RU2833198C1 - Salt of arylaminoquinazoline-containing compound and method for preparation and use thereof - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a salt of an arylaminoquinazoline-containing compound of formula 2, or a hydrate thereof. Method is carried out by reacting an arylaminoquinazoline-containing compound of formula 1, with HA in a solvent, isolating a salt of an arylaminoquinazoline-containing compound of formula 2, or a hydrate thereof, where HA is hydrochloric acid; n is 2; and reaction temperature is (40–90) °C; and the reaction solvent is selected from one or a combination of two of ethyl acetate, methanol or water. Obtained hydrate is a tetrahydrate.

EFFECT: obtaining a dihydrochloride salt of a compound of formula 2 or a hydrate thereof with high output and purity, which also have good crystalline properties, solubility and stability.

2 cl, 19 dwg, 16 tbl,

15 ex

Description

Cross-reference to related applications

The present invention claims the priority and benefit of Chinese Patent Application No. 202011022290.1, filed in the China Patent Office on September 25, 2020, the disclosure of which is incorporated herein by reference in its entirety.

Field of technology

The present invention relates to the field of pharmaceutical chemistry and in particular relates to salts of arylaminoquinazoline-containing compounds and methods for their preparation and use.

State of the art

Protein tyrosine kinases (PTKs) are a very important member of the protein kinase family. PTKs transfer the γ-phosphate group of adenosine triphosphate to the tyrosine residue of the substrate protein and complete the transfer of information between cells by phosphorylating phenolic hydroxyl groups, which plays a crucial role in the development and regulation of cells and the differentiation, migration and apoptosis of tumor cells and other processes. If PTKs are out of control during the regulation process, it will affect the correct activation of their downstream signaling pathway, which in turn will lead to dysfunction of cell proliferation regulation and cause many diseases. For example, excessive tyrosine kinase activity causes receptor phosphorylation and accordingly activates downstream signaling, which leads to excessive signaling, proliferation and anti-apoptosis of cells, promoting cell survival and the formation of malignant neoplasms. Thus, the use of tyrosine kinases as new targets for the development of inhibitors of this type of kinases that inhibit the overexpression of tyrosine kinases and restore their physiological balance has become a hot spot of research in the field of molecular targeting antitumor agents with great development prospects.

Epidermal growth factor receptor (EGFR), fibroblast growth factor receptors (FGFR), platelet-derived growth factor receptor (PDGFR), rearranged upon transfection (RET) proteins encoded by the PET proto-oncogene, etc. are important members of the PTC and important targets for tumor treatment.

EGFR is a cell growth factor that can bind to receptor tyrosine kinases, including EGFR (ErbB-1), human epidermal growth factor receptor type 2 HER2 (ErbB-2), human epidermal growth factor receptor type 3 HER3 (ErbB-3) and human epidermal growth factor receptor type 4 HER4 (ErbB-4), among which EGFR and HER2 are the most closely tumor-associated targets of the EGFR family members. Studies have shown that EGFR exhibits overexpression, gene mutation or gene fusion in various tumors such as lung cancer, gastric cancer, epidermoid cancer, renal cancer, ovarian cancer, etc.

FGFR mainly includes four subtypes, i.e. FGFR1/2/3/4, which are overexpressed or overactivated by gene amplification, mutation, fusion or ligand induction and play an important role in tumor cell proliferation, invasion and migration and tumor angiogenesis. Studies have shown that FGFRs are overexpressed or overactivated in various tumors such as non-small cell lung cancer, gastric cancer, colorectal cancer, esophageal cancer, liver cancer, biliary tract cancer, etc.

Normal physiological functions of RET include kidney development, nervous system development, maintenance and renewal of sperm stem cells, myelomonocyte differentiation, lymphoid tissue formation, etc., which is expressed in cells such as human intestinal ganglion cells, neuroblastoma, pheochromocytoma, medullary thyroid carcinoma, thyroid C cells and melanoma. In recent years, through in-depth studies of RET, it has been found that hyperactivation of RET in tumors can significantly promote proliferation, survival, invasion, metastasis, tumor inflammation and so on for various tumors, and RET is overexpressed in thyroid cancer (e.g., medullary thyroid cancer, papillary thyroid cancer), colorectal cancer, pancreatic cancer, melanoma, etc.

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 having inhibitory activity against RET, VEGFR (vascular endothelial growth factor receptor), FGFR, EGFR, FLT (Fms-like tyrosine kinase receptor or Fms-related tyrosine kinase), etc.

WO 2016023330 A1 relates to arylaminoquinazoline-containing compounds as tyrosine kinase inhibitors and describes Compound 1 and an analogue, a method for its preparation and its medical use.

The essence of the invention

The present inventors have found that Compound 1 has very low water solubility and does not meet the general solubility requirements for drugs in the form of solid oral dosage forms (it should be higher than 0.1 g/L), let alone the development of other dosage forms of drugs (e.g. injections and solutions). In addition, the water solubility of a drug is also a major factor affecting the solubility, absorption and pharmacokinetic properties of a drug. Therefore, it is necessary to modify Compound 1 to optimize its physicochemical properties and improve its properties required for the preparation of a drug.

In a first aspect of the present invention, there is provided a salt of an arylaminoquinazoline-containing compound represented by formula 2, a solvate or a hydrate thereof:

Where

HA is hydrochloric acid, sulfuric acid, oxalic acid or maleic acid;

n is an integer or half-integer in the range 1/2 to 2; and,

when HA is hydrochloric acid, n is 0.5, 1.5, or 2.

In another aspect of the present invention, there is provided a crystalline form of a salt of an arylaminoquinazoline-containing compound represented by formula 2, a solvate or a hydrate thereof:

Where

HA is hydrochloric acid, sulfuric acid, oxalic acid or maleic acid;

n is an integer or half-integer in the range 1/2 to 2; and,

when HA is hydrochloric acid, n is 0.5, 1.5, or 2.

In another aspect of the present invention, there is provided a pharmaceutical composition comprising the above-mentioned salt of an arylaminoquinazoline-containing compound represented by formula 2, a solvate or hydrate thereof, or a crystalline form of a salt of an arylaminoquinazoline-containing compound represented by formula 2, a solvate or hydrate thereof, and one or more pharmaceutically acceptable carriers.

In another aspect of the present invention, there is provided the use of the above-mentioned salt of the arylaminoquinazoline-containing compound represented by formula 2, a solvate or hydrate thereof, or a crystalline form of the salt of the arylaminoquinazoline-containing compound represented by formula 2, a solvate or hydrate thereof, or the above-mentioned pharmaceutical composition in the preparation of a medicinal product as a receptor tyrosine kinase inhibitor.

The present invention also provides the use of the above-mentioned salt of the arylaminoquinazoline-containing compound represented by formula 2, its solvate or hydrate, or a crystalline form of the salt of the arylaminoquinazoline-containing compound represented by formula 2, its solvate or hydrate, or the above-mentioned pharmaceutical composition in the preparation of an antitumor drug.

In another aspect of the present invention, there is also provided the use of the above-mentioned salt of the arylaminoquinazoline-containing compound represented by formula 2, a solvate or hydrate thereof, or a crystalline form of the salt of the arylaminoquinazoline-containing compound represented by formula 2, a solvate or hydrate thereof, or the above-mentioned pharmaceutical composition for the treatment of a disease associated with receptor tyrosine kinase.

The present invention also provides the use of the above-mentioned salt of the arylaminoquinazoline-containing compound represented by formula 2, its solvate or hydrate, or a crystalline form of the salt of the arylaminoquinazoline-containing compound represented by formula 2, its solvate or hydrate, or the above-mentioned pharmaceutical composition for treating a tumor.

In another aspect of the present invention, there is also provided a method of treating a disease associated with a receptor tyrosine kinase in a patient, comprising administering to the patient a therapeutically effective amount of the above-mentioned salt of an arylaminoquinazoline-containing compound represented by formula 2, a solvate or hydrate thereof, or a crystalline form of a salt of an arylaminoquinazoline-containing compound represented by formula 2, a solvate or hydrate thereof, or the above-mentioned pharmaceutical composition.

The present invention also provides a method for treating a tumor in a patient, comprising administering to the patient a therapeutically effective amount of the above-mentioned salt of an arylaminoquinazoline-containing compound represented by formula 2, a solvate or hydrate thereof, or a crystalline form of a salt of an arylaminoquinazoline-containing compound represented by formula 2, a solvate or hydrate thereof, or the above-mentioned pharmaceutical composition.

In another aspect of the present invention, there is also provided the above-mentioned salt of the arylaminoquinazoline-containing compound represented by formula 2, a solvate or hydrate thereof, or a crystalline form of the salt of the arylaminoquinazoline-containing compound represented by formula 2, a solvate or hydrate thereof, or the above-mentioned pharmaceutical composition, for use in treating a disease associated with receptor tyrosine kinase.

In another aspect of the present invention, there is also provided the above-mentioned salt of the arylaminoquinazoline-containing compound represented by formula 2, a solvate or hydrate thereof, or a crystalline form of a salt of the arylaminoquinazoline-containing compound represented by formula 2, a solvate or hydrate thereof, or the above-mentioned pharmaceutical composition, for use in treating a tumor.

In another aspect of the present invention, there is provided a method for producing a salt of an arylaminoquinazoline-containing compound represented by formula 2, a solvate thereof, or a hydrate thereof, comprising reacting an arylaminoquinazoline-containing compound represented by formula 1 with an acid (HA) in a suitable solvent and then isolating to obtain a salt of an arylaminoquinazoline-containing compound represented by formula 2, a solvate thereof, or a hydrate thereof:

Where

HA is hydrochloric acid, sulfuric acid, oxalic acid or maleic acid;

n is an integer or half-integer in the range 1/2 to 2; and when HA is hydrochloric acid, n is 0.5, 1.5, or 2.

Brief description of the drawings

Fig. 1 shows an X-ray diffraction pattern of crystalline form I of the dihydrochloride salt of Compound 1, its solvate or hydrate, obtained in Example 1.

Fig. 2 shows an X-ray diffraction pattern of crystalline form II of the dihydrochloride salt of Compound 1, its solvate or hydrate, obtained in Example 2.

Fig. 3 shows the X-ray diffraction pattern of the sulfate salt of Compound 1 obtained in Example 3.

Fig. 4 shows the X-ray diffraction pattern of the maleate salt of Compound 1 obtained in Example 4.

Fig. 5 shows the X-ray diffraction pattern of the monohydrochloride salt of Compound 1 obtained in Comparative Example 1.

Fig. 6 shows the X-ray diffraction pattern of the malate salt of Compound 1 obtained in Comparative Example 2.

Fig. 7 shows the X-ray diffraction pattern of the oxalate salt of Compound 1 obtained in Example 9.

