Salt of compound containing aromatic aminoquinazoline and preparation method and application thereof

Abstract

Provided are a salt of an aromatic aminoquinazoline compound shown in formula 2, a solvate or hydrate thereof, and a preparation method and application thereof. The prepared salt has good crystallinity, and has significantly improved solubility in water relative to the free form compound. Preferably, the salt form and crystal form can exist stably, and therefore, has better drugability relative to the free form compound or other salts.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority and benefits of Chinese Patent Application No. 202011022290.1 ​​filed with the State Intellectual Property Office of China on September 25, 2020, and the contents disclosed in said application are incorporated herein by reference in their entirety. Technical Field

[0003] The present invention belongs to the field of pharmaceutical chemistry, and specifically relates to salts of compounds containing aromatic aminoquinazolines, and preparation methods and applications thereof. Background Art

[0004] Protein tyrosine kinases (PTKs) are a very important member of the protein kinase family. PTKs transfer the γ-phosphate group on adenosine triphosphate to the protein tyrosine residue of the substrate, and complete the information transmission between cells by phosphorylating the phenolic hydroxyl group. They play a vital role in cell development, regulation, and differentiation, migration, and apoptosis of tumor cells. If PTKs lose control during the regulation process, it will affect the correct activation of its downstream signaling pathways, thereby causing dysfunction of cell proliferation regulation and triggering many diseases. For example, excessive tyrosine kinase activity causes receptor phosphorylation and activates downstream signals, leading to excessive cell transformation, proliferation, resistance to cell apoptosis, and promotion of cell survival, thereby forming malignant tumors. Therefore, using tyrosine kinase as a new target to develop this type of kinase inhibitor to inhibit the overexpression of tyrosine kinase and restore its physiological balance has become a research hotspot in the field of molecular targeted anti-tumor and has great development prospects.

[0005] Epidermal Growth Factor Receptor (EGFR), Fibroblast Growth Factor Receptors (FGFRs), Platelet-derived Growth Factor Receptor (PDGFR), and RET protein encoded by the Rearranged during Transfection (RET) oncogene are important members of PTKs and are important targets for tumor treatment.

[0006] EGFR is a cell growth factor that can bind to receptor tyrosine kinase, including EGFR (ErbB-1), human epidermal growth factor receptor type 2 HER2 (ErbB-2), human epidermal growth factor receptor type 3 HER3 (ErbB-3) and human epidermal growth factor receptor type 4 HER4 (ErbB-4). Among them, EGFR and HER2 are the targets most closely related to tumors among EGFR family members. Studies have shown that EGFR is overexpressed, mutated or fused in many tumors such as lung cancer, gastric cancer, epidermoid carcinoma, renal cancer, ovarian cancer, etc.

[0007] FGFR mainly includes four subtypes, FGFR1 / 2 / 3 / 4, which are overexpressed or overactivated through gene amplification, mutation, fusion or ligand induction, and play an important role in tumor cell proliferation, invasion and migration, and tumor angiogenesis. 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, biliary tract cancer, etc.

[0008] The normal physiological functions of RET include kidney development, development of the nervous system, maintenance and renewal of sperm stem cells, differentiation of myelomonocytic cells, formation of lymphoid tissue, etc. It is expressed in human intestinal ganglion cells, neuroblastoma, pheochromocytoma, medullary thyroid carcinoma, thyroid C cells and melanoma cells. In recent years, through in-depth research on RET, it has been found that excessive activation of RET in tumors has a significant promoting effect on the proliferation, survival, invasion, metastasis and tumor inflammation of various tumors. RET is overexpressed in thyroid cancer (e.g., medullary thyroid carcinoma, papillary thyroid cancer), colorectal cancer, pancreatic cancer, melanoma, etc.

[0009] Compound 1, whose chemical name is 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-[(4-N,N-dimethylamino)butoxy]quinazoline, is a multi-target inhibitor with inhibitory activities against RET, VEGFR (vascular endothelialgrowth factor receptor, VEGFR), FGFR, EGFR, FLT (FMS-liketyrosine kinase or Fms Related Receptor Tyrosine Kinase).

[0010]

[0011] WO2016023330A1 relates to aromatic aminoquinazoline-containing compounds as tyrosine kinase inhibitors, and describes compound 1 and its analogs, preparation methods and medical uses. SUMMARY OF THE INVENTION

[0013] The inventors of the present application found that compound 1 has very poor water solubility and cannot meet the general requirements of solid oral dosage forms for drug solubility (should be greater than 0.1 g / L), not to mention the development of other drug dosage forms (e.g., injections, solutions). Moreover, the water solubility of drugs is also the main factor affecting drug dissolution, absorption and pharmacokinetic properties. Therefore, it is necessary to modify compound 1 to optimize its physicochemical properties and improve its drugability.

[0014] In one aspect, the present application provides a salt, a solvate or a hydrate thereof of a compound containing an aromatic aminoquinazoline as shown in Formula 2:

[0015]

[0016] in,

[0017] HA is hydrochloric acid, sulfuric acid, oxalic acid or maleic acid;

[0018] n is an integer or half integer from 1 / 2 to 2; and

[0019] When HA is hydrochloric acid, n is 0.5, 1.5 or 2.

[0020] On the other hand, the present application provides a crystalline form of a salt, a solvate or a hydrate thereof of a compound containing an aromatic aminoquinazoline as shown in Formula 2:

[0021]

[0022] in,

[0023] HA is hydrochloric acid, sulfuric acid, oxalic acid or maleic acid;

[0024] n is an integer or half integer from 1 / 2 to 2; and

[0025] When HA is hydrochloric acid, n is 0.5, 1.5 or 2.

[0026] On the other hand, the present application provides a pharmaceutical composition comprising a salt of a compound containing an aromatic aminoquinazoline as shown in the aforementioned formula 2, a solvate or a hydrate thereof, or a crystalline form of a salt of a compound containing an aromatic aminoquinazoline as shown in formula 2, a solvate or a hydrate thereof, and one or more pharmaceutically acceptable carriers.

[0027] On the other hand, the present application provides a salt of the aromatic aminoquinazoline-containing compound shown in the aforementioned formula 2, a solvate or a hydrate thereof, a crystalline form of a salt of the aromatic aminoquinazoline-containing compound shown in formula 2, a solvate or a hydrate thereof, or the aforementioned pharmaceutical composition for use in the preparation of a drug as a receptor tyrosine kinase inhibitor.

[0028] The present application also provides the use of a salt of the aromatic aminoquinazoline-containing compound shown in the aforementioned formula 2, a solvate or a hydrate thereof, a crystalline form of a salt of the aromatic aminoquinazoline-containing compound shown in formula 2, a solvate or a hydrate thereof, or the aforementioned pharmaceutical composition in the preparation of anti-tumor drugs.

[0029] On the other hand, the present application also provides the use of a salt of the aromatic aminoquinazoline-containing compound shown in the aforementioned formula 2, a solvate or a hydrate thereof, a crystalline form of a salt of the aromatic aminoquinazoline-containing compound shown in formula 2, a solvate or a hydrate thereof, or the aforementioned pharmaceutical composition in the treatment of receptor tyrosine kinase-related diseases.

[0030] The present application also provides the use of a salt of the aromatic aminoquinazoline-containing compound shown in the aforementioned formula 2, a solvate or a hydrate thereof, a crystalline form of a salt of the aromatic aminoquinazoline-containing compound shown in formula 2, a solvate or a hydrate thereof, or the aforementioned pharmaceutical composition in the treatment of tumors.

[0031] On the other hand, 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 a salt of the aromatic aminoquinazoline-containing compound shown in the aforementioned Formula 2, a solvate or hydrate thereof, a crystalline form of a salt of the aromatic aminoquinazoline-containing compound shown in Formula 2, a solvate or hydrate thereof, or the aforementioned pharmaceutical composition.

[0032] 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 a salt of the aromatic aminoquinazoline-containing compound shown in the aforementioned formula 2, a solvate or hydrate thereof, a crystalline form of a salt of the aromatic aminoquinazoline-containing compound shown in formula 2, a solvate or hydrate thereof, or the aforementioned pharmaceutical composition.

[0033] On the other hand, the present application also provides a salt of the aromatic aminoquinazoline-containing compound shown in the aforementioned formula 2, a solvate or a hydrate thereof, a crystalline form of the salt of the aromatic aminoquinazoline-containing compound shown in formula 2, a solvate or a hydrate thereof, or the aforementioned pharmaceutical composition for treating receptor tyrosine kinase-related diseases.

[0034] On the other hand, the present application also provides a salt of the aromatic aminoquinazoline-containing compound shown in the aforementioned formula 2, a solvate or a hydrate thereof, a crystalline form of a salt of the aromatic aminoquinazoline-containing compound shown in formula 2, a solvate or a hydrate thereof, or the aforementioned pharmaceutical composition for treating tumor diseases.

[0035] On the other hand, the present application provides a method for preparing a salt of a compound containing an aromatic amino quinazoline as shown in Formula 2, a solvate or a hydrate thereof, comprising reacting the compound containing an aromatic amino quinazoline as shown in Formula 1 with an acid (HA) in a suitable solvent, and isolating the salt of the compound containing an aromatic amino quinazoline as shown in Formula 2, a solvate or a hydrate thereof:

[0036]

[0037] in,

[0038] HA is hydrochloric acid, sulfuric acid, oxalic acid or maleic acid;

[0039] n is an integer or half integer from 1 / 2 to 2; and

[0040] When HA is hydrochloric acid, n is 0.5, 1.5 or 2. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 : XRPD spectrum of the dihydrochloride salt of compound 1 obtained in Example 1, its solvate or hydrate of Form I.

[0042] Figure 2 : XRPD spectrum of the dihydrochloride salt of compound 1 obtained in Example 2, its solvate or hydrate of Form II.

[0043] Figure 3 : XRPD spectrum of the sulfate salt of compound 1 obtained in Example 3.

[0044] Figure 4 : XRPD spectrum of the maleate salt of compound 1 obtained in Example 4.

[0045] Figure 5 : XRPD spectrum of the monohydrochloride salt of compound 1 obtained in Comparative Example 1.

[0046] Figure 6 : XRPD spectrum of the malate salt of compound 1 obtained in Comparative Example 2.

