Pharmaceutically acceptable salt of tyrosine kinase inhibitor, crystal, preparation method, and use

Abstract

The present invention relates to a pharmaceutically acceptable salt of a tyrosine kinase inhibitor, a crystal, a preparation method, and a use, and in particular to a pharmaceutically acceptable salt of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenamide, a crystal form and a preparation method therefor, and a pharmaceutical composition containing a therapeutically effective amount of the crystal form, and a use thereof in treating cancer.

Description

Pharmaceutically acceptable salts, crystals of a tyrosine kinase inhibitor, methods of preparation and uses thereof TECHNICAL FIELD

[0001] The present application relates to the field of biological medicine, in particular to a pharmaceutically acceptable salt of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide, a crystal form thereof, a preparation method thereof, a pharmaceutical composition containing a therapeutically effective amount of the crystal form, and an application thereof in treating cancer. BACKGROUND

[0002] Cancer is a serious threat to people's life and quality of life, so finding highly effective and low-toxic anti-tumor drugs is a challenging and significant task in life sciences today. Receptor tyrosine kinase is a class of transmembrane proteins involved in signal transduction. Studies have shown that more than 50% of proto-oncogene and oncogene products have tyrosine kinase activity, and their abnormal expression will lead to tumorigenesis. Tyrosine kinase inhibitors have been on the market since 2001 and have become a new type of anticancer drug. Epidermal growth factor receptor (Her2 and EGFR) is a member of the receptor tyrosine kinase family, and the epidermal growth factor receptor pathway plays a very important role in the process of tumor occurrence and development, and has become one of the most important research and development targets in the field of tumor treatment. The drugs of this type that have been on the market include erlotinib, gefitinib, lapatinib (Tykerb, GW572016), afatinib, neratinib, and osimertinib, etc.

[0003] ZL201480003627.0 discloses a preparation method of compound (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide. The drug molecule has obvious advantages in pharmacokinetics and efficacy. The chemical structure and preparation method of compound AMX3009 are specifically disclosed, but the salt formation and crystal form of AMX3009 are not studied. The salt type and crystal form of the active ingredient of the drug often affect the chemical stability of the drug, and different crystallization conditions and storage conditions may lead to changes in the crystal structure of the compound, and sometimes other forms of crystal may also be produced.

[0004] Therefore, it is of great significance to further study the influence of the salt type and crystal form of compound AMX3009 on the inhibitory activity and stability, so as to obtain AMX3009 salt crystals with high inhibitory activity and excellent stability to meet the actual application and production needs. SUMMARY

[0005] To solve the above technical problems, the present application provides a pharmaceutically acceptable salt of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinoline)-2-butenediamide (AMX3009), a crystal form thereof, a preparation method thereof, a pharmaceutical composition containing a therapeutically effective amount of the crystal form, and the use thereof in the treatment of cancer.

[0006] The present application provides the following technical solutions:

[0007] The present application provides a pharmaceutically acceptable salt of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinoline)-2-butenediamide, which is a maleate salt, a mesylate salt, a p-toluenesulfonate salt, a phosphate salt, an L-malate salt, a succinate salt, a sulfate salt, a hydrochloride salt, a tartrate salt, an acetate salt, a trifluoroacetate salt, a citrate salt, a hydrobromide salt, or a fumarate salt.

[0008] Further, the pharmaceutically acceptable salt of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinoline)-2-butenediamide is preferably a compound having the following general structure:

[0009] wherein n is 1, 2, or 3;

[0010] A is maleic acid, methanesulfonic acid, p-toluenesulfonic acid, phosphoric acid, L-malic acid, succinic acid, sulfuric acid, hydrochloric acid, tartaric acid, acetic acid, trifluoroacetic acid, citric acid, hydrobromic acid, or fumaric acid.

[0011] Further, the pharmaceutically acceptable salt of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinoline)-2-butenediamide includes but is not limited to several in the following table:

[0012] Further, the pharmaceutically acceptable salt of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide is more preferably a dimaleate salt. Compared with (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide, the dimaleate salt has obvious advantages in solubility, bioavailability and pharmacokinetics, and has good drugability. In addition, compared with other salts (such as L-malate salt) of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide, the dimaleate salt has better physical stability and stronger drugability.