Fig. 8 shows the DSC-TGA thermogram of crystalline form I of the dihydrochloride salt of Compound 1, its solvate or hydrate, obtained in Example 1.

Fig. 9 shows the thermogravimetric analysis (TGA) of the crystalline form II of the dihydrochloride salt of Compound 1, its solvate or hydrate, obtained in Example 2.

Fig. 10 shows an X-ray diffraction pattern of crystalline form I of the dihydrochloride salt, its solvate or hydrate, obtained in Example 1, after long-term stability testing.

Fig. 11 shows an X-ray diffraction pattern of crystalline form III of the dihydrochloride salt of Compound 1, its solvate or hydrate, obtained in Example 5.

Fig. 12 shows the DSC-TGA thermogram of crystalline form III of the dihydrochloride salt of Compound 1, its solvate or hydrate, obtained in Example 5.

Fig. 13 shows an X-ray diffraction pattern of crystalline form IV of the dihydrochloride salt of Compound 1, its solvate or hydrate, obtained in Example 6.

Fig. 14 shows the DSC-TGA thermogram of crystalline form IV of the dihydrochloride salt of Compound 1, its solvate or hydrate, obtained in Example 6.

Fig. 15 shows an X-ray diffraction pattern of crystalline form V of the dihydrochloride salt of Compound 1, its solvate or hydrate, obtained in Example 7.

Fig. 16 shows the DSC-TGA thermogram of crystalline form V of the dihydrochloride salt of Compound 1, its solvate or hydrate, obtained in Example 7.

Fig. 17 shows an X-ray diffraction pattern of crystalline form VII of the dihydrochloride salt of Compound 1, its solvate or hydrate, obtained in Example 8.

Fig. 18 shows the DSC-TGA thermogram of the crystalline form VII of the dihydrochloride salt of Compound 1, its solvate or hydrate, obtained in Example 8.

Fig. 19 shows an X-ray diffraction pattern of crystalline form II of the dihydrochloride salt of Compound 1, its solvate or hydrate, obtained in Example 10.

Detailed description of the invention

In a first aspect of the present invention, there is provided a salt of an arylaminoquinazoline-containing compound represented by formula 2, a solvate or a hydrate thereof:

where HA is an acid;

n is an integer or half-integer between 1/2 and 2 (that is, n is 0.5, 1, 1.5, or 2).

In some embodiments of the present invention, HA is hydrochloric acid, sulfuric acid, oxalic acid, maleic acid, or malic acid. In some embodiments of the present invention, HA is hydrochloric acid, sulfuric acid, or maleic acid. In some embodiments of the present invention, HA is hydrochloric acid.

In some embodiments of the present invention, HA is hydrochloric acid, sulfuric acid, oxalic acid or maleic acid, and n is an integer or half-integer in the range from 1/2 to 2 (i.e., 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 invention, n is 1 or 2.

In some embodiments of the present invention, the salt of the arylaminoquinazoline-containing compound, a solvate thereof, or a hydrate thereof is a hydrochloride salt of the arylaminoquinazoline-containing compound represented by formula 3, a solvate thereof, or a hydrate thereof:

where n is 0.5, 1.5 or 2.

In some embodiments of the present invention, the solvate is selected from the group consisting of an acetonitrile/water solvate and an ethanol solvate.

In some embodiments of the present invention, the hydrate is selected from the group consisting of a hemihydrate, a monohydrate, and a tetrahydrate.

In some embodiments of the present invention, the salt of the arylaminoquinazoline-containing compound, its solvate, or hydrate thereof is a hydrochloride salt represented by formula 3', or a hydrate thereof:

where n is an integer from 1 to 2; m is an integer or half-integer in the range from 0 to 4 (that is, m is 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, or 4); and, when n is 1, m is an integer or half-integer in the range from 1 to 4 (that is, m is 0.5, 1, 1.5, 2, 2.5, 3, 3.5, or 4). In some embodiments of the present invention, n is 2 and m is 0, 0.5, 1, or 4. In some embodiments of the present invention, n is 2 and m is 0 or 4.

In some embodiments of the present invention, the salt of the arylaminoquinazoline-containing compound, its solvate, or hydrate thereof is a dihydrochloride salt represented by formula 3'', or a hydrate thereof:

where m is an integer or half-integer in the range 0 to 4 (that is, m is 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, or 4).

In some embodiments of the present invention, the salt of the arylaminoquinazoline-containing compound, its solvate or hydrate is a dihydrochloride salt represented by formula 3-1:

In some embodiments of the present invention, the salt of the arylaminoquinazoline-containing compound, its solvate or hydrate is a dihydrochloride salt tetrahydrate represented by formula 3-2:

In another aspect of the present invention, there is provided a crystalline form of a salt of an arylaminoquinazoline-containing compound represented by formula 2, a solvate or a hydrate thereof:

where HA is an acid;

n is an integer or half-integer between 1/2 and 2 (that is, n is 0.5, 1, 1.5, or 2).

In some embodiments of the present invention, HA is hydrochloric acid, sulfuric acid, oxalic acid, maleic acid, or malic acid. In some embodiments of the present invention, HA is hydrochloric acid, sulfuric acid, or maleic acid. In some embodiments of the present invention, HA is hydrochloric acid.

In some embodiments of the present invention, HA is hydrochloric acid, sulfuric acid, oxalic acid or maleic acid and n is an integer or half-integer in the range from 1/2 to 2 (i.e., 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 invention, n is 1 or 2.

In some embodiments of the present invention, the crystalline form of the salt of the arylaminoquinazoline-containing compound, a solvate or a hydrate thereof is a crystalline form of the hydrochloride salt of the arylaminoquinazoline-containing compound represented by formula 3, a solvate or a hydrate thereof:

where n is 0.5, 1.5 or 2.

In some embodiments of the present invention, the crystalline form of the salt of the arylaminoquinazoline-containing compound, its solvate, or hydrate is a crystalline form of the dihydrochloride salt represented by formula 3-1, its solvate, or hydrate:

In some embodiments of the present invention, the crystalline form of the dihydrochloride salt represented by formula 3-1, a solvate or a hydrate thereof is selected from one or more of crystalline form I, crystalline form II, crystalline form III, crystalline form IV, crystalline form V and crystalline form VII.

In some embodiments of the present invention, crystalline form I is a crystalline form of the dihydrochloride salt represented by formula 3-1:

In some embodiments of the present invention, crystalline form II is a crystalline form of the dihydrochloride salt tetrahydrate represented by formula 3-2:

In some embodiments of the present invention, the crystalline form of the dihydrochloride salt represented by formula 3-1, its solvate or hydrate (crystalline form I) has characteristic diffraction peaks at the following 2θ angles (°): 12.4±0.2°, 18.8±0.2°, 20.3±0.2° and 24.6±0.2° in an X-ray powder diffraction pattern with Cu-Kα radiation;

or has characteristic diffraction peaks at the following 2θ angles (°): 9.8±0.2°, 12.4±0.2°, 18.8±0.2°, 20.3±0.2° and 24.6±0.2° in the X-ray powder diffraction pattern with Cu-Kα radiation;

or has characteristic diffraction peaks at the following 2θ angles (°): 8.1±0.2°, 9.8±0.2°, 12.4±0.2°, 18.8±0.2°, 20.3±0.2°, 24.6±0.2° and 29.9±0.2° in the X-ray powder diffraction pattern with Cu-Kα radiation;

or has characteristic diffraction peaks at the following 2θ angles (°): 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° and 29.9±0.2° in the X-ray diffraction pattern of the powder with Cu-Kα radiation;

or has characteristic diffraction peaks at the following 2θ angles (°): 8.1±6.2°, 9.8±6.2°, 12.4±0.2°, 16.1±6.2°, 18.8±6.2°, 19.3±0.2°, 26.3±6.2°, 24.6±6.2°, 28.6±0.2°, 29.9±0.2° and 30.9±0.2° in an X-ray powder diffraction pattern with Cu-Kα radiation; and preferably, the relative intensities of the above characteristic peaks are as follows:

preferably the relative intensities of the above characteristic peaks are as follows:

or the X-ray diffraction pattern of the powder with Cu-Kα radiation has diffraction peaks at the following angles 2θ (°):

preferably the relative intensities of the above diffraction peaks are as follows:

or the X-ray diffraction pattern of the powder with Cu-Kα radiation is essentially the same as shown in Fig. 1.

In some embodiments of the present invention, the crystalline form of the dihydrochloride salt represented by formula 3-1, a solvate or a hydrate thereof (crystalline form I) has two distinctive endothermic peaks in the range of 200-320°C in a DSC thermogram, the onset temperatures of which are 219.1±3°C and 235.1±3°C, respectively, and the peak values are at 231.0±3°C and 284.2±3°C, respectively, as measured by DSC-TGA. The TGA thermogram of the hydrochloride salt shows that decomposition occurs at 205.6±3°C. Alternatively, crystalline Form I of the dihydrochloride salt represented by formula 3-1 has a DSC-TGA thermogram substantially as shown in Fig. 8.

In some embodiments of the present invention, the crystalline form of the dihydrochloride salt represented by formula 3-1, its solvate or hydrate (crystalline form I) has a DSC thermogram having endothermic peaks at 231.0±5°C and 284.2±5°C, respectively.

In some embodiments of the present invention, the crystalline form of the dihydrochloride salt represented by formula 3-1, its solvate or hydrate (crystalline form I) has a TGA thermogram in which decomposition occurs at 205.6±5°C.

In some embodiments of the present invention, the crystalline form of the dihydrochloride salt represented by formula 3-1, a solvate or a hydrate thereof (crystalline form I) has a DSC thermogram substantially as shown in Fig. 8.

In some embodiments of the present invention, the crystalline form of the dihydrochloride salt represented by formula 3-1, a solvate or a hydrate thereof (crystalline form I) has a TGA thermogram substantially as shown in Fig. 8.