[0047] Figure 7 : XRPD spectrum of the oxalate of compound 1 obtained in Example 9.

[0048] Figure 8 : DSC-TGA diagram of the crystalline form I of the dihydrochloride salt of compound 1, its solvate or hydrate obtained in Example 1.

[0049] Fig. 9 : Thermogravimetric analysis (TGA) diagram of Form II of the dihydrochloride salt of Compound 1, its solvate or hydrate obtained in Example 2.

[0050] Fig.10: XRPD spectrum of Form I of the dihydrochloride obtained in Example 1, its solvate or hydrate after long-term stability test.

[0051] Fig.11 : XRPD spectrum of the dihydrochloride salt of compound 1 obtained in Example 5, its solvate or hydrate form III.

[0052] Fig.12 : DSC-TGA diagram of the crystalline form III of the dihydrochloride salt of compound 1, its solvate or hydrate obtained in Example 5.

[0053] Fig.13 : XRPD spectrum of the dihydrochloride salt of compound 1 obtained in Example 6, its solvate or hydrate form IV.

[0054] Fig.14 : DSC-TGA chart of Form IV of the dihydrochloride salt of Compound 1, its solvate or hydrate obtained in Example 6.

[0055] Fig.15 : XRPD spectrum of the crystalline form V of the dihydrochloride salt of compound 1, its solvate or hydrate obtained in Example 7.

[0056] Fig.16 : DSC-TGA chart of Form V of the dihydrochloride salt of Compound 1, its solvate or hydrate obtained in Example 7.

[0057] Fig.17 : XRPD spectrum of the dihydrochloride salt of compound 1 obtained in Example 8, its solvate or hydrate form VII.

[0058] Fig.18 : DSC-TGA chart of Form VII of the dihydrochloride salt of Compound 1, its solvate or hydrate obtained in Example 8.

[0059] Fig.19 : XRPD spectrum of the dihydrochloride salt of compound 1 obtained in Example 10, its solvate or hydrate of Form II. DETAILED DESCRIPTION OF THE INVENTION

[0061] On the one hand, the present application provides a salt of a compound containing an aromatic aminoquinazoline as shown in Formula 2, a solvate or a hydrate thereof:

[0062]

[0063] Among them, HA is an acid;

[0064] n is an integer or a half integer from 1 / 2 to 2, that is, n is 0.5, 1, 1.5 or 2.

[0065] In some embodiments of the present application, HA is hydrochloric acid, sulfuric acid, oxalic acid, maleic acid or malic acid. In some embodiments of the present application, HA is hydrochloric acid, sulfuric acid or maleic acid. In some embodiments of the present application, HA is hydrochloric acid.

[0066] In some embodiments of the present application, HA is hydrochloric acid, sulfuric acid, oxalic acid or maleic acid, and n is an integer or half integer of 1 / 2-2, that is, n is 0.5, 1, 1.5 or 2; and when HA is hydrochloric acid, n is 0.5, 1.5 or 2. In some embodiments of the present application, n is 1 or 2.

[0067] In some embodiments of the present application, the salt of the aromatic aminoquinazoline-containing compound, its solvate or hydrate is the hydrochloride of the aromatic aminoquinazoline-containing compound shown in Formula 3, its solvate or hydrate:

[0068]

[0069] Where n is 0.5, 1.5 or 2.

[0070] In some embodiments of the present application, the solvate is selected from acetonitrile / water solvate and ethanol solvate.

[0071] In some embodiments of the present application, the hydrate is selected from hemihydrate, monohydrate and tetrahydrate.

[0072] In some embodiments of the present application, the salt, solvate or hydrate of the aromatic aminoquinazoline-containing compound is a hydrochloride or a hydrate thereof as shown in Formula 3':

[0073]

[0074] Wherein, n is an integer of 1-2; m is an integer or a half integer of 0-4, i.e., 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 a half integer of 1-4, i.e., m is 0.5, 1, 1.5, 2, 2.5, 3, 3.5 or 4. In some embodiments of the present application, n is 2 and m is 0, 0.5, 1 or 4. In some embodiments of the present application, n is 2 and m is 0 or 4.

[0075] In some embodiments of the present application, the salt, solvate or hydrate of the aromatic aminoquinazoline-containing compound is a dihydrochloride or a hydrate thereof as shown in Formula 3":

[0076]

[0077] wherein m is an integer or half integer of 0-4, i.e., m is 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5 or 4.

[0078] In some embodiments of the present application, the salt of the aromatic aminoquinazoline-containing compound, its solvate or hydrate is a dihydrochloride salt shown in Formula 3-1:

[0079]

[0080] In some embodiments of the present application, the salt, solvate or hydrate of the aromatic aminoquinazoline-containing compound is a dihydrochloride tetrahydrate as shown in Formula 3-2:

[0081]

[0082] On the other hand, the present application provides a crystalline form of a salt, a solvate or a hydrate thereof of a compound containing an aromatic aminoquinazoline as shown in Formula 2:

[0083]

[0084] Among them, HA is an acid;

[0085] n is an integer or a half integer from 1 / 2 to 2, that is, n is 0.5, 1, 1.5 or 2.

[0086] In some embodiments of the present application, HA is hydrochloric acid, sulfuric acid, oxalic acid, maleic acid or malic acid. In some embodiments of the present application, HA is hydrochloric acid, sulfuric acid or maleic acid. In some embodiments of the present application, HA is hydrochloric acid.

[0087] In some embodiments of the present application, HA is hydrochloric acid, sulfuric acid, oxalic acid or maleic acid, and n is an integer or half integer of 1 / 2-2, that is, n is 0.5, 1, 1.5 or 2; and when HA is hydrochloric acid, n is 0.5, 1.5 or 2. In some embodiments of the present application, n is 1 or 2.

[0088] In some embodiments of the present application, the crystalline form of the salt of the aromatic aminoquinazoline-containing compound, its solvate or hydrate is the crystalline form of the hydrochloride of the aromatic aminoquinazoline-containing compound, its solvate or hydrate shown in Formula 3:

[0089]

[0090] Where n is 0.5, 1.5 or 2.

[0091] In some embodiments of the present application, the crystalline form of the salt, solvate or hydrate thereof of the aromatic aminoquinazoline-containing compound is a crystalline form of the dihydrochloride, solvate or hydrate thereof as shown in Formula 3-1:

[0092]

[0093] In some embodiments of the present application, the crystalline form of the dihydrochloride salt represented by Formula 3-1, its solvate or hydrate is selected from one or more of Form I, Form II, Form III, Form IV, Form V, and Form VII.

[0094] In some embodiments of the present application, the crystalline form I is a crystalline form of the dihydrochloride salt shown in formula 3-1:

[0095]

[0096] In some embodiments of the present application, the crystalline form II is a crystalline form of a dihydrochloride tetrahydrate as shown in formula 3-2:

[0097]

[0098] In some embodiments of the present application, the crystalline form of the dihydrochloride salt, its solvate or hydrate represented by the formula 3-1 (crystalline form I), using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has characteristic diffraction peaks at the following positions: 12.4±0.2°, 18.8±0.2°, 20.3±0.2°, 24.6±0.2°;

[0099] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has characteristic diffraction peaks at the following positions: 9.8±0.2°, 12.4±0.2°, 18.8±0.2°, 20.3±0.2°, 24.6±0.2°;

[0100] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has characteristic diffraction peaks at the following positions: 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°;

[0101] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has characteristic diffraction peaks at the following positions: 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°;

[0102] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has characteristic diffraction peaks at the following positions: 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°;

[0103] Preferably, the relative intensity of the above characteristic peaks is:

[0104] Peak position 2θ angle (°) Relative peak intensity % Peak position 2θ angle (°) Relative peak intensity % 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 ;

[0105] Preferably, the relative intensity of the above characteristic peaks is:

[0106] Peak position 2θ angle (°) Relative peak intensity % Peak position 2θ angle (°) Relative peak intensity % 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

[0107] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has diffraction peaks at the following positions:

[0108] Peak position 2θ angle (°) Peak position 2θ angle (°) Peak position 2θ angle (°) 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

[0109] Preferably, the relative intensity of the above diffraction peak is:

[0110]

[0111] Alternatively, using Cu-Kα radiation, with substantially Figure 1 The X-ray powder diffraction pattern is shown.

[0112] In some embodiments of the present application, the crystalline form (crystalline form I) of the dihydrochloride salt, its solvate or hydrate shown in formula 3-1 is measured by DSC-TGA, and its DSC graph shows two obvious endothermic peaks in the range of 200 to 320°C, and the starting points of the endothermic peaks appear at 219.1±3°C and 235.1±3°C, respectively, and the peak values ​​appear at 231.0±3°C and 284.2±3°C, respectively; the TGA graph of the hydrochloride shows that decomposition begins at 205.6±3°C; or, the crystalline form I of the dihydrochloride salt shown in formula 3-1 has substantially the following Figure 8 DSC-TGA graph shown.

[0113] In some embodiments of the present application, the crystalline form of the dihydrochloride salt, its solvate or hydrate represented by Formula 3-1 (Form I) has endothermic peaks at 231.0±5°C and 284.2±5°C in its DSC graph, respectively.

[0114] In some embodiments of the present application, the crystalline form of the dihydrochloride salt, its solvate or hydrate represented by Formula 3-1 (Form I) begins to decompose at 205.6±5°C on its TGA chart.

[0115] In some embodiments of the present application, the crystalline form of the dihydrochloride salt, its solvate or hydrate shown in Formula 3-1 (crystalline form I) has substantially the following Figure 8 DSC graph shown.

[0116] In some embodiments of the present application, the crystalline form of the dihydrochloride salt, its solvate or hydrate shown in Formula 3-1 (crystalline form I) has substantially the following Figure 8 TGA graph shown.

