Trisubstituted quinazoline derivative, acid addition salt thereof, and pharmaceutical composition and use thereof

Abstract

Disclosed in the present application are a trisubstituted quinazoline derivative, an acid addition salt thereof, and a pharmaceutical composition and a use thereof. Specifically, the trisubstituted quinazoline derivative is (E)-4-(dimethylamino)-N-(4-((4-(4-fluorophenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide. Further disclosed in the present application is an acid addition salt, a solvate or a hydrate of (E)-4-(dimethylamino)-N-(4-((4-(4-fluorophenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide, or a pharmaceutical composition thereof. The substances disclosed in the present application can be used for the prevention, inhibition, or treatment of cancer.

Description

Trisubstituted quinazoline derivatives and acid addition salts thereof and pharmaceutical compositions and uses thereof

[0001] This application claims priority to the Chinese patent application filed on February 5, 2024, with application number 202410164123.2, and invention name “Trisubstituted quinazoline derivatives, acid addition salts thereof, pharmaceutical compositions and uses thereof”, the contents of which should be understood as incorporated into this application by reference. Technical Field

[0002] The present invention relates to, but is not limited to, the field of medical technology, and in particular to trisubstituted quinazoline derivatives, acid addition salts thereof, pharmaceutical compositions and uses thereof. The trisubstituted quinazoline derivative is (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide. Background Art

[0003] Protein kinases represent a large family of enzymes that catalyze the phosphorylation of target protein substrates. Phosphorylation generally involves the transfer of a phosphate group from ATP to a protein substrate. Common sites of attachment of the phosphate group to the protein substrate include, for example, tyrosine, serine, or threonine residues. Due to their activity in numerous cellular processes, protein kinases have become important therapeutic targets.

[0004] The human epidermal growth factor receptor (HER) kinase family includes HER1 (erbB1, EGFR), HER2 (erbB2, NEU), HER3 (erbB3), and HER4 (erbB4). The HER kinase family plays an important regulatory role in cellular physiological processes.

[0005] EGFR, also known as HER1 or ErbB1, is found in many tumors with mutant EGFR, and numerous EGFR mutations have been identified. The effects of mutant EGFR may include: sustained activation of cells with ligand-independent receptors; disruption of receptor downregulation mechanisms due to deletion of certain EGFR domains; activation of aberrant signaling pathways; and inhibition of apoptosis. Mutants arise from deletions, mutations, and rearrangements of the EGFR gene.

[0006] HER3 overexpression is common in breast cancer, detected in 50-70% of breast cancers. HER3 also contributes to resistance to targeted therapies in breast cancer, activating downstream signaling pathways such as PI3K / AKT through bypass mechanisms, promoting cancer cell survival and proliferation, thereby counteracting the killing effects of therapeutic drugs on cancer cells.

[0007] Interaction of HER4 (ErbB4) with its ligand promotes receptor dimerization, kinase activation, and phosphorylation-dependent signaling cascades, such as the mitogen-activated protein kinase (MAPK) and PI3K / Akt cascades. ErbB4 is a fully functional RTK that can function as both homodimers and heterodimers. It is activated by at least seven EGF-related peptide growth factors: neuregulins (NRG-1, NRG-2, NRG-3, and NRG-4), HB-EGF, beta-cell protein (BTC), and epiregulin (ER). Furthermore, unlike other ERBB members, ErbB4 has been shown to undergo regulated intracellular proteolysis (RIP), resulting in the generation of a soluble intracellular domain (ICD). The released ErbB4 ICD is capable of translocating to the nucleus and regulating transcription. ErbB4 and its ligands may play important roles in normal cardiovascular and neurodevelopment, mammary differentiation, and pathological conditions such as heart disease and cancer.

[0008] HER2, a member of the human epidermal growth factor receptor (EGFR) family of proteins, is overexpressed in a variety of tumor cells. The main mechanisms of action include gene amplification, protein overexpression, and alterations in the tyrosine kinase domain. Studies have shown that HER2 gene amplification and / or HER2 protein overexpression are present in a variety of malignant tumor tissues, including 30% of breast cancer, 25%-30% of ovarian cancer, 35%-45% of pancreatic cancer, 30%-80% of esophageal adenocarcinoma and squamous cell carcinoma, and 2%-5% of colorectal cancer. Most studies have shown that HER2 protein expression is associated with poor prognosis in breast and ovarian cancer. HER2 mutations occur in approximately 1-3% of non-small cell lung cancers, 90% of which are exon 20 insertion mutations.

[0009] Therefore, compounds that can inhibit the activity of HER2 protein kinase are highly desired, and the present invention aims to invent therapeutic drugs for HER2-related cancers. Summary of the Invention

[0010] In a first aspect, the present application provides a trisubstituted quinazoline derivative, an acid addition salt thereof, or a solvate or hydrate thereof, wherein the trisubstituted quinazoline derivative is (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazoline-6-yl)but-2-enamide, having a chemical structure shown in Formula I below:

[0011] In a second aspect, the present application provides a method for preparing (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide, its acid addition salt or their solvates or hydrates.

[0012] In a third aspect, the present application provides a pharmaceutical composition comprising (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide, its acid addition salt, or its solvate or hydrate.

[0013] In a fourth aspect, the present application provides the use of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide, its acid addition salt or its solvate or hydrate, or its pharmaceutical composition in the preparation of drugs for preventing, inhibiting or treating cancer.

[0014] In a fifth aspect, the present application provides (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide, its acid addition salt or its solvate or hydrate, or its pharmaceutical composition for use as a medicine.

[0015] In the sixth aspect, the present application provides (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide, its acid addition salt or its solvate or hydrate, or its pharmaceutical composition for preventing, inhibiting or treating cancer.

[0016] In the seventh aspect, the present application provides a method for preventing, inhibiting or treating cancer, which comprises administering a therapeutically effective amount of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide, its acid addition salt or their solvate or hydrate, or their pharmaceutical composition to a subject in need thereof.

[0017] Summary of the Figures

[0018] The accompanying drawings are used to provide an understanding of the technical solution of the present application and constitute a part of the specification. Together with the embodiments of the present application, they are used to explain the technical solution of the present application, but do not constitute a limitation to the technical solution of the present application.

[0019] Figure 1 is an XPRD diagram of the maleate salt form A of the present application;

[0020] Figure 2 is a TGA diagram of maleate salt form A of the present application;

[0021] Figure 3 is the NMR spectrum of the maleate salt form A of the present application;

[0022] Figure 4 is an XPRD diagram of the maleate salt form B of the present application;

[0023] FIG5 is a TGA diagram of maleate salt form B of the present application;

[0024] Figure 6 is an XRPD pattern of maleate salt Form C of the present application;

[0025] Figure 7 is the NMR spectrum of maleate salt form C of the present application;

[0026] FIG8 is an XPRD diagram of the hydrochloride salt form S-1 of the present application;

[0027] Figure 9 is an XPRD diagram of the hydrochloride salt form S-2 of the present application;

[0028] Figure 10 is an XPRD diagram of the sulfate salt crystal form S-3 of the present application;

[0029] Figure 11 is an XPRD diagram of the sulfate salt crystal form S-4 of the present application;

[0030] Figure 12 is an XPRD diagram of the sulfate salt crystal form S-5 of the present application;

[0031] Figure 13 is an XPRD diagram of the tartrate salt form S-6 of the present application;

[0032] Figure 14 is an XPRD diagram of the fumarate salt form S-7 of the present application;

[0033] Figure 15 is an XPRD diagram of the p-toluenesulfonate crystalline form S-8 of the present application;

[0034] Figure 16 is an XPRD diagram of the free base crystalline form F-1 of the present application;

[0035] FIG17 is a DSC diagram of the free base crystalline form F-1 of the present application;

[0036] Figure 18 is a TGA diagram of the free base crystalline form F-1 of the present application;

[0037] Figure 19 is an XPRD diagram of the free base crystalline form F-2 of the present application;

[0038] Figure 20 is a DSC graph of the free base crystalline form F-2 of the present application;

[0039] Figure 21 is a TGA chart of the free base crystalline form F-2 of the present application;

[0040] Figure 22 is an XPRD diagram of the free base crystalline form F-3 of the present application;

[0041] FIG23 is a DSC diagram of the free base crystalline form F-3 of the present application;

[0042] Figure 24 is a TGA chart of the free base crystalline form F-3 of the present application;

[0043] Figure 25 is an XPRD diagram of the free base crystalline form F-4 of the present application;

[0044] Figure 26 is an XPRD diagram of the free base crystalline form F-5 of the present application;

[0045] Figure 27 is an XPRD diagram of the free base crystalline form F-6 of the present application;

[0046] Figure 28 is an XPRD diagram of another maleate salt form A of the present application;

[0047] Figure 29 is a comparison of the in vivo efficacy of the maleate salt and neratinib of the present application.

[0048] Details

[0049] The present application provides (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide, its acid addition salt or its solvate or hydrate or its pharmaceutical composition. The compound or pharmaceutical composition has good stability and is easy to handle, is suitable as a drug, and can be used to prevent, inhibit or treat cancer, especially having a preventive or therapeutic effect on patients with HER2-positive advanced cancer.

[0050] In an embodiment of the first aspect, the present application provides a trisubstituted quinazoline derivative, an acid addition salt thereof, or a solvate or hydrate thereof (hereinafter referred to as (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide, an acid addition salt thereof, or a solvate or hydrate thereof), wherein the chemical structure of the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide is shown in Formula I below:

[0051] In some embodiments of the first aspect, the present application provides (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide as shown in Formula I.

[0052] In some embodiments of the first aspect, the present application provides (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide as shown in Formula I, which is in solid form.

[0053] In some embodiments of the first aspect, the present application provides (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide as shown in Formula I, which is in the form of a crystalline solid.

[0054] In some embodiments of the first aspect, the present application provides (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide as shown in Formula I, which is in an amorphous solid form.

[0055] In some embodiments of the first aspect, the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide as shown in Formula I provided herein is in the form of a hydrate. In one embodiment, the water content of the hydrate is 2.1 wt% to 10.0 wt%, or, the water content is 2.2 wt% to 9.2 wt%, or 2.3 wt% to 9.1 wt%, or 2.3 wt% to 8.0 wt%, or 2.1 wt% to 4.1 wt%, or 2.2 wt% to 4.0 wt%, Or 2.8wt% to 4.0wt%, or 2.9wt%, or 3.0wt%, or 3.1wt%, or 3.2wt%, or 3.3wt%, or 3.3wt%, or 3.4wt%, or 3.5wt%, or 3.6wt%, or 3.7wt%, or 3.8wt%, or 3.9wt%, or 4.0wt%; in one embodiment, the hydrate is a monohydrate such as 0.25 hydrate (1 / 4 hydrate), hemihydrate (1 / 2 hydrate), monohydrate, 5 / 4 hydrate, sesquihydrate, dihydrate, or trihydrate, etc.

[0056] In some embodiments of the first aspect, the present application provides (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide hydrate as shown in Formula I, which is in the form of a crystalline solid.

[0057] In one embodiment of the first aspect, the present application provides a crystalline form F-1 of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide, wherein the crystalline form F-1 has a purity greater than 90%; in some embodiments, the crystalline form F-1 is a hydrate; in some embodiments, the X-ray powder diffraction pattern of the crystalline form F-1 includes at least one of the characteristic peaks at 2θ of approximately 5.9±0.2 degrees, 9.8±0.2 degrees, 21.6±0.2 degrees, and 25.8±0.2 degrees; in some embodiments, the X-ray powder diffraction pattern of the crystalline form F-1 includes at least one of the characteristic peaks at 2θ of approximately 5.9±0.2 degrees, 9.8±0.2 degrees, 21.6±0.2 degrees, and 25.8±0.2 degrees. In some embodiments, the X-ray powder diffraction pattern of Form F-1 further comprises characteristic peaks at 2θ of approximately 12.9±0.2 degrees, 17.6±0.2 degrees, 20.7±0.2 degrees, 21.1±0.2 degrees, 25.3±0.2 degrees and 30.6±0.2 degrees; In some embodiments, the X-ray powder diffraction pattern thereof comprises characteristic peaks at 2θ of approximately 5.9±0.2 degrees, 9.8±0.2 degrees, 12.9±0.2 degrees, 17.6±0.2 degrees, 20.7±0.2 degrees, 21.1±0.2 degrees, 21.6±0.2 degrees, 25.3±0.2 degrees, 25.8±0.2 degrees and 30.6±0.2 degrees. In one embodiment, the X-ray powder diffraction pattern thereof comprises the following characteristic peaks:

[0058] In one embodiment of the first aspect, the crystalline form F-1 of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide provided herein has an X-ray powder diffraction pattern substantially the same as that shown in Figure 16.

[0059] In one embodiment of the first aspect, the crystalline form F-1 of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide provided herein has a DSC (differential scanning calorimetry) thermogram substantially the same as that shown in Figure 17.

[0060] In one embodiment of the first aspect, the crystalline form F-1 of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide provided herein has a thermogravimetric analysis (TGA) graph substantially the same as that shown in Figure 18.

[0061] In one embodiment of the first aspect, the present application provides a crystalline form F-2 of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide, wherein the crystalline form F-2 has a purity greater than 90%; in some embodiments, the crystalline form F-2 is a hydrate; in some embodiments, the X-ray powder diffraction pattern of the crystalline form F-2 includes at least one of the characteristic peaks at 2θ of approximately 5.8±0.2 degrees, 9.6±0.2 degrees, 20.7±0.2 degrees and 21.6±0.2 degrees; in some embodiments, the X-ray powder diffraction pattern of the crystalline form F-2 includes The X-ray powder diffraction pattern of Form F-2 further comprises characteristic peaks at about 5.8±0.2 degrees, 9.6±0.2 degrees, 20.7±0.2 degrees, and 21.6±0.2 degrees of 2θ; in some embodiments, the X-ray powder diffraction pattern of Form F-2 further comprises characteristic peaks at about 6.1±0.2 degrees, 12.8±0.2 degrees, 19.1±0.2 degrees, and 20.9±0.2 degrees of 2θ; in some embodiments, the X-ray powder diffraction pattern thereof comprises characteristic peaks at about 5.8±0.2 degrees, 6.1±0.2 degrees, 9.6±0.2 degrees, 12.8±0.2 degrees, 19.1±0.2 degrees, 20.7±0.2 degrees, 20.9±0.2 degrees, and 21.6±0.2 degrees of 2θ. In one embodiment, the X-ray powder diffraction pattern thereof comprises the following characteristic peaks:

[0062] In one embodiment of the first aspect, the crystalline form F-2 of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide provided herein has an X-ray powder diffraction pattern substantially the same as that shown in Figure 19.

[0063] In one embodiment of the first aspect, the crystalline form F-2 of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide provided herein has a DSC (differential scanning calorimetry) thermogram substantially the same as that shown in Figure 20.

[0064] In one embodiment of the first aspect, the crystalline form F-2 of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide provided herein has a thermogravimetric analysis (TGA) graph substantially the same as that shown in Figure 21.

[0065] In one embodiment of the first aspect, the present application provides a crystalline form F-3 of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide, wherein the crystalline form F-3 has a purity greater than 90%; in some embodiments, the crystalline form F-3 is a hydrate; in some embodiments, the X-ray powder diffraction pattern of the crystalline form F-3 includes at least one of the characteristic peaks at 2θ of approximately 20.2±0.2 degrees, 21.0±0.2 degrees, 24.1±0.2 degrees, and 25.3±0.2 degrees; in some embodiments, the X-ray powder diffraction pattern of the crystalline form F-3 includes at least one of the characteristic peaks at 2θ of approximately 20.2±0.2 degrees, 21.0±0.2 degrees, 24.1±0.2 degrees, and 25.3±0.2 degrees. 2 degrees, 21.0±0.2 degrees, 24.1±0.2 degrees and 25.3±0.2 degrees 2θ characteristic peaks; in some embodiments, the X-ray powder diffraction pattern of the crystalline form F-3 further comprises characteristic peaks at about 8.2±0.2 degrees, 11.8±0.2 degrees, 17.8±0.2 degrees, 25.5±0.2 degrees and 26.7±0.2 degrees 2θ characteristic peaks; in some embodiments, its X-ray powder diffraction pattern comprises characteristic peaks at about 8.2±0.2 degrees, 11.8±0.2 degrees, 17.8±0.2 degrees, 20.2±0.2 degrees, 21.0±0.2 degrees, 24.1±0.2 degrees, 25.3±0.2 degrees, 25.5±0.2 degrees and 26.7±0.2 degrees 2θ characteristic peaks. In one embodiment, its X-ray powder diffraction pattern comprises the following characteristic peaks:

[0066] In one embodiment of the first aspect, the crystalline form F-3 of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide provided herein has an X-ray powder diffraction pattern substantially the same as that shown in Figure 22.