[0013] Further, the pharmaceutically acceptable salt of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide can be prepared according to the conventional salt preparation method in the field. For example, (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide is stirred with an acid in the presence of a solvent to obtain the pharmaceutically acceptable salt. The acid is an organic acid or an inorganic acid, which can be selected from one of maleic acid, methanesulfonic acid, p-toluenesulfonic acid, phosphoric acid, L-malic acid, succinic acid, sulfuric acid, hydrochloric acid, tartaric acid, acetic acid, trifluoroacetic acid, citric acid, hydrobromic acid and fumaric acid.

[0014] The second aspect of the present application provides a crystal form of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide dimaleate salt, including anhydrous crystal forms A, B, C, F and hydrate crystal forms D, E, H, K, R and V.

[0015] Further, using Cu-Kα as the radiation source, the X-ray powder diffraction pattern expressed by the 2θ angle has characteristic peaks at 4.98±0.2°, 10.41±0.2°, 15.16±0.2° and 19.72±0.2° for the crystal form A. More preferably, the X-ray powder diffraction pattern of the crystal form A has characteristic peaks at 4.98±0.2°, 5.98±0.2°, 10.41±0.2°, 14.76±0.2°, 15.16±0.2°, 16.21±0.2°, 19.72±0.2°, 22.09±0.2°, 25.80±0.2° and 34.81±0.2°.

[0016] Further, the DSC pattern of the crystal Form A shows a melting endotherm peak around 144 °C.

[0017] Further, the X-ray powder diffraction pattern of the crystal Form B has characteristic peaks at 4.68±0.2°, 14.41±0.2°, 16.70±0.2°, 18.73±0.2°, more preferably, the X-ray powder diffraction pattern of the crystal Form B has characteristic peaks at 4.68±0.2°, 7.75±0.2°, 9.90±0.2°, 13.40±0.2°, 14.03±0.2°, 14.41±0.2°, 16.70±0.2°, 17.64±0.2°, 18.73±0.2°, 25.52±0.2°, 26.38±0.2°, 33.07±0.2°, using Cu-Ka as the radiation source and the diffraction angles expressed in degrees 2 theta.

[0018] Further, the X-ray powder diffraction pattern of the crystal Form C has characteristic peaks at 4.82±0.2°, 14.41±0.2°, 15.41±0.2°, 19.24±0.2°, more preferably, the X-ray powder diffraction pattern of the crystal Form C has characteristic peaks at 4.82±0.2°, 9.56±0.2°, 14.12±0.2°, 14.41±0.2°, 15.41±0.2°, 19.24±0.2°, 19.69±0.2°, 25.72±0.2°, using Cu-Ka as the radiation source and the diffraction angles expressed in degrees 2 theta.

[0019] Further, the X-ray powder diffraction pattern of the crystal Form D has characteristic peaks at 5.93±0.2°, 7.91±0.2°, 14.86±0.2°, 20.33±0.2°, 25.36±0.2°, 26.05±0.2°, more preferably, the X-ray powder diffraction pattern of the crystal Form D has characteristic peaks at 3.37±0.2°, 3.96±0.2°, 5.93±0.2°, 7.91±0.2°, 14.86±0.2°, 16.06±0.2°, 19.20±0.2°, 20.33±0.2°, 21.81±0.2°, 25.36±0.2°, 26.05±0.2°, 27.28±0.2°, using Cu-Ka as the radiation source and the diffraction angles expressed in degrees 2 theta.

[0020] Further, the X-ray powder diffraction pattern of the crystalline Form E has characteristic peaks at 5.16±0.2°, 6.75±0.2°, 15.65±0.2°, 16.67±0.2°, 17.84±0.2°, 23.45±0.2°, 25.07±0.2°, when Cu-Ka is used as the radiation source and the diffraction angles are given in terms of 2 theta; more preferably, the X-ray powder diffraction pattern of the crystalline Form E has characteristic peaks at 5.13±0.2°, 6.71±0.2°, 15.61±0.2°, 16.62±0.2°, 17.79±0.2°, 18.06±0.2°, 18.85±0.2°, 23.4±0.2°, 25.02±0.2°, 26.09±0.2°, 26.65±0.2°, 27.92±0.2°, after silicon powder correction; more preferably, the X-ray powder diffraction pattern of the crystalline Form E has characteristic peaks at 5.16±0.2°, 6.75±0.2°, 15.65±0.2°, 16.67±0.2°, 17.84±0.2°, 18.09±0.2°, 18.90±0.2°, 23.45±0.2°, 25.07±0.2°, 26.12±0.2°, 26.74±0.2°, 27.98±0.2°, after silicon powder correction.