[0117] In some embodiments of the present application, the crystalline form of the dihydrochloride salt, its solvate or hydrate represented by Formula 3-1 (Form II) has characteristic diffraction peaks at the following positions using Cu-Kα radiation and a powder X-ray diffraction pattern expressed in 2θ angles (°): 6.0±0.2°, 6.8±0.2°, 12.4±0.2°, 26.0±0.2°;

[0118] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has characteristic diffraction peaks at the following positions: 6.0±0.2°, 6.8±0.2°, 12.4±0.2°, 15.5±0.2°, 26.0±0.2°;

[0119] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has characteristic diffraction peaks at the following positions: 6.0±0.2°, 6.8±0.2°, 12.4±0.2°, 15.5±0.2°, 25.4±0.2°, 26.0±0.2°;

[0120] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) 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°, 24.4±0.2°, 25.4±0.2°, 26.0±0.2°;

[0121] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) 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°, 22.7±0.2°, 24.4±0.2°, 25.4±0.2°, 26.0±0.2°;

[0122] Preferably, the relative intensity of the characteristic peak is:

[0123]

[0124] Preferably, the relative intensity of the characteristic peak is:

[0125] Peak position 2θ angle (°) Relative peak intensity % Peak position 2θ angle (°) Relative peak intensity % 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 ;

[0126] Preferably, the relative intensity of the characteristic peak is:

[0127] Peak position 2θ angle (°) Relative peak intensity % Peak position 2θ angle (°) Relative peak intensity % 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 ;

[0128] Preferably, the relative intensity of the characteristic peak is:

[0129] Peak position 2θ angle (°) Relative peak intensity % Peak position 2θ angle (°) Relative peak intensity % 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 ;

[0130] Alternatively, the crystalline form of the dihydrochloride salt, its solvate or hydrate represented by the formula 3-1 (form II), using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) 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°;

[0131] Alternatively, the crystalline form of the dihydrochloride salt, its solvate or hydrate represented by the formula 3-1 (crystalline form II) has a diffraction peak at the following positions in a powder X-ray diffraction pattern expressed in 2θ angle (°) using Cu-Kα radiation:

[0132] Peak position 2θ angle (°) Peak position 2θ angle (°) Peak position 2θ angle (°) 6.0 18.0 26.0 6.8 20.5 27.5 12.4 22.7 15.5 24.4 17.5 25.4

[0133] Preferably, the relative peak intensity of the above diffraction peak is:

[0134]

[0135] Preferably, the relative peak intensity of the above diffraction peak is:

[0136]

[0137] Alternatively, the crystalline form (form II) of the dihydrochloride salt, its solvate or hydrate represented by formula 3-1, using Cu-Kα radiation, has substantially Figure 2 or Fig.19 The X-ray powder diffraction pattern is shown.

[0138] In some embodiments of the present application, the crystalline form of the dihydrochloride salt, its solvate or hydrate represented by formula 3-1 (form II) is measured using TGA, and its TGA graph shows a weight loss of 12.24±0.20% in the range of 50-140°C.

[0139] Alternatively, the crystalline form of the dihydrochloride salt, its solvate or hydrate (form II) shown in formula 3-1 has substantially Fig. 9 TGA graph shown.

[0140] In some embodiments of the present application, the crystalline form of the dihydrochloride salt, its solvate or hydrate represented by the formula 3-1 (form III), using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has characteristic diffraction peaks at the following positions: 12.7±0.2°, 13.3±0.2°, 23.3±0.2°, 29.3±0.2°;

[0141] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has characteristic diffraction peaks at the following positions: 12.7±0.2°, 13.3±0.2°, 17.2±0.2°, 23.3±0.2°, 29.3±0.2°;

[0142] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) 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°;

[0143] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) 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°;

[0144] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) 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°;

[0145] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has characteristic diffraction peaks at the following positions: 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°;

[0146] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has characteristic diffraction peaks at the following positions: 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°;

[0147] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has diffraction peaks at the following positions:

[0148]

[0149]

[0150] Alternatively, using Cu-Kα radiation, with substantially Fig.11 The X-ray powder diffraction pattern is shown.

[0151] In some embodiments of the present application, the dihydrochloride salt, its solvate or hydrate crystalline form (Form III) represented by Formula 3-1 is measured using DSC, and its DSC graph has endothermic peaks at 101.52±5°C and 183.70±5°C, respectively.

[0152] In some embodiments of the present application, the dihydrochloride salt, its solvate or hydrate crystalline form (Form III) represented by Formula 3-1 is measured using TGA, and its TGA graph shows a weight loss of 6.3±0.20% in the range of room temperature to 120°C.

[0153] Alternatively, the crystalline form of the dihydrochloride salt, its solvate or hydrate shown in Formula 3-1 (Form III) has substantially the following Fig.12 DSC-TGA graph shown.

[0154] In some embodiments of the present application, the crystalline form of the dihydrochloride salt, its solvate or hydrate represented by Formula 3-1 (Form IV) has characteristic diffraction peaks at the following positions using Cu-Kα radiation and a powder X-ray diffraction pattern expressed in 2θ angles (°): 5.4±0.2°, 8.2±0.2°, 13.0±0.2°, 16.5±0.2°;

[0155] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has characteristic diffraction peaks at the following positions: 5.4±0.2°, 8.2±0.2°, 12.0±0.2°, 13.0±0.2°, 16.5±0.2°, 22.8±0.2°;

[0156] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has characteristic diffraction peaks at the following positions: 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°;

[0157] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has characteristic diffraction peaks at the following positions: 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°;

[0158] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) 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°;

[0159] Alternatively, using Cu—Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) 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°;

[0160] Alternatively, using Cu—Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) 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°;

[0161] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has diffraction peaks at the following positions:

[0162]

[0163] Alternatively, using Cu-Kα radiation, with substantially Fig.13 The X-ray powder diffraction pattern is shown.

[0164] In some embodiments of the present application, the dihydrochloride salt, its solvate or hydrate crystalline form (Form IV) represented by Formula 3-1 is measured using DSC, and its DSC graph has endothermic peaks at 68.81±5°C and 177.55±5°C, respectively.

[0165] In some embodiments of the present application, the crystalline form of the dihydrochloride salt, its solvate or hydrate represented by Formula 3-1 (Form IV) is measured using TGA, and its TGA graph shows a weight loss of 3.9±0.20% in the range of room temperature to 150°C.

[0166] Alternatively, the crystalline form of the dihydrochloride salt, its solvate or hydrate (Form IV) shown in Formula 3-1 has substantially the following Fig.14 DSC-TGA graph shown.

[0167] In some embodiments of the present application, the crystalline form of the dihydrochloride salt, its solvate or hydrate represented by Formula 3-1 (Form V) has characteristic diffraction peaks at the following positions using Cu-Kα radiation and a powder X-ray diffraction pattern expressed in 2θ angles (°): 8.4±0.2°, 9.6±0.2°, 19.8±0.2°, 29.2±0.2°;

[0168] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has characteristic diffraction peaks at the following positions: 8.4±0.2°, 9.6±0.2°, 10.5±0.2°, 19.3±0.2°, 19.8±0.2°, 29.2±0.2°;

[0169] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has characteristic diffraction peaks at the following positions: 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°;

[0170] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has characteristic diffraction peaks at the following positions: 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°;

[0171] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has characteristic diffraction peaks at the following positions: 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°;

[0172] Alternatively, using Cu—Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has characteristic diffraction peaks at the following positions: 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°;

[0173] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has diffraction peaks at the following positions:

[0174]

[0175] Alternatively, using Cu-Kα radiation, with substantially Fig.15 The X-ray powder diffraction pattern is shown.

[0176] In some embodiments of the present application, the dihydrochloride salt, its solvate or hydrate crystalline form (Form V) shown in Formula 3-1 is measured using DSC, and its DSC graph has endothermic peaks at 48.29±5°C, 153.99±5°C and 190.59±5°C, respectively.

[0177] In some embodiments of the present application, the crystalline form of the dihydrochloride salt, its solvate or hydrate represented by Formula 3-1 (Form V) is measured using TGA, and its TGA graph shows a weight loss of 7.3±0.20% in the range of room temperature to 200°C.

[0178] Alternatively, the crystalline form of the dihydrochloride salt, its solvate or hydrate (crystalline form V) represented by formula 3-1 has substantially the following Fig.16 DSC-TGA graph shown.

[0179] In some embodiments of the present application, the dihydrochloride salt, its solvate or hydrate crystalline form (Form VII) represented by Formula 3-1 has characteristic diffraction peaks at the following positions using Cu-Kα radiation and a powder X-ray diffraction pattern expressed in 2θ angles (°): 8.3±0.2°, 11.9±0.2°, 12.9±0.2°, 14.6±0.2°;

[0180] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has characteristic diffraction peaks at the following positions: 6.5±0.2°, 8.3±0.2°, 11.9±0.2°, 12.9±0.2°, 14.6±0.2°, 16.5±0.2°;

[0181] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has characteristic diffraction peaks at the following positions: 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°;

[0182] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has characteristic diffraction peaks at the following positions: 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°;

[0183] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has characteristic diffraction peaks at the following positions: 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°;

[0184] Alternatively, using Cu—Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has characteristic diffraction peaks at the following positions: 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°;

[0185] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has diffraction peaks at the following positions:

[0186]

[0187]

[0188] Alternatively, using Cu-Kα radiation, with substantially Fig.17 The X-ray powder diffraction pattern is shown.

[0189] In some embodiments of the present application, the dihydrochloride salt, its solvate or hydrate crystalline form (Form VII) represented by Formula 3-1 is measured using DSC, and its DSC graph has endothermic peaks at 87.64±5°C and 182.15±5°C, respectively.

[0190] In some embodiments of the present application, the dihydrochloride salt, its solvate or hydrate crystalline form (Form VII) represented by Formula 3-1 is measured using TGA, and its TGA graph shows a weight loss of 1.4±0.20% in the range of room temperature to 120°C.

[0191] Alternatively, the crystalline form of the dihydrochloride salt, its solvate or hydrate (Form VII) represented by Formula 3-1 has substantially the following Fig.18 DSC-TGA graph shown.

[0192] In some embodiments of the present application, the salt, solvate or hydrate of the aromatic aminoquinazoline-containing compound is a sulfate as shown in Formula 4:

[0193]

[0194] n is an integer or a half integer of 1-2, that is, n is 1, 1.5 or 2.

[0195] In some embodiments of the present application, the salt of the aromatic aminoquinazoline-containing compound is a sulfate as shown in Formula 4-1:

[0196]

[0197] In some embodiments of the present application, the crystalline form of the salt, solvate or hydrate thereof of the aromatic aminoquinazoline-containing compound is a crystalline form of a sulfate, solvate or hydrate thereof as shown in Formula 4:

[0198]

[0199] n is an integer or a half integer of 1-2, that is, n is 1, 1.5 or 2.