[0067] In one embodiment of the first aspect, the crystalline form F-3 of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide provided herein has a DSC (differential scanning calorimetry) thermogram substantially the same as that shown in Figure 23.

[0068] In one embodiment of the first aspect, the crystalline form F-3 of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide provided herein has a thermogravimetric analysis (TGA) graph substantially the same as that shown in Figure 24.

[0069] In one embodiment of the first aspect, the present application provides a crystalline form F-4 of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide, wherein the crystalline form F-4 has a purity greater than 90%; in some embodiments, the X-ray powder diffraction pattern of the crystalline form F-4 includes at least one of the characteristic peaks at 2θ of approximately 6.0±0.2 degrees, 9.8±0.2 degrees, 21.2±0.2 degrees, and 25.9±0.2 degrees; in some embodiments, the X-ray powder diffraction pattern of the crystalline form F-4 includes at least one of the characteristic peaks at 2θ of approximately 6.0±0.2 degrees, 9.8±0.2 degrees, 21.2±0.2 degrees, and 25.9±0.2 degrees. 2 degrees, 9.8±0.2 degrees, 21.2±0.2 degrees and 25.9±0.2 degrees 2θ characteristic peaks; in some embodiments, the X-ray powder diffraction pattern of the crystalline form F-4 further comprises characteristic peaks at about 7.2±0.2 degrees, 13.0±0.2 degrees, 17.6±0.2 degrees and 20.8±0.2 degrees 2θ characteristic peaks; in some embodiments, its X-ray powder diffraction pattern comprises characteristic peaks at about 6.0±0.2 degrees, 7.2±0.2 degrees, 9.8±0.2 degrees, 13.0±0.2 degrees, 17.6±0.2 degrees, 20.8±0.2 degrees, 21.2±0.2 degrees and 25.9±0.2 degrees 2θ characteristic peaks. In one embodiment, its X-ray powder diffraction pattern comprises the following characteristic peaks:

[0070] In one embodiment of the first aspect, the crystalline form F-4 of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide provided herein has an X-ray powder diffraction pattern substantially the same as that shown in Figure 25.

[0071] In one embodiment of the first aspect, the present application provides a crystalline form F-5 of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide, wherein the crystalline form F-5 has a purity greater than 90%; in some embodiments, the X-ray powder diffraction pattern of the crystalline form F-5 includes at least one of the characteristic peaks at 2θ of approximately 6.0±0.2 degrees, 11.8±0.2 degrees, 21.1±0.2 degrees, and 22.3±0.2 degrees; in some embodiments, the X-ray powder diffraction pattern of the crystalline form F-5 includes at least one of the characteristic peaks at 2θ of approximately 6.0±0.2 degrees, 11.8±0.2 degrees, 21.1±0.2 degrees, and 22.3±0.2 degrees. 2 degrees, 21.1±0.2 degrees and 22.3±0.2 degrees 2θ characteristic peaks; in some embodiments, the X-ray powder diffraction pattern of the crystalline form F-5 further comprises characteristic peaks at about 6.1±0.2 degrees, 8.2±0.2 degrees, 20.3±0.2 degrees, 24.3±0.2 degrees and 26.8±0.2 degrees 2θ characteristic peaks; in some embodiments, its X-ray powder diffraction pattern comprises characteristic peaks at about 6.0±0.2 degrees, 6.1±0.2 degrees, 8.2±0.2 degrees, 11.8±0.2 degrees, 20.3±0.2 degrees, 21.1±0.2 degrees, 22.3±0.2 degrees, 24.3±0.2 degrees and 26.8±0.2 degrees 2θ characteristic peaks. In one embodiment, its X-ray powder diffraction pattern comprises the following characteristic peaks:

[0072] In one embodiment of the first aspect, the crystalline form F-5 of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide provided herein has an X-ray powder diffraction pattern substantially the same as that shown in Figure 26.

[0073] In one embodiment of the first aspect, the present application provides a crystalline form F-6 of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide, wherein the crystalline form F-6 has a purity greater than 90%; in some embodiments, the X-ray powder diffraction pattern of the crystalline form F-6 includes at least one of the characteristic peaks at 2θ of approximately 5.6±0.2 degrees, 17.2±0.2 degrees, 17.8±0.2 degrees, and 23.8±0.2 degrees; in some embodiments, the X-ray powder diffraction pattern of the crystalline form F-6 includes at least one of the characteristic peaks at 2θ of approximately 5.6±0.2 degrees, 17.2±0.2 degrees, 17.8±0.2 degrees, and 23.8±0.2 degrees. and 23.8±0.2 degrees 2θ; in some embodiments, the X-ray powder diffraction pattern of the crystalline form F-6 further comprises characteristic peaks at about 12.1±0.2 degrees, 16.8±0.2 degrees, 21.3±0.2 degrees, 23.0±0.2 degrees, 23.5±0.2 degrees and 24.5±0.2 degrees 2θ; in some embodiments, its X-ray powder diffraction pattern comprises characteristic peaks at about 5.6±0.2 degrees, 12.1±0.2 degrees, 16.8±0.2 degrees, 17.2±0.2 degrees, 17.8±0.2 degrees, 21.3±0.2 degrees, 23.0±0.2 degrees, 23.5±0.2 degrees, 23.8±0.2 degrees and 24.5±0.2 degrees 2θ. In one embodiment, its X-ray powder diffraction pattern comprises the following characteristic peaks:

[0074] In one embodiment of the first aspect, the crystalline form F-6 of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide provided herein has an X-ray powder diffraction pattern substantially the same as that shown in Figure 27.

[0075] In some embodiments of the first aspect, the present application provides (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enoamide acid addition salts or solvates or hydrates thereof, wherein the acid in the acid addition salt is hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, fumaric acid, malonic acid, succinic acid, tartaric acid, citric acid, fumaric acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, xinafoic acid or benzoic acid.

[0076] In one embodiment of the first aspect, the present application provides (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide hydrochloride or a solvate or hydrate thereof.

[0077] In one embodiment of the first aspect, the present application provides (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide sulfate or a solvate or hydrate thereof.

[0078] In one embodiment of the first aspect, the present application provides (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate or a solvate or hydrate thereof.

[0079] In one embodiment of the first aspect, the present application provides (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide fumarate or a solvate or hydrate thereof.

[0080] In one embodiment of the first aspect, the present application provides (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide tartrate or a solvate or hydrate thereof.

[0081] In one embodiment of the first aspect, the present application provides (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide p-toluenesulfonate or a solvate or hydrate thereof.

[0082] In some embodiments of the first aspect, the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-eneamide acid addition salt provided herein is in the form of a solvate, wherein the solvate includes but is not limited to a solvate formed by one or more solvents selected from the group consisting of water, ethanol, ethylene glycol, (S)-propylene glycol, (R)-propylene glycol, and methyl tert-butyl ether. When the solvent molecule is water, the solvate is a hydrate. The solvate and / or hydrate is preferably present in solid form. The solvate and / or hydrate is preferably present in crystalline solid form. The solvate can also be an intermediate solvate used to prepare a more desirable solvate; the solvent in the intermediate solvate includes but is not limited to one or more selected from the group consisting of methanol, methyl tert-butyl ether, ethyl acetate, and methyl acetate.

[0083] In some embodiments of the first aspect, the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enoamide acid addition salt provided herein is in the form of a hydrate, such as a 0.25 hydrate (1 / 4 hydrate), a hemihydrate (1 / 2 hydrate), a monohydrate, a 5 / 4 hydrate, a sesquihydrate, a dihydrate, or a trihydrate, etc.

[0084] In some embodiments of the first aspect, the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enoamide acid addition salt provided herein is in the form of an anhydrous form, for example, its water content does not exceed 0.5 wt%, 0.4 wt%, 0.3 wt%, 0.2 wt%, 0.1 wt% or 0.09 wt% water.

[0085] In one embodiment of the first aspect, the present application provides (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enoamide acid addition salt or their solvates or hydrates, which are in solid form, preferably, in crystalline solid form.

[0086] In one embodiment of the first aspect, the present application provides (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enoamide acid addition salt or their solvates or hydrates, which are in solid form, preferably, in amorphous solid form.

[0087] In one embodiment of the first aspect, the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enoamide acid addition salt or a solvate or hydrate thereof provided herein is a crystalline (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enoamide maleate salt or a solvate or hydrate thereof, wherein the molar ratio of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enoamide to maleic acid is 1:1 or 1:2.

[0088] In one embodiment of the first aspect, the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enoamide acid addition salt or a solvate or hydrate thereof provided herein is amorphous (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enoamide maleate or a solvate or hydrate thereof, wherein the molar ratio of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enoamide to maleic acid is 1:1 or 1:2.

[0089] In one embodiment of the first aspect, the present application provides (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate, wherein the maleate is an anhydrate.

[0090] In one embodiment of the first aspect, the present application provides (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate hydrate.

[0091] In some embodiments of the first aspect, the present application provides (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate hydrate, wherein the molar ratio of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide to maleic acid is 1:2; in one embodiment, the hydrate The water content is from 2.1 wt% to 10.0 wt%, or, the water content is from 2.2 wt% to 9.2 wt%, or 2.3 wt% to 9.1 wt%, or 2.3 wt% to 8.0 wt%, or 2.1 wt% to 3.1 wt%, or 2.2 wt% to 2.8 wt%, or 2.3 wt% to 2.6 wt%, or 2.3 wt%, or 2.4 wt%, or 2.5 wt%, or 2.6 wt%; in one embodiment, the hydrate is a monohydrate.

[0092] In some embodiments of the first aspect, the present application provides (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate, wherein the molar ratio of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide to maleic acid is 1:2, and the maleate is anhydrous.

[0093] In one embodiment of the first aspect, the present application provides (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate, wherein the molar ratio of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide to maleic acid is 1:1.

[0094] In some embodiments of the first aspect, the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enoamide acid addition salt or a solvate or hydrate thereof provided herein is crystalline.

[0095] In one embodiment of the first aspect, the present application provides crystalline (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide hydrochloride or a solvate or hydrate thereof.

[0096] In one embodiment of the first aspect, the present application provides amorphous (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide hydrochloride or a solvate or hydrate thereof.

[0097] In one embodiment of the first aspect, the present application provides crystalline (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide sulfate or a solvate or hydrate thereof.

[0098] In one embodiment of the first aspect, the present application provides amorphous (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide sulfate or a solvate or hydrate thereof.

[0099] In one embodiment of the first aspect, the present application provides crystalline (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate, which is an anhydrate.

[0100] In one embodiment of the first aspect, the present application provides amorphous (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate, which is an anhydrate.

[0101] In one embodiment of the first aspect, the present application provides crystalline (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate hydrate.

[0102] In one embodiment of the first aspect, the present application provides amorphous (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate hydrate.

[0103] In one embodiment of the first aspect, the present application provides crystalline (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide fumarate or a solvate or hydrate thereof.

[0104] In one embodiment of the first aspect, the present application provides amorphous (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide fumarate or a solvate or hydrate thereof.

[0105] In one embodiment of the first aspect, the present application provides crystalline (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide tartrate or a solvate or hydrate thereof.

[0106] In one embodiment of the first aspect, the present application provides amorphous (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide tartrate or a solvate or hydrate thereof.

[0107] In one embodiment of the first aspect, the present application provides crystalline (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide p-toluenesulfonate or a solvate or hydrate thereof.

[0108] In one embodiment of the first aspect, the present application provides amorphous (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide p-toluenesulfonate or a solvate or hydrate thereof.

[0109] In some embodiments of the first aspect, the present application provides crystalline (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide hydrochloride, wherein the molar ratio of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide to HCl is 1:1.

[0110] In some embodiments of the first aspect, the present application provides crystalline (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide sulfate, wherein the molar ratio of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide to sulfuric acid is 1:1.

[0111] In some embodiments of the first aspect, the present application provides crystalline (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate or a hydrate thereof, wherein the molar ratio of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide to maleic acid is 1:1 or 1:2.

[0112] In one embodiment of the first aspect, the present application provides crystalline (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate or a hydrate thereof, wherein the molar ratio of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide to maleic acid is 1:2; in one embodiment, the maleate or its hydrate is crystalline; in one embodiment, the maleate hydrate is a monohydrate; in one embodiment, the maleate is an anhydrate.

[0113] In one embodiment of the first aspect, the present application provides a crystalline form A of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate hydrate, wherein the molar ratio of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide to maleic acid in the crystalline form A is 1:2; preferably, the crystalline form A has a purity greater than 90%; in some embodiments, the X-ray powder diffraction pattern of the crystalline form A includes characteristic peaks at 2θ of approximately 5.1±0.2 degrees, 5.7±0.2 degrees, 18.4±0.2 degrees, and 26.9±0.2 degrees. At least one of; in some embodiments, the X-ray powder diffraction pattern of Form A includes characteristic peaks at about 5.1±0.2 degrees, 5.7±0.2 degrees, 18.4±0.2 degrees and 26.9±0.2 degrees 2θ; in some embodiments, the X-ray powder diffraction pattern of Form A also includes characteristic peaks at about 18.0±0.2 degrees, 20.4±0.2 degrees, 21.1±0.2 degrees and 25.5±0.2 degrees 2θ; in some embodiments, its X-ray powder diffraction pattern includes characteristic peaks at about 5.1±0.2 degrees, 5.7±0.2 degrees, 18.0±0.2 degrees, 18.4±0.2 degrees, 20.4±0.2 degrees, 21.1±0.2 degrees, 25.5±0.2 degrees and 26.9±0.2 degrees 2θ. In one embodiment, its X-ray powder diffraction pattern includes the following characteristic peaks:

[0114] In one embodiment of the first aspect, the crystalline Form A of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate hydrate provided herein has an X-ray powder diffraction pattern substantially the same as that shown in Figure 1.

[0115] In one embodiment of the first aspect, the present application provides a crystalline form A of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate hydrate, wherein the water content of the crystalline form A is 2.1 wt% to 10.0 wt%, or, the water content is 2.2 wt% to 9.2 wt%, or 2.3 wt% to 9.1 wt%, or 2.3 wt% to 8.0 wt%, or 2.1 wt% to 3.1 wt%, or 2.2 wt% to 2.8 wt%, or 2.3 wt% to 2.6 wt%, or 2.3 wt%, or 2.4 wt%, or 2.5 wt%, or 2.6 wt%; in one embodiment, the crystalline form A is a monohydrate.

[0116] In one embodiment of the first aspect, the crystalline Form A of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate hydrate provided herein has a thermogravimetric analysis (TGA) graph substantially the same as that shown in Figure 2.

[0117] In one embodiment of the first aspect, the present application provides crystalline (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate, wherein the molar ratio of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide to maleic acid is 1:2; and the maleate is anhydrous.

[0118] In one embodiment of the first aspect, the present application provides a crystalline form B of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate, wherein the molar ratio of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide to maleic acid in the crystalline form B is 1:2, and preferably, the crystalline form B has a purity greater than 90%; in some embodiments, the X-ray powder diffraction pattern of the crystalline form B includes at least one of characteristic peaks at 2θ of approximately 5.1±0.2 degrees, 9.8±0.2 degrees, 10.1±0.2 degrees, 19.4±0.2 degrees, and 20.3±0.2 degrees; in some embodiments, the crystalline form B has a X-ray powder diffraction pattern of approximately 5.1±0.2 degrees, 9.8±0.2 degrees, 10.1±0.2 degrees, 19.4±0.2 degrees, and 20.3±0.2 degrees. The X-ray powder diffraction pattern of Form B includes characteristic peaks at 2θ of approximately 5.1±0.2 degrees, 9.8±0.2 degrees, 10.1±0.2 degrees, 19.4±0.2 degrees, and 20.3±0.2 degrees; in some embodiments, the X-ray powder diffraction pattern of Form B also includes characteristic peaks at 2θ of approximately 7.0±0.2 degrees, 18.4±0.2 degrees, 19.6±0.2 degrees, 22.3±0.2 degrees, and 25.1±0.2 degrees. In some embodiments, the X-ray powder diffraction pattern of Form B includes characteristic peaks at 2θ of approximately 5.1±0.2 degrees, 7.0±0.2 degrees, 9.8±0.2 degrees, 10.1±0.2 degrees, 18.4±0.2 degrees, 19.4±0.2 degrees, 19.6±0.2 degrees, 20.3±0.2 degrees, 22.3±0.2 degrees and 25.1±0.2 degrees. In one embodiment, the X-ray powder diffraction pattern of Form B includes the following characteristic peaks:

[0119] In one embodiment of the first aspect, the crystalline Form B of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate provided herein has an X-ray powder diffraction pattern substantially the same as that shown in Figure 4.