In some embodiments of the present invention, the crystalline form of the dihydrochloride salt represented by formula 3-1, its solvate or hydrate (crystalline form II) has characteristic diffraction peaks at the following 2θ angles (°): 6.0±9.2°, 6.8±0.2°, 12.4±0.2° and 26.9±0.2° in an X-ray powder diffraction pattern with Cu-Kα radiation;

or has characteristic diffraction peaks at the following 2θ angles (°): 6.0±6.2°, 6.8±6.2°, 12.4±6.2°, 15.5±0.2° and 26.6±0.2° in the X-ray powder diffraction pattern with Cu-Kα radiation;

or has characteristic diffraction peaks at the following 2θ angles (°): 6.0±9.2°, 6.8±0.2°, 12.4±0.2°, 15.5±0.2°, 25.4±9.2° and 26.0±0.2° in the X-ray powder diffraction pattern with Cu-Kα radiation;

or has characteristic diffraction peaks at the following 2θ angles (°): 6.0±6.2°, 6.8±0.2°, 12.4±0.2°, 15.5±0.2°, 18.0±6.2°, 24.4±6.2°, 25.4±0.2° and 26.0±6.2° in the X-ray diffraction pattern of the powder with Cu-Kα radiation;

or has characteristic diffraction peaks at the following 2θ angles (°): 6.0±6.2°, 6.8±0.2°, 12.4±0.2°, 15.5±6.2°, 18.0±0.2°, 22.7±0.2°, 24.4±0.2°, 25.4±0.2° and 26.6±0.2° in the X-ray powder diffraction pattern with Cu-Kα radiation; and

preferably the relative intensities of the above characteristic peaks are as follows:

preferably the relative intensities of the above characteristic peaks are as follows:

preferably the relative intensities of the above characteristic peaks are as follows:

preferably the relative intensities of the above characteristic peaks are as follows:

or the crystalline form of the dihydrochloride salt represented by formula 3-1, its solvate or hydrate (crystalline form II) has characteristic diffraction peaks at the following 2θ angles (°): 6.6±0.2°, 6.8±0.2°, 12.4±0.2°, 15.5±0.2°, 18.6±0.2°, 26.5±6.2°, 22.7±6.2°, 24.4±6.2°, 25.4±6.2°, 26.0±6.2° and 27.5±6.2° in the X-ray powder diffraction pattern with Cu-Kα radiation;

or the crystalline form of the dihydrochloride salt represented by formula 3-1, its solvate or hydrate (crystalline form II) has characteristic diffraction peaks at the following 2θ angles (°) in the X-ray powder diffraction pattern with Cu-Kα radiation:

preferably the relative intensities of the above diffraction peaks are as follows:

preferably the relative intensities of the above diffraction peaks are as follows:

or the crystalline form of the dihydrochloride salt represented by formula 3-1, its solvate or hydrate (crystalline form II) has an X-ray powder diffraction pattern with Cu-Kα radiation substantially as shown in Fig. 2 or Fig. 19.

In some embodiments of the present invention, the crystalline form of the dihydrochloride salt represented by formula 3-1, its solvate or hydrate (crystalline form II) has a TGA thermogram with a mass loss of 12.24±0.20% in the range of 50-140°C, as measured by TGA.

Alternatively, the crystalline form of the dihydrochloride salt represented by formula 3-1, its solvate or hydrate (crystalline form II) has a TGA thermogram substantially as shown in Fig. 9.

In some embodiments of the present invention, the crystalline form of the dihydrochloride salt represented by formula 3-1, its solvate or hydrate (crystalline form III) has characteristic diffraction peaks at the following 2θ angles (°): 12.7±9.2°, 13.3±9.2°, 23.3±0.2° and 29.3±0.2° in an X-ray powder diffraction pattern with Cu-Kα radiation;

or has characteristic diffraction peaks at the following 2θ angles (°): 12.7±0.2°, 13.3±9.2°, 17.2±9.2°, 23.3±0.2° and 29.3±0.2° in the X-ray diffraction pattern of the powder with Cu-Kα radiation;

or has characteristic diffraction peaks at the following 2θ angles (°): 11.5±0.2°, 11.9±0.2°, 12.7±0.2°, 13.3±0.2°, 17.2±0.2°, 23.3±0.2° and 29.3±0.2° in the X-ray diffraction pattern of the powder with Cu-Kα radiation;

or has characteristic diffraction peaks at the following 2θ angles (°): 11.5±0.2°, 11.9±9.2°, 12.2±0.2°, 12.7±0.2°, 13.3±0.2°, 17.2±0.2°, 23.3±9.2° and 29.3±0.2° in the X-ray diffraction pattern of the powder with Cu-Kα radiation;

or has characteristic diffraction peaks at the following 2θ angles (°): 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° and 29.3±0.2° in the X-ray powder diffraction pattern with Cu-Kα radiation;

or has characteristic diffraction peaks at the following 2θ angles (°): 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° and 29.3±0.2° in the X-ray diffraction pattern of powder with Cu-Kα radiation;

or has characteristic diffraction peaks at the following 2θ angles (°): 8.4±9.2°, 11.5±9.2°, 11.9±9.2°, 12.2±9.2°, 12.7±9.2°, 13.3±0.2°, 17.2±0.2°, 17.6±9.2°, 23.6±0.2°, 23.3±0.2°, 24.6±0.2°, 28.8±0.2° and 29.3±0.2° in the X-ray diffraction pattern of the powder with Cu-Kα radiation;

or has characteristic diffraction peaks at the following 2θ angles (°) in the X-ray powder diffraction pattern with Cu-Kα radiation:

or the X-ray diffraction pattern of the powder with Cu-Kα radiation is essentially as shown in Fig. 11.

In some embodiments of the present invention, a crystalline form of the dihydrochloride salt represented by formula 3-1, a solvate or a hydrate thereof (crystalline form III) has a DSC thermogram having endothermic peaks at 101.52±5°C and 183.70±5°C, respectively, as measured by DSC.

In some embodiments of the present invention, the crystalline form of the dihydrochloride salt represented by formula 3-1, a solvate or a hydrate thereof (crystalline form III) has a TGA thermogram with a mass loss of 6.3±0.20% over the range from room temperature to 120°C, as measured by TGA.

Alternatively, the crystalline form of the dihydrochloride salt represented by formula 3-1, its solvate or hydrate (crystalline form III) has a DSC-TGA thermogram substantially as shown in Fig. 12.

In some embodiments of the present invention, the crystalline form of the dihydrochloride salt represented by formula 3-1, its solvate or hydrate (crystalline form IV) has characteristic diffraction peaks at the following 2θ angles (°): 5.4±6.2°, 8.2±0.2°, 13.6±0.2° and 16.5±0.2° in an X-ray powder diffraction pattern with Cu-Kα radiation;

or has characteristic diffraction peaks at the following 2θ angles (°): 5.4±0.2°, 8.2±0.2°, 12.0±0.2°, 13.0±0.2°, 16.5±0.2° and 22.8±0.2° in the X-ray diffraction pattern of the powder with Cu-Kα radiation;

or has characteristic diffraction peaks at the following 2θ angles (°): 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° and 29.0±0.2° in the X-ray diffraction pattern of powder with Cu-Kα radiation;

or has characteristic diffraction peaks at the following 2θ angles (°): 5.4±6.2°, 8.2±6.2°, 11.3±0.2°, 12.6±0.2°, 13.6±6.2°, 16.5±0.2°, 17.8±0.2°, 19.4±0.2°, 22.8±6.2° and 29.6±0.2° in the X-ray diffraction pattern of the powder with Cu-Kα radiation;

or has characteristic diffraction peaks at the following 2θ angles (°): 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° and 29.0±0.2° in the X-ray diffraction pattern of the powder with Cu-Kα radiation;

or has characteristic diffraction peaks at the following 2θ angles (°): 5.4±6.2°, 6.4±0.2°, 7.4±0.2°, 8.2±6.2°, 10.8±0.2°, 11.3±6.2°, 12.0±6.2°, 13.6±0.2°, 14.6±0.2°, 16.5±0.2°, 17.8±6.2°, 19.4±6.2°, 22.8±0.2° and 29.0±0.2° in the X-ray diffraction pattern of the powder with Cu-Kα radiation;

or has characteristic diffraction peaks at the following 2θ angles (°): 5.4±6.2°, 6.4±0.2°, 7.4±0.2°, 8.2±6.2°, 10.8±0.2°, 11.3±6.2°, 12.0±6.2°, 13.6±0.2°, 14.2±0.2°, 14.6±0.2°, 16.5±6.2°, 16.9±6.2°, 17.8±6.2°, 19.4±6.2°, 22.8±6.2° and 29.0±6.2° in the X-ray diffraction pattern of powder with Cu-Kα radiation;

or has diffraction peaks at the following 2θ angles (°) in the X-ray powder diffraction pattern with Cu-Kα radiation:

or the X-ray diffraction pattern of the powder with Cu-Kα radiation is essentially the same as shown in Fig. 13.

In some embodiments of the present invention, the crystalline form of the dihydrochloride salt represented by formula 3-1, a solvate or a hydrate thereof (crystalline form IV) has a DSC thermogram having endothermic peaks at 68.81±5°C and 177.55±5°C, respectively, as measured by DSC.

In some embodiments of the present invention, the crystalline form of the dihydrochloride salt represented by formula 3-1, a solvate or a hydrate thereof (crystalline form IV) has a TGA thermogram having a mass loss of 3.9±0.20% over the range from room temperature to 150°C, as measured by TGA.

Alternatively, the crystalline form of the dihydrochloride salt represented by formula 3-1, its solvate or hydrate (crystalline form IV) has a DSC-TGA thermogram substantially as shown in Fig. 14.

In some embodiments of the present invention, the crystalline form of the dihydrochloride salt represented by formula 3-1, its solvate or hydrate (crystalline form V) has characteristic diffraction peaks at the following 2θ angles (°): 8.4±6.2°, 9.6±0.2°, 19.8±0.2° and 29.2±0.2° in an X-ray powder diffraction pattern with Cu-Kα radiation;

or has characteristic diffraction peaks at the following 2θ angles (°): 8.4±0.2°, 9.6±0.2°, 10.5±0.2°, 19.3±0.2°, 19.8±0.2° and 29.2±0.2° in the X-ray diffraction pattern of the powder with Cu-Kα radiation;

or has characteristic diffraction peaks at the following 2θ angles (°): 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° and 29.2±0.2° in the X-ray diffraction pattern of the powder with Cu-Kα radiation;

or has characteristic diffraction peaks at the following 2θ angles (°): 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° and 29.2±0.2° in the X-ray diffraction pattern of the powder with Cu-Kα radiation;

or has characteristic diffraction peaks at the following 2θ angles (°): 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° and 29.2±0.2° in the X-ray diffraction pattern of the powder with Cu-Kα radiation;

or has characteristic diffraction peaks at the following 2θ angles (°): 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° and 29.5±0.2° in the X-ray diffraction pattern of the powder with Cu-Kα radiation;

or has diffraction peaks at the following 2θ angles (°) in the X-ray powder diffraction pattern with Cu-Kα radiation:

or the X-ray diffraction pattern of the powder with Cu-Kα radiation is essentially as shown in Fig. 15.

In some embodiments of the present invention, a crystalline form of the dihydrochloride salt represented by formula 3-1, a solvate or a hydrate thereof (crystalline form V) has a DSC thermogram having endothermic peaks at 48.29±5°C, 153.99±5°C and 190.59±5°C, respectively, as measured by DSC.