[0200] In some embodiments of the present application, the crystalline form of the salt, solvate or hydrate of the aromatic aminoquinazoline compound is a crystalline form of a sulfate, solvate or hydrate thereof as shown in Formula 4-1:

[0201]

[0202] In some embodiments of the present application, the crystalline form of the sulfate, its solvate or hydrate represented by Formula 4-1 is its crystalline form I.

[0203] In some embodiments of the present application, the crystalline form of the sulfate, solvate or hydrate thereof represented by Formula 4-1 (Form I) has characteristic peaks at the following positions in X-ray powder diffraction expressed in 2θ angles using Cu-Kα radiation: 12.4±0.2°, 15.5±0.2°, 24.8±0.2°, 25.9±0.2°;

[0204] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has characteristic diffraction peaks at the following positions: 6.8±0.2°, 8.5±0.2°, 12.4±0.2°, 15.5±0.2°, 24.8±0.2°, 25.9±0.2°;

[0205] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has characteristic diffraction peaks at the following positions: 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°;

[0206] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has characteristic diffraction peaks at the following positions: 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°;

[0207] Preferably, the relative intensity of the characteristic peak is:

[0208] Peak position 2θ angle (°) Relative peak intensity % Peak position 2θ angle (°) Relative peak intensity % 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

[0209] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has diffraction peaks at the following positions:

[0210] Peak position 2θ angle (°) Peak position 2θ angle (°) Peak position 2θ angle (°) 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

[0211] Preferably, the relative peak intensity of the above diffraction peak is:

[0212]

[0213] Alternatively, using Cu-Kα radiation, with substantially Figure 3 The X-ray powder diffraction pattern is shown.

[0214] In some embodiments of the present application, the salt, solvate or hydrate of the aromatic aminoquinazoline-containing compound is a maleate salt shown in Formula 5:

[0215]

[0216] n is an integer or a half integer of 1-2, that is, n is 1, 1.5 or 2.

[0217] In some embodiments of the present application, the salt of the aromatic aminoquinazoline-containing compound is a maleate salt as shown in Formula 5-1:

[0218]

[0219] In some embodiments of the present application, the crystalline form of the salt, solvate or hydrate thereof of the aromatic aminoquinazoline-containing compound is a crystalline form of a maleate, solvate or hydrate thereof as shown in Formula 5:

[0220]

[0221] n is an integer or a half integer of 1-2, that is, n is 1, 1.5 or 2.

[0222] In some embodiments of the present application, the salt of the aromatic aminoquinazoline-containing compound, its solvate or hydrate is a crystalline form of a maleate, its solvate or hydrate as shown in Formula 5-1:

[0223]

[0224] In some embodiments of the present application, the crystalline form of the maleate salt, its solvate or hydrate represented by Formula 5-1 is its crystalline form I.

[0225] In some embodiments of the present application, the crystalline form of the maleate salt, its solvate or hydrate represented by Formula 5-1 (Form I) has characteristic peaks at the following positions of X-ray powder diffraction expressed in 2θ angle using Cu-Kα radiation: 4.9±0.2°, 7.6±0.2°, 16.7±0.2°, 24.9±0.2°;

[0226] Alternatively, using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ degrees has characteristic peaks at the following positions: 4.4±0.2°, 4.9±0.2°, 7.6±0.2°, 16.7±0.2°, 20.6±0.2°, 24.9±0.2°;

[0227] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has characteristic diffraction peaks at the following positions: 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°;

[0228] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has characteristic diffraction peaks at the following positions: 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°;

[0229] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has characteristic diffraction peaks at the following positions: 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°;

[0230] Preferably, the relative intensity of the characteristic peak is:

[0231] Peak position 2θ angle (°) Relative peak intensity % Peak position 2θ angle (°) Relative peak intensity % 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

[0232] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has diffraction peaks at the following positions:

[0233] Peak position 2θ angle (°) Peak position 2θ angle (°) Peak position 2θ angle (°) 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

[0234] Preferably, the relative peak intensity of the above diffraction peak is:

[0235]

[0236]

[0237] Alternatively, using Cu-Kα radiation, with substantially Figure 4 The X-ray powder diffraction pattern is shown.

[0238] In some embodiments of the present application, the salt, solvate or hydrate of the aromatic aminoquinazoline-containing compound is an oxalate salt as shown in Formula 6:

[0239]

[0240] n is an integer or a half integer of 0.5-2, that is, n is 0.5, 1, 1.5 or 2.

[0241] In some embodiments of the present application, the salt of the aromatic aminoquinazoline-containing compound is an oxalate salt as shown in Formula 6-1:

[0242]

[0243] In some embodiments of the present application, the crystalline form of the salt, solvate or hydrate thereof of the aromatic aminoquinazoline-containing compound is the crystalline form of the oxalate, solvate or hydrate thereof as shown in Formula 6:

[0244]

[0245] n is an integer or a half integer of 0.5-2, that is, n is 0.5, 1, 1.5 or 2.

[0246] In some embodiments of the present application, the crystalline form of the salt, solvate or hydrate thereof of the aromatic aminoquinazoline-containing compound is the crystalline form of the oxalate, solvate or hydrate thereof as shown in Formula 6-1:

[0247]

[0248] In some embodiments of the present application, the crystalline form of the oxalate, its solvate or hydrate represented by Formula 6-1 is its crystalline form I.

[0249] In some embodiments of the present application, the crystalline form of the oxalate salt, its solvate or hydrate represented by Formula 6-1 (Form I) has characteristic peaks at the following positions in X-ray powder diffraction expressed in 2θ angles using Cu-Kα radiation: 5.9±0.2°, 9.9±0.2°, 17.5±0.2°, 21.5±0.2°, 19.8±0.2°;

[0250] Alternatively, using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ degrees 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°, 23.0±0.2°, 25.5±0.2°;

[0251] Alternatively, using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ degrees has characteristic peaks at the following positions: 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°;

[0252] Alternatively, using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ degrees has characteristic peaks at the following positions: 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°;

[0253] Alternatively, using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ degrees has characteristic peaks at the following positions: 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°;

[0254] Alternatively, using Cu—Kα radiation, the X-ray powder diffraction expressed in 2θ degrees has characteristic peaks at the following positions: 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°;

[0255] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angle (°) has diffraction peaks at the following positions:

[0256] Peak position 2θ angle (°) Peak position 2θ angle (°) Peak position 2θ angle (°) 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

[0257] Alternatively, using Cu-Kα radiation, with substantially Figure 7 The X-ray powder diffraction pattern is shown.

[0258] On the other hand, the present application provides a pharmaceutical composition comprising a salt of the aromatic aminoquinazoline-containing compound represented by the aforementioned Formula 2, a solvate or a hydrate thereof.

[0259] In some embodiments of the present application, the pharmaceutical composition comprises a crystalline form of a salt of the aromatic aminoquinazoline-containing compound represented by the aforementioned Formula 2, or a solvate or hydrate thereof.

[0260] In some embodiments of the present application, the pharmaceutical composition comprises the dihydrochloride salt of the aromatic aminoquinazoline-containing compound represented by the aforementioned formula 3-1, or a crystalline form of a solvate or a hydrate thereof.

[0261] In some embodiments of the present application, the pharmaceutical composition comprises one or more of the dihydrochloride salt of the aromatic aminoquinazoline-containing compound shown in the aforementioned formula 3-1, its solvate or hydrate in crystalline form I, crystalline form II, crystalline form III, crystalline form IV, crystalline form V or crystalline form VII.

[0262] In some embodiments of the present application, the pharmaceutical composition comprises a salt of the aromatic aminoquinazoline-containing compound represented by the aforementioned Formula 2, a solvate or a hydrate thereof, and one or more pharmaceutically acceptable carriers.

[0263] In some embodiments of the present application, the pharmaceutical composition comprises a salt of the aromatic aminoquinazoline-containing compound represented by the aforementioned Formula 2, a crystalline form of a solvate or a hydrate thereof, and one or more pharmaceutically acceptable carriers.

[0264] In some embodiments of the present application, the pharmaceutical composition comprises the dihydrochloride salt of the aromatic aminoquinazoline-containing compound represented by the aforementioned formula 3-1, a crystalline form of its solvate or hydrate, and one or more pharmaceutically acceptable carriers.

[0265] In some embodiments of the present application, the pharmaceutical composition comprises the dihydrochloride salt of the aromatic aminoquinazoline-containing compound shown in the aforementioned formula 3-1, one or more of its solvates or hydrates in crystalline form I, crystalline form II, crystalline form III, crystalline form IV, crystalline form V or crystalline form VII, and one or more pharmaceutically acceptable carriers.

[0266] In some embodiments of the present application, the pharmaceutical composition comprises a therapeutically effective amount of a salt of the aromatic aminoquinazoline-containing compound represented by the aforementioned Formula 2, a solvate or a hydrate thereof, and one or more pharmaceutically acceptable carriers.

[0267] The pharmaceutical composition of the present application can be prepared by conventional methods in the art, for example, by mixing a salt of the aromatic aminoquinazoline-containing compound represented by Formula 2, a solvate or a hydrate thereof with one or more pharmaceutically acceptable carriers.

[0268] On the other hand, the present application provides a salt of the aromatic aminoquinazoline-containing compound shown in the aforementioned formula 2, a solvate or a hydrate thereof, a crystalline form of the salt of the aromatic aminoquinazoline-containing compound shown in the aforementioned formula 2, a solvate or a hydrate thereof, or the aforementioned pharmaceutical composition for use in the preparation of a drug as a receptor tyrosine kinase inhibitor.

[0269] In some embodiments of the present application, the receptor tyrosine kinase is one or more of VEGFR, FLT, FGFR, RET, EGFR and mutants thereof.

[0270] On the other hand, the present application also provides the use of a salt of the aromatic aminoquinazoline-containing compound shown in the aforementioned formula 2, a solvate or a hydrate thereof, a crystalline form of a salt of the aromatic aminoquinazoline-containing compound shown in the aforementioned formula 2, a solvate or a hydrate thereof, or the aforementioned pharmaceutical composition in the treatment of receptor tyrosine kinase-related diseases.