[0120] In one embodiment of the first aspect, the present application provides a crystalline form B of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate, wherein the crystalline form B is an anhydrate.

[0121] In one embodiment of the first aspect, the crystalline Form B of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate provided herein has a thermogravimetric analysis (TGA) graph substantially the same as that shown in Figure 5.

[0122] In one embodiment of the first aspect, the present application provides crystalline (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate, wherein the molar ratio of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide to maleic acid is 1:1.

[0123] In one embodiment of the first aspect, the present application provides a crystalline form C of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate, wherein the molar ratio of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide to maleic acid in the crystalline form C is 1:1, preferably, the crystalline form C has greater than 9 0% purity; in some embodiments, the X-ray powder diffraction pattern of the crystalline Form C includes at least one of the characteristic peaks at 2θ of approximately 5.4±0.2 degrees, 5.8±0.2 degrees, 18.2±0.2 degrees, 18.7±0.2 degrees, 19.0±0.2 degrees and 26.8±0.2 degrees; in some embodiments, the X-ray powder diffraction pattern of the crystalline Form C includes at least one of the characteristic peaks at 2θ of approximately 5.4±0.2 degrees, 5.8±0.2 degrees, 18.2±0.2 degrees, 18.7±0.2 degrees, 19.0±0.2 degrees and 26.8±0.2 degrees. .8±0.2 degrees 2θ characteristic peak; In some embodiments, the X-ray powder diffraction pattern of the crystalline Form C further comprises characteristic peaks at about 6.1±0.2 degrees, 22.3±0.2 degrees and 25.6±0.2 degrees 2θ characteristic peak; In some embodiments, the X-ray powder diffraction pattern of the crystalline Form C comprises characteristic peaks at about 5.4±0.2 degrees, 5.8±0.2 degrees, 6.1±0.2 degrees, 18.2±0.2 degrees, 18.7±0.2 degrees, 19.0±0.2 degrees, 22.3±0.2 degrees, 25.6±0. 2 degrees and 26.8±0.2 degrees; in some embodiments, the X-ray powder diffraction pattern of Form C includes characteristic peaks at 2θ of approximately 5.4±0.2 degrees, 5.8±0.2 degrees, 6.1±0.2 degrees, 18.2±0.2 degrees, 18.7±0.2 degrees, 19.0±0.2 degrees, 19.8±0.2 degrees, 21.5±0.2 degrees, 22.3±0.2 degrees, 22.8±0.2 degrees, 23.7±0.2 degrees, 25.6±0.2 degrees and 26.8±0.2 degrees. In one embodiment, the X-ray powder diffraction pattern of Form C includes the following characteristic peaks:

[0124] In one embodiment of the first aspect, the crystalline Form C of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate provided herein has an X-ray powder diffraction pattern substantially the same as that shown in Figure 6.

[0125] In one embodiment of the first aspect, the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide hydrochloride provided herein is crystalline, preferably, in Form S-1, wherein the Form S-1 of the hydrochloride has a purity greater than 90%; in some embodiments, the X-ray powder diffraction pattern of the Form S-1 includes at least one of the characteristic peaks at 2θ of approximately 6.1±0.2 degrees, 15.5±0.2 degrees, 18.1±0.2 degrees, 19.7±0.2 degrees, and 24.1±0.2 degrees; in some embodiments, the X-ray powder diffraction pattern of the Form S-1 includes at least one of the characteristic peaks at 2θ of approximately 6.1±0.2 degrees, 15.5±0.2 degrees, 18.1±0.2 degrees, 19.7±0.2 degrees, and 24.1±0.2 degrees. In some embodiments, the X-ray powder diffraction pattern of the crystalline Form S-1 further comprises characteristic peaks at 2θ of approximately 8.1±0.2 degrees, 19.7±0.2 degrees, and 24.1±0.2 degrees; in some embodiments, the X-ray powder diffraction pattern of the crystalline Form S-1 further comprises characteristic peaks at 2θ of approximately 14.9±0.2 degrees, 22.6±0.2 degrees, 23.3±0.2 degrees, 25.6±0.2 degrees, and 26.0±0.2 degrees; in some embodiments, the X-ray powder diffraction pattern of the crystalline Form S-1 comprises characteristic peaks at 2θ of approximately 6.1±0.2 degrees, 14.9±0.2 degrees, 15.5±0.2 degrees, 18.1±0.2 degrees, 19.7±0.2 degrees, 22.6±0.2 degrees, 23.3±0.2 degrees, 24.1±0.2 degrees, 25.6±0.2 degrees, and 26.0±0.2 degrees. In one embodiment, the X-ray powder diffraction pattern includes the following characteristic peaks:

[0126] In one embodiment of the first aspect, the crystalline form S-1 of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide hydrochloride provided herein has an X-ray powder diffraction pattern substantially the same as that shown in Figure 8.

[0127] In one embodiment of the first aspect, the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide hydrochloride provided herein is in the form S-2, and the form S-2 of the hydrochloride has a purity greater than 90%; in some embodiments, the X-ray powder diffraction pattern of the form S-2 includes at least one of the characteristic peaks at 2θ of approximately 18.8±0.2 degrees, 19.5±0.2 degrees, 20.4±0.2 degrees, 25.4±0.2 degrees, 25.8±0.2 degrees, and 26.3±0.2 degrees; in some embodiments, the X-ray powder diffraction pattern of the form S-2 includes at least one of the characteristic peaks at 2θ of approximately 18.8±0.2 degrees, 19.5±0.2 degrees, 20.4±0.2 degrees, 25.4±0.2 degrees, 25.8±0.2 degrees, and 26.3±0.2 degrees. , 20.4±0.2 degrees, 25.4±0.2 degrees, 25.8±0.2 degrees and 26.3±0.2 degrees 2θ; in some embodiments, the X-ray powder diffraction pattern of the crystalline Form S-2 further includes characteristic peaks at approximately 6.2±0.2 degrees, 12.6±0.2 degrees, 28.7±0.2 degrees and 29.9±0.2 degrees 2θ; in some embodiments, the X-ray powder diffraction pattern of the crystalline Form S-2 includes characteristic peaks at approximately 6.2±0.2 degrees, 12.6±0.2 degrees, 18.8±0.2 degrees, 19.5±0.2 degrees, 20.4±0.2 degrees, 25.4±0.2 degrees, 25.8±0.2 degrees, 26.3±0.2 degrees, 28.7±0.2 degrees and 29.9±0.2 degrees 2θ. In one embodiment, the X-ray powder diffraction pattern includes the following characteristic peaks:

[0128] In one embodiment of the first aspect, the crystalline form S-2 of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide hydrochloride provided herein has an X-ray powder diffraction pattern substantially the same as that shown in Figure 9.

[0129] In one embodiment of the first aspect, the sulfate salt of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide provided herein is crystalline, preferably, in crystalline form S-3, wherein the crystalline form S-3 of the sulfate salt has a purity of greater than 90%; in some embodiments, the X-ray powder diffraction pattern of the crystalline form S-3 includes at least one of the characteristic peaks at 2θ of approximately 5.2±0.2 degrees, 16.0±0.2 degrees, 25.4±0.2 degrees, and 26.1±0.2 degrees; in some embodiments, the X-ray powder diffraction pattern of the crystalline form S-3 includes at least one of the characteristic peaks at 2θ of approximately 5.2±0.2 degrees, 16.0±0.2 degrees, 25.4±0.2 degrees, and 26.1±0.2 degrees. 2 degrees, 16.0±0.2 degrees, 25.4±0.2 degrees and 26.1±0.2 degrees; in some embodiments, its X-ray powder diffraction pattern further comprises characteristic peaks at 2θ of about 17.7±0.2 degrees, 22.5±0.2 degrees, 24.5±0.2 degrees, 25.1±0.2 degrees and 26.6±0.2 degrees; or, its X-ray powder diffraction pattern comprises characteristic peaks at 2θ of about 5.2±0.2 degrees, 16.0±0.2 degrees, 17.7±0.2 degrees, 22.5±0.2 degrees, 24.5±0.2 degrees, 25.1±0.2 degrees, 25.4±0.2 degrees, 26.1±0.2 degrees and 26.6±0.2 degrees. In one embodiment, its X-ray powder diffraction pattern comprises the following characteristic peaks:

[0130] In one embodiment of the first aspect, the crystalline form S-3 of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide sulfate provided herein has an X-ray powder diffraction pattern substantially the same as that shown in Figure 10.

[0131] In one embodiment of the first aspect, the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide sulfate provided herein is in the crystalline form S-4. Preferably, the crystalline form S-4 of the sulfate has a purity greater than 90%. In some embodiments, the X-ray powder diffraction pattern of the crystalline form S-4 includes at least one of the characteristic peaks at 2θ of approximately 5.0±0.2 degrees, 20.6±0.2 degrees, 24.4±0.2 degrees, and 25.8±0.2 degrees. In some embodiments, the X-ray powder diffraction pattern of the crystalline form S-4 includes at least one of the characteristic peaks at 2θ of approximately 5.0±0.2 degrees, 20.6±0.2 degrees, 24.4±0.2 degrees, and 25.8±0.2 degrees. Characteristic peaks at 2θ of about 5.0±0.2 degrees, 20.6±0.2 degrees, 24.4±0.2 degrees and 25.8±0.2 degrees; in some embodiments, its X-ray powder diffraction pattern also includes characteristic peaks at 2θ of about 14.7±0.2 degrees, 16.7±0.2 degrees, 18.7±0.2 degrees and 23.0±0.2 degrees; or, its X-ray powder diffraction pattern includes characteristic peaks at 2θ of about 5.0±0.2 degrees, 14.7±0.2 degrees, 16.7±0.2 degrees, 18.7±0.2 degrees, 20.6±0.2 degrees, 23.0±0.2 degrees, 24.4±0.2 degrees and 25.8±0.2 degrees. In one embodiment, its X-ray powder diffraction pattern includes the following characteristic peaks:

[0132] In one embodiment of the first aspect, the crystalline form S-4 of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide sulfate provided herein has an X-ray powder diffraction pattern substantially the same as that shown in Figure 11.

[0133] In one embodiment of the first aspect, the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide sulfate provided herein is in the crystalline form S-5. Preferably, the crystalline form S-5 of the sulfate has a purity greater than 90%. In some embodiments, the X-ray powder diffraction pattern of the crystalline form S-5 includes at least one of the characteristic peaks at 2θ of approximately 21.0±0.2 degrees, 22.7±0.2 degrees, 24.7±0.2 degrees, and 26.4±0.2 degrees. In some embodiments, the X-ray powder diffraction pattern of the crystalline form S-5 includes at least one of the characteristic peaks at 2θ of approximately 21.0±0.2 degrees, 22.7±0.2 degrees, 24.7±0.2 degrees, and 26.4±0.2 degrees. In some embodiments, the X-ray powder diffraction pattern further comprises characteristic peaks at about 5.5±0.2 degrees, 18.9±0.2 degrees, 19.7±0.2 degrees, 22.3±0.2 degrees and 23.3±0.2 degrees 2θ; or, the X-ray powder diffraction pattern comprises characteristic peaks at about 5.5±0.2 degrees, 18.9±0.2 degrees, 19.7±0.2 degrees, 21.0±0.2 degrees, 22.3±0.2 degrees, 22.7±0.2 degrees, 23.3±0.2 degrees, 24.7±0.2 degrees and 26.4±0.2 degrees 2θ. In one embodiment, the X-ray powder diffraction pattern comprises the following characteristic peaks:

[0134] In one embodiment of the first aspect, the crystalline form S-5 of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide sulfate provided herein has an X-ray powder diffraction pattern substantially the same as that shown in Figure 12.

[0135] In one embodiment of the first aspect, the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide tartrate provided herein is crystalline, preferably, in crystalline form S-6, and the crystalline form S-6 of the tartrate has a purity greater than 90%; in some embodiments, the X-ray powder diffraction pattern of the crystalline form S-6 includes at least one of the characteristic peaks at 2θ of approximately 20.2±0.2 degrees, 20.6±0.2 degrees, 23.5±0.2 degrees, and 27.4±0.2 degrees; in some embodiments, the X-ray powder diffraction pattern of the crystalline form S-6 is Including characteristic peaks at 2θ of about 20.2±0.2 degrees, 20.6±0.2 degrees, 23.5±0.2 degrees, and 27.4±0.2 degrees; in some embodiments, its X-ray powder diffraction pattern also includes characteristic peaks at 2θ of about 18.7±0.2 degrees, 24.1±0.2 degrees, 24.9±0.2 degrees, and 36.5±0.2 degrees; or, its X-ray powder diffraction pattern includes characteristic peaks at 2θ of about 18.7±0.2 degrees, 20.2±0.2 degrees, 20.6±0.2 degrees, 23.5±0.2 degrees, 24.1±0.2 degrees, 24.9±0.2 degrees, 27.4±0.2 degrees, and 36.5±0.2 degrees. In one embodiment, its X-ray powder diffraction pattern includes the following characteristic peaks:

[0136] In one embodiment of the first aspect, the crystalline form S-6 of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide tartrate provided herein has an X-ray powder diffraction pattern substantially the same as that shown in Figure 13.

[0137] In one embodiment of the first aspect, the fumarate salt of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide provided herein is crystalline, preferably, in crystalline form S-7, wherein the crystalline form S-7 of the fumarate salt has a purity greater than 90%; in some embodiments, the X-ray powder diffraction pattern of the crystalline form S-7 includes at least one of the characteristic peaks at 2θ of approximately 6.9±0.2 degrees, 17.9±0.2 degrees, 22.7±0.2 degrees, 24.2±0.2 degrees, 25.4±0.2 degrees, and 25.7±0.2 degrees; in some embodiments, the X-ray powder diffraction pattern of the crystalline form S-7 includes at least one of the characteristic peaks at 2θ of approximately 6.9±0.2 degrees, 17.9±0.2 degrees, 22.7±0.2 degrees, 24.2±0.2 degrees, 25.4±0.2 degrees, and 25.7±0.2 degrees. In one embodiment, the X-ray powder diffraction pattern further comprises characteristic peaks at about 8.8±0.2 degrees, 24.9±0.2 degrees and 28.1±0.2 degrees 2θ; In one embodiment, the X-ray powder diffraction pattern comprises characteristic peaks at about 6.9±0.2 degrees, 8.8±0.2 degrees, 17.9±0.2 degrees, 22.7±0.2 degrees, 24.2±0.2 degrees, 24.9±0.2 degrees, 25.4±0.2 degrees, 25.7±0.2 degrees and 28.1±0.2 degrees 2θ; In one embodiment, the X-ray powder diffraction pattern comprises characteristic peaks at about 6.9±0.2 degrees, 8.8±0.2 degrees, 17.9±0.2 degrees, 22.7±0.2 degrees, 24.2±0.2 degrees, 24.9±0.2 degrees, 25.4±0.2 degrees, 25.7±0.2 degrees and 28.1±0.2 degrees 2θ; In one embodiment, the X-ray powder diffraction pattern comprises the following characteristic peaks:

[0138] In one embodiment of the first aspect, the crystalline form S-7 of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide fumarate provided herein has an X-ray powder diffraction pattern substantially the same as that shown in Figure 14.