[0021] Further, the X-ray powder diffraction pattern of the crystalline Form F has characteristic peaks at 4.57±0.2°, 12.93±0.2°, 15.5±0.2°, 18.44±0.2°, when Cu-Ka is used as the radiation source and the diffraction angles are given in terms of 2 theta; more preferably, the X-ray powder diffraction pattern of the crystalline Form F has characteristic peaks at 4.57±0.2°, 7.06±0.2°, 8.51±0.2°, 12.93±0.2°, 15.5±0.2°, 18.44±0.2°, 19.33±0.2°, 20.23±0.2°, 20.94±0.2°, 25.58±0.2°, 25.85±0.2°, 26.31±0.2°.

[0022] Further, the X-ray powder diffraction pattern of the crystalline Form H has characteristic peaks at 3.67±0.2°, 5.51±0.2°, 11.04±0.2°, 19.73±0.2°, 26.48±0.2°, 27.86±0.2°, more preferably 3.67±0.2°, 5.51±0.2°, 7.15±0.2°, 7.36±0.2°, 11.04±0.2°, 11.45±0.2°, 19.73±0.2°, 20.48±0.2°, 21.66±0.2°, 25.79±0.2°, 26.48±0.2°, 27.86±0.2°, using Cu-Ka as the radiation source and the diffraction angles expressed in degrees 2 theta.

[0023] Further, the X-ray powder diffraction pattern of the crystalline Form K has characteristic peaks at 5.16±0.2°, 6.96±0.2°, 15.54±0.2°, 23.34±0.2°, 25.43±0.2°, 27.91±0.2°, more preferably 5.16±0.2°, 6.96±0.2°, 13.86±0.2°, 15.54±0.2°, 17.67±0.2°, 19.62±0.2°, 23.34±0.2°, 23.79±0.2°, 24.34±0.2°, 25.43±0.2°, 27.50±0.2°, 27.91±0.2°, using Cu-Ka as the radiation source and the diffraction angles expressed in degrees 2 theta.

[0024] Further, the X-ray powder diffraction pattern of the crystalline Form R has characteristic peaks at 4.67±0.2°, 8.52±0.2°, 9.21±0.2°, 15.13±0.2°, 18.60±0.2°, 19.69±0.2°, more preferably 4.67±0.2°, 4.93±0.2°, 7.53±0.2°, 8.52±0.2°, 9.21±0.2°, 12.49±0.2°, 15.13±0.2°, 16.28±0.2°, 16.98±0.2°, 18.60±0.2°, 19.69±0.2°, 27.34±0.2°, using Cu-Ka as the radiation source and the diffraction angles expressed in degrees 2 theta.

[0025] Further, the X-ray powder diffraction pattern of the crystal form V has characteristic peaks at 8.56±0.2°, 10.10±0.2°, 14.16±0.2°, 16.58±0.2°, 18.20±0.2°, 19.19±0.2°, 20.28±0.2°, 23.77±0.2°, 26.03±0.2°, more preferably, the X-ray powder diffraction pattern of the crystal form V has characteristic peaks at 8.56±0.2°, 10.10±0.2°, 13.48±0.2°, 14.16±0.2°, 16.58±0.2°, 18.20±0.2°, 18.40±0.2°, 19.19±0.2°, 20.28±0.2°, 22.28±0.2°, 23.77±0.2°, 26.03±0.2°, using Cu-Kα as the radiation source, expressed in terms of 2θ angles.