In some embodiments of the present invention, the crystalline form of the dihydrochloride salt represented by formula 3-1, a solvate or a hydrate thereof (crystalline form V) has a TGA thermogram having a mass loss of 7.3±0.20% over the range from room temperature to 200°C, as measured by TGA.

Alternatively, the crystalline form of the dihydrochloride salt represented by formula 3-1, its solvate or hydrate (crystalline form V) has a DSC-TGA thermogram substantially as shown in Fig. 16.

In some embodiments of the present invention, the crystalline form of the dihydrochloride salt represented by formula 3-1, its solvate or hydrate (crystalline form VII) has characteristic diffraction peaks at the following 2θ angles (°): 8.3±0.2°, 11.9±0.2°, 12.9±0.2° and 14.6±0.2° in an X-ray powder diffraction pattern with Cu-Kα radiation;

or has characteristic diffraction peaks at the following 2θ angles (°): 6.5±0.2°, 8.3±0.2°, 11.9±0.2°, 12.9±0.2°, 14.6±0.2° and 16.5±0.2° in the X-ray powder diffraction pattern with Cu-Kα radiation;

or has characteristic diffraction peaks at the following 2θ angles (°): 6.5±6.2°, 8.3±0.2°, 11.9±6.2°, 12.9±6.2°, 14.6±0.2°, 16.5±0.2°, 17.6±0.2° and 24.4±0.2° in the X-ray diffraction pattern of powder with Cu-Kα radiation;

or has characteristic diffraction peaks at the following 2θ angles (°): 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° and 29.6±0.2° in the X-ray diffraction pattern of the powder with Cu-Kα radiation;

or has characteristic diffraction peaks at the following 2θ angles (°): 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° and 29.6±0.2° in the X-ray diffraction pattern of powder with Cu-Kα radiation;

or has characteristic diffraction peaks at the following 2θ angles (°): 6.5±6.2°, 8.3±0.2°, 11.9±0.2°, 12.9±6.2°, 14.6±6.2°, 16.5±0.2°, 17.6±0.2°, 18.8±6.2°, 20.4±0.2°, 22.2±0.2°, 23.6±0.2°, 24.4±0.2°, 24.8±0.2° and 29.6±0.2° in the X-ray diffraction pattern of powder with Cu-Kα radiation;

or has diffraction peaks at the following 2θ angles (°) in the X-ray powder diffraction pattern with Cu-Kα radiation:

or the X-ray diffraction pattern of the powder with Cu-Kα radiation is essentially as shown in Fig. 17.

In some embodiments of the present invention, the crystalline form of the dihydrochloride salt represented by formula 3-1, its solvate or hydrate (crystalline form VII) has a DSC thermogram with endothermic peaks at 87.64±5°C and 182.15±5°C, respectively, as measured by DSC.

In some embodiments of the present invention, the crystalline form of the dihydrochloride salt represented by formula 3-1, a solvate or a hydrate thereof (crystalline form VII) has a TGA thermogram with a mass loss of 1.4±0.20% over the range from room temperature to 120°C, as measured by TGA.

Alternatively, the crystalline form of the dihydrochloride salt represented by formula 3-1, its solvate or hydrate (crystalline form VII) has a DSC-TGA thermogram substantially as shown in Fig. 18.

In some embodiments of the present invention, the salt of the arylaminoquinazoline-containing compound, solvate or hydrate thereof is a sulfate salt represented by formula 4:

n is an integer or half-integer between 1 and 2 (that is, n is 1, 1.5, or 2).

In some embodiments of the present invention, the salt of the arylaminoquinazoline-containing compound is a sulfate salt represented by formula 4-1:

In some embodiments of the present invention, the crystalline form of the salt of the arylaminoquinazoline-containing compound, its solvate, or hydrate is a crystalline form of the sulfate salt represented by formula 4, its solvate, or hydrate:

n is an integer or half-integer in the range 1 to 2 (that is, n is 1, 1.5, or 2).

In some embodiments of the present invention, the crystalline form of the salt of the arylaminoquinazoline-containing compound, its solvate, or hydrate is a crystalline form of a sulfate salt represented by formula 4-1, its solvate, or hydrate:

In some embodiments of the present invention, the crystalline form of the sulfate salt represented by formula 4-1, a solvate or a hydrate thereof is crystalline form I.

In some embodiments of the present invention, the crystalline form of the sulfate salt represented by formula 4-1, its solvate or hydrate (crystalline form I) has characteristic peaks at the following 2θ angles: 12.4±9.2°, 15.5±0.2°, 24.8±0.2° and 25.9±0.2° in an X-ray powder diffraction pattern with Cu-Kα radiation;

or has characteristic diffraction peaks at the following 2θ angles (°): 6.8±9.2°, 8.5±0.2°, 12.4±0.2°, 15.5±0.2°, 24.8±9.2° and 25.9±0.2° in the X-ray diffraction pattern of powder with Cu-Kα radiation;

or has characteristic diffraction peaks at the following 2θ angles (°): 6.8±9.2°, 8.5±0.2°, 12.4±0.2°, 13.6±0.2°, 15.5±9.2°, 24.8±9.2° and 25.9±9.2° in the X-ray diffraction pattern of the powder with Cu-Kα radiation;

or has characteristic diffraction peaks at the following 2θ angles (°): 6.8±9.2°, 8.5±0.2°, 12.4±9.2°, 13.6±9.2°, 15.5±0.2°, 17.9±0.2°, 19.6±0.2°, 24.8±0.2°, 25.9±0.2° in the X-ray powder diffraction pattern with Cu-Kα radiation; and

preferably the relative intensities of the above characteristic peaks are as follows:

or the X-ray powder diffraction pattern expressed in 29° angle values using Cu-Kα radiation has diffraction peaks at the following positions:

preferably, the relative peak intensities for the above diffraction peaks are as follows:

or the X-ray diffraction pattern of the powder with Cu-Kα radiation is essentially the same as shown in Fig. 3.

In some embodiments of the present invention, the salt of the arylaminoquinazoline-containing compound, solvate or hydrate thereof is a maleate salt represented by formula 5:

n is an integer or half-integer between 1 and 2 (that is, n is 1, 1.5, or 2).

In some embodiments of the present invention, the salt of the arylaminoquinazoline-containing compound is a maleate salt represented by formula 5-1:

In some embodiments of the present invention, the crystalline form of the salt of the arylaminoquinazoline-containing compound, its solvate, or hydrate is a crystalline form of the maleate salt represented by formula 5, its solvate, or hydrate:

n is an integer or half-integer between 1 and 2 (that is, n is 1, 1.5, or 2).

In some embodiments of the present invention, the crystalline form of the salt of the arylaminoquinazoline-containing compound, its solvate, or hydrate is a crystalline form of the maleate salt represented by formula 5-1, its solvate, or hydrate:

In some embodiments of the present invention, the crystalline form of the maleate salt represented by formula 5-1, its solvate or hydrate is its crystalline form I.

In some embodiments of the present invention, the crystalline form of the maleate salt represented by formula 5-1, its solvate or hydrate (crystalline form I) has characteristic peaks at the following 2θ angles (°): 4.9±9.2°, 7.6±0.2°, 16.7±0.2° and 24.9±0.2° in an X-ray powder diffraction pattern with Cu-Kα radiation;

or has characteristic peaks at the following 2θ angles (°): 4.4±0.2°, 4.9±0.2°, 7.6±9.2°, 16.7±9.2°, 29.6±9.2° and 24.9±9.2° in the X-ray powder diffraction pattern with Cu-Kα radiation;

or has characteristic diffraction peaks at the following angles 2θ (°): 4.4±9.2°, 4.9±0.2°, 7.6±9.2°, 13.3±9.2°, 16.7±9.2°, 19.6±9.2°, 29.6±9.2°, 24.9±0.2° in the X-ray diffraction pattern of powder with Cu-Kα radiation;

or has characteristic diffraction peaks at the following angles 2θ (°): 4.4±9.2°, 4.9±0.2°, 7.6±0.2°, 13.3±9.2°, 16.7±0.2°, 18.9±9.2°, 19.6±0.2°, 29.6±9.2°, 24.9±0.2°, 26.3±0.2° in the X-ray diffraction pattern of powder with Cu-Kα radiation;

or has characteristic diffraction peaks at the following angles 2θ (°): 4.4±9.2°, 4.9±0.2°, 7.6±0.2°, 11.4±0.2°, 13.3±9.2°, 14.2±0.2°, 16.7±9.2°, 18.9±9.2°, 19.6±0.2°, 20.6±0.2°, 24.9±0.2°, 26.3±0.2° in the X-ray diffraction pattern of powder with Cu-Kα radiation;

and preferably the relative intensities of the above characteristic peaks are as follows:

or the powder X-ray diffraction pattern expressed in 2θ angle (°) values using Cu-Kα radiation has the following diffraction peaks:

preferably the relative intensities of the above diffraction peaks are as follows:

or the X-ray powder diffraction pattern with Cu-Kα radiation is essentially as shown in Fig. 4.

In some embodiments of the present invention, the salt of the arylaminoquinazoline-containing compound, solvate or hydrate thereof is an oxalate salt represented by formula 6:

n is an integer or half-integer between 0.5 and 2 (that is, n is 0.5, 1, 1.5, or 2).

In some embodiments of the present invention, the salt of the arylaminoquinazoline-containing compound is an oxalate salt represented by the formula

In some embodiments of the present invention, the crystalline form of the salt of the arylaminoquinazoline-containing compound, its solvate, or hydrate is a crystalline form of the oxalate salt represented by formula 6, its solvate, or hydrate:

n is an integer or half-integer between 0.5 and 2 (that is, n is 0.5, 1, 1.5, or 2).

In some embodiments of the present invention, the crystalline form of the salt of the arylaminoquinazoline-containing compound, its solvate, or hydrate is a crystalline form of the oxalate salt represented by formula 6-1, its solvate, or hydrate:

In some embodiments of the present invention, the crystalline form of the oxalate salt represented by formula 6-1, its solvate or hydrate is its crystalline form I.