[0139] In one embodiment of the first aspect, the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide p-toluenesulfonate provided herein is crystalline, preferably, in crystalline form S-8, wherein the crystalline form S-8 of the p-toluenesulfonate has a purity greater than 90%; in some embodiments, the X-ray powder diffraction pattern of the crystalline form S-8 includes at least one of the characteristic peaks at 2θ of approximately 5.7±0.2 degrees, 18.6±0.2 degrees, 20.2±0.2 degrees, 23.4±0.2 degrees, and 25.5±0.2 degrees; in some embodiments, the X-ray powder diffraction pattern of the crystalline form S-8 includes at least one of the characteristic peaks at 2θ of approximately 5.7±0.2 degrees, 18.6±0.2 degrees, 20.2±0.2 degrees, 23.4±0.2 degrees, and 25.5±0.2 degrees. In one embodiment, the X-ray powder diffraction pattern further comprises characteristic peaks at about 8.9±0.2 degrees, 10.1±0.2 degrees, 24.4±0.2 degrees, 25.0±0.2 degrees and 31.7±0.2 degrees 2θ; In one embodiment, the X-ray powder diffraction pattern comprises characteristic peaks at about 5.7±0.2 degrees, 8.9±0.2 degrees, 10.1±0.2 degrees, 18.6±0.2 degrees, 20.2±0.2 degrees, 23.4±0.2 degrees, 24.4±0.2 degrees, 25.0±0.2 degrees, 25.5±0.2 degrees and 31.7±0.2 degrees 2θ; In one embodiment, the X-ray powder diffraction pattern comprises characteristic peaks at about 5.7±0.2 degrees, 8.9±0.2 degrees, 10.1±0.2 degrees, 18.6±0.2 degrees, 20.2±0.2 degrees, 23.4±0.2 degrees, 24.4±0.2 degrees, 25.0±0.2 degrees, 25.5±0.2 degrees and 31.7±0.2 degrees 2θ; In one embodiment, the X-ray powder diffraction pattern comprises the following characteristic peaks:

[0140] In one embodiment of the first aspect, the crystalline form S-8 of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide p-toluenesulfonate provided herein has an X-ray powder diffraction pattern substantially the same as that shown in Figure 15.

[0141] In a second aspect, the present application provides a method for preparing the acid addition salt of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide or its solvate or hydrate according to the first aspect, the preparation method comprising mixing and reacting (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide (free base) and an acid in an organic solvent or a mixture of an organic solvent and water, and then performing solid-liquid separation to obtain the acid addition salt of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide or its solvate or hydrate.

[0142] In some embodiments of the second aspect, the organic solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, ethyl acetate, dichloromethane and acetonitrile; optionally, the organic solvent is anhydrous or aqueous, such as 90% v / v ethanol.

[0143] In some embodiments of the second aspect, the present application provides a method for preparing an acid addition salt of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide or a solvate or hydrate thereof, the preparation method comprising preparing (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide (free base) by the following steps:

[0144] (1)7-Fluoro-N 4 -(4-(4-fluorophenoxy)phenyl)-6-nitroquinazolin-4-amine reacts with sodium ethoxide to obtain 7-ethoxy-N4-(4-(4-fluorophenoxy)phenyl)-6-nitroquinazolin-4-amine;

[0145] (2) 7-ethoxy-N4-(4-(4-fluorophenoxy)phenyl)-6-nitroquinazolin-4-amine is subjected to reduction reaction to obtain 7-ethoxy-N4-(4-(4-fluorophenoxy)phenyl)-6-nitroquinazolin-4-amine. 4 -(4-(4-fluorophenoxy)phenyl)quinazoline-4,6-diamine;

[0146] (3)7-ethoxy-N 4 -(4-(4-fluorophenoxy)phenyl)quinazoline-4,6-diamine reacts with diethylphosphinoacetic acid to obtain diethyl (2-((7-ethoxy-4-((4-(4-fluorophenoxy)phenyl)amino)quinazolin-6-yl)amino)-2-oxoethyl)phosphonate;

[0147] (4) Diethyl (2-((7-ethoxy-4-((4-(4-fluorophenoxy)phenyl)amino)quinazolin-6-yl)amino)-2-oxoethyl)phosphonate reacts with 2-dimethylaminoacetaldehyde to give (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide (free base);

[0148] Furthermore, in step (1), an anhydrous ethanol solution of sodium ethoxide may be added dropwise; and / or

[0149] Step (2) can be carried out by palladium carbon hydrogenation or iron powder and acetic acid reduction; and / or

[0150] The reaction described in step (3) is that N, N-carbonyldiimidazole reacts with diethylphosphinoacetic acid first and then reacts with 7-ethoxy-N 4 -(4-(4-fluorophenoxy)phenyl)quinazoline-4,6-diamine reaction; and / or

[0151] Step (4) controlling the temperature of the reaction system to -10 to 0°C; then adding dropwise the sodium bisulfite salt of 2-dimethylaminoacetaldehyde; and recrystallizing with n-heptane after the reaction is completed.

[0152] In some embodiments of the second aspect, the present application provides a method for preparing (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide (free base) form F-1, the preparation method comprising mixing (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide (free base) with ethyl acetate. The product is prepared by combining the following: mixing the mixture, heating to reflux to dissolve, naturally cooling to room temperature to crystallize (i.e., standing to crystallize), stirring at room temperature for more than 1 hour, filtering the obtained solid with suction, and drying the obtained product; or, mixing (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide (free base) with n-heptane, water, or a solvent system of methanol and water (e.g., a volume ratio of 1:2), stirring at room temperature for 12-24 hours, filtering the obtained solid with suction, and drying the obtained product.

[0153] In some embodiments of the second aspect, the present application provides a method for preparing (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide (free base) crystalline form F-2, the preparation method comprising mixing (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide (free base) with ethyl acetate, heating to reflux to dissolve, then naturally cooling to room temperature for crystallization (i.e., standing for crystallization), and filtering the solid to obtain the product and drying it.

[0154] In some embodiments of the second aspect, the present application provides a method for preparing (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide (free base) crystalline form F-3, the preparation method comprising (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide (free base) and an acetone-water solvent system (e.g., a volume ratio of 3:2) or an ethanol aqueous solution (e.g., 80% v / v ) are mixed, the temperature is raised to reflux for dissolution, and then naturally cooled to room temperature for crystallization (i.e., standing for crystallization), and then stirred at room temperature for more than 1 hour, and the solid obtained by suction filtration is dried to obtain the product; alternatively, (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide (free base) is mixed with ethyl acetate, acetonitrile, an acetone-water solvent system (e.g., a volume ratio of 1:1), an ethanol and water solvent system (e.g., a volume ratio of 1:1), or isopropanol, and stirred at room temperature for 12-24 hours, and filtered, and the solid obtained is dried to obtain the product.

[0155] In some embodiments of the second aspect, the present application provides a method for preparing (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide (free base) crystalline form F-4, the preparation method comprising mixing (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide (free base) with acetonitrile or ethyl acetate-n-heptane solvent system (for example, a volume ratio of 1:1), heating to reflux to dissolve, then naturally cooling to room temperature to crystallize (i.e., standing to crystallize), and then stirring at room temperature for more than 1 hour, filtering and drying the solid obtained.

[0156] In some embodiments of the second aspect, the present application provides a method for preparing (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide (free base) crystalline form F-5, the preparation method comprising mixing (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide (free base) with a methanol-water solvent system (e.g., a volume ratio of 9:4), heating to reflux to dissolve, then naturally cooling to room temperature for crystallization (i.e., standing for crystallization), and then stirring at room temperature for more than 1 hour, filtering and drying the solid obtained.

[0157] In some embodiments of the second aspect, the present application provides a method for preparing (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide (free base) crystalline form F-6, the preparation method comprising mixing (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide (free base) with isopropanol, heating to reflux to dissolve, then naturally cooling to room temperature to crystallize (i.e., standing to crystallize), then stirring at room temperature for more than 1 hour, filtering the obtained solid and drying it.

[0158] In some embodiments of the second aspect, the present application provides a method for preparing (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate crystalline form A, the preparation method comprising (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate crystalline form A. Enamide (free base) and maleic acid are stirred in acetone at room temperature for half an hour, and the solid obtained by filtration is dried to obtain the product; alternatively, (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide (free base) and maleic acid are stirred in methanol or 90% ethanol at room temperature for half an hour, then the temperature is cooled to about -5°C and allowed to stand for more than 2 hours or overnight, and the precipitated solid is filtered and dried to obtain the product.

[0159] In some embodiments of the second aspect, the present application provides a method for preparing (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate form B, which comprises stirring (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide (free base) and maleic acid in ethyl acetate at room temperature for half an hour, and then filtering the solid to obtain the product and drying it.

[0160] In some embodiments of the second aspect, the present application provides a method for preparing (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate form C, which comprises stirring (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide (free base) and maleic acid in anhydrous ethanol or acetonitrile at room temperature for half an hour, and then filtering the solid to obtain the product and drying it.

[0161] In some embodiments of the second aspect, the present application provides a method for preparing (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide hydrochloride form S-1, which comprises stirring (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide (free base) and hydrochloric acid in anhydrous ethanol at room temperature for half an hour, cooling to about -5°C and standing for more than 2 hours or overnight, and filtering and drying the precipitated solid.

[0162] In some embodiments of the second aspect, the present application provides a method for preparing (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide sulfate crystal form S-3, which comprises stirring (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide (free base) and sulfuric acid in anhydrous ethanol at room temperature for half an hour, and then filtering the obtained solid and drying it.

[0163] In some embodiments of the second aspect, the present application provides a method for preparing (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide tartrate crystalline form S-6, the preparation method comprising (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide (free base) and tartaric acid in an acetone-water solvent system (e.g., a volume ratio of 4:1), anhydrous ethanol The product can be obtained by stirring the product at room temperature for half an hour in a 90% ethanol-water solvent system (e.g., a volume ratio of 3:1), an isopropanol-water solvent system (e.g., a volume ratio of 3:1), or an acetonitrile-water solvent system (e.g., a volume ratio of 12:1), and filtering the resulting solid to obtain the product. Alternatively, (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide (free base) and tartaric acid in 90% ethanol at room temperature for half an hour, then cooling the temperature to about -5°C and allowing the mixture to stand for more than 2 hours or overnight. The precipitated solid can then be filtered and dried to obtain the product.

[0164] In some embodiments of the second aspect, the present application provides a method for preparing (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide fumarate crystalline form S-7, the method comprising: (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide (free base) and fumaric acid are stirred in methanol at room temperature for half an hour, then cooled to about -5°C and allowed to stand for more than 2 hours or overnight, and the precipitated solid is filtered and dried.

[0165] In some embodiments of the second aspect, the present application provides a method for preparing (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide p-toluenesulfonate crystalline form S-8, the method comprising: (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide (free base) and p-toluenesulfonic acid are stirred in acetonitrile at room temperature for half an hour, then cooled to about -5°C and allowed to stand for more than 2 hours or overnight, and the precipitated solid is filtered and dried.

[0166] In a third aspect, the present application provides a pharmaceutical composition comprising the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide, its acid addition salt, or their solvates or hydrates according to the first aspect.

[0167] In some embodiments of the third aspect, the pharmaceutical composition may further be formulated with an excipient.

[0168] In some embodiments of the third aspect, the pharmaceutical composition is a solid oral dosage form.

[0169] In some embodiments of the third aspect, the unit dose of the pharmaceutical composition is 25 mg to 700 mg, or 35 mg to 500 mg, or 40 mg to 400 mg, or 50 mg to 350 mg, or 50 mg to 250 mg; or the unit dose is 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg 6mg, 57mg, 58mg, 59mg, 60mg, 61mg, 62mg, 63mg, 64mg, 65mg, 66mg, 67mg, 68mg, 69mg, 70mg, 71mg, 72mg, 73mg, 74 mg, 75mg, 76mg, 77mg, 78mg, 79mg, 80mg, 81mg, 82mg, 83mg, 84mg, 85mg, 86mg, 87mg, 88mg, 89mg, 90mg, 91mg, 92mg , 93mg, 94mg, 95mg, 96mg, 97mg, 98mg, 99mg, 100mg, 105mg, 110mg, 115mg, 120mg, 120mg, 125mg, 130mg, 135mg, 1 40mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 210mg, 220mg, 230 or 450 mg, wherein the weight is calculated based on (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide.

[0170] In some embodiments of the third aspect, the present application provides a pharmaceutical composition comprising (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide (free base), or a solvate or hydrate thereof; in some embodiments, the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide (free base) is an amorphous solid form; in some embodiments, the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide (free base) is a crystalline solid form; basically comprising one or a mixture of two or more of crystalline forms F-1 to F-6.

[0171] In some embodiments of the third aspect, the present application provides a pharmaceutical composition comprising an acid addition salt of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enoamide or a solvate or hydrate thereof; wherein the acid in the acid addition salt is hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, fumaric acid, malonic acid, succinic acid, tartaric acid, citric acid, fumaric acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, cinnamic acid or benzoic acid.

[0172] In some embodiments, the present application provides a pharmaceutical composition comprising (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide hydrochloride or a solvate or hydrate thereof. In some examples, the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide hydrochloride or a solvate or hydrate thereof can be a crystalline solid form or an amorphous solid form as described above; in some embodiments, the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide hydrochloride or a solvate or hydrate thereof is one of crystalline forms S-1 and S-2 or a mixture of both.

[0173] In some embodiments, the present application provides a pharmaceutical composition comprising (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate or a solvate or hydrate thereof. In some examples, the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate or a solvate or hydrate thereof can be a crystalline solid form or an amorphous solid form as described above; in some embodiments, the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate or a solvate or hydrate thereof is one of Form A, Form B and Form C, or a mixture of both.

[0174] In some embodiments, the present application provides a pharmaceutical composition comprising (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide sulfate or a solvate or hydrate thereof. In some examples, the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide sulfate or a solvate or hydrate thereof can be a crystalline solid form or an amorphous solid form as described above; in some embodiments, the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide sulfate or a solvate or hydrate thereof is one of crystalline forms S-3, S-4 and S-5, or a mixture of both.

[0175] In some embodiments, the present application provides a pharmaceutical composition comprising (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide tartrate or a solvate or hydrate thereof. In some examples, the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide tartrate or a solvate or hydrate thereof is as described above, and can be a crystalline solid form or an amorphous solid form; in some embodiments, the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide tartrate or a solvate or hydrate thereof is crystalline form S-6.

[0176] In some embodiments, the present application provides a pharmaceutical composition comprising (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide fumarate or a solvate or hydrate thereof. In some examples, the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide fumarate or a solvate or hydrate thereof is as described above, and can be a crystalline solid form or an amorphous solid form; in some embodiments, the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide fumarate or a solvate or hydrate thereof is crystalline form S-7.

[0177] In some embodiments, the present application provides a pharmaceutical composition comprising (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide p-toluenesulfonate or a solvate or hydrate thereof. In some examples, the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide p-toluenesulfonate or a solvate or hydrate thereof can be a crystalline solid form or an amorphous solid form as described above; in some embodiments, the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide p-toluenesulfonate or a solvate or hydrate thereof is crystalline form S-8.

[0178] In a fourth aspect, the present application provides the use of the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide, its acid addition salt or their solvate or hydrate of the first aspect, or the pharmaceutical composition of the third aspect in the preparation of a drug for preventing, inhibiting or treating cancer.

[0179] In the fifth aspect, the present application provides the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide, its acid addition salt or their solvate or hydrate or the pharmaceutical composition of the third aspect of the first aspect, for use as a medicine.

[0180] In the sixth aspect, the present application provides the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide, its acid addition salt or their solvate or hydrate or the pharmaceutical composition of the third aspect of the first aspect, for use in preventing, inhibiting or treating cancer.

[0181] In the seventh aspect, the present application provides a method for preventing, inhibiting or treating cancer, which comprises administering a therapeutically effective amount of the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enoamide acid of the first aspect, its addition salt or their solvate or hydrate or the pharmaceutical composition of the third aspect to a subject in need thereof.

[0182] In the embodiments of the fourth, sixth, and seventh aspects of the present application, the cancer is a HER2-positive cancer, in particular a HER2-positive advanced cancer; the HER2-positivity includes but is not limited to any one or a combination of HER2 protein overexpression, HER2 gene amplification, and HER2 gene mutation; in particular, the cancer is selected from one or more of breast cancer, ovarian cancer, epithelial cancer, colorectal cancer, renal cancer, bladder cancer, laryngeal cancer, esophageal cancer, salivary gland cancer, submandibular cancer, gastric cancer, and lung cancer, in particular breast cancer, ovarian cancer, gastric cancer, and / or colorectal cancer; more particularly, cancer with brain metastasis, including but not limited to breast cancer with brain metastasis, ovarian cancer with brain metastasis, gastric cancer with brain metastasis, and / or colorectal cancer with brain metastasis.