[0026] In the present application, "crystal" or "crystal form" can be characterized by X-ray powder diffraction. Those skilled in the art will appreciate that X-ray powder diffraction patterns can vary depending on the conditions of the instrument, the preparation of the sample, and the purity of the sample. The relative intensities of the diffraction peaks in an X-ray powder diffraction pattern can also vary with experimental conditions, and therefore the relative intensities of the diffraction peaks cannot be used as the sole or determining factor in identifying a crystal form. In fact, the relative intensities of the diffraction peaks in an X-ray powder diffraction pattern are related to the preferred orientation of the crystals, and the intensities of the diffraction peaks shown in the present application are illustrative and not for absolute comparison. Thus, those skilled in the art will appreciate that the X-ray powder diffraction pattern of the crystal form claimed in the present application need not be identical to the X-ray powder diffraction pattern shown in the examples herein, and any crystal form having an X-ray powder diffraction pattern with peaks identical or similar to those in the patterns is within the scope of the present application. Those skilled in the art can compare the X-ray powder diffraction pattern of the present application with the X-ray powder diffraction pattern of an unknown crystal form to determine whether the two sets of patterns reflect the same or different crystal forms.

[0027] The third aspect of the present application provides a preparation method of the crystal form A, B, C, D, E, F, H, K, R, V of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide dimaleate salt according to the second aspect. Wherein,

[0028] The preparation method of the crystal form A comprises:

[0029] dissolving AMX3009 and maleic acid in a first organic solvent, stirring to precipitate crystals, and separating and drying to obtain the crystal form A; the first organic solvent is selected from one or more of isopropyl alcohol, acetonitrile, tetrahydrofuran, methyl isobutyl ketone, chloroform, acetone, ethyl acetate, 1,4-dioxane, isopropyl acetate, methyl tert-butyl ether, 2-methyltetrahydrofuran, and toluene;

[0030] or, dissolving the di-maleic acid salt of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide in acetonitrile, and volatilizing to precipitate a solid to obtain the crystal form A; preferably, the solution obtained by dissolving the di-maleic acid salt of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide in acetonitrile is subjected to a filtration treatment before the volatilization treatment, and the volatilization treatment is performed at 50°C.

[0031] or, dissolving the di-maleic acid salt of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide in methanol, adding an anti-solvent, stirring to precipitate a solid, and obtaining the crystal form A; the anti-solvent is methyl tert-butyl ether, 2-methyltetrahydrofuran, or toluene.

[0032] or, dissolving the di-maleic acid salt of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide in acetone or acetonitrile, and performing a cooling treatment to precipitate a solid to obtain the crystal form A; preferably, the solution obtained by dissolving the di-maleic acid salt of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide in acetone or acetonitrile is subjected to a filtration treatment before the cooling treatment, and the cooling treatment is specifically cooling from 50°C to 5°C at a cooling rate of 0.1°C / min.

[0033] The preparation method of the crystal form B comprises the following steps: dissolving AMX3009 and maleic acid in an appropriate amount of isopropyl alcohol, stirring to precipitate crystals at 35°C, filtering and separating the solid, and drying to obtain the crystal form B.

[0034] The preparation method of the crystal form C comprises the following steps: dissolving the di-maleic acid salt of AMX3009 in an appropriate amount of ethanol, stirring to precipitate crystals at room temperature, centrifugally separating the solid, and drying at room temperature to obtain the crystal form C.

[0035] The preparation method of the crystal form D comprises the following steps: dissolving AMX3009 dimaleate in a proper amount of dimethylacetamide, adding 2-methyltetrahydrofuran while stirring, dissolving the obtained solid in 2-methyltetrahydrofuran, stirring at room temperature to crystallize, centrifuging the solid and drying at room temperature to obtain the crystal form D.

[0036] The preparation method of the crystal form E comprises the following steps: stirring AMX3009 dimaleate in an aqueous system, centrifuging the solid and drying at room temperature to obtain the crystal form E; the stirring temperature is preferably 10-30°C, and the stirring time is 3-6 days, for example, 5 days.

[0037] Further, the aqueous system is a mixed system of an organic solvent and water, preferably, the volume percentage of water in the mixed system is not less than 3%, for example, the volume ratio of the organic solvent to water in the mixed system is (85-97):(3-15); preferably, the organic solvent is acetone, 1,4-dioxane or isopropanol.

[0038] The preparation method of the crystal form F comprises the following steps: dissolving AMX3009 dimaleate in methanol / ethyl acetate (1:4, v / v), stirring at 40-60°C to crystallize, centrifuging the solid and drying at room temperature to obtain the crystal form F.