In some embodiments of the present invention, the crystalline form of the oxalate salt represented by formula 6-1, its solvate or hydrate (crystalline form I) has characteristic peaks at the following 2θ angles (°): 5.9±0.2°, 9.9±0.2°, 17.5±0.2°, 21.5±0.2° and 19.8±0.2° in an X-ray powder diffraction pattern with Cu-Kα radiation;

or has characteristic peaks at the following 2θ angles (°): 5.9±0.2°, 9.9±0.2°, 17.5±0.2°, 21.5±9.2°, 19.8±9.2°, 23.9±0.2° and 25.5±0.2° in the X-ray powder diffraction pattern with Cu-Kα radiation;

or has characteristic peaks at the following 2θ angles (°): 5.9±0.2°, 9.9±0.2°, 17.5±0.2°, 18.4±9.2°, 21.5±9.2°, 19.8±9.2°, 23.0±9.2°, 24.4±9.2° and 25.5±9.2° in the X-ray powder diffraction pattern with Cu-Kα radiation;

or has characteristic peaks at the following 2θ angles (°): 5.9±0.2°, 9.9±0.2°, 17.5±0.2°, 18.4±9.2°, 21.5±0.2°, 19.8±9.2°, 23.0±9.2°, 23.5±9.2°, 24.4±0.2°, 25.5±9.2° and 26.6±0.2° in the X-ray powder diffraction pattern with Cu-Kα radiation;

or has characteristic peaks at the following 2θ angles (°): 5.9±0.2°, 9.9±0.2°, 10.7±0.2°, 17.5±9.2°, 18.4±9.2°, 21.5±9.2°, 19.8±9.2°, 23.0±9.2°, 23.5±9.2°, 24.4±0.2°, 25.5±0.2°, 26.6±0.2° and 27.3±0.2° in the X-ray powder diffraction pattern with Cu-Kα radiation;

or has characteristic peaks at the following 2θ angles (°): 5.9±0.2°, 9.9±0.2°, 10.7±0.2°, 17.5±9.2°, 18.4±9.2°, 21.5±9.2°, 19.8±9.2°, 29.3±9.2°, 23.0±9.2°, 23.5±0.2°, 24.4±0.2°, 25.5±9.2°, 26.6±9.2°, 27.3±0.2° and 27.9±0.2° in the X-ray powder diffraction pattern with Cu-Kα radiation;

or has diffraction peaks at the following 2θ angles (°) in the X-ray powder diffraction pattern with Cu-Kα radiation:

or the X-ray powder diffraction pattern with Cu-Kα radiation is essentially as shown in Fig. 7.

In another aspect of the present invention, there is provided a pharmaceutical composition comprising the above-mentioned salt of an arylaminoquinazoline-containing compound represented by formula 2, a solvate or a hydrate thereof.

In some embodiments of the present invention, the pharmaceutical composition comprises the above-mentioned crystalline form of a salt of an arylaminoquinazoline-containing compound represented by formula 2, a solvate or a hydrate thereof.

In some embodiments of the present invention, the pharmaceutical composition comprises the above-mentioned crystalline form of the dihydrochloride salt of the arylaminoquinazoline-containing compound represented by formula 3-1, a solvate or hydrate thereof.

In some embodiments of the present invention, the pharmaceutical composition comprises one or more of the above crystalline form I, crystalline form II, crystalline form III, crystalline form IV, crystalline form.

V or crystalline form VII of the dihydrochloride salt of an arylaminoquinazoline-containing compound represented by formula 3-1, its solvate or hydrate.

In some embodiments of the present invention, the pharmaceutical composition comprises the above-mentioned salt of an arylaminoquinazoline-containing compound represented by formula 2, a solvate or hydrate thereof, and one or more pharmaceutically acceptable carriers.

In some embodiments of the present invention, the pharmaceutical composition comprises the above-mentioned crystalline form of a salt of an arylaminoquinazoline-containing compound represented by formula 2, a solvate or hydrate thereof, and one or more pharmaceutically acceptable carriers.

In some embodiments of the present invention, the pharmaceutical composition comprises the above-mentioned crystalline form of the dihydrochloride salt of the arylaminoquinazoline-containing compound represented by formula 3-1, a solvate or hydrate thereof, and one or more pharmaceutically acceptable carriers.

In some embodiments of the present invention, the pharmaceutical composition comprises one or more of the above crystalline form I, crystalline form II, crystalline form III, crystalline form IV, crystalline form.

V or crystalline form VII of the dihydrochloride salt of an arylaminoquinazoline-containing compound represented by formula 3-1, a solvate or hydrate thereof, and one or more pharmaceutically acceptable carriers.

In some embodiments of the present invention, the pharmaceutical composition comprises a therapeutically effective amount of the above-mentioned salt of an arylaminoquinazoline-containing compound represented by formula 2, a solvate or hydrate thereof, and one or more pharmaceutically acceptable carriers.

The pharmaceutical composition of the present invention can be prepared by conventional methods known in the art, for example, by mixing a salt of an arylaminoquinazoline-containing compound represented by formula 2, a solvate or a hydrate thereof with one or more pharmaceutically acceptable carriers.

In another aspect of the present invention, there is provided the use of the above-mentioned salt of the arylaminoquinazoline-containing compound represented by formula 2, a solvate or hydrate thereof, or the above-mentioned crystalline form of the salt of the arylaminoquinazoline-containing compound represented by formula 2, a solvate or hydrate thereof, or the above-mentioned pharmaceutical composition in the preparation of a medicament as a receptor tyrosine kinase inhibitor.

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

In another aspect of the present invention, there is also provided the use of the above-mentioned salt of the arylaminoquinazoline-containing compound represented by formula 2, a solvate or hydrate thereof, or the above-mentioned crystalline form of the salt of the arylaminoquinazoline-containing compound represented by formula 2, a solvate or hydrate thereof, or the above-mentioned pharmaceutical composition for the treatment of a disease associated with receptor tyrosine kinase.

In another aspect of the present invention, there is also provided a method of treating a disease associated with a receptor tyrosine kinase in a patient, comprising administering to the patient a therapeutically effective amount of the above-mentioned salt of an arylaminoquinazoline-containing compound represented by formula 2, a solvate or hydrate thereof, or the above-mentioned crystalline form of a salt of an arylaminoquinazoline-containing compound represented by formula 2, a solvate or hydrate thereof, or the above-mentioned pharmaceutical composition.

In another aspect of the present invention, there is also provided the above-mentioned salt of the arylaminoquinazoline-containing compound represented by formula 2, a solvate or hydrate thereof, or the above-mentioned crystalline form of the salt of the arylaminoquinazoline-containing compound represented by formula 2, a solvate or hydrate thereof, or the above-mentioned pharmaceutical composition for use in treating a disease associated with receptor tyrosine kinase.

In some embodiments of the present invention, the receptor tyrosine kinase-associated disease mentioned in the aspects of the invention above is a disease caused by one or more of VEGFR, FLT, FGFR, RET, EGFR and mutants thereof. In some embodiments of the present invention, the disease is a cell proliferative disease. In some embodiments of the present invention, the disease comprises a disorder of the expression, level or activity of one or more of the VEGFR, FLT, FGFR, RET and EGFR proteins. In some embodiments of the present invention, the cell proliferative disease is a tumor or cancer. In some embodiments of the present invention, the tumor comprises thyroid cancer, biliary tract cancer, epidermoid cancer, melanoma, colorectal cancer, gastric cancer, esophageal cancer, pancreatic cancer, kidney cancer, liver cancer, lung cancer or ovarian cancer. In some embodiments of the present invention, the thyroid cancer is medullary thyroid cancer and the lung cancer is non-small cell lung cancer. In some embodiments of the present invention, the non-small cell lung cancer is RET-fusion non-small cell lung cancer.

In another aspect of the present invention, there is also provided the use of the above-mentioned salt of the arylaminoquinazoline-containing compound represented by formula 2, a solvate or hydrate thereof, or the above-mentioned crystalline form of the salt of the arylaminoquinazoline-containing compound represented by formula 2, a solvate or hydrate thereof, or the above-mentioned pharmaceutical composition, in the manufacture of an antitumor drug.

In another aspect of the present invention, there is also provided the use of the above-mentioned salt of the arylaminoquinazoline-containing compound represented by formula 2, a solvate or hydrate thereof, or the above-mentioned crystalline form of the salt of the arylaminoquinazoline-containing compound represented by formula 2, a solvate or hydrate thereof, or the above-mentioned pharmaceutical composition, in the treatment of a tumor.

In another aspect of the present invention, there is also provided a method of treating a tumor in a patient, comprising administering to the patient a therapeutically effective amount of the above-mentioned salt of an arylaminoquinazoline-containing compound represented by formula 2, a solvate or hydrate thereof, or the above-mentioned crystalline form of a salt of an arylaminoquinazoline-containing compound represented by formula 2, a solvate or hydrate thereof, or the above-mentioned pharmaceutical composition.

In another aspect of the present invention, there is also provided the above-mentioned salt of the arylaminoquinazoline-containing compound represented by formula 2, a solvate or hydrate thereof, or the above-mentioned crystalline form of the salt of the arylaminoquinazoline-containing compound represented by formula 2, a solvate or hydrate thereof, or the above-mentioned pharmaceutical composition for use in treating a tumor.

In some embodiments of the present invention, the tumor or tumor disease mentioned in the aspects of the invention above includes thyroid cancer, biliary tract cancer, epidermoid cancer, melanoma, colorectal cancer, gastric cancer, esophageal cancer, pancreatic cancer, kidney cancer, liver cancer, lung cancer or ovarian cancer. In some embodiments of the present invention, the thyroid cancer is medullary thyroid cancer and the lung cancer is non-small cell lung cancer. In some embodiments of the present invention, the non-small cell lung cancer is RET-fusion non-small cell lung cancer. In some embodiments of the present invention, the tumor or tumor disease is a tumor or tumor disease caused by one or more of VEGFR, FLT, FGFR, RET, EGFR and mutants thereof. In some embodiments of the present invention, the tumor or tumor disease comprises a dysregulation of the expression, level, or activity of one or more proteins of VEGFR, FLT, FGFR, RET, and EGFR.

The above term "patient" includes all members of the animal kingdom, including, but not limited to, mammals (e.g. mice, rats, cats, monkeys, dogs, pigs, etc.) and humans.

In another aspect of the present invention, there is provided a method for producing a salt of an arylaminoquinazoline-containing compound represented by formula 2, a solvate thereof, or a hydrate thereof, comprising reacting an arylaminoquinazoline-containing compound represented by formula 1 with an acid (HA) in a suitable solvent, isolating the salt of the arylaminoquinazoline-containing compound represented by formula 2, a solvate thereof, or a hydrate thereof:

Where

HA is an acid; and

n is an integer or half-integer in the range 1/2 to 2.

In some embodiments of the present invention, HA is hydrochloric acid, sulfuric acid, oxalic acid, maleic acid, or malic acid.

In some embodiments of the present invention, the molar ratio of the arylaminoquinazoline-containing compound represented by formula 1 to the acid is 1:1-2.5, preferably 1:1-2.

In some embodiments of the present invention, the reaction temperature is 10-90°C, preferably 40-70°C.

In some embodiments of the present invention, the reaction solvent is selected from one or a combination of two of alcohols, ketones, nitriles, water or heterocycloalkanes; preferably one or a combination of two of ethyl acetate, methanol, ethanol, water, acetonitrile, acetone, tetrahydrofuran, DMF, NMP, isopropanol, n-propanol, DMA, dioxane; more preferably ethyl acetate, methanol or water.