[0271] On the other hand, 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 a salt of the aromatic aminoquinazoline-containing compound shown in the aforementioned formula 2, a solvate or hydrate thereof, a crystalline form of a salt of the aromatic aminoquinazoline-containing compound shown in the aforementioned formula 2, a solvate or hydrate thereof, or the aforementioned pharmaceutical composition.

[0272] On the other hand, the present application also provides a salt of the aromatic aminoquinazoline-containing compound shown in the aforementioned formula 2, a solvate or a hydrate thereof, a crystalline form of the salt of the aromatic aminoquinazoline-containing compound shown in the aforementioned formula 2, a solvate or a hydrate thereof, or the aforementioned pharmaceutical composition for treating receptor tyrosine kinase-related diseases.

[0273] In some embodiments of the present application, 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. In some embodiments of the present application, the disease is a cell proliferative disease. In some embodiments of the present application, the disease involves the disorder of expression, level or activity of one or more proteins in VEGFR, FLT, FGFR, RET and EGFR. In some embodiments of the present application, the cell proliferative disease is a tumor or cancer. In some embodiments of the present application, the tumor includes thyroid cancer, biliary tract cancer, epidermoid cancer, melanoma, colorectal cancer, gastric cancer, esophageal cancer, pancreatic cancer, renal cancer, liver cancer, lung cancer or ovarian cancer. In some embodiments of the present application, the thyroid cancer is medullary thyroid cancer, and the lung cancer is non-small cell lung cancer. In some embodiments of the present application, the non-small cell lung cancer is RET fusion non-small cell lung cancer.

[0274] On the other hand, the present application also provides the use of a salt of the aromatic aminoquinazoline-containing compound shown in the aforementioned formula 2, a solvate or a hydrate thereof, a crystalline form of a salt of the aromatic aminoquinazoline-containing compound shown in the aforementioned formula 2, a solvate or a hydrate thereof, or the aforementioned pharmaceutical composition in the preparation of anti-tumor drugs.

[0275] On the other hand, the present application also provides the use of a salt of the aromatic aminoquinazoline-containing compound shown in the aforementioned formula 2, a solvate or a hydrate thereof, a crystalline form of a salt of the aromatic aminoquinazoline-containing compound shown in the aforementioned formula 2, a solvate or a hydrate thereof, or the aforementioned pharmaceutical composition in the treatment of tumors.

[0276] On the other hand, 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 a salt of the aromatic aminoquinazoline-containing compound shown in the aforementioned formula 2, a solvate or a hydrate thereof, a crystalline form of a salt of the aromatic aminoquinazoline-containing compound shown in the aforementioned formula 2, a solvate or a hydrate thereof, or the aforementioned pharmaceutical composition.

[0277] On the other hand, the present application also provides a salt of the aromatic aminoquinazoline-containing compound shown in the aforementioned formula 2, a solvate or a hydrate thereof, a crystalline form of the salt of the aromatic aminoquinazoline-containing compound shown in the aforementioned formula 2, a solvate or a hydrate thereof, or the aforementioned pharmaceutical composition for treating tumor diseases.

[0278] In some embodiments of the present application, the tumor or tumor disease described in the above aspects includes thyroid cancer, biliary cancer, epidermoid cancer, melanoma, colorectal cancer, gastric cancer, esophageal cancer, pancreatic cancer, kidney cancer, liver cancer, lung cancer or ovarian cancer. In some embodiments of the present application, the thyroid cancer is medullary thyroid cancer, and the lung cancer is non-small cell lung cancer. In some embodiments of the present application, the non-small cell lung cancer is RET fusion non-small cell lung cancer. In some embodiments of the present application, 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. In some embodiments of the present application, the tumor or tumor disease involves the disorder of one or more protein expression, level or activity in VEGFR, FLT, FGFR, RET and EGFR.

[0279] 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.

[0280] On the other hand, the present application provides a method for preparing a salt of a compound containing an aromatic amino quinazoline as shown in Formula 2, a solvate or a hydrate thereof, comprising reacting the compound containing an aromatic amino quinazoline as shown in Formula 1 with an acid (HA) in a suitable solvent, and isolating the salt of the compound containing an aromatic amino quinazoline as shown in Formula 2, a solvate or a hydrate thereof:

[0281]

[0282] in,

[0283] HA is an acid;

[0284] n is an integer or a half integer from 1 / 2 to 2.

[0285] In some embodiments of the present application, the HA is hydrochloric acid, sulfuric acid, oxalic acid, maleic acid or malic acid.

[0286] In some embodiments of the present application, the molar ratio of the aromatic aminoquinazoline-containing compound represented by Formula 1 to the acid is 1:1 to 2.5, preferably 1:1 to 2.

[0287] In some embodiments of the present application, the reaction temperature is 10-90°C, preferably 40-70°C.

[0288] In some embodiments of the present application, the reaction solvent is selected from one or a combination of two of alcohols, ketones, nitriles, water or heterocycloalkane solvents; preferably one or a combination of two of ethyl acetate, methanol, ethanol, water, acetonitrile, acetone, tetrahydrofuran, DMF, NMP, isopropanol, n-propanol, DMA, and dioxane; further preferably ethyl acetate, methanol or water.

[0289] In some embodiments of the present application, 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.

[0290] In some embodiments of the present application, when the above-mentioned reaction solvents are in two combinations, they can be added separately, that is, the good solvent is added first and the poor solvent is added later.

[0291] In some embodiments of the present application, a salt of the aromatic aminoquinazoline-containing compound represented by Formula 2, a solvate or a hydrate thereof is isolated in a crystalline form.

[0292] In some embodiments of the present application, the reaction is completed, the temperature of the cooling crystallization is -5 to 35°C, preferably 0 to 25°C, the crystallization is stirred for 0.5 to 24 hours, the solid is separated, and dried to obtain the salt of the aromatic aminoquinazoline-containing compound shown in Formula 2. Preferably, the temperature of collecting the salt is 10°C, and the crystallization time is 0.5 to 12 hours.

[0293] In some embodiments of the present application, the separation step comprises separating the salt of the aromatic aminoquinazoline compound represented by Formula 2 from the crystal solution by using a suitable method such as filtration and centrifugation.

[0294] In some embodiments of the present application, the drying method may be any suitable known method, preferably drying. Specific drying conditions are, for example, using a vacuum drying oven, preferably at a temperature of 30 to 65°C, more preferably 40 to 55°C; preferably, the drying time is 1 to 50 hours, more preferably 1 to 16 hours, and further preferably 3 to 6 hours. Regardless of the drying method used, it is preferred that the residual solvent content in the obtained product meets the quality standards.

[0295] The aromatic aminoquinazoline-containing compound shown in Formula 1 can be prepared by referring to the methods disclosed in the prior art, such as the method described in WO2016023330A1, and the contents of the above document are incorporated herein by reference.

[0296] Definition and Description

[0297] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient.

[0298] The term "solvate" or "solvate" refers to an association formed by one or more solvent molecules and the compound represented by Formula 2 of the present application, including an association containing both water molecules and one or more other solvent molecules.

[0299] The term "hydrate" refers to an association formed by one or more water molecules and the compound of Formula 2 of the present application. The hydrate in the present application includes the dihydrochloride tetrahydrate of the compound of Formula 3-2.

[0300] Unless otherwise specified, the "2θ", "2θ angle" or "2θ angle" mentioned in this application refers to the diffraction angle, with the unit of ° or degree, and the error range of 2θ can be ±0.5, ±0.4, ±0.3, ±0.2 or ±0.1°.

[0301] Unless otherwise specified, the "heating temperature", "cooling temperature" or "crystallization temperature" mentioned in this application is in ℃ or degrees Celsius, and the error range can be ±10, ±5, ±4, ±3, ±2 or ±1℃.

[0302] The term "substantially as shown" means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99% of the peaks in the X-ray powder diffraction pattern, DSC pattern, or TGA pattern are shown in the pattern. Further, when the content of a certain crystal form in the product gradually decreases, some diffraction peaks in its powder X-ray diffraction pattern attributable to the crystal form may become less due to the detection sensitivity of the instrument.

[0303] The term "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, a small angle peak, a sharp peak shape, and a relative peak intensity of 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.

[0304] The term "cell proliferative disorder" refers to conditions in which a population of cells grows at a rate that is slower or faster than expected under given physiological circumstances and conditions.

[0305] The term "tumor" includes benign tumors, malignant tumors and borderline tumors, among which malignant tumors are collectively referred to as cancer.

[0306] The term "treatment" 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. As used herein, "treatment" encompasses any treatment of a patient's disease, including: (a) suppressing the symptoms of the disease, i.e., preventing its development; or (b) alleviating the symptoms of the disease, i.e., causing regression of the disease or symptoms.

[0307] The term "effective amount" or "therapeutically effective amount" means an amount of a compound of the present application that (i) treats a particular disease, or (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease. The term "therapeutically effective amount" means an amount of a compound that, when administered to a patient for treating a disease, is sufficient to achieve treatment of the disease. The amount of a compound of the present application that constitutes a "therapeutically effective amount" varies 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 based on their own knowledge and the present disclosure.

[0308] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to those carriers that have no significant irritation to organisms and do not impair the biological activity and properties of the active compound.

[0309] The compounds in the present application can be prepared by a variety of synthesis methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitution methods known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0310] The chemical reactions of the specific embodiments of the present application are carried out in a suitable solvent, which must be suitable for the chemical changes of the present application and the reagents or materials required. In order to obtain the compounds of the present application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction processes based on the existing embodiments.

[0311] The present application will be described in detail below through examples, which do not imply any limitation to the present application.

[0312] All solvents used in this application were commercially available and used without further purification.

[0313] The following abbreviations are used in this application: DMF: N,N-dimethylformamide; NMP: N-methylpyrrolidone; DMA: N,N-dimethylaniline.