[0183] In the embodiment schemes of the fourth aspect, the sixth aspect to the seventh aspect of the present application, the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enoamide acid of the first aspect, its addition salt or their solvate or hydrate or the pharmaceutical composition of the third aspect. In some embodiments, an administration mode of the present application is a unit dosage form, with a unit dose of 25 mg to 700 mg, or 35 mg to 500 mg, or 40 mg to 400 mg, or 50 mg to 350 mg; or 50 mg to 250 mg, or a unit dose of 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57mg, 58mg, 59mg, 60mg, 61mg, 62mg, 63mg, 64mg, 65mg, 66mg, 67mg, 68mg, 69mg, 70mg, 71mg, 72mg, 73mg, 74mg, 75mg, 76mg, 77mg, 78mg, 79mg, 80mg, 81mg, 82mg, 83mg, 84mg, 85mg, 86mg, 87mg, 88mg, 89mg, 90mg, 91mg, 92mg, 93mg, 94mg, 9 5mg, 96mg, 97mg, 98mg, 99mg, 100mg, 105mg, 110mg, 115mg, 120mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg , 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg , 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg or 450 mg, wherein the weight is calculated as (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide; suitable unit dosage forms include tablets in sachets or bottles, capsules and powders.In one embodiment, the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enoacid, its addition salt, or its solvate or hydrate, or its pharmaceutical composition of the present application can be administered orally; it can be administered from 1 to 6 times a day, more usually from 1 to 4 times a day, or once a day. The therapeutically effective amount will be known to those skilled in the art; the therapeutically effective amount may also depend on the form of the compound, the mode of administration, and the severity of the condition being treated; the therapeutically effective amount is 0.01-500 mg / kg, preferably 0.01-50 mg / kg, further 0.1-10 mg / kg; the number of administrations is 1 to 4 times a day. For example, satisfactory results may be obtained with the compounds of the present application when administered in the range of about 0.5 mg / kg to about 10 mg / kg body weight per day, but generally an effective dose is between about 0.5 mg / kg / day to about 8 mg / kg / day.

[0184] the term

[0185] Unless expressly indicated otherwise, the term "approximately" is synonymous with "about." When used with respect to a recited amount, value, or duration, the term "approximately" or "about" refers to ±10%, ±8%, ±6%, ±5%, ±4%, or ±2% of the recited amount, value, or duration; in one embodiment, "approximately" and "approximately" refer to ±5% of the recited amount, value, or duration; in another embodiment, "approximately" and "approximately" refer to ±2% of the recited amount, value, or duration. When the term "approximately" or "about" is used with respect to recited XRPD peaks, the term refers to the recited X-ray powder diffraction peaks at 2θ±0.3°, 2θ±0.2°, or 2θ±0.1°; in one embodiment, the term "approximately" or "approximately" refers to the recited X-ray powder diffraction peaks at 2θ±0.2°; in another embodiment, the term "approximately" or "approximately" refers to the recited X-ray powder diffraction peaks at 2θ±0.1°. When the terms "approximately" or "about" are used when reciting a temperature or a temperature range, these terms refer to the recited temperature or temperature range ±5°C, ±2°C, or ±1°C; in one embodiment, the terms "approximately" or "approximately" refer to the recited temperature or temperature range ±2°C; in another embodiment, the terms "approximately" and "approximately" refer to the recited temperature or temperature range ±1°C.

[0186] As used herein, the term "acid addition salt" refers to a pharmaceutically acceptable salt of an amine-type compound that is suitable for pharmaceutical use, preferably for use in humans and lower animals without excessive stimulation, allergic reactions, etc. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J Pharmaceutical Sciences, 66: 1-19 (1977), which is incorporated herein by reference. As generally described below, the salts can be prepared in situ during the final isolation and purification of the trisubstituted quinazoline derivatives of the present invention, or separately prepared by reacting the free base functional group with a suitable reagent. For example, the type of acid addition salt includes, but is not limited to, acid addition salts formed by reacting the free base form of the compound with a pharmaceutically acceptable acid such as an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or an organic acid such as acetic acid, propionic acid, glycolic acid, oxalic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, fumaric acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, xinafoic acid, benzoic acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, or salicylic acid. In one embodiment, the salt precipitates and crystallizes (i.e., if crystalline) after cooling (slowly or rapidly). In addition, the present invention also includes hemi-salts, mono-salts, di-salts, tri-salts, and poly-salts of the compounds of the present invention. Similarly, the present invention also includes the compound, its salt, or hemihydrate, monohydrate, dihydrate, trihydrate, and polyhydrate forms. In some embodiments, the acid addition salts of the compound include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate or metaphosphate, acetate, propionate, hexanoate, cyclopentanepropionate, glycolate, pyruvate, lactate, malonate, succinate, malate, maleate, oxalate, fumarate, trifluoroacetate, tartrate, citrate, fumarate, benzoate, 3-(4-hydroxybenzoyl)benzoate, cinnamate, mandelate, methanesulfonate, ethanesulfonate, 1 , 2-ethanedisulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, p-toluenesulfonate, 2-naphthalenesulfonate, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylate, glucoheptonate, 4',4-methylenebis-(3-hydroxy-2-ene-1-carboxylate), 3-phenylpropionate, pivalate, tert-butylacetate, lauryl sulfate, gluconate, glutamate, hydroxynaphthoate, salicylate, stearate, muconate, butyrate, phenylacetate, phenylbutyrate, valproate, etc. In a preferred embodiment, the compound is a hydrochloride, sulfate, maleate, tartrate, fumarate, or p-toluenesulfonate, or a hydrate thereof, such as a monohydrate.

[0187] As used herein, the term "crystalline" means having a regularly repeating arrangement of molecules or external surface planes. Crystal forms may differ in thermodynamic stability, physical parameters, x-ray structure, and method of preparation.

[0188] As used herein, the term "anhydrous" refers to a crystalline form that does not contain a crystalline lattice of water molecules.

[0189] "Hydrate" or "solvate" refers to a crystalline form of a compound combined with water or other solvent molecules. These solvent molecules (such as water or organic solvents) are physically or chemically bound to the main compound and become part of the crystal structure.

[0190] As used herein, the term "substantially the same" means taking into account the typical variability of a particular method. For example, with reference to X-ray diffraction peak positions, the term "substantially the same" means taking into account the typical variability of peak positions and intensities. Those skilled in the art will understand that peak positions (2θ) will show some variability, typically up to ±0.2 degrees. In addition, those skilled in the art will understand that relative peak intensities will show variability between devices, as well as variability due to crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be considered only as qualitative measurements. Substantially identical peak shape, peak position, and peak intensity are equivalent to the same crystalline form, even though there are differences in some details of the X-ray diffraction pattern, which may be caused by the sample preparation process and / or testing.

[0191] "Crystal form" or "crystal modification" or "polymorphic form" or "polymorph" refers to the phenomenon in which the same chemical substance exists in different crystal structures. These different crystal structures may differ in molecular arrangement, lattice parameters and physicochemical properties, but may have the same chemical composition.

[0192] As used herein, the term "amorphous" refers to the non-crystalline solid state form of matter; amorphous solids consist of a disordered arrangement of molecules and have no distinguishable crystal lattice.

[0193] As used herein, the term "substantially pure" with respect to a crystalline form means that the crystalline form of the compound contains at least 90% by weight, preferably at least 95% by weight, more preferably at least 97% by weight, and most preferably at least 99% by weight of the specified crystalline form (e.g., Form A). Alternatively, it will be understood that "substantially phase pure" means that the crystalline form contains less than 10% by weight, preferably less than 5% by weight, more preferably less than 3% by weight, and most preferably less than 1% by weight of impurities, including other polymorphs, solvates, or amorphous forms.

[0194] As used herein, "substantially pure" includes "substantially phase pure" and / or "substantially chemically pure," wherein "substantially phase pure" refers to the purity relative to other solid forms of the compound and does not necessarily mean a high degree of chemical purity relative to other compounds; "substantially chemically pure" refers to a substance with extremely high purity and extremely low impurity content, which can generally meet the requirements of most chemical experiments or industrial applications. Although it may not be absolutely 100% pure, its purity is sufficient to ensure that it will not significantly affect the results in a specific application.

[0195] As used herein, "seed crystals" refer to small crystals introduced during the crystallization process to promote the crystallization of the target substance. They act as templates, guiding the orderly arrangement of molecules or ions in a solution or melt to form larger crystals.

[0196] As used herein, the term "therapeutically effective amount" refers to an amount of a compound administered that alleviates to some extent one or more symptoms of the disorder being treated. With reference to the treatment of cancer, a therapeutically effective amount refers to an amount that: (1) reduces tumor size, (2) inhibits (i.e., slows to some extent, preferably stops) tumor metastasis, (3) inhibits to some extent (i.e., slows to some extent, preferably stops) tumor growth or tumor invasion, and / or (4) alleviates to some extent (or preferably eliminates) one or more signs or symptoms associated with cancer.

[0197] As used herein, "individual" or "subject" refers to an animal used for experiment or research; preferably, the animal is a mammal; "individual" or "subject" is a primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, etc. In one embodiment, the "individual" or "subject" is a human.

[0198] As used herein, the terms “a,” “an,” and “the,” and any similar referents, in the context of the claims and the specification, should be understood to include both the singular and the plural, unless explicitly stated otherwise or the context clearly indicates a singular meaning.

[0199] As used herein, the term "treat" is defined as the application or administration of a therapeutic agent to a patient, or to a tissue or cell line isolated from a patient, who has a disease, a symptom of a disease, or a predisposition to the disease, with the intention of curing, reversing, alleviating, resolving, altering, correcting, alleviating, improving, or otherwise affecting the disease, a symptom of a disease, or a predisposition to the disease.

[0200] As used herein, the term "preventing" any disease or condition means delaying the onset or development or progression of the disease or condition.

[0201] As used herein, the terms "include" or "comprising" and "consisting of" mean "including."

[0202] As used herein, the term "pharmaceutical combination" or "combination product" or "combination product" refers to a pharmaceutical composition that can be administered to a patient in need of treatment, which can be in any conventional formulation (for example, in the form of powder, granules, pills, capsules, lozenges, solutions, suspensions or patches, etc.).

[0203] "Co-administration" or "combination administration", "combination administration", "combination therapy" or "combination therapy" includes the administration of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enolamic acid, an addition salt thereof, or a solvate or hydrate thereof, or a pharmaceutical composition thereof, and one or more therapeutic agents as part of a specific treatment regimen intended to provide a beneficial effect from the combined action of these therapeutic agents; the combined administration of these therapeutic agents is generally carried out within a defined time period (usually minutes, hours, days or weeks, depending on the combination selected). "Combination therapy" or "combination therapy" is intended to include sequential administration of these therapeutic agents, i.e., wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents or at least two therapeutic agents in a substantially simultaneous manner. For example, substantially simultaneous administration can be achieved by administering to the subject a single dose having a fixed ratio of each or more therapeutic agents or multiple separate doses of each therapeutic agent. Sequential or substantially simultaneous administration of each therapeutic agent is achieved by any suitable route, including but not limited to oral, intravenous, intramuscular, and direct absorption through mucosal tissues. The therapeutic agents can be administered by the same route or by different routes. The order in which the therapeutic agents are administered is not strictly critical. DETAILED DESCRIPTION

[0204] 1. Powder X-ray Diffraction (XRPD, or XRD)

[0205] Instrument name: X-ray powder diffractometer

[0206] Instrument model: Ultima IV / Miniflex

[0207] Merchant: Rigaku

[0208] Detector: D / tex high energy and high speed detector.

[0209] Testing conditions:

[0210] X-ray: Cu / 40KV / 40mA

[0211] Wavelength: 0.15406nm

[0212] Scanning speed: 60.000 degrees / min / 10.000 degrees / min.

[0213] Sampling width: 0.0200 degrees / 0.0200 degrees

[0214] Scanning range: 4.0000 to 60.0000 degrees / 3.0000 to 60.0000 degrees.

[0215] 2. Thermogravimetric analysis (TGA)

[0216] TGA experimental instrument: American TA Q5000

[0217] Test method: heating from room temperature to 300.00℃ at 10.00℃ / min / heating from room temperature to 300.00℃ at 5.00℃ / min.

[0218] 3. Nuclear Magnetic Resonance Analysis (NMR)

[0219] NMR instrument: Superconducting high-resolution nuclear magnetic resonance spectrometer Bruce AVANCE II 400 MHz.

[0220] 4. LC-MS

[0221] LC-MS instrument: Agilent 6120 Single Quadrupole liquid chromatography-mass spectrometer.

[0222] Example 1 Preparation of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide

[0223] 7-Fluoro-N 4 -(4-(4-fluorophenoxy)phenyl)-6-nitroquinazolin-4-amine (980g) and anhydrous ethanol (9.8L) were cooled to 5-10°C, and an anhydrous ethanol solution of sodium ethoxide (1611g, 21%) was slowly added dropwise over 1 hour. The mixture was heated to 60-70°C and reacted for 16 hours. The reaction solution was cooled and slowly poured into a mixed solution of dichloromethane and water (20L / 20L), and the liquids were separated; the separated aqueous phase was extracted again with dichloromethane (13L), the organic phases were combined, washed with water (13L), and the liquids were separated; the organic phase was dried over anhydrous sodium sulfate, dried under reduced pressure, and then slurried with n-heptane, filtered, and dried to obtain a yellow solid 7-ethoxy-N 4 -(4-(4-fluorophenoxy)phenyl)-6-nitroquinazolin-4-amine, 940 g, yield 89.9%. LC-MS: M+1=420.9

[0224] At room temperature, 7-ethoxy-N 4 -(4-(4-fluorophenoxy)phenyl)-6-nitroquinazolin-4-amine (200g) was dissolved in tetrahydrofuran (2L) and added to a 5L reaction flask together with anhydrous ethanol (1L). 10% wet palladium carbon (20g) was added and stirred evenly. The reaction solution was added to a 5L autoclave. Hydrogen was introduced and pressurized to 0.3MPa, the temperature was raised to 50-55°C, and the reaction was carried out for 5 hours to obtain a crude product. The crude product was mixed with the crude product obtained from other batches and dried under reduced pressure. After beating with n-heptane, filtering and drying (15-20°C), an orange solid IM1 (i.e., 7-ethoxy-N 4 -(4-(4-fluorophenoxy)phenyl)quinazoline-4,6-diamine), 600 g, purity 99.76%, yield 81%. LC-MS: M+1 = 391.2.

[0225] At room temperature, add N,N-carbonyldiimidazole (126.2 g) and tetrahydrofuran (0.3 L) to a 5 L three-necked reaction flask and stir evenly; add a solution of diethylphosphinoacetic acid (150 g) in tetrahydrofuran (0.3 L) dropwise; heat to 40 ° C and stir for 30 min. 4 143 g of 4-(4-fluorophenoxy)phenyl)quinazoline-4,6-diamine was suspended in tetrahydrofuran (0.9 L) and added to the above reaction system. The reaction was continued at 40°C for at least 2 h. After completion of the reaction, the mixture was filtered while hot and dried by rotary evaporation. The mixture was then recrystallized from 95% ethanol. Filtered and dried with suction to obtain 170 g of IM2 (diethyl (2-((7-ethoxy-4-((4-(4-fluorophenoxy)phenyl)amino)quinazolin-6-yl)amino)-2-oxoethyl)phosphonate) as a yellow solid with a purity of 99.41% and a yield of 77.8%. LC-MS: M+1 = 569.2.

[0226] At room temperature, IM2 (156 g), tetrahydrofuran (0.78 L), and anhydrous lithium chloride (13.9 g) were added to a 5 L three-necked flask, stirred, and cooled to below -5°C. Potassium hydroxide solution (154 g / 0.77 L water) was added dropwise, maintaining the system temperature at -10 to 0°C. 2-dimethylaminoacetaldehyde sodium bisulfite (105 g / 0.315 L water) was then added dropwise. After the reaction was complete, the mixture was spin-dried to obtain a crude solid compound, the title compound. This was then recrystallized from n-heptane and filtered to dryness to obtain the title compound, (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide, 110 g, with a purity of 99.20%. LC-MS: M+1 = 502.2, M+2 / 2 = 251.6. 1HNMR(DMSO-d6,400MHz):1.457(t,J1=6.8,J2=7.2,3H),2.188(s,6H),3.092(t,J1=0.8,J2=5.2,2H),4.275(q,J1=6.8,J2=7.2 2H),6.598(s,1H),6.793-6.832(m,1H),7.017-7.089(m,4H),7.202-7.246(m,3H),7. 797(q,J1=3.2,J2=2.4,1H),8.461(s,1H),8.925(s,1H),9.505(s,1H),9.697(s,1H).