In some embodiments of the present invention, the reaction solvent is a combination of methanol and ethyl acetate. In some embodiments of the present invention, the reaction solvent is water. In some embodiments of the present invention, the reaction solvent is a combination of methanol and acetonitrile. In some embodiments of the present invention, the reaction solvent is a combination of water and acetonitrile. In some embodiments of the present invention, the reaction solvent is ethanol.

In some embodiments of the present invention, when the above reaction solvent is a combination of two types of solvents, they can be added separately. That is, a good solvent is added before a poor solvent.

In some embodiments of the present invention, the isolation results in the production of a crystalline form of a salt of the arylaminoquinazoline-containing compound represented by formula 2, a solvate or a hydrate thereof.

In some embodiments of the present invention, after completion of the reaction, the cooling and crystallization temperatures are from -5 to 35°C, preferably from 0 to 25°C, stirring for crystallization is continued for from 0.5 to 24 hours, and the solid is isolated and dried to obtain a salt of an arylaminoquinazoline-containing compound represented by formula 2. Preferably, the salt collection temperature is 10°C and the crystallization time is from 0.5 to 12 hours.

In some embodiments of the present invention, the isolation step comprises isolating the resulting arylaminoquinazoline-containing compound salt represented by formula 2 from the crystallization solution using a suitable method such as filtration, centrifugation, etc.

In some embodiments of the present invention, the drying method may be any suitable known method, preferably calcination. Specific drying conditions are, for example, the use of a vacuum drying oven, preferably at a temperature of 30 to 65°C, more preferably at a temperature of 40 to 55°C; and the drying time is preferably from 1 to 50 hours, more preferably from 1 to 16 hours, and even more preferably from 3 to 6 hours. Regardless of which drying method is used, it is desirable that the residual amount of solvent in the resulting product meets the quality standard.

The arylaminoquinazoline-containing compound represented by formula 1 can be prepared by a method disclosed in the prior art, such as the method described in patent application WO 2016023330 A1, the contents of which are incorporated herein by reference in their entirety.

Definition and description

Unless otherwise specified, the following terms and expressions used in this application have the following meanings. A specific phrase or term without a specific definition is not to be considered vague or unclear, but is to be understood in its ordinary meaning. When a trade name appears in the text, it is understood to refer to the corresponding commercial product or its active ingredient.

The term "solvate" refers to an aggregate or complex that contains one or more molecules of a solvent and a compound represented by formula 2 of the present invention, including an aggregate containing both water molecules and one or more molecules of another solvent.

The term "hydrate" refers to an aggregate or complex that contains one or more molecules of water and a compound represented by formula 2 of the present invention. The hydrate of the present invention includes a tetrahydrate of the dihydrochloride salt of the compound represented by formula 3-2.

Unless otherwise specified, “2θ,” “2θ angle,” or “2θ angles” as used in the present invention refer to a diffraction angle whose unit is “°” or “degree” and the 2θ error range may be ±0.5, ±0.4, ±0.3, ±0.2, or ±0.1°.

Unless otherwise specified, the unit of measurement of the “heating temperature,” “cooling temperature,” or “crystallization temperature” described in the present invention is “°C” or “degree Celsius,” and the error range may be ±10, ±5, ±4, ±3, ±2, or ±1°C.

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 are shown in the drawings in the X-ray powder diffraction pattern or the DSC thermogram, or the TGA thermogram. In addition, when the content of a certain crystalline form in a product is gradually reduced, some of the diffraction peaks attributed to this crystalline form in its X-ray powder diffraction pattern may decrease due to the detection limit of the instrument.

The term "characteristic diffraction peak" refers to a diffraction peak that can be used to represent a crystalline form in an X-ray powder diffraction pattern, which refers to the position of the peak, the shape of the peak and the relative intensity of the diffraction peak, for example, low-angle peaks, a sharp peak shape and diffraction peaks whose relative peak intensity is at least 3% or more, or at least 5% or more, or at least 10% or more, or at least 20% or more, or at least 30% or more, or at least 40% or more, or at least 50% or more, or at least 60% or more, or at least 70% or more, or at least 75% or more.

The term "cell proliferative disorder" refers to a disorder in which the growth rate of a cell population is lower or higher than the expected rate for a given physiological status and condition.

The term tumor includes benign tumors, malignant tumors, and borderline tumors, where malignant tumors are also collectively referred to as cancer.

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. "Treatment" as used herein includes any treatment of a disease in a patient, including: (a) suppression of the symptoms of a disease, i.e., arresting its progression; or (b) alleviation of the symptoms of a disease, i.e., causing regression of the disease or symptoms.

The term "effective amount" or "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats a particular disease or (ii) alleviates, reduces or eliminates one or more symptoms of a particular disease. The term "therapeutically effective amount" means an amount of a compound sufficient to achieve treatment of a disease when administered to a patient for treatment of the disease. The amount of a compound of the present invention constituting a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the route of administration and the age of the mammal to be treated, but can be generally determined by those skilled in the art based on their knowledge and the present invention.

The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to those carriers that do not have a significant irritating effect on the body and do not impair the biological activity and characteristics of the active compound.

The compounds of the present invention can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art. Preferred embodiments include, but are not limited to, examples of the present invention.

The chemical reactions of specific embodiments of the present invention are carried out in suitable solvents adapted to the chemical variations of the present invention and with the required reagents or materials. In order to prepare the compounds of the present invention, those skilled in the art sometimes need to modify or select synthetic steps or reaction schemes based on existing embodiments.

The present invention will be described in detail by means of examples, which are not intended to limit the present invention.

All solvents used in the present invention are commercially available and can be used without further purification.

The following abbreviations are used in the present invention: DMF: N,N-dimethylformamide; NMP: N-methylpyrrolidone; DMA: N,N-dimethylaniline.

Technical result

The present invention provides salts of an arylaminoquinazoline-containing compound represented by formula 2, their solvates or hydrates and crystalline forms of salts of an arylaminoquinazoline-containing compound represented by formula 2, their solvates or hydrates, which have one or more of the following advantages.

The salts of the arylaminoquinazoline-containing compound represented by formula 2, their solvates or hydrates have good solid state properties and also good crystalline properties. In particular, the dihydrochloride salt, the sulfate salt, the maleate salt, the monohydrochloride salt, the oxalate salt, the malate salt and their solvates or hydrates have good crystalline properties.

The solubility of the dihydrochloride salt, sulfate salt, maleate salt, oxalate salt and their solvates or hydrates in water or an aqueous solution is significantly improved, in particular the dihydrochloride salt, sulfate salt, maleate salt and their solvates or hydrates.

In addition, preferred salts and crystalline forms thereof (e.g., dihydrochloride salt, dihydrochloride salt tetrahydrate, sulfate salt, maleate salt and crystalline forms thereof) have excellent storage stability, chemical stability, thermal stability and/or mechanical stability.

The salts of the arylaminoquinazoline-containing compound represented by formula 2, their solvates or hydrates in the present invention, preferably the dihydrochloride salt, the sulfate salt, the maleate salt, the oxalate salt and their solvate or hydrate, and more preferably the dihydrochloride salts, their solvates or hydrates, have the best properties required for the preparation of a drug, are suitable for storage as active ingredients, and can be made into various dosage forms of drugs according to clinical needs.

Examples

The technical solutions of the present invention will be described in detail below with reference to specific examples. The following examples merely illustrate and explain the present invention and should not be considered as limiting the protection scope of the present invention. All technologies implemented based on the above content of the present invention are included in the protection scope of the present invention.

Unless otherwise stated, the starting materials and reagents used in the following examples are commercially available or can be prepared by known methods.

In the following examples, the analysis and detection conditions were as follows: 1. Content

Detection Instrument: Agilent 1260 (LC1260-3-DAD) High Performance Liquid Chromatograph

Column: C18 4.6*250 mm, 5 µm

Test conditions: Wavelength 252 nm; column temperature 45°C;

2. Solubility (water and buffer with pH 2.0)

Detection Instrument: Agilent 1260 High Performance Liquid Chromatograph

Detection medium: purified water, disodium hydrogen phosphate buffer with pH 2.0

Preparation of control solution: An appropriate amount of the reference substance Compound 1 was taken, accurately weighed, completely dissolved in the solvent, and diluted to a concentration of 100 μg/mL. 10 μL of the prepared solution was accurately measured, and the content of Compound 1 was determined by HPLC.

3. X-ray powder diffraction (XRPD)

(1) Detection instrument: Bruker D2 PHASER X-ray powder diffractometer

Test conditions:

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

X-ray wavelength: CuKα, K(Å): 1.5406;

Voltage and current: 30 kV, 10 mA;

Scanning range: 3~40°2θ;

Total scanning time: 40 min;

Scanning speed: 0.5 sec/step;

Sample amount: 3 mg (Examples 1-4)

Configuration software: Diffrac Plus XRD Commander

Analysis Software: MDI Jade 6.0

(2) Detection instrument: Bruker D8 Advance X-ray powder diffractometer

Test conditions:

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

X-ray wavelength: CuKα, K(Å):1.5418;

Voltage and current: 40 kV, 40 mA;

Scanning range: 3~40°2θ;

Scanning speed: 0.2 sec/step;

Sample amount: 5-10mg (Examples 5-8).

4. Thermogravimetric analysis (TGA)

(1) Detection instrument: METTLER and SDT Q600 thermogravimetric analyzer

Test method: 5 mg of sample (Examples 1-4) was weighed and placed in a platinum TGA test vessel, the sample was heated from 40°C to 300°C at a heating rate of 5K/min under dry nitrogen purging at a flow rate of 40 ml/min.

Software for device control: NETZSCH-proteus-6

Analysis software: Proteus Analysis

(2) Detection device: Discovery TGA 55 thermogravimetric analyzer (TA Instruments, US)

Test method: About 2-5 mg of sample (Examples 5-8) was placed in a weighed open aluminum container and the instrument automatically weighed and recorded the mass. The sample was then heated from room temperature to the final temperature in a heating furnace at a heating rate of 10°C/min. The purge gas was _N2 and the flow rates were 40 ml/min (sample chamber) and 25 ml/min (equilibration chamber), respectively.

5. Differential scanning calorimetry-thermogravimetry (DSC-TGA) analysis

Detection apparatus: NETZSCH STA449F3 synchronous thermal analyzer Test method: The sample (approximately 3 mg) was weighed and placed in an aluminum oxide test crucible, the sample was heated from 20°C to 340°C at a heating rate of 10K/min under the condition of purging with dry nitrogen (protective gas) at a flow rate of 20 ml/min.