[0314] Beneficial Effects

[0315] The present application provides a salt of a compound containing an aromatic amino quinazoline as shown in Formula 2, a solvate or a hydrate thereof, and a crystalline form of a salt of a compound containing an aromatic amino quinazoline as shown in Formula 2, a solvate or a hydrate thereof, which have one or more of the following beneficial effects:

[0316] The salts of the aromatic aminoquinazoline-containing compounds shown in Formula 2, their solvates or hydrates have good solid properties, and further, good crystalline properties, especially the dihydrochloride, sulfate, maleate, monohydrochloride, oxalate, malate, and their solvates or hydrates have good crystalline properties.

[0317] The solubility of the dihydrochloride, sulfate, maleate, oxalate, and their solvates or hydrates in water or aqueous solutions is significantly improved, especially the dihydrochloride, sulfate, maleate, and their solvates or hydrates.

[0318] Furthermore, it is preferred that the salt and its crystalline form (eg, dihydrochloride, dihydrochloride tetrahydrate, sulfate, maleate and its crystalline form) have excellent storage stability, chemical stability, thermal stability and / or mechanical stability.

[0319] The salts, solvates or hydrates thereof of the aromatic aminoquinazoline-containing compounds shown in Formula 2 of the present application, especially the dihydrochloride, sulfate, maleate, oxalate, and solvates or hydrates thereof, more especially the dihydrochloride and solvates or hydrates thereof, have better drugability, are suitable for storage as raw materials, and can be developed into different pharmaceutical dosage forms according to clinical needs. DETAILED DESCRIPTION

[0320] The technical solution of the present application will be further described in detail below in conjunction with specific embodiments. The following embodiments are only for exemplary purposes to illustrate and explain the present application, and should not be construed as limiting the scope of protection of the present application. All technologies implemented based on the above content of the present application are included in the scope that the present application is intended to protect.

[0321] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0322] In the following examples, the analysis and detection conditions are as follows:

[0323] 1. Content

[0324] Detection instrument: Agilent 1260 (LC1260-3-DAD) high performance liquid chromatograph

[0325] Column: C18 4.6*250mm, 5μm

[0326] Test conditions: wavelength 252nm; column temperature 45℃;

[0327] 2. Solubility (water and pH 2.0 buffer)

[0328] Detection instrument: Agilent 1260 high performance liquid chromatograph

[0329] Detection medium: purified water, pH 2.0 phosphoric acid-disodium hydrogen phosphate buffer

[0330] Preparation of reference solution: Take an appropriate amount of the reference compound of formula 1, accurately weigh it, add a solvent to completely dissolve it, and dilute it to make a 100 μg / mL solution, accurately measure 10uL, and use HPLC to determine the content of compound 1 in the reference solution.

[0331] 3. X-Ray Powder Diffraction (XRPD)

[0332] (1) Testing instrument: Bruker D2 PHASER powder X-ray diffractometer

[0333] Test conditions:

[0334] Light tube type: Cu target, ceramic X-ray tube;

[0335] X-ray wavelength: CuKα, 1.5406;

[0336] Voltage and current: 30kV, 10mA;

[0337] Scanning range: 3-40°2θ;

[0338] Total scanning time: 40min;

[0339] Scanning speed: 0.5 seconds / step;

[0340] Sample dosage: 3 mg (Examples 1-4)

[0341] Acquisition software: Diffrac Plus XRD Commander

[0342] Analysis software: MDI Jade 6.0

[0343] (2) Testing instrument: Bruker D8 Advance powder X-ray diffractometer

[0344] Test conditions:

[0345] Light tube type: Cu target, ceramic X-ray tube;

[0346] X-ray wavelength: CuKα, 1.5418;

[0347] Voltage and current: 40kV, 40mA;

[0348] Scanning range: 3-40°2θ;

[0349] Scanning speed: 0.2 seconds / step;

[0350] Sample dosage: 5-10 mg (Examples 5-8).

[0351] 4. Thermogravimetric Analysis (TGA)

[0352] (1) Testing instruments: METTLER and SDT Q600 thermogravimetric analyzer

[0353] Test method: Weigh 5 mg of sample (Examples 1-4), place in a TGA platinum pan for testing, and heat the sample from 40°C to 300°C at a heating rate of 5K / min under the condition of 40 mL / min dry nitrogen.

[0354] Instrument control software: NETZSCH-proteus-6

[0355] Analysis software: Proteus Analysis

[0356] (2) Testing instrument: Discovery TGA 55 thermogravimetric analyzer (TA Instruments, US)

[0357] Test method: About 2-5 mg of sample (Examples 5-8) was placed in an open aluminum pan with peeled skin, and the instrument automatically weighed and recorded the weight. The sample was then heated in a heating furnace at a heating rate of 10°C / min from room temperature to the final temperature. The airflow was N 2 The flow rates were 40 mL / min (sample chamber) and 25 mL / min (equilibrium chamber), respectively.

[0358] 5. Differential Scanning Calorimetry-Thermogravimetric Analysis (DSC-TGA)

[0359] Testing instrument: NETZSCH STA449F3 synchronous thermal analyzer

[0360] Test method: Weigh the sample (about 3 mg) and place it in an alumina crucible for testing. Heat the sample from 20°C to 340°C at a heating rate of 10K / min under the condition of 20mL / min dry nitrogen (protective gas).

[0361] Instrument control software: NETZSCH-proteus

[0362] Analysis software: Proteus Analysis

[0363] 6. Differential Scanning Calorimetry (DSC)

[0364] Detection instrument: Discovery DSC 250 differential scanning calorimeter (TA Instruments, US)

[0365] Test method: Weigh 2-5 mg of sample (Examples 5-8) and place it in a perforated sealed aluminum pan, and accurately record the sample weight. Then heat the sample from 25°C to the final temperature at a heating rate of 10°C / min. The airflow is N 2 , flow rate is 50mL / min.

[0366] 7. Chloride

[0367] Testing instrument: Dionex ICS-900 ion chromatograph

[0368] Column: Dionex Ion Pac AS11-HC anion chromatography column (specification: 4×250 mm)

[0369] Experimental operation:

[0370] Preparation of test sample solution: Take an appropriate amount of the test sample, accurately weigh it, dissolve it with eluent (12.5 mmol / L sodium hydroxide solution) and quantitatively dilute it into a solution containing approximately 0.5 mg of the test sample per 1 mL, shake well, and use it as the test sample solution.

[0371] Preparation of reference solution: Take an appropriate amount of sodium chloride (equivalent to 18 mg of chloride ion), accurately weigh it, place it in a 250 mL volumetric flask, dissolve it with eluent and make up to volume, shake well, and use it as the reference solution.

[0372] Determination method: Accurately measure 10 μL 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.

[0373] 8. H NMR spectroscopy

[0374] Instrument model: Bruker Advance 600 NMR spectrometer

[0375] Assay conditions: DMSO-d 6 The solvent was tested at room temperature (~25°C)

[0376] 9. Solubility determination in biological solvents

[0377] The preparation process of the biosolubility media (SGF, FeSSIF and FaSSIF) used for solubility determination is shown in the table below:

[0378]

[0379] Test method: Add the sample to be tested into the biosolvent to prepare a solution or suspension with a target concentration of 10 mg / mL. The resulting solution or suspension is continuously shaken at 200 rpm at 37°C. Filter the suspension after 0.5 hours and determine the compound concentration in the filtrate using HPLC.

[0380] Preparation Example 1: Preparation of Compound 1

[0381]

[0382] With reference to the method described in Example 22 of patent document WO2016023330A1, the compound represented by formula 1 was prepared as a light brown solid.

[0383] 1 H-NMR (600 MHz, 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=2.4H z,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).

[0384] Example 1: Preparation of dihydrochloride salt of compound 1

[0385]

[0386] Weigh compound 1 (10 g, 21.58 mmol) obtained in Preparation Example 1 into an eggplant-shaped bottle, add methanol solvent (110 mL), heat to 55±5°C, stir until dissolved, add hydrochloric acid (3.7 mL, 44.4 mmol) dropwise, stir for 20 minutes, slowly add 200 mL of ethyl acetate, cool to 5±5°C, stir for 2±1 h, filter, wash the filter cake with ethyl acetate (20 mL) to obtain white dihydrochloride (11 g), with a yield of 94.8%.

[0387] 1 H-NMR (600 MHz, DMSO-d6 )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).

[0388] The chloride ion content was determined by ion chromatography and the stoichiometric ratio of the hydrochloride was calculated (see the table below). It can be inferred that the base / acid ratio of the hydrochloride is 1:2.

[0389]

[0390] The obtained hydrochloride sample was subjected to X-ray powder diffraction, which showed good crystallinity and was named Form I of dihydrochloride. Its XRPD characterization spectrum is as follows: Figure 1 The main diffraction peak data are shown in Table 1. The sample was taken for DSC-TGA test, and there were two endothermic peaks, endothermic peak 1: an endothermic peak starting point at 219.1 ° C, reaching a peak near 231.0 ° C; endothermic peak 2: an endothermic peak starting point at 235.1 ° C, reaching a peak near 284.2 ° C, and decomposition occurred at about 205 ° C (see Figure 8 ). PLM shows that its crystalline particles have regular morphology.

[0391] Table 1 XRPD diffraction peak data of the crystalline form I of the dihydrochloride obtained in Example 1

[0392]

[0393] Example 2: Preparation of dihydrochloride tetrahydrate of compound 1

[0394]

[0395] Weigh compound 1 (5 g, 10.8 mmol) obtained in Preparation Example 1 into an eggplant-shaped bottle, add purified water (20 mL), drop concentrated hydrochloric acid (2.0 mL, 24 mmol), stir and heat to 80±5°C until completely dissolved, after the dropwise addition is complete, slowly cool to room temperature, filter, and wash the filter cake with a small amount of purified water to obtain a white solid dihydrochloride tetrahydrate (2.82 g), with a yield of 43%. The formation of salt was confirmed by H NMR.

[0396] The free base content was calculated by HPLC (see the table below), and it can be inferred that the base / acid ratio of the hydrochloride hydrate is 1:2.

[0397]

[0398] The crystal water content of the hydrochloride hydrate of Example 2 was further detected by TGA, and the weight loss was 12.24%. It can be inferred that the alkali / crystallization water ratio of the hydrochloride hydrate is 1:4. The TGA test spectrum is shown in Fig. 9 .

[0399] The obtained dihydrochloride tetrahydrate sample was subjected to X-ray powder diffraction, and the obtained solid showed good crystallinity and was named Form II. Its XRPD characterization spectrum is shown as follows: Figure 2 The main diffraction peak data are shown in Table 2.