[0227] Example 2 Preparation of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate Form A

[0228] Preparation of maleate salt form A:

[0229] At room temperature, 278.9 mg (0.56 mmol, 1.0 eq) of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide (from Example 1) was weighed into a 50 ml single-necked flask and dissolved with 12 ml of 90% isopropanol. Separately, 129 mg (1.11 mmol, 2.0 eq) of maleic acid was weighed and dissolved in 1 ml of 90% isopropanol. The solution was then added dropwise to the reaction flask. The mixture was stirred at room temperature overnight, filtered, rinsed with a small amount of 90% isopropanol, and air-dried at 40°C for 8 h to yield 346 mg of a yellow solid (maleate salt Form A).

[0230] Its XPRD, TGA and NMR are shown in Figures 1-3. The XPRD spectrum data are as follows:

[0231] Similarly, Form A was prepared in the following manner:

[0232] Its XPRD is shown in Figure 28.

[0233] Example 3 Preparation of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate Form B

[0234] Preparation of maleate salt form B:

[0235] At room temperature, 247.3 mg (0.493 mmol, 1.0 eq) of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide (from Example 1) was weighed into a 50 ml single-necked flask and 3 ml of 95% ethanol was added and stirred to dissolve. Separately, 114.5 mg (0.986 mmol, 2.0 eq) of maleic acid was weighed and dissolved in 2 ml of 95% ethanol (aqueous solution) and added dropwise to the reaction flask. The temperature was raised to 60°C for dissolution. An additional 37 ml of 95% ethanol was added until the solid was completely dissolved. The mixture was allowed to stand in an oil bath and naturally cooled to room temperature for crystallization overnight. The mixture was filtered and air-dried at 40°C for 7 h to obtain 194 mg of a solid (maleate salt Form B). Its XPRD and TGA data are shown in Figures 4-5. The XPRD spectrum data are shown below:

[0236] Example 4 Preparation of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate Form C

[0237] Preparation of maleate salt form C:

[0238] At room temperature, 231 mg (0.46 mmol, 1.0 eq) of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide (from Example 1) was weighed into a 5 ml plastic tube and 1 ml of anhydrous ethanol was added and stirred to dissolve. Separately, 53.5 mg (0.46 mmol, 1.0 eq) of maleic acid was weighed and dissolved in 0.2 ml of anhydrous ethanol. The mixture was then added dropwise to the plastic tube from the previous step and stirred at room temperature for 25 min, resulting in the precipitation of a large amount of solid. After standing overnight, the mixture was filtered, rinsed with 0.2 ml of anhydrous ethanol, and air-dried at 40°C for 1 hour 50 minutes to obtain 171 mg of a yellow solid (maleate salt Form C). Its XPRD and NMR are shown in Figures 6-7. The XPRD spectrum data are shown below:

[0239] Example 5 Preparation of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide hydrochloride crystalline form

[0240] Preparation of hydrochloride salt form S-1:

[0241] At room temperature, 221 mg (0.44 mmol, 1.0 eq) of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide (from Example 1) was weighed into a 5 ml plastic tube and dissolved with 1 ml of anhydrous ethanol. Separately, 45 mg of hydrochloric acid (36%) (0.44 mmol, 1.0 eq) was weighed and dissolved in 0.2 ml of anhydrous ethanol. The solution was then added dropwise to the tube and stirred at room temperature for 1 hour. No solid precipitated. After standing overnight at 0-5°C, a white solid precipitated. This was filtered and air-dried at 40°C for 4 hours and 10 minutes to yield 159 mg of a yellow solid. Its XPRD is shown in Figure 8; the values ​​are as follows:

[0242] Preparation of hydrochloride salt form S-2:

[0243] The operation is the same as above for Form S-1:

[0244] The S-2 XRPD of the hydrochloride salt form is shown in Figure 9; the values ​​are as follows:

[0245] Example 6 Preparation of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide sulfate crystalline form

[0246] Preparation of sulfate crystal form S-3:

[0247] At room temperature, 243 mg (0.48 mmol, 1.0 eq) of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide (from Example 1) was weighed into a 5 ml plastic tube and dissolved with 1 ml of anhydrous ethanol. Separately, 48 mg of sulfuric acid (0.48 mmol, 1.0 eq) was weighed and dissolved in 0.2 ml of anhydrous ethanol and added dropwise to the previous tube. Stirring was performed at room temperature for 35 minutes, resulting in the precipitation of a large amount of white solid. Filtered and dried under forced air at 40°C for 4 hours to yield 225 mg of a white solid. Its XPRD is shown in Figure 10; the values ​​are as follows:

[0248] Preparation of sulfate crystal forms S-4 and S-5:

[0249] Operation of isomorph S-3:

[0250] The XRPD patterns of sulfate salt forms S-4 and S-5 are shown in Figures 11-12.

[0251] The values ​​of the XRPD pattern of sulfate salt form S-4 are as follows:

[0252] The values ​​of the XRPD pattern of sulfate salt form S-5 are as follows:

[0253] Example 7 Preparation of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide tartrate crystalline form

[0254] Preparation of tartrate crystal form S-6: same as Example 6

[0255] The XRPD of tartrate salt form S-6 is shown in Figure 13; the values ​​are as follows:

[0256] Example 8 Preparation of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide fumarate crystalline form

[0257] Preparation of fumarate salt form S-7: same as Example 6

[0258] The XRPD of the fumarate salt form S-7 is shown in Figure 14, and the values ​​are as follows:

[0259] Example 9 Preparation of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide p-toluenesulfonate crystalline form

[0260] Preparation of p-toluenesulfonate crystal form S-8: Same as Example 6

[0261] The XRPD of p-toluenesulfonate salt form S-8 is shown in Figure 15, and the values ​​are as follows:

[0262] Example 10 (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide (free base) in different crystalline forms

[0263] (1) Stirring at room temperature

[0264] The free base of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide was stirred at room temperature for 24 h in different solvent systems (or a mixture of two solvents), filtered, and the obtained solid was dried and characterized (XRPD, DSC-TGA).

[0265] Summary table of free state room temperature stirring crystallization

[0266] (2) Heating and dissolving

[0267] The free form of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide was dissolved in different solvent systems or a mixture of two solvents, such as 90% ethanol, 90% isopropanol, etc., and then naturally cooled to room temperature for crystallization (standing for crystallization). The solution was then stirred at room temperature for more than 1 hour. The solid obtained by filtration was dried and then characterized by DSC-TGA, XRPD.

[0268] Recrystallization was performed twice using ethyl acetate + activated carbon (standing and crystallizing) to obtain Form F-2.

[0269] Among them, the XRPD of crystalline forms F-1 to F-6 are shown in Figures 16, 19, 22 and 25-27; the TGA of crystalline forms F-1, F-2 and F-3 are shown in Figures 18, 21 and 24.

[0270] The values ​​of the XRPD pattern of the free form F-1 are as follows:

[0271] The values ​​of the XRPD pattern of the free form F-2 are as follows:

[0272] The values ​​of the XRPD pattern of the free form F-3 are as follows:

[0273] The values ​​of the XRPD pattern of the free form F-4 are as follows:

[0274] The values ​​of the XRPD pattern of the free form F-5 are as follows:

[0275] The values ​​of the XRPD pattern of the free form F-6 are as follows:

[0276] (3) Systematic characterization of free-state crystal forms

[0277] Comparison of free crystal properties (1)

[0278] Note: “ / ” indicates not tested or not applicable

[0279] Comparison of free crystal properties (2)

[0280] (4) Free state stirring competition test

[0281] The three free crystalline forms (F-1, F-2, and F-3) were mixed and stirred in different solvents. The crystalline forms did not change in water and isopropanol, but were converted into crystalline form F-3 in other solvents (such as n-heptane, ethyl acetate, and a 1:1 mixture thereof; 90% ethanol, 90% isopropanol).

[0282] Example 11 Solubility Test of Different Crystal Forms of (E)-4-(Dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide

[0283] Solubility study refers to the general rules of Part II of the 2020 edition of the Chinese Pharmacopoeia

[0284] Example 12 Stability Test of (E)-4-(Dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide Maleic Acid Form A

[0285] Solid Stability Study - Established with reference to the General Rules 0512 of Part IV of the 2020 edition of the Chinese Pharmacopoeia

[0286] 1. Instrument: Agilent HPLC, Agilent-1100

[0287] 2. Chromatographic conditions

[0288] Chromatographic column: YMC Triart C18 4.6×250mm, 5μm

[0289] Mobile phase A: 0.02 mol / L ammonium acetate buffer (1.54 g ammonium acetate dissolved in 1000 ml water, 1 ml triethylamine added, and the pH adjusted to 6.00 ± 0.05 with glacial acetic acid)

[0290] Mobile phase B: methanol-acetonitrile (13:87)

[0291] Detection wavelength: 250nm

[0292] Flow rate: 1.0ml / min

[0293] Injection volume: 15 μl

[0294] Column temperature: 30°C

[0295] Run time: 75 minutes

[0296] Elution gradient:

[0297] 3. Solution Preparation

[0298] Blank solution (diluent): methanol-acetonitrile-water (9:6:10)

[0299] Test sample solution: Weigh an appropriate amount of the test sample, dissolve it in diluent and dilute it to a solution containing approximately 0.5 mg per 1 ml.

[0300] 4. Calculation

[0301] The purity of individual impurities and main peaks was calculated by area normalization method.

[0302] (1) In the salt formation experiment, maleate, hydrochloride, and sulfate were able to obtain solids, among which maleate obtained two different crystal forms, both of which had good crystallinity;

[0303] (2) In the stability experiment, after 21 days at room temperature, the maleate salt form C showed obvious degradation and the maximum single impurity increased significantly; the maleate salt A had better stability.

[0304] Example 13 Investigation of different crystalline forms of different acid salts of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide

[0305] (1) Scale-up preparation

[0306] The (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide hydrochloride form S-1, sulfate form S-3, maleate forms A to C, fumarate form S-7, and p-toluenesulfonate form S-8 were respectively scaled up for preparation.

[0307] (2) System characterization

[0308] Comparison of properties of different salt types (1)

[0309] Comparison of properties of different salt types (2)

[0310] Competition results of suspension stirring between maleate form A and maleate form B in different solvents

[0311] Conclusion: Completely converted to Form A in water and 90% ethanol.

[0312] Test Example 1: Enzymatic Activity of (E)-4-(Dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide Maleate Hydrate - Form A

[0313] Homogeneous time-resolved fluorescence (HTRF) kinase assay

[0314] 1) Prepare 2x ATP & substrate solution and 2x kinase solution using assay buffer.

[0315] 2) Transfer 50 nL of compound to a 384 assay plate using an Echo 655. After centrifugation, add 2.5 μL of 2x kinase solution to the 384 assay plate and incubate at 25°C for 10 minutes.

[0316] 3) Add 2.5 μL of 2x Substrate & ATP solution to the well and incubate for 40-50 minutes.

[0317] 4) Prepare 2x XL665 & antibody solution in detection buffer.

[0318] 5) Add 5 μL of kinase detection reagent to the well and incubate at 25°C for 60 minutes.

[0319] 6) Read the fluorescence signals at 620 nm (cryptate) and 665 nm (XL665) using a microtiter-plate reader.

[0320] 7) Calculate IC by fitting the % inhibition value and the log value of compound concentration to nonlinear regression (dose response - variable slope) using GraphPad 8.0. 50 or IC 90 .

[0321] 8) Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * hillslope)); X: log value of inhibitor concentration; Y: % inhibition rate

[0322] Enzymatic activity data of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate hydrate Form A:

[0323] Test Example 2: Cytological Experiment of (E)-4-(Dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide Maleate Hydrate Form A

[0324] 1. Cell Seeding

[0325] 1) Prepare complete culture medium: Add fetal bovine serum (FBS) and appropriate supplements according to the supplier's information sheet. Mix gently.

[0326] 2) Check the cell name, complete medium, and passage number marked on the culture flask.

[0327] 3) Use a vacuum pump to remove and discard the culture medium.

[0328] 4) Rinse the cell layer briefly with 0.25% (w / v) trypsin-0.038% (w / v) EDTA solution to remove all traces of serum containing trypsin inhibitors.

[0329] 5) Add 3.0 mL of trypsin-EDTA solution to the culture flask and observe the cells under an inverted microscope until the cell layer is dispersed.

[0330] 6) Add 8.0 mL of complete growth medium and gently pipette to aspirate the cells.

[0331] 7) Transfer the cell suspension to a centrifuge tube and centrifuge at 1000 rpm for 5 minutes.

[0332] 8) Discard the supernatant using a vacuum pump.

[0333] 9) Add an appropriate volume of complete culture medium and gently pipette to suspend the cell pellet.

[0334] 10) Count the cells using Vi-cell XR and adjust the cells to an appropriate density.

[0335] 11) Add 100 μL of cell suspension to each well of a 96-well opaque-walled, clear-bottomed plate according to the planned plate layout and place the plate in a CO2 incubator overnight. For SW620 cells, place the plate in a CO2-free incubator.

[0336] 12) Board Layout:

[0337] 2. Preparation and Addition of Compound Plates

[0338] The information of the compounds is shown in the following table

[0339] Compound preparation

[0340] 1) Board preparation of test articles:

[0341] Compounds were prepared at 10 mM in DMSO. According to the table above, a starting working solution (2 mM) and 9 point 3-fold serial dilutions were prepared in DMSO.

[0342] 2) Preparation of Staurosporine Plate:

[0343] Prepare 0.4 mM Staurosporine in DMSO as a working concentration.

[0344] 3) Compound addition:

[0345] Transfer 0.5 μL of diluted compound to a well containing 100 μL of culture medium. The total dilution factor is 200-fold.

[0346] Cells were incubated with compounds for 3 days at 5% CO2 and 37°C. For SW620 cells, cells were incubated with compounds in a CO2-free incubator.

[0347] 3. Reagent Preparation

[0348] 1) Thaw CellTiter-Glo Buffer and equilibrate to room temperature before use.

[0349] 2) Equilibrate the lyophilized CellTiter-Glo substrate to room temperature before use.

[0350] 3) Reconstitute the lyophilized enzyme / substrate mixture by transferring an appropriate volume of CellTiter-Glo Buffer to the amber bottle containing CellTiter-Glo Substrate. This forms the CellTiter-Glo Reagent.

[0351] 4) Gently vortex, spin, or invert the contents to mix and obtain a homogenous solution. The CellTiter-Glo Substrate should dissolve easily within one minute.

[0352] 4. Determination of Measurements

[0353] 1) After corresponding treatment, observe the cell morphology using an inverted microscope.

[0354] 2) Allow the plate and its contents to equilibrate to room temperature for approximately 30 minutes.

[0355] 3) Add 100 μL of CellTiter-Glo reagent to the assay plate using the Multidrop Combi instrument.

[0356] 4) Mix the contents on an orbital shaker for 10 minutes to induce cell lysis.

[0357] 5) Incubate the plate at room temperature for 10 minutes to stabilize the luminescent signal.

[0358] 6) Seal the transparent bottom with white backing tape and record the luminescence using Envision. The settings should be: luminescence, measurement time 0.1 milliseconds.

[0359] Under similar cell experimental conditions, the compound of the present application: (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide inhibited the EC of HCC1419 cell proliferation experiment. 50 It is 0.016μg / ml.

[0360] Compounds with similar structures to the compounds of the present application: (E)-4-(dimethylamino)-N-(4-((4-(4-chloro-phenoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)but-2-enamide inhibit SK-BR-3 cell proliferation assay IC 50 It is 0.221μM.

[0361] Test Example 3: In vivo efficacy study of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide in mice

[0362] Tumor cell lines

[0363] BT-474 human breast cancer cell line (HTB-20™) purchased from ATCC was cultured in RPMI1640 medium supplemented with 10% heat-inactivated fetal bovine serum, 100 U / ml penicillin, 100 μg / ml streptomycin, 1 mM Napyr, 1X MEM-NEAA, 1X MEM vitamins, and 10 μg / mL human insulin at 37°C in a 5% CO₂ atmosphere. Tumor cells were routinely passaged every 5–7 days. Cells in the exponential growth phase were harvested and counted for use in tumor inoculation.

[0364] Tumor vaccination and treatment

[0365] Tumor cells were suspended in PBS + Matrigel (volume ratio 1:1) and inoculated subcutaneously in the right groin of CB17 / SCID mice, with 100 μl inoculated per mouse. Estradiol benzoate (Ningbo Second Hormone Factory) was subcutaneously injected 1 day before inoculation and once a week thereafter, at 40 μg per mouse each time. When the average tumor volume reached approximately 100 mm 3At the same time, the mice were randomly divided into 5 groups according to the tumor volume, with 8 mice in each group, and the mice were medicated according to the predetermined scheme in the experimental design table (poqdx21, i.e., gavage, once a day for 21 consecutive days).