Software for device control: NETZSCH-proteus

Analysis software: Proteus Analysis

6. Differential scanning calorimetry (DSC)

Detection device: Discovery DSC 250 differential scanning calorimeter (TA Instruments, US)

Test method: 2-5 mg of sample (Examples 5-8) was weighed and placed in an airtight aluminum vessel with a hole, and the amount of sample was accurately recorded. Then, the sample was heated from 25°C to the final temperature at a rate of 10°C/min. The purge gas was _N2 and the flow rate was 50 ml/min.

7. Chloride

Detection device: Dionex ICS-900 ion chromatograph

Column: Dionex Ion Ras AS 11-HC anion chromatographic column (size: 4x250 mm)

Experimental methodology:

Preparation of test solution: The required amount of test sample was taken, accurately weighed, dissolved in the eluent (sodium hydroxide solution with a concentration of 12.5 mmol/L), and then quantitatively diluted to a solution with a concentration of 0.5 mg per 1 ml. The solution was shaken well and used as the test solution.

Preparation of control solution: the required amount of sodium chloride (equivalent to 18 mg of chloride ions) was taken, weighed accurately, placed in a 250 ml volumetric flask, dissolved and brought to a constant volume with eluents. The solution was shaken well and used as a control solution.

Method of determination: 10 µl of control and test solutions were accurately measured, introduced into the ion chromatograph and chromatograms were recorded. The content of chlorine ions was calculated from the peak areas using the external standard method.

8. Proton nuclear magnetic resonance spectrum

Instrument model: Bruker Advance 600 NMR spectrometer

Determination conditions: test at room temperature (~25°C) with DMSO-J6 as solvent.

9. Determination of solubility in biological carriers

The procedures for preparing the biological carriers (SGF, FeSSIF and FaSSIF) used for solubility determination are presented in the following table:

Test method: The test sample was added to biological carriers and prepared as a solution or suspension with a target concentration of 10 mg/mL. The resulting solution or suspension was continuously shaken at 200 rpm at 37°C. The suspension was filtered after 0.5 h and the concentration of the compound in the filtrate was determined by HPLC.

Example of obtaining 1: Obtaining Compound 1

The compound represented by formula 1 was obtained as a light brown solid by the method described in Example 22 of patent application WO2016023330A1.

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= 10.2 Hz,.7=2.4 Hz, 1H), 7.54 (t, J=8.4 Hz, 1H), 7.47 (dd, J=8.4 Hz, 7=2.4 Hz, 1H), 7.19 (s, 1H), 4.15 (t, J=6.6 Hz, 2H), 3, 95 (s, ZN), 2.29-2.26 (m, 2N), 2.14 (s, 6N), 1.82-1.79 (m, 2H), 1.59-1.57 (m, 2H).

Example 1: Preparation of the dihydrochloride salt of Compound 1

Compound 1 (10 g, 21.58 mmol) obtained in Preparation Example 1 was weighed into a round-bottomed flask, and methanol (110 mL) was added thereto, heated to 55±5°C and stirred until a clear solution was obtained. Hydrochloric acid (3.7 mL, 44.4 mmol) was added dropwise and stirred for 20 min. 200 mL of ethyl acetate was slowly added, cooled to 5±5°C, stirred for 2±1 h and filtered by suction. The filter cake was washed with ethyl acetate (20 mL) to obtain white dihydrochloride salt (11 g) in 94.8% yield.

^1H -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=9.6 Hz, J=2.4 Hz, 1H), 7.58-7.52 (m, 2H), 7.47 (s, 1H), 4.24 (t, J=6 Hz, 2H), 4.03 (s, 3H), 3, 15-3.14 (m, 2H), 2.76-2.75 (m, 6H), 1.90-1.88 (m, 4H).

The chloride ion content was determined by ion chromatography, the stoichiometric ratio in the hydrochloride salt was calculated (see table below), and it was concluded that the base/acid ratio in the hydrochloride salt was 1:2.

A sample of the obtained hydrochloride salt was subjected to X-ray powder diffraction, and the obtained salt showed good crystallinity and was designated as crystalline form I of dihydrochloride salt with the characteristic X-ray diffraction (XRPD) pattern shown in Fig. 1 and the main diffraction peaks shown in Table 1. The sample was subjected to DSC-TGA test and had 2 endothermic peaks. Endothermic peak 1: the onset of endothermic peak at 219.1°C and the maximum of the peak at about 231.0°C; endothermic peak 2: the onset of endothermic peak at 235.1°C and the maximum of the peak at about 284.2°C; and decomposition occurred at about 205°C (see Fig. 8). The PLM image showed that the crystalline particles had regular morphology.

Example 2: Preparation of tetrahydrate of the dihydrochloride salt of Compound 1

Compound 1 (5 g, 10.8 mmol) obtained in Preparation Example 1 was weighed into a round-bottomed flask, purified water (20 ml) was added thereto, and concentrated hydrochloric acid (2.0 ml, 24 mmol) was added dropwise, stirred and heated to 80±5°C until completely dissolved. After completion of the dropwise addition, the solution was slowly cooled to room temperature and filtered by suction, and the filter cake was washed with a small amount of purified water to obtain dihydrochloride salt tetrahydrate (2.82 g) as a white solid in 43% yield. It was confirmed by proton nuclear magnetic resonance spectrum that the salt was formed.

The free base content was calculated by HPLC (see table below) and it can be concluded that the base/acid ratio in the hydrochloride salt hydrate is 1:2.

In addition, the content of crystal water in the hydrochloride salt hydrate in Example 2 was determined by the TGA method, and the weight loss was 12.24%. It can be concluded that the ratio of the base and crystal water in the hydrochloride salt hydrate is 1:4, and the thermogram of the TGA test is shown in Fig. 9.

The obtained sample of dihydrochloride salt tetrahydrate was subjected to X-ray powder diffraction, the obtained solid had good crystallinity and was designated as crystalline form II with the characteristic X-ray diffraction (XRPD) pattern shown in Fig. 2 and the main diffraction peaks shown in Table 2.

Example 3: Preparation of sulfate salt of Compound 1

Compound 1 (4 g, 8.6 mmol) obtained in Preparation Example 1 was weighed into a round-bottomed flask, methanol (10 ml) was added thereto, heated to 60±5°C and stirred until a clear solution was obtained. 50% sulfuric acid solution (1.0 ml, 8.6 mmol) was added dropwise and stirred for 10 min, and 30 ml of ethyl acetate was slowly added. The reaction system was cooled to room temperature and stirred for an additional 1 h and filtered by suction. The filter cake was washed with ethyl acetate (20 ml) to obtain a white sulfate salt (4.13 g) in 85.2% yield. Melting point: 164-168°C. It was confirmed that the salt was formed by proton nuclear magnetic resonance spectrum.

The free base content was calculated by HPLC (see table below) and it can be concluded that the base/acid ratio in the sulfate salt was 1:1.

The obtained sulfate salt sample was subjected to X-ray powder diffraction, the obtained sulfate salt showed good crystallinity and was designated as crystalline form I sulfate salt with the characteristic X-ray diffraction (XRPD) pattern shown in Fig. 3 and the main diffraction peaks shown in Table 3.

Example 4: Preparation of maleate salt of Compound 1

Compound 1 (5 g, 10.8 mmol) obtained in Preparation Example 1, maleic acid (1.5 g, 13.0 mmol) and methanol (10 mL) were weighed and added to a reaction flask, heated to 55±5°C and stirred until a clear solution was obtained. Ethyl acetate (30 mL) was added thereto, cooled to room temperature, stirred for additional 2 h and filtered by suction, and the filter cake was washed with ethyl acetate (30 mL) to obtain white maleate salt (2.22 g) in 35.5% yield. Melting point: 138-142°C. It was confirmed by proton nuclear magnetic resonance spectrum that the salt was formed.

The free base content was calculated by HPLC (see table below) and it can be concluded that the base/acid ratio in the maleate salt was 1:1.

The obtained maleate salt sample was subjected to powder X-ray diffraction, the obtained maleate salt showed good crystallinity and was designated as crystalline form I of maleate salt, the characteristic X-ray diffraction pattern of which is shown in Fig. 4 and the main diffraction peaks are shown in Table 4.

Example 5: Preparation of crystalline form III of the dihydrochloride salt of Compound 1

The sample from Example 1 (about 7 mg) was weighed, dissolved in methanol (0.2 ml) and filtered and the filtrate was collected. Acetonitrile (1 ml) was then added to the filtrate, stirred overnight and filtered by suction to give a white solid. The resulting solid was subjected to X-ray powder diffraction, the obtained material was in crystalline form and it was designated as crystalline form III of the dihydrochloride salt, the characteristic X-ray diffraction (XRPD) pattern of which is shown in Fig. 11 and the main diffraction peaks are shown in Table 5. The sample was subjected to DSC-TGA test and it had 2 endothermic peaks. Endothermic peak 1: the onset of the endothermic peak at 72.28 °C and the maximum of the peak at about 101.52 °C; endothermic peak 2: the onset of the endothermic peak was at 172.06°C and the maximum of the peak was at about 183.70°C. The mass loss was 6.2684% from room temperature to 120°C and decomposition occurred at about 225°C (see Fig. 12).

Example 6: Preparation of crystalline form IV of the dihydrochloride salt of Compound 1

A sample from Example 1 (about 7 mg) was weighed, dissolved in water (0.2 ml) and filtered and the filtrate was collected. Acetonitrile (7 ml) was then added to the filtrate, stirred for 24 h and filtered by suction to give a white solid. The resulting solid was subjected to X-ray powder diffraction, the obtained material was in crystalline form and it was designated as crystalline form IV of the dihydrochloride salt, the characteristic X-ray diffraction (XRPD) pattern of which is shown in Fig. 13 and the main diffraction peaks are shown in Table 6. The resulting solid was subjected to DSC-TGA test and 2 endothermic peaks were obtained. Endothermic peak 1: the onset of the endothermic peak at 49.50 °C and the maximum of the peak at about 68.81 °C; endothermic peak 2: the onset of the endothermic peak was at 164.55°C and the maximum of the peak was at about 177.55°C. The mass loss was 3.9478% from room temperature to 150°C and decomposition occurred at about 215°C (see Fig. 14).