[0039] The preparation method of the crystal form H comprises the following steps: placing AMX3009 dimaleate in a bottle, and placing the bottle in a sealed bottle containing water with the opening exposed to the air, carrying out gas-solid penetration to obtain the crystal form H.

[0040] The preparation method of the crystal form K comprises the following steps: heating AMX3009 dimaleate crystal form E to 75-100°C at a heating rate of 5-10°C / min, and then cooling to room temperature to obtain the crystal form K.

[0041] The preparation method of the crystal form R comprises the following steps: carrying out dynamic moisture adsorption test on AMX3009 dimaleate crystal form A at a humidity of 0%RH-90%RH-0%RH to obtain AMX3009 dimaleate crystal form R.

[0042] The preparation method of the crystal form V comprises the following steps: suspending and stirring AMX3009 dimaleate in isopropanol / water (volume ratio 98 / 2) to obtain AMX3009 dimaleate crystal form V.

[0043] The fourth aspect of the present application provides a pharmaceutical composition comprising the pharmaceutically acceptable salt of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide of the first aspect and / or the dimaleate salt crystal form A, B, C, D, E, F, H, K, R, V of the second aspect and a pharmaceutically acceptable carrier.

[0044] The fifth aspect of the present application provides the use of the pharmaceutically acceptable salt of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide of the first aspect, the dimaleate salt crystal form A, B, C, D, E, F, H, K, R, V of the second aspect or the pharmaceutical composition of the fourth aspect in the preparation of a medicament for treating a disease associated with a protein kinase, which is an EGFR receptor tyrosine kinase or a HER-2 receptor tyrosine kinase.

[0045] Further, the medicament is administered alone or in combination with other therapeutic agents.

[0046] The present application also provides the use of the pharmaceutically acceptable salt of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide of the first aspect, the dimaleate salt crystal form A, B, C, D, E, F, H, K, R, V of the second aspect or the pharmaceutical composition of the fourth aspect in the preparation of a medicament for treating a cancer, which includes but is not limited to EGFR drug-resistant mutant lung cancer, head and neck cancer, Her2-positive gastric cancer, breast cancer, colorectal cancer.

[0047] Further, the medicament is administered alone or in combination with other therapeutic agents.

[0048] By means of the above technical solution, the present application has at least the following advantages:

[0049] The application provides a kind of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl) amino)-6-quinazoline)-2-butene amide and its dimaleate salt crystal form, compared with (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl) amino)-6-quinazoline)-2-butene amide compound, its pharmaceutically acceptable salt has obvious advantages in solubility, bioavailability and pharmacokinetics, and good drug property, especially AMX3009 dimaleate salt, in EGFR drug-resistant mutant lung cancer cell inhibition rate test, it shows high inhibitory activity, and compared with other salt types, such as L-maleate salt, the physical stability of dimaleate salt is better, and the drug property is stronger.

[0050] In addition, the application provides a series of AMX3009 dimaleate salt anhydrous crystal forms and hydrate crystal forms, wherein the anhydrous crystal form A has high solubility, high exposure in animal body, long half-life, high oral bioavailability, good bioavailability, and the crystal form shows good stability, and is suitable for drug preparation application. The hydrate crystal form E has high solubility, good stability, and also has good application prospect in drug preparation. BRIEF DESCRIPTION OF DRAWINGS

[0051] FIG. 1 is a DSC graph of AMX3009 L-maleate salt;

[0052] FIG. 2 is a TGA graph of AMX3009 L-maleate salt;

[0053] FIG. 3 is an X-ray powder diffraction pattern of AMX3009 dimaleate salt type A crystal;

[0054] FIG. 4 is a DSC graph of AMX3009 dimaleate salt type A crystal;

[0055] FIG. 5 is a TGA graph of AMX3009 dimaleate salt type A crystal;

[0056] FIG. 6 is an X-ray powder diffraction pattern of AMX3009 dimaleate salt type B crystal; 1 HNMR graph;

[0057] FIG. 7 is an X-ray powder diffraction pattern of AMX3009 dimaleate salt type B crystal;

[0058] FIG. 8 is an X-ray powder diffraction pattern of AMX3009 dimaleate salt type C crystal;

[0059] FIG. 9 is an X-ray powder diffraction pattern of AMX3009 dimaleate salt type F crystal;

[0060] FIG. 10 is an X-ray powder diffraction pattern of AMX3009 dimaleate salt type D crystal;

