效量的前述式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物、式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物的结晶形式或前述药物组合物。
本申请还提供了一种治疗患者的肿瘤疾病的方法，包括向患者施用治疗有效量的前述式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物、式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物的结晶形式或前述药物组合物。
又一方面，本申请还提供了用于治疗受体酪氨酸激酶相关疾病的前述式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物、式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物的结晶形式或前述药物组合物。
再一方面，本申请还提供了用于***疾病的前述式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物、式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物的结晶形式或前述药物组合物。
又一方面，本申请提供了一种式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物的制备方法，包括将式1所示的含芳氨基喹唑啉的化合物与酸(HA)在适宜溶剂中进行反应，分离得到式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物：
Figure PCTCN2021120328-appb-000004
其中，
HA是盐酸、硫酸、草酸或马来酸；
n为1/2-2的整数或半整数；以及
当HA为盐酸时，n为0.5、1.5或2。
附图说明
图1：实施例1所得化合物1的二盐酸盐、其溶剂合物或水合物的晶型I的XRPD谱图。
图2：实施例2所得化合物1的二盐酸盐、其溶剂合物或水合物的晶型II的XRPD谱图。
图3：实施例3所得化合物1的硫酸盐的XRPD谱图。
图4：实施例4所得化合物1的马来酸盐的XRPD谱图。
图5：对比例1所得化合物1的单盐酸盐的XRPD谱图。
图6：对比例2所得化合物1的苹果酸盐的XRPD谱图。
图7：实施例9所得化合物1的草酸盐的XRPD谱图。
图8：实施例1所得化合物1的二盐酸盐、其溶剂合物或水合物的晶型I的DSC-TGA图。
图9：实施例2所得化合物1的二盐酸盐、其溶剂合物或水合物的晶型II的热失重分析(TGA)图。
图10：实施例1所得二盐酸盐、其溶剂合物或水合物的晶型I在长期稳定性测试后的XRPD谱图。
图11：实施例5所得化合物1的二盐酸盐、其溶剂合物或水合物的晶型III的XRPD谱图。
图12：实施例5所得化合物1的二盐酸盐、其溶剂合物或水合物的晶型III的DSC-TGA图。
图13：实施例6所得化合物1的二盐酸盐、其溶剂合物或水合物的晶型IV的XRPD谱图。
图14：实施例6所得化合物1的二盐酸盐、其溶剂合物或水合物的晶型IV的DSC-TGA图。
图15：实施例7所得化合物1的二盐酸盐、其溶剂合物或水合物的晶型V的XRPD谱图。
图16：实施例7所得化合物1的二盐酸盐、其溶剂合物或水合物的晶型V的DSC-TGA图。
图17：实施例8所得化合物1的二盐酸盐、其溶剂合物或水合物的晶型VII的XRPD谱图。
图18：实施例8所得化合物1的二盐酸盐、其溶剂合物或水合物的晶型VII的DSC-TGA图。
图19：实施例10所得化合物1的二盐酸盐、其溶剂合物或水合物的晶型II的XRPD谱图。
发明详述
一方面，本申请提供了一种如式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物：
Figure PCTCN2021120328-appb-000005
其中，HA是酸；
n为1/2-2的整数或半整数，即n为0.5、1、1.5或2。
本申请的一些实施方案中，HA为盐酸、硫酸、草酸、马来酸或苹果酸。本申请的一些实施方案中，HA为盐酸、硫酸或马来酸。本申请的一些实施方案中，HA为盐酸。
本申请的一些实施方案中，HA为盐酸、硫酸、草酸或马来酸，n为1/2-2的整数或半整数，即n为0.5、1、1.5或2；且当HA为盐酸时，n为0.5、1.5或2。本申请的一些实施方案中，n为1或2。
本申请的一些实施方案中，所述含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物为式3所示的含芳氨基喹唑啉的化合物的盐酸盐、其溶剂合物或水合物：
Figure PCTCN2021120328-appb-000006
其中n为0.5、1.5或2。
本申请的一些实施方案中，所述溶剂合物选自乙腈/水溶剂合物和乙醇溶剂合物。
本申请的一些实施方案中，所述水合物选自半水合物、一水合物和四水合物。
本申请的一些实施方案中，所述含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物为式3’所示的盐酸盐或其水合物：
Figure PCTCN2021120328-appb-000007
其中，n为1-2的整数；m为0-4的整数或半整数，即m为0、0.5、1、1.5、2、2.5、3、3.5或4；且当n为1时，m为1-4的整数或半整数，即m为0.5、1、1.5、2、2.5、3、3.5或4。本申请的一些实施方案中，n为2且m为0、0.5、1或4。本申请的一些实施方案中，n为2且m为0或4。
本申请的一些实施方案中，所述含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物为式3”所示的二盐酸盐或其水合物：
Figure PCTCN2021120328-appb-000008
其中，m为0-4的整数或半整数，即m为0、0.5、1、1.5、2、2.5、3、3.5或4。
本申请的一些实施方案中，所述含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物为式3-1所示的二盐酸盐：
Figure PCTCN2021120328-appb-000009
本申请的一些实施方案中，所述含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物为式3-2所示的二盐酸盐四水合物：
Figure PCTCN2021120328-appb-000010
另一方面，本申请提供了如式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物的结晶形式：
Figure PCTCN2021120328-appb-000011
其中，HA是酸；
n为1/2-2的整数或半整数，即n为0.5、1、1.5或2。
本申请的一些实施方案中，HA为盐酸、硫酸、草酸、马来酸或苹果酸。本申请的一些实施方案中，HA为盐酸、硫酸或马来酸。本申请的一些实施方案中，HA为盐酸。
本申请的一些实施方案中，HA为盐酸、硫酸、草酸或马来酸，n为1/2-2的整数或半整数，即n为0.5、1、1.5或2；且当HA为盐酸时，n为0.5、1.5或2。本申请的一些实施方案中，n为1或2。
本申请的一些实施方案中，所述含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物的结晶形式为式3所示的含芳氨基喹唑啉的化合物的盐酸盐、其溶剂合物或水合物的结晶形式：
Figure PCTCN2021120328-appb-000012
其中n为0.5、1.5或2。
本申请的一些实施方案中，所述含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物的结晶形式为式3-1所示的二盐酸盐、其溶剂合物或水合物的结晶形式：
Figure PCTCN2021120328-appb-000013
本申请的一些实施方案中，所述式3-1所示的二盐酸盐、其溶剂合物或水合物的结晶形式选自晶型I、晶型II、晶型III、晶型IV、晶型V、晶型VII中的一种或多种。
本申请的一些实施方案中，所述晶型I为式3-1所示的二盐酸盐的结晶形式：
Figure PCTCN2021120328-appb-000014
本申请的一些实施方案中，所述晶型II为式3-2所示的二盐酸盐四水合物的结晶形式：
Figure PCTCN2021120328-appb-000015
本申请的一些实施方案中，所述式3-1所示的二盐酸盐、其溶剂合物或水合物的结晶形式(晶型I)，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：12.4±0.2°、18.8±0.2°、20.3±0.2°、24.6±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：9.8±0.2°、 12.4±0.2°、18.8±0.2°、20.3±0.2°、24.6±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：8.1±0.2°、9.8±0.2°、12.4±0.2°、18.8±0.2°、20.3±0.2°、24.6±0.2°、29.9±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：8.1±0.2°、9.8±0.2°、12.4±0.2°、18.8±0.2°、19.3±0.2°、20.3±0.2°、24.6±0.2°、28.6±0.2°、29.9±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：8.1±0.2°、9.8±0.2°、12.4±0.2°、16.1±0.2°、18.8±0.2°、19.3±0.2°、20.3±0.2°、24.6±0.2°、28.6±0.2°、29.9±0.2°、30.9±0.2°；
优选地，上述特征峰的相对强度为：
峰位置2θ角(°) 相对峰强度％ 峰位置2θ角(°) 相对峰强度％
8.1 3-15 20.3 8-30
9.8 5-30 24.6 10-55
12.4 10-30 28.6 5-20
16.1 2-15 29.9 5-30
18.8 60-100 30.9 5-20
19.3 5-20    
；
优选地，上述特征峰的相对强度为：
峰位置2θ角(°) 相对峰强度％ 峰位置2θ角(°) 相对峰强度％
8.1 3-15 20.3 8-30
9.8 5-20 24.6 10-40
12.4 10-30 28.6 5-20
16.1 4-15 29.9 5-20
18.8 80-100 30.9 5-20
19.3 5-20    
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有衍射峰：
峰位置2θ角(°) 峰位置2θ角(°) 峰位置2θ角(°)
8.1 20.3 28.3
9.8 21.7 28.6
10.2 22.3 29.9
12.4 23.0 30.9
15.6 24.6 32.3
16.1 25.0 34.0
16.8 26.0 36.5
18.8 26.1 37.7
19.3 27.7  
优选地，上述衍射峰的相对强度为：
Figure PCTCN2021120328-appb-000016
或者，使用Cu-Kα辐射，具有基本上如图1所示的X-射线粉末衍射图谱。
本申请的一些实施方案中，所述式3-1所示的二盐酸盐、其溶剂合物或水合物的结晶形式(晶型I)，使用DSC-TGA测定，其DSC图在200～320℃范围内出现两个明显的吸热峰，所述吸热峰的起始点分别出现在219.1±3℃和235.1±3℃处，峰值分别出现在231.0±3℃和284.2±3℃处；该盐酸盐的TGA图显示在205.6±3℃处开始发生分解；或者，所述式3-1所示的二盐酸盐的晶型I，具有基本如图8所示的DSC-TGA图。
本申请的一些实施方案中，所述式3-1所示的二盐酸盐、其溶剂合物或水合物的结晶形式(晶型I)， 其DSC图在231.0±5℃和284.2±5℃处分别有吸热峰。
本申请的一些实施方案中，所述式3-1所示的二盐酸盐、其溶剂合物或水合物的结晶形式(晶型I)，其TGA图在205.6±5℃处开始发生分解。