Example 7: Preparation of the dihydrochloride salt solvate (crystal form V) of Compound 1 in ethanol

A sample from Example 1 (about 30 mg) was weighed, dissolved in ethanol (1 ml), stirred at 50 °C for 30 min and then filtered while hot. The filtrate was cooled to room temperature, stirred for an additional 3 days and filtered by suction to give a white solid. The resulting solid was subjected to X-ray powder diffraction, the resulting material was in crystalline form and was designated as crystalline form V (solvate in ethanol, 1:1), the characteristic XRPD pattern of which is shown in Fig. 15 and the main diffraction peaks are shown in Table 7. The resulting solid was subjected to DSC-TGA testing and 3 endothermic peaks were obtained. Endothermic peak 1: onset of endothermic peak at 28.37 °C and maximum of peak at about 48.29 °C; endothermic peak 2: the onset of the endothermic peak at 114.96°C and the maximum of the peak at about 153.99°C; and endothermic peak 3: the onset of the endothermic peak at 179.32°C and the maximum of the peak at about 190.59°C. The weight loss was 7.2663% from room temperature to 200°C (see Fig. 16).

Example 8: Preparation of crystalline form VII of the dihydrochloride salt of Compound 1

A sample of the crystalline form III obtained in Example 5 was heated to 130°C and collected to obtain a white solid. The obtained solid was subjected to X-ray powder diffraction, the obtained material was in crystalline form and it was designated as crystalline form VII of the dihydrochloride salt, the characteristic X-ray diffraction pattern (XRPD) of which is shown in Fig. 17 and the main diffraction peaks are shown in Table 8. The obtained solid was subjected to DSC-TGA test and 2 endothermic peaks were obtained. Endothermic peak 1: the onset of the endothermic peak at 66.54°C and the maximum of the peak at about 87.64°C; endothermic peak 2: the onset of the endothermic peak at 169.59°C and the maximum of the peak at about 182.15°C. The mass loss was 1.3751% from room temperature to 120°C (see Fig. 18).

Comparative Examples 1 and 2: Preparation of the monohydrochloride salt and mala hydrochloride salt of Compound 1

Example 9: Preparation of oxalate salt of Compound 1

Three samples (5 g, 10.8 mmol) of Production Example 1 were placed in reaction flasks, and the production of a monohydrochloride salt represented by formula 3-3, a malate salt represented by formula 7-1, and an oxalate salt represented by formula 6-1 was carried out under the same reaction conditions as in Example 3, according to the reaction conditions shown in the table below. The results are shown in Table 9. It was confirmed by proton nuclear magnetic resonance spectrum that the salt was formed.

Example 10: Preparation of the tetrahydrate of the dihydrochloride salt

The sample from Example 1 (about 369 mg) was weighed and a water/acetone mixture (1:1, v/v, total amount: 5 ml) was added thereto and stirred overnight at room temperature. The white solid was collected by filtration and dried overnight under vacuum at 50°C. The solid was determined to be dihydrochloride salt tetrahydrate by identification. The obtained solid was subjected to X-ray powder diffraction, and the obtained substance was in crystalline form and had the characteristic X-ray diffraction (XRPD) pattern shown in Fig. 19.

Test Example 1: Solubility Test

The salts obtained in Production Example 1, Examples 1-4 and 9 and Comparative Examples 1 and 2 were tested for solubility in water and a buffer solution with a pH of 2.0. The test results are shown in the table below:

Results: Compared with Production Example 1, all the samples of Examples 1 to 4 and Example 9 had higher solubility in water, and the solubility of all the samples of Examples 1 to 4 in water was at least 100 times higher, and the solubility of the dihydrochloride salt was the best among all the samples. The samples of the monohydrochloride salt and the malate salt were dissolved in water, the resulting systems were gelatinous, and it is possible that the samples underwent crystalline transformation in water, but the dissolution effect was weak, so that these systems showed an undissolved state.

The samples obtained in Examples 1 to 4 with better solubility (>10 mg/mL) were further selected to determine the solubility of these samples in a buffer solution with pH 2.0, wherein Preparation Example 1 was taken as a control. From the above results, it can be seen that the solubility of Preparation Example 1 was significantly improved, the solubility of the samples obtained in Examples 1 and 4 was still slightly better than that of Preparation Example 1, and the solubility of the samples obtained in Examples 2 and 3 was slightly lower than that of Preparation Example 1 under acidic conditions. In the simulated gastric juice environment, although the solubility of Examples 1 and 4 was reduced, it was still better than that of the free base of the compound of Preparation Example 1.

In addition, according to the general requirements for the solubility of active ingredients in finished dosage forms, the solubility of the active ingredient is more than 0.1 g/L for a solid oral dosage form and 10 g/L for solution forms such as injections and oral liquid forms. More importantly, the solubility of the active ingredients should correspond to the clinically necessary concentration of the dosage form. Based on the solubility results in Table 10, Examples 1 to 4 and Example 9 can be considered for the preparation of solid oral dosage forms, and Examples 1 to 4 can be considered for the preparation of solutions such as injections and oral liquid forms.

Test Example 2: Solubility Test in Biological Carriers The samples from Example 1 and Example 10 (20 mg each) were weighed and added to Hev various biological carriers (2 ml) to conduct a solubility test; the results are shown in Table 11.

Results: The samples obtained in Example 1 and Example 10 were able to maintain good solubility in biological carriers with different pH, and the dissolution rate was high.

Test Example 3: Long-Term Stability Test An appropriate number of salt samples obtained in Examples 1 to 4 and 9 were sealed with polyethylene film and placed under conditions of 40±2°C and 75%±5% RH (relative humidity) for 5 months, and long-term stability tests were performed. The following results were obtained:

X-ray diffraction pattern of crystalline form I of the dihydrochloride salt

Compound 1 obtained in Example 1 after long-term stability testing is shown in Fig. 10.

Results: After 5 months of storage, all crystalline salt samples from Examples 1–4 and 9 were stable; the purity of the products did not decrease significantly, and the crystalline form of each sample remained unchanged.

Test Example 4: Solid Stability Test The dihydrochloride salt of Example 1 and the dihydrochloride salt tetrahydrate of Example 2 and Example 10 were placed under 40°C/75%RH (open) conditions for 7 days to conduct a stability test. The results are shown in Table 14.

Results: The dihydrochloride salt and dihydrochloride salt tetrahydrate of Compound 1 obtained in Examples 1-2 and Example 10 maintained chemical stability and crystal stability under the condition of 40°C/75%RH (open) for 7 days. Therefore, the samples obtained in Examples 1-2 and Example 10 had good thermal stability and met the storage requirements of active ingredients.

Test Example 5: Mechanical Stability Test

An appropriate amount of the dihydrochloride salt of Example 1 was mechanically milled for 5 minutes and X-ray powder diffraction was performed. The results showed that the crystalline form was unchanged.

Test Example 6: Solubility Test in Common Organic Solvents

The solubility test of the sample from Preparation Example 1 in various organic solvents was carried out using the method of the Pharmacopoeia (Volume II, General Examples), and the solubility of the sample from Example 1 in various organic solvents was estimated using the gravimetric method; the results are shown in Table 15.

Results: Compound 1 from Preparation Example 1 had good solubility in various common organic solvents (all >10 mg/mL), while the dihydrochloride salt from Example 1 showed good solubility only in methanol and had very low solubility in other seven commonly used organic solvents. Therefore, it was concluded that a suitable common organic solvent was used to prepare the dihydrochloride salt and completely separate the (unreacted) free base from the dihydrochloride salt. The dihydrochloride salt was obtained with higher yield (weight loss was low due to the low solubility of the dihydrochloride salt in organic solvents) and purity.

In addition, a crystalline form corresponding to the dihydrochloride salt of Example 1 was obtained in the above-mentioned common organic solvents, showing that the crystalline form was stable in common organic solvents.

Case Study 7: Pharmacodynamic Experiment in a Nude Mice Model of Human Melanoma A375 Tumor Xenografts

A suspension of well-growing human melanoma A375 cells was inoculated into the subcutaneous tissue of the axilla of the forelimbs of female nude nu/nu mice in a volume of 0.1 ml, containing approximately 1× ¹⁰⁷ tumor cells. When the tumor volume grew to 100 ^mm3 or more, mice with good tumor growth were selected and the animals were evenly distributed into 5 groups depending on the tumor volume: placebo group, vandetanib 12.5 mg/kg group, vandetanib 25 mg/kg group, sample from Example 1 12.5 mg/kg group and sample from Example 1 25 mg/kg group, with each group having 6 animals. The placebo group was orally administered distilled water, and the other groups were orally administered the corresponding test drugs in a dosage volume of 20 ml/kg once a day and continuously for 20 days. After the administration, the animals were kept under normal conditions, and the antitumor effect of the test drugs was observed dynamically using the method of measuring the diameter of tumors. At the end of the experiment (day 21), the animals were sacrificed, the linear dimensions of the tumor were measured and the tumors were weighed, and the degree of tumor inhibition was calculated.

Vandetanib:

Results: Example 1 was able to significantly inhibit tumor growth in a dose-dependent manner compared to the placebo group and had a superior tumor inhibition effect compared to the control drug vandetanib.

The effective dose obtained in the mouse model was converted to the equivalent dose for adult humans according to the conversion factor between human and animal body surface areas (see Methodology of Pharmacological Experiment, edited by Shuyun Xu). 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 adult humans (70 kg), respectively. Single oral doses are 95.9 mg and 191.8 mg for adult humans (70 kg). If a small injection or solution (5 ml) is prepared, the solubility of the drug should reach 11.51 mg/ml and 23.02 mg/ml or more, respectively (the absolute bioavailability for dogs and monkeys in animal pharmacokinetic experiments is approximately 60% and therefore the oral availability for humans is calculated as 60%). Similarly, the preparation of a liquid dosage form in small volumes (less than 5 ml) requires higher solubility of the drug. Based on the results of the dissolution test in Table 10, for the preparation of a liquid dosage form of 5 ml, if the administered dose is 1.37 mg/kg, then Examples 1, 2 and 4 can meet the solubility requirement; if the administered dose is 2.74 mg/kg, then the samples obtained in Examples 1 and 2 can meet the solubility requirement.

Thus, the inventors, after screening and examining the salt forms of Compound 1, found that the solubility of the dihydrochloride salt, sulfate salt and maleate salt was significantly improved compared with Compound 1. They met the general solubility requirements of active ingredients of solid preparations and liquid preparations, and the crystalline forms of the obtained salts had good stability. Of the three salts, the dihydrochloride salt has the best performance, can meet the solubility requirements of small-volume liquid preparations, has good antitumor effect in vivo, and can potentially be used for the development of drugs in various dosage forms.

Claims (8)

1. A method for producing a salt of an arylaminoquinazoline-containing compound represented by formula 2 or a hydrate thereof, comprising reacting an arylaminoquinazoline-containing compound represented by formula 1 with HA in a solvent, isolating the salt of the arylaminoquinazoline-containing compound represented by formula 2 or a hydrate thereof: , Where HA is hydrochloric acid; n is 2; and the reaction temperature is 40-90°C; and the reaction solvent is selected from one or a combination of two of ethyl acetate, methanol or water. 2. The method according to claim 1, wherein the hydrate is a tetrahydrate.