[0400] Table 2 XRPD diffraction peak data of dihydrochloride tetrahydrate crystals obtained in Example 2

[0401]

[0402] Example 3: Preparation of Sulfate Salt of Compound 1

[0403]

[0404] Weigh compound 1 (4 g, 8.6 mmol) obtained in Preparation Example 1 into an eggplant-shaped bottle, add methanol (10 mL), heat to 60±5°C, stir until dissolved, add 50% sulfuric acid (1.0 mL, 8.6 mmol) dropwise, stir for 10 minutes, slowly add 30 mL of ethyl acetate, cool to room temperature and continue stirring to react for 1 hour, filter with suction, wash the filter cake with ethyl acetate (20 mL), and obtain white sulfate (4.13 g), with a yield of 85.2%, melting point: 164-168°C. The formation of salt was confirmed by H NMR spectrum.

[0405] The free base content was calculated by HPLC (see table below), and it can be inferred that the base / acid ratio of the sulfate salt is 1:1.

[0406]

[0407] The obtained sulfate sample was subjected to X-ray powder diffraction. The obtained sulfate exhibited good crystallinity and was named Form I of sulfate. Its XRPD characterization spectrum is shown as follows: Figure 3 The main diffraction peak data are shown in Table 3.

[0408] Table 3 XRPD diffraction peak data of the crystal form I of the sulfate obtained in Example 3

[0409]

[0410] Example 4: Preparation of maleate salt of compound 1

[0411]

[0412] Weigh compound 1 (5 g, 10.8 mmol) obtained in Preparation Example 1, maleic acid (1.5 g, 13.0 mmol) and methanol (10 mL) into a reaction bottle, heat to 55±5°C, stir until dissolved, add ethyl acetate (30 mL), cool to room temperature and continue stirring for 2 h, filter, wash the filter cake with ethyl acetate (30 mL) to obtain white maleate (2.22 g), yield 35.5%, melting point: 138-142°C. H NMR spectrum confirmed that the salt had been formed.

[0413] The free base content was calculated by HPLC (see table below), and it can be inferred that the base / acid ratio of the maleate salt is 1:1.

[0414] name Theoretical stoichiometric ratio (base / acid) Theoretical alkali content (%) Measured alkali content (%) Example 4 1:1 79.97％ 79.12％

[0415] The obtained maleate sample was subjected to X-ray powder diffraction. The obtained maleate showed good crystallinity and was named as maleate crystal form I. Its XRPD characterization spectrum is as follows: Figure 4 The main diffraction peak data are shown in Table 4.

[0416] Table 4 XRPD diffraction peak data of the crystalline form I of the maleate obtained in Example 4

[0417]

[0418] Example 5: Preparation of Form III of the dihydrochloride salt of Compound 1

[0419] The sample of Example 1 (about 7 mg) was weighed and dissolved in methanol (0.2 mL), filtered and the filtrate was collected, and then acetonitrile (1 mL) was added to the filtrate, stirred overnight, and filtered to obtain a white solid. The obtained solid was subjected to X-ray powder diffraction, which was a crystalline form, named Form III of dihydrochloride, and its XRPD characterization spectrum was as follows: Fig.11 The main diffraction peak data are shown in Table 5. The sample was tested by DSC-TGA. There were two endothermic peaks: endothermic peak 1: an endothermic peak starting point at 72.28°C, reaching a peak value near 101.52°C; endothermic peak 2: an endothermic peak starting point at 172.06°C, reaching a peak value near 183.70°C; the weight loss was 6.2684% between room temperature and 120°C, and decomposition occurred at about 225°C (see Fig.12 ).

[0420] Table 5 XRPD diffraction peak data of Form III of dihydrochloride obtained in Example 5

[0421]

[0422] Example 6: Preparation of Form IV of the dihydrochloride salt of Compound 1

[0423] The sample of Example 1 (about 7 mg) was weighed, dissolved in water (0.2 mL), filtered and the filtrate was collected, and then acetonitrile (7 mL) was added to the filtrate, stirred for 24 h, and filtered to obtain a white solid. The obtained solid was subjected to X-ray powder diffraction, which was a crystalline form, named Form IV of dihydrochloride, and its XRPD characterization spectrum was as follows: Fig.13 The main diffraction peak data are shown in Table 6. The sample was tested by DSC-TGA. There were two endothermic peaks: endothermic peak 1: an endothermic peak starting point at 49.50°C and a peak value at around 68.81°C; endothermic peak 2: an endothermic peak starting point at 164.55°C and a peak value at around 177.55°C; the weight loss was 3.9478% between room temperature and 150°C, and decomposition occurred at around 215°C (see Fig.14 ).

[0424] Table 6 XRPD diffraction peak data of Form IV of dihydrochloride obtained in Example 6

[0425]

[0426] Example 7: Preparation of Compound 1 Dihydrochloride Ethanol Solvate (Form V)

[0427] The sample of Example 1 (about 30 mg) was weighed and dissolved in ethanol (1 mL). After stirring at 50°C for 30 min, the mixture was filtered while hot. The filtrate was cooled to room temperature and stirred for 3 days. The mixture was filtered to obtain a white solid. The obtained solid was subjected to X-ray powder diffraction, which was a crystalline form named Form V (ethanol solvate, 1:1). The XRPD characterization spectrum is shown as follows: Fig.15 The main diffraction peak data are shown in Table 7. The sample was taken for DSC-TGA test, and there were three endothermic peaks: endothermic peak 1: an endothermic peak starting point at 28.37°C, reaching a peak value near 48.29°C; endothermic peak 2: an endothermic peak starting point at 114.96°C, reaching a peak value near 153.99°C; endothermic peak 3: an endothermic peak starting point at 179.32°C, reaching a peak value near 190.59°C; the weight loss was 7.2663% between room temperature and 200°C (see Fig.16 ).

[0428] Table 7 XRPD diffraction peak data table of Form V obtained in Example 7

[0429]

[0430] Example 8: Preparation of Form VII of the dihydrochloride salt of Compound 1

[0431] The crystal form III obtained in Example 5 was heated to 130°C and then collected to obtain a white solid. The obtained solid was subjected to X-ray powder diffraction, which was a crystalline form named as the crystal form VII of the dihydrochloride salt. Its XRPD characterization spectrum is as follows: Fig.17 The main diffraction peak data are shown in Table 8. The sample was tested by DSC-TGA. There were two endothermic peaks: endothermic peak 1: an endothermic peak starting point at 66.54°C and a peak value near 87.64°C; endothermic peak 2: an endothermic peak starting point at 169.59°C and a peak value near 182.15°C; the weight loss was 1.3751% between room temperature and 120°C (see Fig.18 ).

[0432] Table 8 XRPD diffraction peak data of the crystalline form VII of the dihydrochloride obtained in Example 8

[0433]

[0434] Comparative Example 1-2: Preparation of Monohydrochloride and Malate of Compound 1

[0435] Example 9: Preparation of Oxalate of Compound 1

[0436] Three portions of the sample of Preparation Example 1 (5 g, 10.8 mmol) were taken into a reaction bottle, and the monohydrochloride of Formula 3-3, the malate of Formula 7-1, and the oxalate of Formula 6-1 were prepared according to the reaction conditions in the following table. The operation process was the same as that of Example 3, and the results are shown in Table 9. The formation of salt was confirmed by H NMR spectrum.

[0437]

[0438] Table 9 Salt formation reaction conditions and results

[0439]

[0440] Note: ① The method for confirming the base / acid ratio of Comparative Example 1: determination of chloride ion content; ② The method for confirming the base / acid ratio of Comparative Example 2 and Example 9: nuclear magnetic hydrogen spectrum, and determination of free base content.

[0441] Example 10: Preparation of dihydrochloride tetrahydrate

[0442] The sample of Example 1 (about 369 mg) was weighed and added to water / acetone (1:1, v / v, total amount 5 mL), and stirred overnight at room temperature. A white solid was collected by filtration and dried overnight at 50°C in vacuum. After testing, it was found to be dihydrochloride tetrahydrate. The obtained solid was subjected to X-ray powder diffraction, which was a crystalline form. Its XRPD characterization spectrum is as follows: Fig.19 shown.

[0443] Test Example 1: Solubility Test

[0444] The solubility of the salts obtained in Preparation Example 1, Examples 1-4 and 9 and Comparative Examples 1-2 was tested in water and pH 2.0 buffer. The test results are shown in the following table:

[0445] Table 10 Solubility results of different samples

[0446]

[0447] Note: / : Not tested.

[0448] Results: Compared with Preparation Example 1, the samples of Examples 1-4 and Example 9 all achieved an increase in solubility in water, and the samples of Examples 1-4 all achieved an increase in solubility in water by at least 100 times, among which the dihydrochloride salt had the best solubility. After the monohydrochloride salt and malate salt samples were dissolved in water, the system became jelly-like, which may be due to the crystal transformation of the samples in water and the poor dissolution effect, making the system appear as a non-solution state.

[0449] Further, Examples 1-4 with good solubility (>10 mg / mL) were selected, and Preparation Example 1 was used as a control to detect the solubility of the samples in pH 2.0 buffer. From the above results, it can be seen that under acidic conditions, the solubility of Preparation Example 1 is significantly improved, the solubility of Examples 1 and 4 is still slightly better than that of Preparation Example 1, and the solubility of Examples 2 and 3 is slightly lower than that of Preparation Example 1. In the environment of simulated gastric fluid, although the solubility of Examples 1 and 4 is reduced, it is still better than the free base compound of Preparation Example 1.

[0450] In addition, according to the general requirements of drug dosage forms for the solubility of raw materials, solid oral dosage forms require the solubility of the drug in water to be greater than 0.1 g / L, and solution preparations such as injections or oral liquids require the solubility of the drug to be above 10 g / L. More importantly, the solubility of the drug should meet the dosage concentration required for clinical use. Based on the solubility results in Table 10, Examples 1-4 and Example 9 can be considered for the preparation of solid oral dosage forms, and Examples 1-4 can further be considered for the preparation of solution preparations such as injections or oral liquids.