本申请的一些实施方案中，所述式3-1所示的二盐酸盐、其溶剂合物或水合物的结晶形式(晶型I)，其具有基本如图8所示的DSC图。
本申请的一些实施方案中，所述式3-1所示的二盐酸盐、其溶剂合物或水合物的结晶形式(晶型I)，其具有基本如图8所示的TGA图。
本申请的一些实施方案中，所述式3-1所示的二盐酸盐、其溶剂合物或水合物的结晶形式(晶型II)，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：6.0±0.2°、6.8±0.2°、12.4±0.2°、26.0±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：6.0±0.2°、6.8±0.2°、12.4±0.2°、15.5±0.2°、26.0±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：6.0±0.2°、6.8±0.2°、12.4±0.2°、15.5±0.2°、25.4±0.2°、26.0±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：6.0±0.2°、6.8±0.2°、12.4±0.2°、15.5±0.2°、18.0±0.2°、24.4±0.2°、25.4±0.2°、26.0±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：6.0±0.2°、6.8±0.2°、12.4±0.2°、15.5±0.2°、18.0±0.2°、22.7±0.2°、24.4±0.2°、25.4±0.2°、26.0±0.2°；
优选地，所述特征峰的相对强度为：
峰位置2θ角(°) 相对峰强度％ 峰位置2θ角(°) 相对峰强度％
6.0 20-100 22.7 4-25
6.8 70-100 24.4 5-30
12.4 10-60 25.4 5-40
15.5 8-30 26.0 20-90
18.0 5-45    
；
优选地，所述特征峰的相对强度为：
峰位置2θ角(°) 相对峰强度％ 峰位置2θ角(°) 相对峰强度％
6.0 20-60 22.7 5-25
6.8 80-100 24.4 5-30
12.4 10-40 25.4 10-40
15.5 8-30 26.0 20-60
18.0 5-30    
；
优选地，所述特征峰的相对强度为：
峰位置2θ角(°) 相对峰强度％ 峰位置2θ角(°) 相对峰强度％
6.0 36.7 22.7 9.1
6.8 100.0 24.4 14.8
12.4 22.1 25.4 21.4
15.5 17.3 26.0 47.8
18.0 11.9    
；
优选地，所述特征峰的相对强度为：
峰位置2θ角(°) 相对峰强度％ 峰位置2θ角(°) 相对峰强度％
6.0 100.0 22.7 5.4
6.8 81.3 24.4 13.0
12.4 52.8 25.4 10.1
15.5 9.5 26.0 83.7
18.0 38.5    
；
或者，所述式3-1所示的二盐酸盐、其溶剂合物或水合物的结晶形式(晶型II)，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：6.0±0.2°、6.8±0.2°、12.4±0.2°、 15.5±0.2°、18.0±0.2°、20.5±0.2°、22.7±0.2°、24.4±0.2°、25.4±0.2°、26.0±0.2°、27.5±0.2°；
或者，所述式3-1所示的二盐酸盐、其溶剂合物或水合物的结晶形式(晶型II)，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有衍射峰：
峰位置2θ角(°) 峰位置2θ角(°) 峰位置2θ角(°)
6.0 18.0 26.0
6.8 20.5 27.5
12.4 22.7  
15.5 24.4  
17.5 25.4  
优选地，上述衍射峰的相对峰强度为：
Figure PCTCN2021120328-appb-000017
优选地，上述衍射峰的相对峰强度为：
Figure PCTCN2021120328-appb-000018
或者，所述式3-1所示的二盐酸盐、其溶剂合物或水合物的结晶形式(晶型II)，使用Cu-Kα辐射，具有基本上如图2或图19所示的X-射线粉末衍射图谱。
本申请的一些实施方案中，所述式3-1所示的二盐酸盐、其溶剂合物或水合物的结晶形式(晶型II)使用TGA测定，其TGA图在50～140℃范围失重12.24±0.20％。
或者，所述式3-1所示的二盐酸盐、其溶剂合物或水合物的结晶形式(晶型II)具有基本如图9所示的TGA图。
本申请的一些实施方案中，所述式3-1所示的二盐酸盐、其溶剂合物或水合物的结晶形式(晶型III)，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：12.7±0.2°、13.3±0.2°、23.3±0.2°、29.3±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：12.7±0.2°、13.3±0.2°、17.2±0.2°、23.3±0.2°、29.3±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：11.5±0.2°、11.9±0.2°、12.7±0.2°、13.3±0.2°、17.2±0.2°、23.3±0.2°、29.3±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：11.5±0.2°、11.9±0.2°、12.2±0.2°、12.7±0.2°、13.3±0.2°、17.2±0.2°、23.3±0.2°、29.3±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：11.5±0.2°、11.9±0.2°、12.2±0.2°、12.7±0.2°、13.3±0.2°、17.2±0.2°、17.6±0.2°、23.0±0.2°、23.3±0.2°、29.3±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：8.4±0.2°、11.5±0.2°、11.9±0.2°、12.2±0.2°、12.7±0.2°、13.3±0.2°、17.2±0.2°、17.6±0.2°、23.0±0.2°、23.3±0.2°、24.6±0.2°、29.3±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：8.4±0.2°、11.5±0.2°、11.9±0.2°、12.2±0.2°、12.7±0.2°、13.3±0.2°、17.2±0.2°、17.6±0.2°、23.0±0.2°、23.3±0.2°、24.6±0.2°、28.8±0.2°、29.3±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有衍射峰：
峰位置2θ角(°) 峰位置2θ角(°) 峰位置2θ角(°) 峰位置2θ角(°)
6.4 12.7 18.3 29.3
6.6 13.3 19.1 30.2
7.8 14.8 23.0 35.6
8.4 15.4 23.3  
11.5 16.7 24.6  
11.9 17.2 25.5  
12.2 17.6 28.8  
；
或者，使用Cu-Kα辐射，具有基本上如图11所示的X-射线粉末衍射图谱。
本申请的一些实施方案中，所述式3-1所示的二盐酸盐、其溶剂合物或水合物的结晶形式(晶型III)，使用DSC测定，其DSC图在101.52±5℃和183.70±5℃处分别有吸热峰。
本申请的一些实施方案中，所述式3-1所示的二盐酸盐、其溶剂合物或水合物的结晶形式(晶型III)，使用TGA测定，其TGA图在室温～120℃范围失重6.3±0.20％。
或者，所述式3-1所示的二盐酸盐、其溶剂合物或水合物的结晶形式(晶型III)，其具有基本如图12所示的DSC-TGA图。
本申请的一些实施方案中，所述式3-1所示的二盐酸盐、其溶剂合物或水合物的结晶形式(晶型IV)，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：5.4±0.2°、8.2±0.2°、13.0±0.2°、16.5±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：5.4±0.2°、8.2±0.2°、12.0±0.2°、13.0±0.2°、16.5±0.2°、22.8±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：5.4±0.2°、8.2±0.2°、12.0±0.2°、13.0±0.2°、16.5±0.2°、17.8±0.2°、22.8±0.2°、29.0±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：5.4±0.2°、8.2±0.2°、11.3±0.2°、12.0±0.2°、13.0±0.2°、16.5±0.2°、17.8±0.2°、19.4±0.2°、22.8±0.2°、29.0±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：5.4±0.2°、6.4±0.2°、7.4±0.2°、8.2±0.2°、11.3±0.2°、12.0±0.2°、13.0±0.2°、16.5±0.2°、17.8±0.2°、19.4±0.2°、22.8±0.2°、29.0±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：5.4±0.2°、6.4±0.2°、7.4±0.2°、8.2±0.2°、10.8±0.2°、11.3±0.2°、12.0±0.2°、13.0±0.2°、14.6±0.2°、16.5±0.2°、17.8±0.2°、19.4±0.2°、22.8±0.2°、29.0±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：5.4±0.2°、6.4±0.2°、7.4±0.2°、8.2±0.2°、10.8±0.2°、11.3±0.2°、12.0±0.2°、13.0±0.2°、14.2±0.2°、14.6±0.2°、16.5±0.2°、16.9±0.2°、17.8±0.2°、19.4±0.2°、22.8±0.2°、29.0±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有衍射峰：
峰位置2θ角(°) 峰位置2θ角(°) 峰位置2θ角(°) 峰位置2θ角(°) 峰位置2θ角(°)
5.4 12.0 16.9 23.6 31.5
6.4 13.0 17.4 24.9 33.1
7.4 14.2 17.8 25.9  
8.2 14.6 18.1 27.9  
10.8 14.9 19.4 28.6  
11.3 16.5 22.8 29.0  
；
或者，使用Cu-Kα辐射，具有基本上如图13所示的X-射线粉末衍射图谱。
本申请的一些实施方案中，所述式3-1所示的二盐酸盐、其溶剂合物或水合物的结晶形式(晶型IV)，使用DSC测定，其DSC图在68.81±5℃和177.55±5℃处分别有吸热峰。
本申请的一些实施方案中，所述式3-1所示的二盐酸盐、其溶剂合物或水合物的结晶形式(晶型IV)，使用TGA测定，其TGA图在室温～150℃范围失重3.9±0.20％。
或者，所述式3-1所示的二盐酸盐、其溶剂合物或水合物的结晶形式(晶型IV)，具有基本如图14所示的DSC-TGA图。