[0366] Tumor Measurements and Endpoints

[0367] Tumor volume was measured twice a week and calculated according to the formula: TV = 0.5 × long diameter × short diameter 2.

[0368] T / C values ​​were calculated based on tumor volume, where T is the mean relative tumor volume (RTV) of each treatment group and C is the mean relative tumor volume (RTV) of the vehicle control group. RTV is the ratio of the post-dose tumor volume to the pre-dose tumor volume.

[0369] a. Tumor growth inhibition rate (%)

[0370] TGI (tumor growth inhibition rate) = (1-T / C) × 100%

[0371] T / C = RTV of treatment group / RTV of control group

[0372] Treatment was considered effective when the tumor growth inhibition rate was ≥60% and statistically significant (p<0.05).

[0373] b. Tumor volume ratio T / C (%) of treatment group / control group

[0374] Tumor volume ratio of treatment group / control group T / C (%) = RTV of treatment group / RTV of control group × 100%.

[0375] Efficacy evaluation criteria: T / C (%)>40% was ineffective, T / C (%)≤40% and p<0.05 was effective.

[0376] Compound: (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate hydrate Form A; ML900179-neratinib;

[0377] Treatment with Form A (ML900110, 10, 20, and 40 mg / kg, once daily for 21 consecutive days) and neratinib (20 mg / kg, once daily for 21 consecutive days) resulted in 100%, 100%, 100%, and 95% tumor growth inhibition (TGI), respectively. At the end of treatment, all mice treated with (10, 20, and 40 mg / kg) achieved complete tumor regression, while the majority (87.5%) of mice treated with neratinib (20 mg / kg) also achieved complete tumor regression. Form A exhibited superior antitumor efficacy at a dose of 10 mg / kg compared to neratinib at a dose of 20 mg / kg. Therefore, in an oral efficacy study in mice, the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate of the present invention exhibited significantly superior tumor inhibition compared to neratinib at the same dose. The results are shown in Figure 29.

[0378] Test Example 4: Pharmacokinetics of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide in rats

[0379] Dosage regimen: Rats were intravenously (IV) and orally administered with the compound of Example 1. Rats were fasted for at least 12 hours before administration and had free access to water. Rats were fed 4 hours after administration.

[0380] Intravenous administration: Collect 0.2 ml of blood from the retroorbital venous plexus before administration (0 h) and at 5 min, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10, and 24 h after administration. Place the blood in an EDTA-K2 anticoagulant tube and centrifuge at 11,000 rpm for 5 min (4°C). Separate the plasma within 30 min and store in a refrigerator below 60°C until testing.

[0381] Single oral administration: 0.2 ml of blood was collected from the retroorbital venous plexus before administration (0 h) and 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10, 24 and 48 h after administration, and placed in an EDTA-K2 anticoagulant tube. The sample was processed in the same way as above.

[0382] (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide showed a higher bioavailability of 79.5% in rats, which is a significant improvement over the bioavailability of 48% of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)but-2-enamide (ML900199).

[0383] mpk is the drug mass in mg / animal weight in kg

[0384] Test Example 5: (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide blood-brain barrier assay

[0385] 1. Medication and sample collection

[0386] Thirty SD rats were randomly divided into five groups, with six rats in each time group (half male and half female). 3 mg / kg (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate hydrate Form A was administered orally. The sampling time points were 0 h before administration, and 1 h, 6 h, 10 h, and 24 h after administration.

[0387] After CO2 euthanasia, at least 0.5 mL of blood was collected by cardiac puncture, anticoagulated with EDTA-K2, mixed, and placed on ice. Plasma was separated by centrifugation within 30 minutes (11,000 rpm, 5 minutes, 2-8°C). Plasma samples were stored in an ultra-low temperature freezer until transferred to the client.

[0388] After blood samples were collected from the animals, tissue samples were collected from the brain, heart, liver, spleen, lung, kidney, bladder, pancreas, testicles, ovaries, uterus, stomach wall, small intestine (jejunum), adrenal glands, skin, thymus, skeletal muscle, and fat (abdomen). Tissue samples were rinsed with saline to avoid cross-contamination, blotted dry with filter paper, and placed in labeled tubes (one tube per tissue). Samples were temporarily placed on ice before being stored in an ultra-low temperature freezer.

[0389] After thorough homogenization with a high-speed homogenizer to prepare tissue sample homogenates, the concentrations in plasma, whole blood, and tissue homogenates were determined by LC-MS / MS.

[0390] 2. Determination of tissue samples

[0391] LC-MS / MS was used to determine the levels of ML900110 in whole blood, plasma and tissues of rats at different times after oral administration.

[0392] 3. Results

[0393] The exposure ratio of the present invention compound (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide in the brain and plasma of male rats was 43.6%, and the exposure ratio of the present invention compound (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide in the brain and plasma of female rats was 79.7%, indicating that the present invention compound can pass through the blood-brain barrier.

[0394] Test Example 6: Patients with brain metastases who had intracranial lesions showed significant benefits after treatment with (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate hydrate form A

[0395] Note: QD means once a day dosing

[0396] Test Example 7: In human clinical trials, patients with HER2-positive tumors benefited from treatment with (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate hydrate form A

[0397] 1. Case selection criteria

[0398] Inclusion criteria:

[0399] (1) Aged ≥18 and ≤65 years old, regardless of gender;

[0400] (2) Patients with histologically or cytologically confirmed HER2-positive (overexpression, amplification, and / or mutation) advanced tumors;

[0401] (3) standard treatment has failed or standard treatment is not applicable at this stage;

[0402] (4) at least one evaluable tumor lesion according to RECIST version 1.1;

[0403] (5) ECOG performance score 0-1;

[0404] (6) expected survival time is more than 3 months;

[0405] (7) The level of organ function must meet the following requirements:

[0406] (8) Eligible patients (male and female) of childbearing potential must agree to use reliable contraceptive methods (hormonal or barrier methods or abstinence) with their partners during the trial and for at least 6 months after the last medication; female patients of childbearing age must have a negative blood pregnancy test within 7 days before enrollment;

[0407] (9) The subjects must give their informed consent to the study before the trial and voluntarily sign a written informed consent form.

[0408] Exclusion criteria:

[0409] (1) Patients who have received chemotherapy within 3 weeks before the first use of study drugs; those who have received systemic anti-tumor treatment such as radiotherapy, targeted therapy, immunotherapy, endocrine therapy, etc. within 4 weeks before the first use of study drugs, excluding the following:

[0410] Nitrosourea or mitomycin C within 6 weeks before the first use of study drug;

[0411] For oral fluorouracils and small molecule targeted drugs, this period should be 2 weeks before the first use of the study drug or within 5 half-lives of the drug (whichever is longer);

[0412] For traditional Chinese medicine with anti-tumor indications, the study drug should be used within 2 weeks before the first use;

[0413] · Received other unapproved clinical investigational drugs or treatments within 4 weeks before the first use of the study drug;

[0414] (2) Patients who have undergone major organ surgery (excluding puncture biopsy) or significant trauma within 4 weeks before the first use of the study drug, or who need to undergo elective surgery during the trial;

[0415] (3) The adverse reactions of previous anti-tumor treatment have not recovered to CTCAE 5.0 grade ≤ 1 (excluding toxicities such as alopecia that the investigators judge to have no safety risks);

[0416] (4) Use of strong CYP3A4 inhibitors or inducers within 7 days before the first use of study drug;

[0417] (5) Unable to take the drug orally, or having a condition that seriously affects gastrointestinal absorption (such as chronic diarrhea, intestinal obstruction, etc.) as determined by the researcher;

[0418] (6) history of immunodeficiency, including positive HIV antibody test;

[0419] (7) Patients with unstable central nervous system metastases or meningeal metastases with clinical symptoms, or other evidence indicating that the patient's central nervous system metastases or meningeal metastases have not been controlled, and the researcher judges that the patient is not suitable for inclusion;

[0420] (8) active hepatitis B (defined as HBsAg positive and HBV-DNA titer >1000 copies / ml or 200 IU / ml), with preventive antiviral treatment other than interferon allowed; hepatitis C virus infection (defined as anti-HCV antibody positive);

[0421] (9) Patients with uncontrolled active infection requiring systemic anti-infective treatment or deemed unsuitable for enrollment by the investigator;

[0422] (10) History of severe cardiovascular disease, including but not limited to:

[0423] Severe cardiac rhythm or conduction abnormalities, such as ventricular arrhythmias requiring clinical intervention, II-III degree atrioventricular block, etc.

[0424] Acute coronary syndrome, congestive heart failure, or other grade 3 or higher cardiovascular events within 6 months before the first dose;

[0425] Heart failure with New York Heart Association (NYHA) functional class ≥ II or left ventricular ejection fraction (LVEF) < 50%;

[0426] Clinically uncontrolled hypertension;

[0427] QTc interval ≥450ms for men and ≥470ms for women, or the presence of any factors that increase the risk of QTc prolongation or arrhythmia, such as heart failure, hypokalemia, congenital long QT syndrome, or use of any concomitant medication known to prolong the QT interval (see Appendix 5 for details);

[0428] (11) The third space effusion cannot be controlled clinically and is judged by the researchers to be unsuitable for inclusion;

[0429] (12) known alcohol or drug dependence;

[0430] (13) People with mental disorders or poor compliance;

[0431] (14) Pregnant or lactating women;

[0432] (15) The researcher believes that the subject is not suitable for participation in this clinical study due to any clinical or laboratory abnormalities or other reasons.

[0433] Dosage: 50mg-250mg (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate hydrate form A once daily

[0434] Efficacy:

[0435] Efficacy of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate hydrate, Form A, in subjects with HER2-positive breast cancer

[0436] Efficacy of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate hydrate, Form A, in subjects with HER2-positive colorectal cancer

[0437] Efficacy of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate hydrate form A in subjects with HER2-positive other tumor types

[0438] In this application, unless otherwise specified, all weights related to biological activity are calculated based on the free base.

[0439] This application describes multiple embodiments, but the description is illustrative rather than restrictive, and there may be more embodiments and implementations within the scope of the embodiments described in this application.

Claims

1. A trisubstituted quinazoline derivative, an acid addition salt thereof, or a solvate or hydrate thereof, wherein the trisubstituted quinazoline derivative is (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide, having the chemical structure shown in the following formula I:

2. The trisubstituted quinazoline derivative, its acid addition salt, or its solvate or hydrate according to claim 1, wherein The acid in the acid addition salt is hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, fumaric acid, malonic acid, succinic acid, tartaric acid, citric acid, fumaric acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, xinafoic acid or benzoic acid.

3. The trisubstituted quinazoline derivative, its acid addition salt, or a solvate or hydrate thereof according to claim 1, which is (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide hydrochloride or a solvate or hydrate thereof.

4. The trisubstituted quinazoline derivative, its acid addition salt, or a solvate or hydrate thereof according to claim 1, which is (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide sulfate, or a solvate or hydrate thereof.

5. The trisubstituted quinazoline derivative, its acid addition salt, or a solvate or hydrate thereof according to claim 1, which is (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate or a solvate or hydrate thereof. 6 . The tri-substituted quinazoline derivative according to claim 1 , its acid addition salt, or its solvate or hydrate, which is in a solid form, including an amorphous form and / or a crystalline solid form.

7. The trisubstituted quinazoline derivative according to claim 1, 2 or 5, its acid addition salt or its solvate or hydrate, which is crystalline (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate or its solvate or hydrate, wherein: The molar ratio of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide to maleic acid is 1:1 or 1:

2.

8. The trisubstituted quinazoline derivative, its acid addition salt, or its solvate or hydrate according to claim 5 or 7, which is (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate or maleate hydrate, wherein the molar ratio of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide to maleic acid is 1:2; Preferably, the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate or maleate hydrate is crystalline; Preferably, the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate salt hydrate is a monohydrate, optionally crystalline; Preferably, the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate salt is anhydrous, optionally crystalline.

9. The trisubstituted quinazoline derivative, its acid addition salt, or its solvate or hydrate according to claim 1, which is crystalline form A of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate hydrate, and the molar ratio of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide to maleic acid in the crystalline form A is 1:2; preferably, the crystalline form A has a purity greater than 90%.

10. The trisubstituted quinazoline derivative, its acid addition salt, or its solvate or hydrate according to claim 9, wherein: The X-ray powder diffraction pattern of the crystalline form A includes at least one of characteristic peaks at 2θ of approximately 5.1±0.2 degrees, 5.7±0.2 degrees, 18.4±0.2 degrees, and 26.9±0.2 degrees; or The X-ray powder diffraction pattern of Form A includes characteristic peaks at approximately 5.1±0.2 degrees, 5.7±0.2 degrees, 18.4±0.2 degrees, and 26.9±0.2 degrees 2θ.

11. The trisubstituted quinazoline derivative, its acid addition salt, or its solvate or hydrate according to claim 10, wherein: The X-ray powder diffraction pattern of the crystalline form A further includes characteristic peaks at approximately 18.0±0.2 degrees, 20.4±0.2 degrees, 21.1±0.2 degrees, and 25.5±0.2 degrees 2θ; or, an X-ray powder diffraction pattern comprising characteristic peaks at approximately 5.1±0.2 degrees, 5.7±0.2 degrees, 18.0±0.2 degrees, 18.4±0.2 degrees, 20.4±0.2 degrees, 21.1±0.2 degrees, 25.5±0.2 degrees, and 26.9±0.2 degrees 2θ; Alternatively, its X-ray powder diffraction pattern includes the following characteristic peaks:

12. The trisubstituted quinazoline derivative, its acid addition salt, or its solvate or hydrate according to any one of claims 9 to 11, wherein The water content of the crystalline form A is 2.1 wt% to 10.0 wt%; or, the crystalline form A is a monohydrate.

13. The trisubstituted quinazoline derivative, its acid addition salt, or its solvate or hydrate according to claim 1, which is a crystalline form B of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate, wherein: The molar ratio of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide to maleic acid in the crystalline form B is 1:2; preferably, the crystalline form B has a purity greater than 90%.

14. The trisubstituted quinazoline derivative, its acid addition salt, or its solvate or hydrate according to claim 13, wherein: The X-ray powder diffraction pattern of the crystalline Form B includes at least one of characteristic peaks at 2θ of approximately 5.1±0.2 degrees, 9.8±0.2 degrees, 10.1±0.2 degrees, 19.4±0.2 degrees, and 20.3±0.2 degrees: Alternatively, the Form B has an X-ray powder diffraction pattern comprising characteristic peaks at approximately 5.1±0.2 degrees, 9.8±0.2 degrees, 10.1±0.2 degrees, 19.4±0.2 degrees, and 20.3±0.2 degrees 2θ.

15. The trisubstituted quinazoline derivative, its acid addition salt, or its solvate or hydrate according to claim 14, wherein: The X-ray powder diffraction pattern of the crystalline form B further includes characteristic peaks at approximately 7.0±0.2 degrees, 18.4±0.2 degrees, 19.6±0.2 degrees, 22.3±0.2 degrees, and 25.1±0.2 degrees 2θ; Alternatively, the Form B has an X-ray powder diffraction pattern comprising characteristic peaks at 2θ of approximately 5.1±0.2 degrees, 7.0±0.2 degrees, 9.8±0.2 degrees, 10.1±0.2 degrees, 18.4±0.2 degrees, 19.4±0.2 degrees, 19.6±0.2 degrees, 20.3±0.2 degrees, 22.3±0.2 degrees, and 25.1±0.2 degrees; Alternatively, the X-ray powder diffraction pattern of the crystalline form B includes the following characteristic peaks:

16. The trisubstituted quinazoline derivative, its acid addition salt, or its solvate or hydrate according to any one of claims 13 to 15, wherein: The crystal form B is an anhydrate.

17. The trisubstituted quinazoline derivative, its acid addition salt, or its solvate or hydrate according to claim 1, which is crystalline form C of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide maleate, wherein: The molar ratio of (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide to maleic acid in the crystalline form C is 1:1; preferably, the crystalline form C has a purity greater than 90%.