[0451] Test Example 2: Solubility Test in Biological Media

[0452] The samples of Example 1 and Example 10 (20 mg each) were weighed, different biosolvents (2 mL) were added, and solubility tests were performed. The results are shown in Table 11.

[0453] Table 11 Solubility of different samples in biological solvents

[0454]

[0455] Results: The samples obtained in Example 1 and Example 10 can maintain good solubility in biological solvents with different pH values ​​and dissolve at a relatively fast rate.

[0456] Test Example 3: Long-term stability test

[0457] Take appropriate amount of salt samples obtained in Examples 1-4 and 9, seal with polyethylene film and place for 5 months at 40±2°C and 75%±5%RH for long-term test. The results are as follows:

[0458] Table 12 Stability results and crystal form test results of different samples

[0459]

[0460] Table 13 XRPD data of the crystal sample of Example 1 after long-term stability test

[0461]

[0462] The XRPD spectrum of the dihydrochloride form I of compound 1 obtained in Example 1 after long-term stability test is as follows: Fig.10 shown.

[0463] Results: After being placed for 5 months, the crystal samples of the salts of Examples 1-4 and 9 were able to stably exist, the purity of the products did not decrease significantly, and the crystal forms of the samples remained unchanged.

[0464] Test Example 4: Solid Stability Test

[0465] The dihydrochloride salt of Example 1 and the dihydrochloride tetrahydrate of Examples 2 and 10 were placed under 40°C / 75% RH (open) conditions for 7 days for stability testing. The results are shown in Table 14.

[0466] Table 14 Stability results and crystal form test results of different samples

[0467]

[0468]

[0469] Results: After being placed under 40°C / 75% RH (open) conditions for 7 days, the dihydrochloride and dihydrochloride tetrahydrate of Compound 1 obtained in Examples 1-2 and 10 were able to maintain chemical stability and crystalline stability. Therefore, the samples obtained in Examples 1-2 and 10 had good thermal stability and met the requirements for storage as raw materials.

[0470] Test Example 5: Mechanical stability test

[0471] An appropriate amount of the dihydrochloride salt of Example 1 was taken and mechanically ground for 5 minutes, and then subjected to X-ray powder diffraction. The results showed that the crystal form did not change.

[0472] Test Example 6: Solubility test in conventional organic solvents

[0473] The solubility of the sample of Preparation Example 1 in different organic solvents was tested using the method in the Pharmacopoeia (General Examples of Part II). The solubility of the sample of Example 1 in different organic solvents was estimated using the gravimetric method. The results are shown in Table 15.

[0474] Table 15 Comparison of the solubility of the sample of Preparation Example 1 and the dihydrochloride of Example 1 in several common organic solvents

[0475]

[0476] Note: The sample of Example 1 (~15 mg) was added to 0.5 mL of different solvents listed in Table 15, and slurried at room temperature and 50°C. The filtered sample was subjected to X-ray powder diffraction, and the crystal form was consistent with the dihydrochloride obtained in Example 1.

[0477] Results: Preparation Example 1 has good solubility in a variety of conventional organic solvents (all > 10 mg / mL), while the dihydrochloride of Example 1 only shows good solubility in methanol, and has very low solubility in the other 7 commonly used organic solvents. Therefore, the dihydrochloride can be prepared by using suitable conventional organic solvents, and the (unreacted) free base and the dihydrochloride can be completely separated, and the dihydrochloride can be obtained with a higher yield (small mass loss caused by dissolution in organic solvents) and high purity.

[0478] In addition, by slurrying in the above conventional organic solvents, the crystal form corresponding to the dihydrochloride salt of Example 1 was obtained, indicating that the crystal form is relatively stable in conventional organic solvents.

[0479] Test Example 7: Efficacy experiment on human melanoma A375 nude mouse transplanted tumor model

[0480] Well-growing human melanoma A375 cell suspension was inoculated into the subcutaneous tissue of the axilla of the forelimbs of nu / nu female nude mice. The inoculation volume was 0.1 mL, containing approximately 1×10 tumor cells. 7 When the tumor grows to 100 mm 3As above, mice with good tumor growth were selected, and the animals were evenly divided into 5 groups according to the tumor volume: blank control group, vandetanib 12.5 mg / kg group, vandetanib 25 mg / kg group, Example 1 sample 12.5 mg / kg group and Example 1 sample 25 mg / kg, with 6 animals in each group. The blank control group was orally administered with distilled water, and the remaining groups were orally administered with the corresponding test drugs, with the administration volume of 20 mL / kg, once a day, and continued to the 20th day. After administration, the animals were raised normally, and the anti-tumor effect of the test drug was dynamically observed by measuring the tumor diameter. At the end of the experiment (21st day), the animals were killed, the tumors were removed, weighed, and the tumor inhibition rate was calculated.

[0481] Vandetanib:

[0482] Table 16 Effects of samples and vandetanib in Example 1 on tumor weight in human melanoma A375 transplantation model

[0483]

[0484] Note: **Compared with the blank control group, p<0.01; #Compared with the same dose of vandetanib group, p<0.05.

[0485] Results: Compared with the blank control group, the sample of Example 1 can significantly inhibit the growth of tumors in a dose-dependent manner, and has a better tumor inhibition effect than the control drug vandetanib.

[0486] According to the conversion coefficient of the body surface area of ​​humans and animals (refer to "Pharmacological Experimental Methodology", editor-in-chief: Xu Shuyun), the effective dose in the mouse model is converted into the equivalent dose for adults. The effective doses of 12.5 mg / kg and 25 mg / kg in the mouse model correspond to the equivalent doses of 1.37 mg / kg and 2.74 mg / kg for adults (70 kg), respectively. The single oral dose for adults (70 kg) is 95.9 mg and 191.8 mg. If a small-sized injection or solution (5 mL) is made, the solubility of the drug needs to reach 11.51 mg / mL and 23.02 mg / mL or more, respectively (the absolute bioavailability of dogs and monkeys in animal pharmacokinetic experiments is about 60%, so the oral availability of humans here is 60%). By analogy, when a smaller-sized liquid preparation (less than 5 mL) is made, the solubility of the drug is required to be higher. Combined with the solubility test results in Table 10, based on the specifications of 5 mL liquid preparation, if the dosage is 1.37 mg / kg, Example 1, Example 2 and Example 4 can meet the solubility requirements; if the dosage is 2.74 mg / kg, Example 1 and Example 2 can meet the solubility requirements.

[0487] In summary, the inventors screened and explored the salt forms of compound 1 and found that the solubility of dihydrochloride, sulfate and maleate was significantly improved compared with compound 1, which met the general requirements of solid preparations and liquid preparations for the solubility of raw materials, and the crystal form of the obtained salt had good stability. Among them, the dihydrochloride performed best, which could meet the solubility requirements of small-scale liquid preparations and had good in vivo anti-tumor effects, and had the potential to be developed into drugs with multiple dosage forms and different specifications.

Claims

1. A crystalline form of the compound represented by formula (3-1), ， It is form I, and using Cu-Kα radiation, its X-ray powder diffraction expressed in 2θ angles has characteristic peaks at the following positions: 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°, and 30.9±0.2°.

2. The crystalline form of the compound according to claim 1, wherein Using Cu-Kα radiation, it has an X-ray powder diffraction pattern as shown in FIG1 .

3. The crystalline form of the compound according to claim 1, wherein The thermogravimetric analysis curve showed that it began to decompose at 205.6±5℃.

4. A crystalline form of the compound represented by formula (3-2), ， Using Cu-Kα radiation, its X-ray powder diffraction expressed in 2θ angles has characteristic 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°, and 27.5±0.2°.

5. The crystalline form of the compound according to claim 4, wherein Using Cu-Kα radiation, it has an X-ray powder diffraction pattern as shown in FIG2 .

6. The crystalline form of the compound according to claim 4, wherein The thermogravimetric analysis curve showed that it lost 12.24±0.20% of its weight in the range of 50℃~140℃.

7. The crystalline form of the compound according to claim 4, wherein It has a thermogravimetric analysis curve as shown in FIG9 .

8. A pharmaceutical composition comprising a crystalline form of a compound according to any one of claims 1 to 3 or a crystalline form of a compound according to any one of claims 4 to 7.

9. The pharmaceutical composition according to claim 8, wherein The pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.

10. Use of a crystalline form of a compound according to any one of claims 1 to 3 or a crystalline form of a compound according to any one of claims 4 to 7 or a pharmaceutical composition according to claim 8 or 9 for the preparation of a receptor tyrosine kinase inhibitor drug.

11. The use according to claim 10, wherein The receptor tyrosine kinase is selected from one or more of VEGFR, FLT, FGFR, RET, EGFR and mutants thereof.

12. The use according to claim 10, wherein The medicine is a medicine for treating cell proliferative diseases.

13. The use according to claim 12, wherein The cell proliferative disease is a tumor.

14. The use according to claim 13, wherein The tumor is thyroid cancer, biliary tract cancer, epidermoid carcinoma, melanoma, colorectal cancer, gastric cancer, esophageal cancer, pancreatic cancer, kidney cancer, liver cancer, lung cancer or ovarian cancer.

15. The use according to claim 14, wherein The thyroid cancer is medullary thyroid carcinoma, and the lung cancer is non-small cell lung cancer.

16. The use according to claim 15, wherein The non-small cell lung cancer is RET fusion non-small cell lung cancer.

17. A method for preparing a compound of formula (2), comprising reacting an aromatic amino group-containing quinazoline compound of formula (1) with HA in a solvent, and separating to obtain a compound of formula (2): ， in, HA is hydrochloric acid; n is 2; The compound represented by formula (2) is a crystalline form of the compound represented by formula (3-1) according to any one of claims 1 to 3 or a crystalline form of the compound represented by formula (3-2) according to any one of claims 4 to 7; The reaction temperature is 10-90°C; and The solvent is one or a combination of ethyl acetate, methanol or water.

18. The preparation method according to claim 17, wherein: The compound represented by formula (2) is a crystalline form of the compound represented by formula (3-1) according to any one of claims 1 to 3, and the solvent is a combination of ethyl acetate and methanol.

19. The preparation method according to claim 17, wherein: The compound represented by formula (2) is a crystalline form of the compound represented by formula (3-2) according to any one of claims 4 to 7, and the solvent is water.

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