本申请的一些实施方案中，所述式3-1所示的二盐酸盐、其溶剂合物或水合物的结晶形式(晶型V)，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：8.4±0.2°、9.6±0.2°、19.8±0.2°、29.2±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：8.4±0.2°、9.6±0.2°、10.5±0.2°、19.3±0.2°、19.8±0.2°、29.2±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：4.2±0.2°、6.4±0.2°、8.4±0.2°、9.6±0.2°、10.5±0.2°、19.3±0.2°、19.8±0.2°、29.2±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：4.2±0.2°、6.4±0.2°、8.4±0.2°、9.6±0.2°、10.5±0.2°、15.1±0.2°、19.3±0.2°、19.8±0.2°、21.2±0.2°、29.2±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：4.2±0.2°、6.4±0.2°、8.4±0.2°、9.6±0.2°、10.5±0.2°、15.1±0.2°、16.9±0.2°、19.3±0.2°、19.8±0.2°、21.2±0.2°、24.6±0.2°、29.2±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：4.2±0.2°、6.4±0.2°、8.4±0.2°、9.6±0.2°、10.5±0.2°、15.1±0.2°、16.9±0.2°、19.3±0.2°、19.8±0.2°、21.2±0.2°、24.6±0.2°、28.9±0.2°、29.2±0.2°、29.5±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有衍射峰：
Figure PCTCN2021120328-appb-000019
或者，使用Cu-Kα辐射，具有基本上如图15所示的X-射线粉末衍射图谱。
本申请的一些实施方案中，所述式3-1所示的二盐酸盐、其溶剂合物或水合物的结晶形式(晶型V)，使用DSC测定，其DSC图在48.29±5℃、153.99±5℃和190.59±5℃处分别有吸热峰。
本申请的一些实施方案中，所述式3-1所示的二盐酸盐、其溶剂合物或水合物的结晶形式(晶型V)，使用TGA测定，其TGA图在室温～200℃范围失重7.3±0.20％。
或者，所述式3-1所示的二盐酸盐、其溶剂合物或水合物的结晶形式(晶型V)，具有基本如图16所示的DSC-TGA图。
本申请的一些实施方案中，所述式3-1所示的二盐酸盐、其溶剂合物或水合物的结晶形式(晶型VII)，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：8.3±0.2°、11.9±0.2°、12.9±0.2°、14.6±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：6.5±0.2°、8.3±0.2°、11.9±0.2°、12.9±0.2°、14.6±0.2°、16.5±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：6.5±0.2°、8.3±0.2°、11.9±0.2°、12.9±0.2°、14.6±0.2°、16.5±0.2°、17.6±0.2°、24.4±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：6.5±0.2°、8.3±0.2°、11.9±0.2°、12.9±0.2°、14.6±0.2°、16.5±0.2°、17.6±0.2°、24.4±0.2°、24.8±0.2°、29.6±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：6.5±0.2°、8.3±0.2°、11.9±0.2°、12.9±0.2°、14.6±0.2°、16.5±0.2°、17.6±0.2°、18.8±0.2°、20.4±0.2°、24.4±0.2°、24.8±0.2°、29.6±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：6.5±0.2°、8.3±0.2°、11.9±0.2°、12.9±0.2°、14.6±0.2°、16.5±0.2°、17.6±0.2°、18.8±0.2°、20.4±0.2°、22.2±0.2°、23.6±0.2°、24.4±0.2°、24.8±0.2°、29.6±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有衍射峰：
Figure PCTCN2021120328-appb-000020
Figure PCTCN2021120328-appb-000021
或者，使用Cu-Kα辐射，具有基本上如图17所示的X-射线粉末衍射图谱。
本申请的一些实施方案中，所述式3-1所示的二盐酸盐、其溶剂合物或水合物的结晶形式(晶型VII)，使用DSC测定，其DSC图在87.64±5℃和182.15±5℃处分别有吸热峰。
本申请的一些实施方案中，所述式3-1所示的二盐酸盐、其溶剂合物或水合物的结晶形式(晶型VII)，使用TGA测定，其TGA图在室温～120℃范围失重1.4±0.20％。
或者，所述式3-1所示的二盐酸盐、其溶剂合物或水合物的结晶形式(晶型VII)，具有基本如图18所示的DSC-TGA图。
本申请的一些实施方案中，所述含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物为式4所示的硫酸盐：
Figure PCTCN2021120328-appb-000022
n为1-2的整数或半整数，即n为1、1.5或2。
本申请的一些实施方案中，所述含芳氨基喹唑啉的化合物的盐为式4-1所示的硫酸盐：
Figure PCTCN2021120328-appb-000023
本申请的一些实施方案中，所述含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物的的结晶形式为式4所示的硫酸盐、其溶剂合物或水合物的结晶形式：
Figure PCTCN2021120328-appb-000024
n为1-2的整数或半整数，即n为1、1.5或2。
本申请的一些实施方案中，所述芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物的结晶形式为式4-1所示的硫酸盐、其溶剂合物或水合物的结晶形式：
Figure PCTCN2021120328-appb-000025
本申请的一些实施方案中，所述式4-1所示的硫酸盐、其溶剂合物或水合物的结晶形式为其晶型I。
本申请的一些实施方案中，所述式4-1所示的硫酸盐、其溶剂合物或水合物的结晶形式(晶型I)，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在以下位置有特征峰：12.4±0.2°、15.5±0.2°、24.8±0.2°、25.9±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：6.8±0.2°、 8.5±0.2°、12.4±0.2°、15.5±0.2°、24.8±0.2°、25.9±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：6.8±0.2°、8.5±0.2°、12.4±0.2°、13.6±0.2°、15.5±0.2°、24.8±0.2°、25.9±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：6.8±0.2°、8.5±0.2°、12.4±0.2°、13.6±0.2°、15.5±0.2°、17.9±0.2°、19.6±0.2°、24.8±0.2°、25.9±0.2°；
优选地，所述特征峰的相对强度为：
峰位置2θ角(°) 相对峰强度％ 峰位置2θ角(°) 相对峰强度％
6.8 37.8 17.9 32.1
8.5 19.6 19.6 21.9
12.4 57.3 24.8 99.3
13.6 19.9 25.9 100.0
15.5 32.4    
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有衍射峰：
峰位置2θ角(°) 峰位置2θ角(°) 峰位置2θ角(°)
6.8 19.6 24.8
8.5 20.7 25.9
12.4 22.1 27.8
13.6 23.1 28.9
15.5 23.6 32.1
17.9    
优选地，上述衍射峰的相对峰强度为：
Figure PCTCN2021120328-appb-000026
或者，使用Cu-Kα辐射，具有基本上如图3所示的X-射线粉末衍射图谱。
本申请的一些实施方案中，所述含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物为式5所示的马来酸盐：
Figure PCTCN2021120328-appb-000027
n为1-2的整数或半整数，即n为1、1.5或2。
本申请的一些实施方案中，所述含芳氨基喹唑啉的化合物的盐为式5-1所示的马来酸盐：
Figure PCTCN2021120328-appb-000028
本申请的一些实施方案中，所述含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物的结晶形式为式5所示的马来酸盐、其溶剂合物或水合物的结晶形式：
Figure PCTCN2021120328-appb-000029
n为1-2的整数或半整数，即n为1、1.5或2。
本申请的一些实施方案中，所述含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物的结晶形式为式5-1所示的马来酸盐、其溶剂合物或水合物的结晶形式：
Figure PCTCN2021120328-appb-000030
本申请的一些实施方案中，所述式5-1所示的马来酸盐、其溶剂合物或水合物的结晶形式为其晶型I。
本申请的一些实施方案中，所述式5-1所示的马来酸盐、其溶剂合物或水合物的结晶形式(晶型I)，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在以下位置有特征峰：4.9±0.2°、7.6±0.2°、16.7±0.2°、24.9±0.2°；
或者，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在以下位置有特征峰：4.4±0.2°、4.9±0.2°、7.6±0.2°、16.7±0.2°、20.6±0.2°、24.9±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：4.4±0.2°、4.9±0.2°、7.6±0.2°、13.3±0.2°、16.7±0.2°、19.6±0.2°、20.6±0.2°、24.9±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：4.4±0.2°、4.9±0.2°、7.6±0.2°、13.3±0.2°、16.7±0.2°、18.9±0.2°、19.6±0.2°、20.6±0.2°、24.9±0.2°、26.3±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：4.4±0.2°、4.9±0.2°、7.6±0.2°、11.4±0.2°、13.3±0.2°、14.2±0.2°、16.7±0.2°、18.9±0.2°、19.6±0.2°、20.6±0.2°、24.9±0.2°、26.3±0.2°；
优选地，所述特征峰的相对强度为：
峰位置2θ角(°) 相对峰强度％ 峰位置2θ角(°) 相对峰强度％
4.4 64.6 16.7 76.8
4.9 100.0 18.9 29.1
7.6 97.1 19.6 38.9
11.4 20.1 20.6 51.0
13.3 36.8 24.9 82.5
14.2 20.1 26.3 32.6
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有衍射峰：
峰位置2θ角(°) 峰位置2θ角(°) 峰位置2θ角(°)
4.4 14.2 20.6
4.9 15.4 21.5
7.6 16.7 23.2
10.6 17.4 24.9
11.4 18.9 26.3
13.3 19.6 26.9
优选地，上述衍射峰的相对峰强度为：
Figure PCTCN2021120328-appb-000031