18. The trisubstituted quinazoline derivative, its acid addition salt, or its solvate or hydrate according to claim 17, wherein: The X-ray powder diffraction pattern of the crystalline Form C includes at least one of characteristic peaks at 2θ of approximately 5.4±0.2 degrees, 5.8±0.2 degrees, 18.2±0.2 degrees, 18.7±0.2 degrees, 19.0±0.2 degrees, and 26.8±0.2 degrees; or the X-ray powder diffraction pattern of the crystalline Form C includes characteristic peaks at 2θ of approximately 5.4±0.2 degrees, 5.8±0.2 degrees, 18.2±0.2 degrees, 18.7±0.2 degrees, 19.0±0.2 degrees, and 26.8±0.2 degrees.

19. The trisubstituted quinazoline derivative, its acid addition salt, or its solvate or hydrate according to claim 18, wherein: The X-ray powder diffraction pattern of the crystalline form C further includes characteristic peaks at approximately 6.1±0.2 degrees, 22.3±0.2 degrees, and 25.6±0.2 degrees 2θ; Alternatively, the Form C has an X-ray powder diffraction pattern comprising characteristic peaks at 2θ of approximately 5.4±0.2 degrees, 5.8±0.2 degrees, 6.1±0.2 degrees, 18.2±0.2 degrees, 18.7±0.2 degrees, 19.0±0.2 degrees, 22.3±0.2 degrees, 25.6±0.2 degrees, and 26.8±0.2 degrees; Alternatively, the Form C has an X-ray powder diffraction pattern comprising characteristic peaks at 2θ of approximately 5.4±0.2 degrees, 5.8±0.2 degrees, 6.1±0.2 degrees, 18.2±0.2 degrees, 18.7±0.2 degrees, 19.0±0.2 degrees, 19.8±0.2 degrees, 21.5±0.2 degrees, 22.3±0.2 degrees, 22.8±0.2 degrees, 23.7±0.2 degrees, 25.6±0.2 degrees, and 26.8±0.2 degrees; Alternatively, the X-ray powder diffraction pattern of the crystalline form C includes the following characteristic peaks:

20. The trisubstituted quinazoline derivative, its acid addition salt, or its solvate or hydrate according to claim 1, which is (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide hydrochloride, and the hydrochloride is crystalline. Preferably, the crystalline form of the hydrochloride has a purity greater than 90%.

21. The trisubstituted quinazoline derivative, its acid addition salt, or its solvate or hydrate according to claim 20, wherein: The crystalline form of the hydrochloride salt is crystalline form S-1 or crystalline form S-2, and the X-ray powder diffraction pattern of the crystalline form S-1 includes at least one of characteristic peaks at 2θ of approximately 6.1±0.2 degrees, 15.5±0.2 degrees, 18.1±0.2 degrees, 19.7±0.2 degrees, and 24.1±0.2 degrees; or The X-ray powder diffraction pattern of the crystalline form S-1 includes characteristic peaks at approximately 6.1±0.2 degrees, 15.5±0.2 degrees, 18.1±0.2 degrees, 19.7±0.2 degrees, and 24.1±0.2 degrees 2θ.

22. The trisubstituted quinazoline derivative, its acid addition salt, or its solvate or hydrate according to claim 21, wherein: The X-ray powder diffraction pattern of the crystalline form S-1 further includes characteristic peaks at 2θ of approximately 14.9±0.2 degrees, 22.6±0.2 degrees, 23.3±0.2 degrees, 25.6±0.2 degrees, and 26.0±0.2 degrees; or, the X-ray powder diffraction pattern of the crystalline form S-1 includes characteristic peaks at 2θ of approximately 6.1±0.2 degrees, 14.9±0.2 degrees, 15.5±0.2 degrees, 18.1±0.2 degrees, 19.7±0.2 degrees, 22.6±0.2 degrees, 23.3±0.2 degrees, 24.1±0.2 degrees, 25.6±0.2 degrees, and 26.0±0.2 degrees; or Its X-ray powder diffraction pattern includes the following characteristic peaks:

23. The trisubstituted quinazoline derivative, its acid addition salt, or its solvate or hydrate according to claim 1, which is (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide sulfate, and the sulfate is crystalline. Preferably, the crystalline form of the sulfate has a purity greater than 90%.

24. The trisubstituted quinazoline derivative, its acid addition salt, or its solvate or hydrate according to claim 23, wherein: The crystalline form of the sulfate salt is Form S-3, Form S-4 or Form S-5, and the X-ray powder diffraction pattern of Form S-3 includes at least one of characteristic peaks at 2θ of approximately 5.2±0.2 degrees, 16.0±0.2 degrees, 25.4±0.2 degrees and 26.1±0.2 degrees; or The X-ray powder diffraction pattern of the crystalline form includes characteristic peaks at approximately 5.2±0.2 degrees, 16.0±0.2 degrees, 25.4±0.2 degrees, and 26.1±0.2 degrees 2θ.

25. The trisubstituted quinazoline derivative, its acid addition salt, or its solvate or hydrate according to claim 24, wherein: The X-ray powder diffraction pattern of the crystalline form S-3 further comprises characteristic peaks at 2θ of approximately 17.7±0.2 degrees, 22.5±0.2 degrees, 24.5±0.2 degrees, 25.1±0.2 degrees, and 26.6±0.2 degrees; or, the X-ray powder diffraction pattern of the crystalline form S-3 comprises characteristic peaks at 2θ of approximately 5.2±0.2 degrees, 16.0±0.2 degrees, 17.7±0.2 degrees, 22.5±0.2 degrees, 24.5±0.2 degrees, 25.1±0.2 degrees, 25.4±0.2 degrees, 26.1±0.2 degrees, and 26.6±0.2 degrees; or Its X-ray powder diffraction pattern includes the following characteristic peaks:

26. A trisubstituted quinazoline derivative, an acid addition salt thereof, or a solvate or hydrate thereof according to claim 1 or 2, which is (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide tartrate, and the tartrate is crystalline, preferably, the crystalline form of the tartrate has a purity greater than 90%.

27. The trisubstituted quinazoline derivative, its acid addition salt, or its solvate or hydrate according to claim 26, wherein: The crystalline form of the tartrate salt is crystalline form S-6, and the X-ray powder diffraction pattern of the crystalline form S-6 includes at least one of characteristic peaks at 2θ of approximately 20.2±0.2 degrees, 20.6±0.2 degrees, 23.5±0.2 degrees, and 27.4±0.2 degrees; or The X-ray powder diffraction pattern of the crystalline form includes characteristic peaks at approximately 20.2±0.2 degrees, 20.6±0.2 degrees, 23.5±0.2 degrees, and 27.4±0.2 degrees 2θ.

28. The trisubstituted quinazoline derivative, its acid addition salt, or its solvate or hydrate according to claim 27, wherein: The X-ray powder diffraction pattern of the crystalline form S-6 further comprises characteristic peaks at 2θ of approximately 18.7±0.2 degrees, 24.1±0.2 degrees, 24.9±0.2 degrees, and 36.5±0.2 degrees; or the X-ray powder diffraction pattern of the crystalline form S-6 comprises characteristic peaks at 2θ of approximately 18.7±0.2 degrees, 20.2±0.2 degrees, 20.6±0.2 degrees, 23.5±0.2 degrees, 24.1±0.2 degrees, 24.9±0.2 degrees, 27.4±0.2 degrees, and 36.5±0.2 degrees; or Its X-ray powder diffraction pattern includes the following characteristic peaks:

29. The trisubstituted quinazoline derivative, acid addition salt thereof, or solvate or hydrate thereof according to claim 1 or 2, which is (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide fumarate, and the fumarate is crystalline. Preferably, the crystalline form of the fumarate has a purity greater than 90%.

30. The trisubstituted quinazoline derivative, its acid addition salt, or its solvate or hydrate according to claim 29, wherein The crystalline form of the fumarate salt is crystalline form S-7, and the X-ray powder diffraction pattern of the crystalline form S-7 includes at least one of characteristic peaks at 2θ of approximately 6.9±0.2 degrees, 17.9±0.2 degrees, 22.7±0.2 degrees, 24.2±0.2 degrees, 25.4±0.2 degrees, and 25.7±0.2 degrees; or The X-ray powder diffraction pattern of the crystalline form S-7 includes characteristic peaks at approximately 6.9±0.2 degrees, 17.9±0.2 degrees, 22.7±0.2 degrees, 24.2±0.2 degrees, 25.4±0.2 degrees, and 25.7±0.2 degrees 2θ.

31. The trisubstituted quinazoline derivative, its acid addition salt, or its solvate or hydrate according to claim 30, wherein: The X-ray powder diffraction pattern of the crystalline form S-7 further includes characteristic peaks at approximately 8.8±0.2 degrees, 24.9±0.2 degrees, and 28.1±0.2 degrees 2θ; or, the X-ray powder diffraction pattern of the crystalline form S-7 includes characteristic peaks at approximately 6.9±0.2 degrees, 8.8±0.2 degrees, 17.9±0.2 degrees, 22.7±0.2 degrees, 24.2±0.2 degrees, 24.9±0.2 degrees, 25.4±0.2 degrees, 25.7±0.2 degrees, and 28.1±0.2 degrees 2θ; or Its X-ray powder diffraction pattern includes the following characteristic peaks:

32. The trisubstituted quinazoline derivative, acid addition salt thereof, or solvate or hydrate thereof according to claim 1 or 2, which is (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide p-toluenesulfonate, and the p-toluenesulfonate is crystalline. Preferably, the crystalline form of the p-toluenesulfonate has a purity greater than 90%.

33. The trisubstituted quinazoline derivative, its acid addition salt, or its solvate or hydrate according to claim 32, wherein: The crystalline form of the p-toluenesulfonate salt is crystalline form S-8, and the X-ray powder diffraction pattern of the crystalline form S-8 includes at least one of the characteristic peaks at 2θ of approximately 5.7±0.2 degrees, 18.6±0.2 degrees, 20.2±0.2 degrees, 23.4±0.2 degrees and 25.5±0.2 degrees; or, the X-ray powder diffraction pattern of the crystalline form S-8 includes characteristic peaks at 2θ of approximately 5.7±0.2 degrees, 18.6±0.2 degrees, 20.2±0.2 degrees, 23.4±0.2 degrees and 25.5±0.2 degrees.

34. The trisubstituted quinazoline derivative, its acid addition salt, or its solvate or hydrate according to claim 33, wherein: The X-ray powder diffraction pattern of the crystalline form S-8 further includes characteristic peaks at 2θ of approximately 8.9±0.2 degrees, 10.1±0.2 degrees, 24.4±0.2 degrees, 25.0±0.2 degrees, and 31.7±0.2 degrees; or, the X-ray powder diffraction pattern thereof includes characteristic peaks at 2θ of approximately 5.7±0.2 degrees, 8.9±0.2 degrees, 10.1±0.2 degrees, 18.6±0.2 degrees, 20.2±0.2 degrees, 23.4±0.2 degrees, 24.4±0.2 degrees, 25.0±0.2 degrees, 25.5±0.2 degrees, and 31.7±0.2 degrees; or Its X-ray powder diffraction pattern includes the following characteristic peaks:

35. The trisubstituted quinazoline derivative according to claim 1, its acid addition salt, or a solvate or hydrate thereof, which is (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide (free base), and is a crystalline solid or an amorphous solid; Optionally, in the form of a hydrate; Optionally, the crystalline form has a purity greater than 90%; Optionally, the (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide (free base) is in the form of any one of Forms F1 to F6.

36. A method for preparing a trisubstituted quinazoline derivative, an acid addition salt thereof, or a solvate or hydrate thereof according to any one of claims 1 to 35, comprising mixing and reacting (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazoline-6-yl)but-2-eneamide (free base) with an acid in an organic solvent or a mixture of an organic solvent and water, and then separating the solid from the liquid to obtain (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazoline-6-yl)but-2-eneamide acid addition salt or a solvate or hydrate thereof, including its crystal form and / or amorphous form.

37. A method for preparing the trisubstituted quinazoline derivative, its acid addition salt, or its solvate or hydrate according to claim 36, comprising the steps of: (1)7-Fluoro-N 4 -(4-(4-fluorophenoxy)phenyl)-6-nitroquinazolin-4-amine reacts with sodium ethoxide to give 7-ethoxy-N 4 -(4-(4-fluorophenoxy)phenyl)-6-nitroquinazolin-4-amine; (2) 7-ethoxy-N 4 -(4-(4-fluorophenoxy)phenyl)-6-nitroquinazolin-4-amine is reduced to give 7-ethoxy-N 4 -(4-(4-fluorophenoxy)phenyl)quinazoline-4,6-diamine; (3)7-ethoxy-N 4 -(4-(4-fluorophenoxy)phenyl)quinazoline-4,6-diamine reacts with diethylphosphinoacetic acid to obtain diethyl (2-((7-ethoxy-4-((4-(4-fluorophenoxy)phenyl)amino)quinazolin-6-yl)amino)-2-oxoethyl)phosphonate; Diethyl (4)(2-((7-ethoxy-4-((4-(4-fluorophenoxy)phenyl)amino)quinazolin-6-yl)amino)-2-oxoethyl)phosphonate reacts with 2-dimethylaminoacetaldehyde to give (E)-4-(dimethylamino)-N-(4-((4-(4-fluoro-phenoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide.

38. A pharmaceutical composition comprising a trisubstituted quinazoline derivative, an acid addition salt thereof, or a solvate or hydrate thereof according to any one of claims 1 to 35; optionally, the pharmaceutical composition is in a unit dose form, the unit dose being 25 mg to 700 mg, or 35 mg to 500 mg, or 40 mg to 400 mg, or 50 mg to 350 mg, or 50 mg to 250 mg.

39. Use of the trisubstituted quinazoline derivative, its acid addition salt, or its solvate or hydrate according to any one of claims 1 to 35, or the pharmaceutical composition according to claim 38 in the preparation of a medicament for preventing, inhibiting or treating cancer, in particular, use of the trisubstituted quinazoline derivative, its acid addition salt, or its solvate or hydrate according to any one of claims 1 to 35, or the pharmaceutical composition according to claim 38 in the preparation of a medicament for preventing, inhibiting or treating cancer.

40. The trisubstituted quinazoline derivative according to any one of claims 1 to 35, its acid addition salt, or its solvate or hydrate, or the pharmaceutical composition according to claim 38, for use in preventing, inhibiting or treating cancer, in particular, for use in preventing, inhibiting or treating brain metastasis cancer.

41. A method for preventing, inhibiting or treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the tri-substituted quinazoline derivative, its acid addition salt, or its solvate or hydrate according to any one of claims 1 to 35, or the pharmaceutical composition according to claim 38.

42. The use according to claim 39, or the trisubstituted quinazoline derivative, its acid addition salt, or its solvate or hydrate, or pharmaceutical composition for use according to claim 40, or the method according to claim 41, wherein The cancer is a HER2-positive cancer; HER2-positivity includes but is not limited to any one or a combination of HER2 protein overexpression, HER2 gene amplification, and HER2 gene mutation; in particular, the cancer is selected from one or more of breast cancer, ovarian cancer, epithelial cancer, colorectal cancer, renal cancer, bladder cancer, laryngeal cancer, esophageal cancer, salivary gland cancer, submandibular cancer, gastric cancer and lung cancer, especially breast cancer, ovarian cancer, gastric cancer and / or colorectal cancer; more particularly, cancer with brain metastasis, including but not limited to breast cancer with brain metastasis, ovarian cancer with brain metastasis, gastric cancer with brain metastasis and / or colorectal cancer with brain metastasis.

43. The use according to claim 39 or 42, or the trisubstituted quinazoline derivative for use according to claim 40 or 42, its acid addition salt or its solvate or hydrate or pharmaceutical composition, or the method according to claim 41 or 42, wherein: The trisubstituted quinazoline derivative, its acid addition salt, or its solvate or hydrate, or the pharmaceutical composition is administered in a unit dose of 25 mg to 700 mg, or 35 mg to 500 mg, or 40 mg to 400 mg, or 50 mg to 350 mg, or 50 mg to 250 mg; the administration frequency is 1 to 4 times a day.

44. The use according to claim 39 or 42, or the trisubstituted quinazoline derivative for use according to claim 40 or 42, its acid addition salt or its solvate or hydrate or pharmaceutical composition, or the method according to claim 41 or 42, wherein: The trisubstituted quinazoline derivative, its acid addition salt or its solvate or hydrate is administered in a therapeutically effective amount of 0.01-500 mg / kg, preferably 0.01-50 mg / kg body weight, further 0.1-10 mg / kg body weight; the administration frequency is 1 to 4 times per day.

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