Figure PCTCN2021120328-appb-000032
或者，使用Cu-Kα辐射，具有基本上如图4所示的X-射线粉末衍射图谱。
本申请的一些实施方案中，所述含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物为式6所示的草酸盐：
Figure PCTCN2021120328-appb-000033
n为0.5-2的整数或半整数，即n为0.5、1、1.5或2。
本申请的一些实施方案中，所述含芳氨基喹唑啉的化合物的盐为式6-1所示的草酸盐：
Figure PCTCN2021120328-appb-000034
本申请的一些实施方案中，所述含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物的结晶形式为式6所示的草酸盐、其溶剂合物或水合物的结晶形式：
Figure PCTCN2021120328-appb-000035
n为0.5-2的整数或半整数，即n为0.5、1、1.5或2。
本申请的一些实施方案中，所述含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物的结晶形式为式6-1所示的草酸盐、其溶剂合物或水合物的结晶形式：
Figure PCTCN2021120328-appb-000036
本申请的一些实施方案中，所述式6-1所示的草酸盐、其溶剂合物或水合物的结晶形式为其晶型I。
本申请的一些实施方案中，所述式6-1所示的草酸盐、其溶剂合物或水合物的结晶形式(晶型I)，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在以下位置有特征峰：5.9±0.2°、9.9±0.2°、17.5±0.2°、21.5±0.2°、19.8±0.2°；
或者，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在以下位置有特征峰：5.9±0.2°、9.9±0.2°、17.5±0.2°、21.5±0.2°、19.8±0.2°、23.0±0.2°、25.5±0.2°；
或者，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在以下位置有特征峰：5.9±0.2°、9.9±0.2°、17.5±0.2°、18.4±0.2°、21.5±0.2°、19.8±0.2°、23.0±0.2°、24.4±0.2°、25.5±0.2°；
或者，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在以下位置有特征峰：5.9±0.2°、9.9±0.2°、 17.5±0.2°、18.4±0.2°、21.5±0.2°、19.8±0.2°、23.0±0.2°、23.5±0.2°、24.4±0.2°、25.5±0.2°、26.6±0.2°；
或者，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在以下位置有特征峰：5.9±0.2°、9.9±0.2°、10.7±0.2°、17.5±0.2°、18.4±0.2°、21.5±0.2°、19.8±0.2°、23.0±0.2°、23.5±0.2°、24.4±0.2°、25.5±0.2°、26.6±0.2°、27.3±0.2°；
或者，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在以下位置有特征峰：5.9±0.2°、9.9±0.2°、10.7±0.2°、17.5±0.2°、18.4±0.2°、21.5±0.2°、19.8±0.2°、20.3±0.2°、23.0±0.2°、23.5±0.2°、24.4±0.2°、25.5±0.2°、26.6±0.2°、27.3±0.2°、27.9±0.2°；
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有衍射峰：
峰位置2θ角(°) 峰位置2θ角(°) 峰位置2θ角(°)
5.9 18.4 25.5
9.9 19.8 26.6
10.7 20.3 27.3
11.7 21.5 27.9
15.1 23.0 29.2
16.3 23.5  
17.5 24.4  
或者，使用Cu-Kα辐射，具有基本上如图7所示的X-射线粉末衍射图谱。
另一方面，本申请提供了一种药物组合物，其包含前述式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物。
本申请的一些实施方案中，所述药物组合物，其包含前述式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物的结晶形式。
本申请的一些实施方案中，所述药物组合物，其包含前述式3-1所示的含芳氨基喹唑啉的化合物的二盐酸盐、其溶剂合物或水合物的结晶形式。
本申请的一些实施方案中，所述药物组合物，其包含前述式3-1所示的含芳氨基喹唑啉的化合物的二盐酸盐、其溶剂合物或水合物的晶型I、晶型II、晶型III、晶型IV、晶型V或晶型VII中的一种或多种。
本申请的一些实施方案中，所述药物组合物包含前述式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物，以及含有一种或多种可药用载体。
本申请的一些实施方案中，所述药物组合物，其包含前述式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物的结晶形式，以及含有一种或多种可药用载体。
本申请的一些实施方案中，所述药物组合物，其包含前述式3-1所示的含芳氨基喹唑啉的化合物的二盐酸盐、其溶剂合物或水合物的结晶形式，以及含有一种或多种可药用载体。
本申请的一些实施方案中，所述药物组合物，其包含前述式3-1所示的含芳氨基喹唑啉的化合物的二盐酸盐、其溶剂合物或水合物的晶型I、晶型II、晶型III、晶型IV、晶型V或晶型VII中的一种或多种，以及含有一种或多种可药用载体。
本申请的一些实施方案中，所述药物组合物包含治疗有效量的前述式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物，以及含有一种或多种可药用载体。
本申请的药物组合物可通过本领域的常规方法制备得到，例如，将式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物与一种或多种可药用载体混合制得。
又一方面，本申请提供了前述式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物、前述式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物的结晶形式或前述药物组合物用于制备作为受体酪氨酸激酶抑制剂的药物中的用途。
本申请的一些实施方案中，所述受体酪氨酸激酶为VEGFR、FLT、FGFR、RET、EGFR和它们的突变体中的一种或多种。
又一方面，本申请还提供了前述式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物、前述式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物的结晶形式或前述药物组合物在治疗受体酪氨酸激酶相关疾病中的用途。
又一方面，本申请还提供了一种治疗患者的受体酪氨酸激酶相关疾病的方法，包括向患者施用治疗有效量的前述式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物、前述式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物的结晶形式或前述药物组合物。
又一方面，本申请还提供了用于治疗受体酪氨酸激酶相关疾病的前述式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物、前述式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物的结晶形式或前述药物组合物。
本申请的一些实施方案中，上述各方面所述的受体酪氨酸激酶相关疾病为VEGFR、FLT、FGFR、RET、 EGFR和它们突变体中的一种或多种导致的疾病。本申请的一些实施方案中，所述疾病为细胞增殖性疾病。本申请的一些实施方案中，所述疾病涉及VEGFR、FLT、FGFR、RET和EGFR中一种或多种蛋白表达、水平或活性的失调。本申请的一些实施方案中，所述细胞增殖性疾病为肿瘤或癌症。本申请的一些实施方案中，所述肿瘤包括甲状腺癌、胆道癌、表皮样癌、黑色素瘤、结直肠癌、胃癌、食管癌、胰腺癌、肾癌、肝癌、肺癌或卵巢癌。本申请的一些实施方案中，所述甲状腺癌为甲状腺髓样癌，所述肺癌为非小细胞肺癌。本申请的一些实施方案中，所述非小细胞肺癌为RET融合型非小细胞肺癌。
又一方面，本申请还提供了前述式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物、前述式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物的结晶形式或前述药物组合物在制备抗肿瘤药物中的用途。
又一方面，本申请还提供了前述式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物、前述式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物的结晶形式或前述药物组合物在***中的用途。
又一方面，本申请还提供了一种治疗患者的肿瘤疾病的方法，包括向患者施用治疗有效量的前述式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物、前述式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物的结晶形式或前述药物组合物。
再一方面，本申请还提供了用于***疾病的前述式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物、前述式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物的结晶形式或前述药物组合物。
本申请的一些实施方案中，上述各方面所述的肿瘤或肿瘤疾病包括甲状腺癌、胆道癌、表皮样癌、黑色素瘤、结直肠癌、胃癌、食管癌、胰腺癌、肾癌、肝癌、肺癌或卵巢癌。本申请的一些实施方案中，所述甲状腺癌为甲状腺髓样癌，所述肺癌为非小细胞肺癌。本申请的一些实施方案中，所述非小细胞肺癌为RET融合型非小细胞肺癌。本申请的一些实施方案中，所述肿瘤或肿瘤疾病为VEGFR、FLT、FGFR、RET、EGFR和它们突变体中的一种或多种导致的肿瘤或肿瘤疾病。本申请的一些实施方案中，所述肿瘤或肿瘤疾病涉及VEGFR、FLT、FGFR、RET和EGFR中一种或多种蛋白表达、水平或活性的失调。
上述的“患者”包括动物界的所有成员，包含但不限于，哺乳动物(例如，小鼠、大鼠、猫、猴子、狗、猪等)和人。
又一方面，本申请提供了一种式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物的制备方法，包括将式1所示的含芳氨基喹唑啉的化合物与酸(HA)在适宜溶剂中进行反应，分离得到式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物：
Figure PCTCN2021120328-appb-000037
其中，
HA是酸；
n为1/2-2的整数或半整数。
本申请的一些实施方案中，所述HA为盐酸、硫酸、草酸、马来酸或苹果酸。
本申请的一些实施方案中，所述式1所示的含芳氨基喹唑啉的化合物与酸的摩尔比为1:1～2.5，优选为1:1～2。
本申请的一些实施方案中，反应温度为10-90℃，优选为40-70℃。
本申请的一些实施方案中，反应溶剂选自醇类、酮类、腈类、水或杂环烷烃类溶剂中的一种或者两种的组合；优选为乙酸乙酯、甲醇、乙醇、水、乙腈、丙酮、四氢呋喃、DMF、NMP、异丙醇、正丙醇、DMA、二氧六环中的一种或者两种的组合；进一步优选为乙酸乙酯、甲醇或水。
本申请的一些实施方案中，反应溶剂为甲醇和乙酸乙酯的组合。本申请的一些实施方案中，反应溶剂为水。本申请的一些实施方案中，反应溶剂为甲醇和乙腈的组合。本申请的一些实施方案中，反应溶剂为水和乙腈的组合。本申请的一些实施方案中，反应溶剂为乙醇。
本申请的一些实施方案中，上述反应溶剂为两种组合时，可分别加入，即先加入良溶剂，后加入不良溶剂。
本申请的一些实施方案中，分离得到结晶形式的式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合 物或水合物。
本申请的一些实施方案中，所述反应进行完毕，降温析晶温度为-5～35℃，优选0～25℃，搅拌析晶0.5～24h，分离固体，干燥，得式2所示的含芳氨基喹唑啉的化合物的盐。优选地，收集盐的温度为10℃，析晶时间为0.5～12h。
本申请的一些实施方案中，所述分离步骤包括采用过滤、离心等适宜的方法将所得式2所示的含芳氨基喹唑啉化合物的盐从结晶液中分离出来。
本申请的一些实施方案中，所述干燥方法可采用任何适宜的已知方法，优选为烘干。具体的干燥条件是，例如，使用真空干燥箱，温度优选30～65℃，更优选为40～55℃；干燥时间优选为1～50h，更优选为1～16h，进一步优选为3～6h。无论采用何种干燥手段，都以所得产品中溶剂残留量符合质量标准为宜。
式1所示的含芳氨基喹唑啉的化合物可参照现有技术公开方法，如WO2016023330A1记载方法进行制备，上述文献内容在此引入作为参考。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在含有下列含义。一个特定的短语或术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文出现商品名时，旨在指代其对应的商品或其活性成分。
术语“溶剂化物”或“溶剂合物”是指一个或多个溶剂分子与本申请的式2所示化合物所形成的缔合物，包括同时含有水分子和一种或多种其它溶剂分子的缔合物。
术语“水合物”是指一个或多个水分子与本申请的式2所示化合物所形成的缔合物。本申请中的水合物包括式3-2所示化合物的二盐酸盐四水合物。
如无特别说明，本申请所述的“2θ”、“2θ角”或“2θ角度”是指衍射角，单位为°或度，2θ的误差范围可以为±0.5、±0.4、±0.3、±0.2或±0.1°。
如无特别说明，本申请所述的“加热温度”、“降温温度”或“析晶温度”，单位为℃或摄氏度，误差范围可以为±10、±5、±4、±3、±2或±1℃。
术语“基本上如图所示”是指X-射线粉末衍射图谱或DSC图谱或TGA图谱中至少50％，或至少60％，或至少70％，或至少80％，或至少90％，或至少95％，或至少96％，或至少97％，或至少98％，或至少99％的峰显示在其图中。进一步地，当产品中某种晶型的含量逐渐降低时，其粉末X-射线衍射图谱中的一些归属于该晶型的衍射峰可能会由于仪器的检测灵敏度的因素而变少。
术语“特征衍射峰”是指在X-射线粉末衍射图谱中，可用于代表该晶型的衍射峰，其与衍射峰的峰位置、峰形和相对峰强度有关，例如，小角度峰，峰形尖锐，且相对峰强度至少3％以上，或至少5％以上，或至少10％以上，或至少20％以上，或至少30％以上，或至少40％以上，或至少50％以上，或至少60％以上，或至少70％以上，或至少75％以上的衍射峰。
术语“细胞增殖性疾病”是指其中的细胞群生长速率低于或高于给定生理状态和条件下的预期速率的病症。
术语“肿瘤”包含良性肿瘤、恶性肿瘤和交界性肿瘤，其中恶性肿瘤又统称为癌症。
术语“治疗”一般是指获得需要的药理和/或生理效应，包括部分或完全稳定或治愈疾病和/或由于疾病产生的作用。本文使用的“治疗”涵盖了对患者疾病的任何治疗，包括：(a)抑制疾病的症状，即阻止其发展；或(b)缓解疾病的症状，即，导致疾病或症状退化。
术语“有效量”或“治疗有效量”意指(i)治疗特定疾病，或(ii)减轻、改善或消除特定疾病的一种或多种症状的本申请化合物的用量。术语“治疗有效量”意指化合物被给予患者用于治疗疾病时，足以实现对该疾病的治疗的量。构成“治疗有效量”的本申请化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
术语“可药用载体”或“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害活性化合物的生物活性及性能的那些载体。
本申请中的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其它化学合成方法的结合所形成的实施方式以及本领域技术人员所熟知的等同替换方式，优选的实施方式包括但不限于本申请的实施例。
本申请具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本申请的化学变化及其所需的试剂或物料。为了获得本申请的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
下面会通过实施例具体描述本申请，这些实施例并不意味着对本申请的任何限制。
本申请所使用的所有溶剂均是市售的，无需进一步纯化即可使用。
本申请采用下述缩略词：DMF：N,N-二甲基甲酰胺；NMP：N-甲基吡咯烷酮；DMA：N,N-二甲基苯胺。
有益效果
本申请提供式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物以及式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物的结晶形式，它们具有以下一种或多种有益效果：
式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物的固体性状良好，进一步地，结晶性状良好，尤其是二盐酸盐、硫酸盐、马来酸盐、单盐酸盐、草酸盐、苹果酸盐、及其溶剂合物或水合物的结晶性状良好。
二盐酸盐、硫酸盐、马来酸盐、草酸盐、及其溶剂合物或水合物在水或水性溶液中溶解度有显著改善，特别是二盐酸盐、硫酸盐、马来酸盐、及其溶剂合物或水合物。
此外，优选盐及其晶型(例如，二盐酸盐、二盐酸盐四水合物、硫酸盐、马来酸盐及其晶型)具有优良的储存稳定性、化学稳定性、热稳定性和/或机械稳定性。
本申请式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物，特别是二盐酸盐、硫酸盐、马来酸盐、草酸盐、及其溶剂合物或水合物，更特别是二盐酸盐及其溶剂合物或水合物具有更好的成药性，适宜作为原料药储存，并可根据临床需要开发成不同的药物剂型。
具体实施方式
下文将结合具体实施例对本申请的技术方案做更进一步的详细说明。下列实施例仅为示例性地说明和解释本申请，而不应被解释为对本申请保护范围的限制。凡基于本申请上述内容所实现的技术均涵盖在本申请旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
以下实施例中，分析检测条件如下：
1、含量
检测仪器：Agilent 1260(LC1260-3-DAD)高效液相色谱仪
柱子：C18 4.6*250mm,5μm
测试条件：波长252nm；柱温45℃；
2、溶解度(水及pH2.0缓冲液)
检测仪器：：Agilent 1260高效液相色谱仪
检测介质：纯化水、pH2.0磷酸-磷酸氢二钠缓冲液
对照品溶液制备：取式1化合物对照品适量，精密称定，加溶剂使其完全溶解，并稀释制成100μg/mL的溶液，精密量取10uL，使用HPLC测定对照品溶液中化合物1的含量。
3、X-射线粉末衍射(X-Ray Powder Diffraction，XRPD)
(1)检测仪器：Bruker D2 PHASER型粉末X-射线衍射仪
测试条件：
光管类型：Cu靶，陶瓷X光管；
X-射线波长：CuKα，
Figure PCTCN2021120328-appb-000038
1.5406；
电压电流：30kV，10mA；
扫描范围：3～40°2θ；
扫描总时间：40min；
扫描速度：0.5秒/步；
样品用量：3mg(实施例1-4)
采集软件：Diffrac Plus XRD Commander
分析软件：MDI Jade 6.0
(2)检测仪器：Bruker D8 Advance型粉末X-射线衍射仪
测试条件：
光管类型：Cu靶，陶瓷X光管；
X-射线波长：CuKα，
Figure PCTCN2021120328-appb-000039
1.5418；
电压电流：40kV，40mA；
扫描范围：3～40°2θ；
扫描速度：0.2秒/步；
样品用量：5-10mg(实施例5-8)。
4、热重分析(Thermogravimetric Analysis，TGA)
(1)检测仪器：METTLER和SDT Q600热重分析仪
测试方法：称取样品5mg(实施例1-4)，置于TGA铂金锅内进行测试，在40mL/min干燥氮气的条件下，以5K/min的升温速率，加热样品从40℃至300℃。
仪器控制软件：NETZSCH-proteus-6
分析软件：Proteus Analysis
(2)检测仪器：Discovery TGA 55型热重分析仪(TA Instruments，US)
测试方法：将约2～5mg样品(实施例5-8)放置于已去皮的敞口铝盘中，仪器自动称重并记录重量。之后样品在加热炉中以10℃/min的升温速率，从室温加热至最终温度。气流为N 2，流速分别为为40mL/min(样品室)和25mL/min(平衡室)。
5、差示扫描量热-热重分析(Differential Scanning Calorimetry-Thermogravimetric Analysis，DSC-TGA)
检测仪器：NETZSCH STA449F3同步热分析仪
测试方法：称取样品(约3mg)，置于三氧化二铝坩埚内进行测试，在20mL/min干燥氮气(保护气体)的条件下，以10K/min的升温速率，加热样品从20℃至340℃。
仪器控制软件：NETZSCH-proteus
分析软件：Proteus Analysis
6、差示扫描量热分析(Differential Scanning Calorimetry，DSC)
检测仪器：Discovery DSC 250型差示扫描量热仪(TA Instruments，US)
测试方法：称量2～5mg样品(实施例5-8)放置于带孔密闭铝盘中，并精确记录样品量。然后将样品以10℃/min的升温速率，从25℃加热至最终温度。气流为N 2，流速为50mL/min。
7、氯化物
检测仪器：戴安ICS-900离子色谱仪
柱子：Dionex Ion Pac AS11-HC阴离子色谱柱(规格：4×250mm)
实验操作：
供试品溶液制备：取供试品适量，精密称定，用淋洗液(12.5mmol/L氢氧化钠溶液)溶解并定量稀释成每1mL中约含供试品0.5mg的溶液，摇匀，作为供试品溶液。
对照品溶液制备：取氯化钠适量(相当于氯离子18mg)，精密称定，置250mL量瓶中，用淋洗液溶解并定容，摇匀，作为对照品溶液。
测定法：精密量取对照品溶液和供试品溶液各10μL，分别注入离子色谱仪，记录色谱图，按外标法以峰面积计算氯离子含量。
8、核磁氢谱
仪器型号：Bruker Advance 600型核磁共振谱仪
测定条件：以DMSO-d 6为溶剂，在室温下(～25℃)进行测试
9、生物溶媒中溶解度测定
用于溶解度测定的生物溶媒介质(SGF，FeSSIF和FaSSIF)的配制过程见下表：
Figure PCTCN2021120328-appb-000040
测试方法：将待测样品加入到生物溶媒介质中，配制成目标浓度为10mg/mL的溶液或混悬液。所得溶液或混悬液在37℃条件下以200rpm的转速持续振摇。在0.5小时将混悬液过滤，使用HPLC测定滤液中的化合物浓度。
制备例1：化合物1的制备
Figure PCTCN2021120328-appb-000041
参考专利文献WO2016023330A1中实施例22所记载的方法，制备得到式1所示化合物，浅棕色固体。
1H-NMR(600MHz,DMSO-d 6)δ:9.53(s,1H),8.36(s,1H),7.80(s,1H),7.66(dd,J＝10.2Hz，J＝2.4Hz,1H),7.54(t,J＝8.4Hz,1H),7.47(dd,J＝8.4Hz，J＝2.4Hz,1H),7.19(s,1H),4.15(t,J＝6.6Hz,2H),3.95(s,3H),2.29-2.26(m,2H),2.14(s,6H),1.82-1.79(m,2H),1.59-1.57(m,2H).
实施例1：化合物1的二盐酸盐的制备
Figure PCTCN2021120328-appb-000042
称取制备例1所得的化合物1(10g，21.58mmol)于茄型瓶中，加入甲醇溶剂(110mL)，升温至55±5℃，搅拌至溶清，滴加盐酸(3.7mL，44.4mmol)，搅拌20分钟，缓慢加入200mL乙酸乙酯，降温至5±5℃，搅拌2±1h，抽滤，滤饼用乙酸乙酯(20mL)洗涤，得白色二盐酸盐(11g)，收率94.8％。
1H-NMR(600MHz,DMSO-d 6)δ:15.41(s,1H),11.78(s,1H),10.44(s,1H),8.80(s,1H),8.42(s,1H),7.78(dd,J＝9.6Hz，J＝2.4Hz,1H),7.58-7.52(m,2H),7.47(s,1H),4.24(t,J＝6Hz,2H),4.03(s,3H),3.15-3.14(m,2H),2.76-2.75(m,6H),1.90-1.88(m,4H).
通过离子色谱法测定氯离子含量，计算该盐酸盐的化学计量比(见下表)，可以推断得到该盐酸盐的碱/酸比为1:2。
Figure PCTCN2021120328-appb-000043
取所得盐酸盐样品进行X-射线粉末衍射，其呈现良好的结晶性，命名为二盐酸盐的晶型I，其XRPD表征谱图如图1所示，主要衍射峰数据如表1。取样品进行DSC-TGA测试，有两个吸热峰，吸热峰1：在219.1℃有一吸热峰起始点，在231.0℃附近达到峰值；吸热峰2：在235.1℃有一吸热峰起始点，在284.2℃附近达到峰值，在205℃左右发生分解(参见图8)。PLM图显示其结晶颗粒为规则形态。
表1实施例1所得二盐酸盐的晶型I的XRPD衍射峰数据表
Figure PCTCN2021120328-appb-000044
实施例2：化合物1的二盐酸盐四水合物的制备
Figure PCTCN2021120328-appb-000045
称取制备例1所得的化合物1(5g，10.8mmol)于茄型瓶中，加入纯化水(20mL)，滴加浓盐酸(2.0mL，24mmol)，搅拌升温至80±5℃至完全溶解，滴加完毕后，缓慢降温至室温，抽滤，滤饼用少量纯化水洗涤，得白色固体状二盐酸盐四水合物(2.82g)，收率43％。经核磁氢谱确证已成盐。
通过HPLC计算自由碱含量(见下表)，可以推断得到该盐酸盐水合物的碱/酸比为1:2。
Figure PCTCN2021120328-appb-000046
进一步通过TGA辅助检测实施例2盐酸盐水合物的结晶水含量，失重12.24％，可以推断得到该盐酸盐水合物的碱/结晶水比例为1：4，其TGA测试图谱见图9。
取所得二盐酸盐四水合物样品进行X-射线粉末衍射，所得固体呈现良好的结晶性，命名为晶型II，其XRPD表征谱图如图2所示，主要衍射峰数据见表2。
表2实施例2所得二盐酸盐四水合物晶体的XRPD衍射峰数据表
Figure PCTCN2021120328-appb-000047
实施例3：化合物1的硫酸盐的制备
Figure PCTCN2021120328-appb-000048
称取制备例1所得的化合物1(4g，8.6mmol)于茄型瓶中，加入甲醇(10mL)，升温至60±5℃，搅拌至溶清，滴加50％硫酸(1.0mL，8.6mmol)，搅拌10分钟，缓慢加入30mL乙酸乙酯，降温至室温继续搅拌反应1h，抽滤，滤饼用乙酸乙酯(20mL)洗涤，得白色硫酸盐(4.13g)，收率85.2％，熔点：164-168℃。经核磁氢谱确证已成盐。
通过HPLC计算自由碱含量(见下表)，可以推断得到该硫酸盐的碱/酸比为1:1。
Figure PCTCN2021120328-appb-000049
取所得硫酸盐样品进行X-射线粉末衍射，所得硫酸盐呈现良好的结晶性，命名成硫酸盐的晶型I，其 XRPD表征谱图如图3所示，主要衍射峰数据如表3。
表3实施例3所得硫酸盐的晶型I的XRPD衍射峰数据表
Figure PCTCN2021120328-appb-000050
实施例4：化合物1的马来酸盐的制备
Figure PCTCN2021120328-appb-000051
称取制备例1所得的化合物1(5g，10.8mmol)、马来酸(1.5g，13.0mmol)和甲醇(10mL)于反应瓶中，升温至55±5℃，搅拌至溶清，再加入乙酸乙酯(30mL)，降温至室温继续搅拌2h，抽滤，滤饼用乙酸乙酯(30mL)洗涤，得白色马来酸盐(2.22g)，收率35.5％，熔点：138-142℃。经核磁氢谱确证已成盐。
通过HPLC计算自由碱含量(见下表)，可以推断得到该马来酸盐的碱/酸比为1:1。
名称 理论计量比(碱/酸) 理论碱含量(％) 实测碱含量(％)
实施例4 1:1 79.97％ 79.12％
取所得马来酸盐样品进行X-射线粉末衍射，所得马来酸盐呈现良好的结晶性，命名成马来酸盐的晶型I，其XRPD表征谱图如图4所示，主要衍射峰数据如表4。
表4实施例4所得马来酸盐的晶型I的XRPD衍射峰数据表
Figure PCTCN2021120328-appb-000052
实施例5：化合物1的二盐酸盐的晶型III的制备
称取实施例1样品(约7mg)，溶于甲醇(0.2mL)中，过滤并收集滤液，然后向滤液中加入乙腈(1mL)，搅拌过夜，抽滤，得白色固体。取所得固体进行X-射线粉末衍射，其为结晶形式，命名为二盐酸盐的晶型III，其XRPD表征谱图如图11所示，主要衍射峰数据如表5。取样品进行DSC-TGA测试，有两个吸热峰，吸热峰1：在72.28℃有一吸热峰起始点，在101.52℃附近达到峰值；吸热峰2：在172.06℃有一吸热峰起始点，在183.70℃附近达到峰值；在室温～120℃之间失重6.2684％，在225℃左右发生分解 (参见图12)。
表5实施例5所得二盐酸盐的晶型III的XRPD衍射峰数据表
Figure PCTCN2021120328-appb-000053
实施例6：化合物1的二盐酸盐的晶型IV的制备
称取实施例1样品(约7mg)，溶于水(0.2mL)中，过滤并收集滤液，然后向滤液中加入乙腈(7mL)，搅拌24h，抽滤，得白色固体。取所得固体进行X-射线粉末衍射，其为结晶形式，命名为二盐酸盐的晶型IV，其XRPD表征谱图如图13所示，主要衍射峰数据如表6。取样品进行DSC-TGA测试，有两个吸热峰，吸热峰1：在49.50℃有一吸热峰起始点，在68.81℃附近达到峰值；吸热峰2：在164.55℃有一吸热峰起始点，在177.55℃附近达到峰值；在室温～150℃之间失重3.9478％，在215℃左右发生分解(参见图14)。
表6实施例6所得二盐酸盐的晶型IV的XRPD衍射峰数据表
Figure PCTCN2021120328-appb-000054
实施例7：化合物1的二盐酸盐乙醇溶剂化物(晶型V)的制备
称取实施例1样品(约30mg)，溶于乙醇(1mL)中，在50℃条件下搅拌30min后趁热过滤，滤液冷却至室温，继续搅拌3天，抽滤，得白色固体。对所得固体进行X-射线粉末衍射，其为结晶形式，命名为晶型V(乙醇溶剂化物，1：1)，其XRPD表征谱图如图15所示，主要衍射峰数据如表7。取样品进行DSC-TGA测试，有三个吸热峰，吸热峰1：在28.37℃有一吸热峰起始点，在48.29℃附近达到峰值；吸热峰2：在114.96℃有一吸热峰起始点，在153.99℃附近达到峰值；吸热峰3：在179.32℃有一吸热峰起始点，在190.59℃附近达到峰值；在室温～200℃之间失重7.2663％(参见图16)。
表7实施例7所得晶型V的XRPD衍射峰数据表
Figure PCTCN2021120328-appb-000055
Figure PCTCN2021120328-appb-000056
实施例8：化合物1的二盐酸盐的晶型VII的制备
取实施例5所得的晶型III，加热到130℃后收集样品，得白色固体。取所得固体进行X-射线粉末衍射，其为结晶形式，命名为二盐酸盐的晶型VII，其XRPD表征谱图如图17所示，主要衍射峰数据如表8。取样品进行DSC-TGA测试，有两个吸热峰，吸热峰1：在66.54℃有一吸热峰起始点，在87.64℃附近达到峰值；吸热峰2：在169.59℃有一吸热峰起始点，在182.15℃附近达到峰值；在室温～120℃之间失重1.3751％(参见图18)。
表8实施例8所得二盐酸盐的晶型VII的XRPD衍射峰数据表
Figure PCTCN2021120328-appb-000057
对比例1-2：化合物1的单盐酸盐和苹果酸盐的制备
实施例9：化合物1的草酸盐的制备
取3份制备例1样品(5g，10.8mmol)于反应瓶中，按照下表的反应条件，进行式3-3所示单盐酸盐、式7-1所示苹果酸盐及式6-1所示草酸盐的制备，操作过程同实施例3，结果见表9。经核磁氢谱确证已成盐。
Figure PCTCN2021120328-appb-000058
表9成盐反应条件及结果
Figure PCTCN2021120328-appb-000059
Figure PCTCN2021120328-appb-000060
注：①对比例1的碱/酸比例确证方法：测定氯离子含量；②对比例2和实施例9的碱/酸比例确证方法：核磁氢谱，及游离碱含量测定。
实施例10：二盐酸盐四水合物的制备
称取实施例1样品(约369mg)，加入到水/丙酮(1:1，v/v，总量5mL)中，室温条件下搅拌过夜。过滤收集得白色固体，50℃真空干燥过夜。经检测，其为二盐酸盐四水合物，取所得固体进行X-射线粉末衍射，其为结晶形式，其XRPD表征谱图如图19所示。
测试例1：溶解度测试
将制备例1、实施例1-4和9及对比例1-2所得盐在水中及pH2.0缓冲液中进行溶解度测试，测试结果如下表所示：
表10不同样品的溶解度结果
Figure PCTCN2021120328-appb-000061
注：/：未检测。
结果：同制备例1相比，实施例1-4和实施例9的样品均实现水中溶解度的提高，实施例1-4的样品均实现水中溶解度至少提高100倍，其中，二盐酸盐的溶解度最好。单盐酸盐和苹果酸盐样品溶于水后，体系成果冻状，可能样品在水中发生晶型转变且溶解效果不佳，使体系呈现出非溶液的状态。
进一步选择溶解度较好(>10mg/mL)的实施例1-4，以制备例1为对照，检测样品在pH2.0缓冲液中的溶解度，从以上结果可以看出，在酸性条件下，制备例1的溶解度明显提高，实施例1和实施例4的溶解度依然较制备例1的溶解度稍好，实施例2和实施例3的溶解度较制备例1略低。在模拟胃液的环境下，实施例1和实施例4的溶解度虽然有所降低，但仍优于制备例1的游离碱化合物。
此外，根据药物剂型对原料药溶解度的一般要求，固体口服剂型要求药物的水中溶解度大于0.1g/L，注射剂或口服液等溶液制剂则要求药物的溶解度在10g/L以上，更重要的是，药物的溶解度应满足临床所需的剂量浓度。基于表10的溶解度结果，实施例1-4及实施例9可考虑制备固体口服剂型，而实施例1-4还可以进一步考虑制备注射剂或口服液等溶液制剂。
测试例2：生物溶媒中的溶解度测试
称取实施例1和实施例10样品(各20mg)，加入不同的生物溶媒(2mL)，进行溶解度测试，结果见表11。
表11不同样品在生物溶媒中的溶解度
Figure PCTCN2021120328-appb-000062
结果：实施例1和实施例10所得样品在不同pH的生物溶媒中，均能保持良好的溶解度，且溶解速度较快。
测试例3：长期稳定性测试
取实施例1-4、9所得盐样品适量，在40±2℃、75％±5％RH条件下，聚乙烯膜封口放置5个月，进行长期试验，结果如下：
表12不同样品的稳定性结果及晶型检测结果
Figure PCTCN2021120328-appb-000063
表13实施例1晶体样品在长期稳定性测试后的XRPD数据表
Figure PCTCN2021120328-appb-000064
实施例1所得化合物1的二盐酸盐的晶型I在长期稳定性测试后的XRPD谱图如图10所示。
结果：在放置5个月后，实施例1-4、9盐的晶体样品均能稳定存在，产品纯度未见明显降低，各样品晶型维持不变。
测试例4：固体稳定性测试
取实施例1的二盐酸盐和实施例2和实施例10的二盐酸盐四水合物，分别放置于40℃/75％RH(开口)条件下7天，进行稳定性测试，结果见表14。
表14不同样品的稳定性结果及晶型检测结果
Figure PCTCN2021120328-appb-000065
结果：在40℃/75％RH(开口)条件下放置7天，实施例1-2和实施例10所得的化合物1的二盐酸盐及二盐酸盐四水合物均能维持化学稳定和晶型稳定，因此，实施例1-2和实施例10所得样品具有较好的热稳定性，符合作为原料药储存的规定。
测试例5：机械稳定性测试
取实施例1的二盐酸盐适量，进行机械研磨5分钟后进行X-射线粉末衍射，结果显示，晶型未发生变化。
测试例6：常规有机溶剂中的溶解度测试
使用药典(二部凡例)中的方法，进行制备例1样品在不同有机溶剂中的溶解度测试，使用重量法估测实施例1样品在不同有机溶剂中的溶解度，结果见表15。
表15制备例1样品与实施例1的二盐酸盐在几种常规有机溶剂中的溶解度对比
Figure PCTCN2021120328-appb-000066
Figure PCTCN2021120328-appb-000067
注：取实施例1样品(～15mg)加入0.5mL表15中所列举的不同溶剂中，室温和50℃条件下进行打浆，取过滤后的样品进行X-射线粉末衍射，晶型与实施例1所得的二盐酸盐均一致。
结果：制备例1在多种常规有机溶剂中溶解度良好(均＞10mg/mL)，而实施例1的二盐酸盐仅在甲醇中表现出良好的溶解度，在其余7种常用有机溶剂种溶解度很小，因此，采用适宜的常规有机溶剂，均可实现二盐酸盐的制备，且能实现(未反应完全的)游离碱与二盐酸盐的完全分离，并能以较高收率(有机溶剂中因溶解而造成的质量损失小)和高纯度获得二盐酸盐。
此外，在以上常规有机溶剂中打浆，均得到实施例1的二盐酸盐对应的晶型，说明该晶型在常规有机溶剂中较稳定。
测试例7：人黑色素瘤A375裸小鼠移植瘤模型药效实验
将生长良好的人黑色素瘤A375细胞悬液接种于nu/nu雌性裸小鼠前肢腋下皮下组织，接种体积为0.1mL，含瘤细胞约1×10 7个。当肿瘤体积长至100mm 3以上，挑选肿瘤生长良好的小鼠，按肿瘤体积将动物均衡分成5组：空白对照组、凡德他尼12.5mg/kg组、凡德他尼25mg/kg组、实施例1样品12.5mg/kg组及实施例1样品25mg/kg，每组6只动物。空白对照组口服给予蒸馏水，其余组口服给予相应的受试药物，给药体积均为20mL/kg，1天1次，连续给药至第20天。给药后动物正常饲养，使用测量瘤径的方法，动态观察受试药的抗肿瘤作用，试验结束(第21天)将动物处死，剥瘤，称重，计算抑瘤率。
凡德他尼：
Figure PCTCN2021120328-appb-000068
表16实施例1样品及凡德他尼对人黑色素瘤A375移植模型瘤重的影响
Figure PCTCN2021120328-appb-000069
注：**与空白对照组比较，p<0.01；#与等剂量的凡德他尼组比较，p<0.05。
结果：与空白对照组比较，实施例1样品能剂量依赖性地、显著抑制肿瘤的生长，且与对照药物凡德他尼相比，具有更好的抑瘤效果。
根据人与动物体表面积的折算系数(参考《药理实验方法学》，主编：徐叔云)，将小鼠模型内的有效剂量折算成成年人的等效剂量，小鼠模型上的有效剂量12.5mg/kg和25mg/kg分别对应成年人(70kg)的等效剂量为1.37mg/kg和2.74mg/kg，成年人(70kg)的口服单次给药量为95.9mg和191.8mg。若制成小规格注射剂或溶液剂(5mL)，药物的溶解度需要分别达到11.51mg/mL和23.02mg/mL以上(动物药代实验中犬和猴的绝对生物利用度均为60％左右，因此，此处人的口服利用度以60％计)，以此类推，制成更小规格(小于5mL)的液体制剂，则对药物的溶解度要求更高。结合表10溶解度检测结果，以5mL液体制剂的规格计，若给药剂量为1.37mg/kg时，实施例1、实施例2及实施例4可符合溶解度要求；若给药剂量为2.74mg/kg时，实施例1和实施例2可符合溶解度要求。
综上，发明人经过对化合物1的盐型进行筛选和摸索，发现较化合物1相比，二盐酸盐、硫酸盐和马来酸盐的溶解度显著提高，符合固体制剂和液体制剂对原料药溶解度的一般要求，且所得盐的晶型具有较好的稳定性。其中，二盐酸盐表现最优，可以符合小规格液体制剂对溶解度的要求且具有良好的体内抗肿瘤效果，具备开发成多种剂型、不同规格的药品的潜力。

Claims (15)

  1. 式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物：
    Figure PCTCN2021120328-appb-100001
    其中，
    HA是盐酸、硫酸、草酸或马来酸；
    n为1/2-2的整数或半整数；以及
    当HA为盐酸时，n为0.5、1.5或2。
  2. 根据权利要求1所述的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物，其中所述盐、其溶剂合物或水合物为式3’所示的盐酸盐或其水合物：
    Figure PCTCN2021120328-appb-100002
    其中，n为1-2的整数；m为0-4的整数或半整数；以及当n为1时，m为1-4的整数或半整数；
    优选地，所述盐、其溶剂合物或水合物为式3”所示的二盐酸盐或其水合物：
    Figure PCTCN2021120328-appb-100003
    其中，m为0-4的整数或半整数；
    进一步优选地，所述盐、其溶剂合物或水合物为式3-1所示的二盐酸盐或式3-2所示的二盐酸盐四水合物：
    Figure PCTCN2021120328-appb-100004
  3. 根据权利要求1所述的含芳氨基喹唑啉化合物的盐、其溶剂合物或水合物，其中所述盐为式4所示的硫酸盐：
    Figure PCTCN2021120328-appb-100005
    n为1-2的整数或半整数；
    优选地，所述盐为式4-1所示的硫酸盐：
    Figure PCTCN2021120328-appb-100006
  4. 根据权利要求1所述的含芳氨基喹唑啉化合物的盐、其溶剂合物或水合物，其中所述盐为式5所示的马来酸盐：
    Figure PCTCN2021120328-appb-100007
    n为1-2的整数或半整数；
    优选地，所述盐为式5-1所示的马来酸盐：
    Figure PCTCN2021120328-appb-100008
  5. 根据权利要求1所述的含芳氨基喹唑啉化合物的盐、其溶剂合物或水合物，其中所述盐为式6所示的草酸盐：
    Figure PCTCN2021120328-appb-100009
    n为0.5-2的整数或半整数；
    优选地，所述盐为式6-1所示的草酸盐：
    Figure PCTCN2021120328-appb-100010
  6. 如式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物的结晶形式：
    Figure PCTCN2021120328-appb-100011
    其中，
    HA是盐酸、硫酸、草酸或马来酸；
    n为1/2-2的整数或半整数；以及
    当HA为盐酸时，n为0.5、1.5或2；
    优选地，如式2所示的含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物的结晶形式为式3所示的含芳氨基喹唑啉的化合物的盐酸盐、其溶剂合物或水合物的结晶形式：
    Figure PCTCN2021120328-appb-100012
    其中n为0.5、1.5或2；
    进一步优选地，所述含芳氨基喹唑啉的化合物的盐、其溶剂合物或水合物的结晶形式为式3-1所示的二盐酸盐、其溶剂合物或水合物的结晶形式：
    Figure PCTCN2021120328-appb-100013
  7. 根据权利要求6所述的含芳氨基喹唑啉化合物的盐、其溶剂合物或水合物的结晶形式，其中所述含芳氨基喹唑啉的化合物的盐的结晶形式为所述式3-1所示的二盐酸盐的晶型I，其使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在以下位置有特征峰：12.4±0.2°、18.8±0.2°、20.3±0.2°、24.6±0.2°；
    或者，其使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：9.8±0.2°、12.4±0.2°、18.8±0.2°、20.3±0.2°、24.6±0.2°；
    或者，其使用Cu-Kα辐射，具有基本上如图1所示的X-射线粉末衍射图谱。
  8. 根据权利要求6所述的含芳氨基喹唑啉化合物的盐、其溶剂合物或水合物的结晶形式，其中所述含芳氨基喹唑啉的化合物的盐的结晶形式为所述式3-2所示的二盐酸盐四水合物的晶体，其使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在以下位置有特征峰：6.0±0.2°、6.8±0.2°、12.4±0.2°、26.0±0.2°；
    或者，其使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：6.0±0.2°、6.8±0.2°、12.4±0.2°、15.5±0.2°、25.4±0.2°、26.0±0.2°；
    或者，其使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：6.0±0.2°、6.8±0.2°、12.4±0.2°、15.5±0.2°、18.0±0.2°、24.4±0.2°、25.4±0.2°、26.0±0.2°；
    或者，其使用Cu-Kα辐射，具有基本上如图2或图19所示的X-射线粉末衍射图谱。
  9. 根据权利要求6所述的含芳氨基喹唑啉化合物的盐、其溶剂合物或水合物的结晶形式，其中所述含芳氨基喹唑啉的化合物的盐的结晶形式为所述式4-1所示的硫酸盐的晶体，其使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在以下位置有特征峰：12.4±0.2°、15.5±0.2°、24.8±0.2°、25.9±0.2°；
    或者，其使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：6.8±0.2°、8.5±0.2°、12.4±0.2°、15.5±0.2°、24.8±0.2°、25.9±0.2°；
    或者，其使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：6.8±0.2°、8.5±0.2°、12.4±0.2°、13.6±0.2°、15.5±0.2°、24.8±0.2°、25.9±0.2°；
    或者，其使用Cu-Kα辐射，具有基本上如图3所示的X-射线粉末衍射图谱。
  10. 根据权利要求6所述的含芳氨基喹唑啉化合物的盐、其溶剂合物或水合物的结晶形式，其中所述含芳氨基喹唑啉的化合物的盐的结晶形式为所述式5-1所示的马来酸盐的晶体，其使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在以下位置有特征峰：4.9±0.2°、7.6±0.2°、16.7±0.2°、24.9±0.2°；
    或者，其使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：4.4±0.2°、4.9±0.2°、7.6±0.2°、16.7±0.2°、20.6±0.2°、24.9±0.2°；
    或者，其使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：4.4±0.2°、4.9±0.2°、7.6±0.2°、13.3±0.2°、16.7±0.2°、19.6±0.2°、20.6±0.2°、24.9±0.2°；
    或者，其使用Cu-Kα辐射，具有基本上如图4所示的X-射线粉末衍射图谱。
  11. 根据权利要求6所述的含芳氨基喹唑啉化合物的盐、其溶剂合物或水合物的结晶形式，其中所述含芳氨基喹唑啉的化合物的盐的结晶形式为所述式6-1所示的草酸盐的晶体，其使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在以下位置有特征峰：5.9±0.2°、9.9±0.2°、17.5±0.2°、21.5±0.2°、19.8±0.2°；
    或者，其使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在以下位置有特征峰：5.9±0.2°、9.9±0.2°、17.5±0.2°、21.5±0.2°、19.8±0.2°、23.0±0.2°、25.5±0.2°；
    或者，其使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在以下位置有特征峰：5.9±0.2°、9.9±0.2°、17.5±0.2°、18.4±0.2°、21.5±0.2°、19.8±0.2°、23.0±0.2°、24.4±0.2°、25.5±0.2°；
    或者，其使用Cu-Kα辐射，具有基本上如图7所示的X-射线粉末衍射图谱。
  12. 药物组合物，其包含根据权利要求1-5中任一项所述的含芳氨基喹唑啉化合物的盐、其溶剂合物或水合物，或根据权利要求6-11中任一项所述的含芳氨基喹唑啉化合物的盐、其溶剂合物或水合物的结晶形式，以及一种或多种可药用的载体。
  13. 根据权利要求1-5中任一项所述的含芳氨基喹唑啉化合物的盐、其溶剂合物或水合物，或根据权利要求6-11中任一项所述的含芳氨基喹唑啉化合物的盐、其溶剂合物或水合物的结晶形式，或根据权利要求12所述的药物组合物用于制备受体酪氨酸激酶抑制剂药物中的用途，所述受体酪氨酸激酶优选为VEGFR、FLT、FGFR、RET、EGFR和它们的突变体中的一种或多种；
    优选地，所述受体酪氨酸激酶抑制剂药物为抗肿瘤药物，优选地所述肿瘤包括甲状腺癌、胆道癌、非小细胞肺癌、表皮样癌、黑色素瘤、结直肠癌、胃癌、食管癌、胰腺癌、肾癌、肝癌、肺癌或卵巢癌。
  14. 如权利要求1所述的含芳氨基喹唑啉化合物的盐、其溶剂合物或水合物的制备方法，包括将式1所示的含芳氨基喹唑啉化合物与HA在溶剂中进行反应，分离得到式2所示的含芳氨基喹唑啉化合物的盐、其溶剂合物或水合物：
    Figure PCTCN2021120328-appb-100014
    其中，
    HA为盐酸、硫酸、草酸或马来酸；
    n为1/2-2的整数或半整数；以及
    当HA为盐酸时，n为0.5、1.5或2。
  15. 如权利要求14所述的含芳氨基喹唑啉化合物的盐、其溶剂合物或水合物的制备方法，其中所述式1所示的含芳氨基喹唑啉的化合物与HA的摩尔比为1：1～2.5，优选为1:1～2；和/或
    反应温度为10-90℃，优选为40-70℃；和/或
    反应溶剂选自醇类、酮类、腈类、水或杂环烷烃类溶剂中的一种或者两种的组合；优选为乙酸乙酯、甲醇、乙醇、水、乙腈、丙酮、四氢呋喃、DMF、NMP、异丙醇、正丙醇、DMA、二氧六环中的一种或者两种的组合；进一步优选为乙酸乙酯、甲醇或水。
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