[0061] Figure 11 is an X-ray powder diffraction pattern of AMX3009 dimaleate Form E crystals;

[0062] Figure 12 is an X-ray powder diffraction pattern of AMX3009 dimaleate Form H crystals;

[0063] Figure 13 is an X-ray powder diffraction pattern of AMX3009 dimaleate Form K crystals;

[0064] Figure 14 is an X-ray powder diffraction pattern of AMX3009 dimaleate Form R crystals;

[0065] Figure 15 is an X-ray powder diffraction pattern of AMX3009 dimaleate Form V crystals;

[0066] Figure 16 is a graph showing the average tumor volume change of AMX3009 and Afatinib in an efficacy experiment. DETAILED DESCRIPTION

[0067] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used in the description herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms "comprises" and / or "comprising", or "includes" and / or "including" when used herein, specify the presence of stated features, integers, steps, operations, elements, or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, or groups thereof. As used herein, the term "consisting of" or "consisting" means "including and limited to".

[0068] The application will be further described with reference to the following examples, which are intended to be illustrative only and not limiting of the application. The following examples are provided to further illustrate the application and should not be construed as limiting the scope of the application.

[0069] Example 1

[0070] This example relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolin-2-yl)but-2-enamide dimaleate, and the preparation process is as follows:

[0071] Under nitrogen protection, (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide (47.4 g, 103.2 mmol, 1 eq), isopropanol (470 mL) were added into a 10 L three-necked flask, stirred, heated to 70 °C, and maleic acid (12.0 g, 103.2 mmol, 1 eq) in isopropanol (235 mL) was added dropwise within one hour. After the addition was completed, the temperature was controlled at 60-65 °C, and the stirring was continued for 12-15 hours. White solid was generated. After slowly cooling to 20-25 °C, the stirring was continued for 1 hour. The white solid was filtered through a Buchner funnel and air-dried at 40-45 °C for 48-50 hours to obtain (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide maleate (46.9 g, 78.9% yield) as a white solid.

[0072] Example 2

[0073] This example relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide dimaleate, which was prepared according to the following procedure:

[0074] Under nitrogen protection, (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide (474.1 g, 1.03 mol, 1 eq), isopropanol (4700 mL) were added into a 10 L three-necked flask, stirred, heated to 70 °C, and maleic acid (239.4 g, 2.06 mmol, 2 eq) in isopropanol (4700 mL) was added dropwise within one hour. After the addition was completed, the temperature was controlled at 60-65 °C, and the stirring was continued for 12-15 hours. White solid was generated. After slowly cooling to 20-25 °C, the stirring was continued for 1 hour. The white solid was filtered through a Buchner funnel and air-dried at 40-45 °C for 48-50 hours to obtain (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide dimaleate (609.0 g, 85.4% yield) as a white solid. Melting point: 138-142 °C.

[0075] 1H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 9.87 (s, 1H), 8.93 (s, 1H), 8.60 (s, 1H), 8.00 - 7.95 (m, 1H), 7.89 - 7.81 (m, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.36 (s, 1H), 7.24 (dt, J = 7.6, 1.4 Hz, 1H), 6.86 - 6.71 (m, 2H), 6.14 (s, 4H), 4.39 (dd, J = 5.8, 3.6 Hz, 2H), 4.22 (s, 1H), 3.98 (d, J = 5.6 Hz, 2H), 3.84 (dd, J = 5.7, 3.6 Hz, 2H), 3.55 (q, J = 7.0 Hz, 2H), 2.82 (s, 6H), 1.14 (t, J = 7.0 Hz, 3H).

[0076] Example 3

[0077] This example relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2- ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenediamide dimaleate salt, and the specific preparation process is as follows:

[0078] Under nitrogen protection, (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenediamide (47.4 g, 103.2 mmol, 1 eq), ethyl acetate (470 mL) were added into a 10 L three-necked flask, stirred, heated to 70°C, and maleic acid (23.9 g, 206.4 mmol, 2 eq) in isopropyl alcohol (470 mL) was added dropwise, and the dropwise addition was controlled to be completed within one hour. After the dropwise addition was completed, the temperature was controlled at 60-65°C, and stirring was continued for 12-15 hours. White solid was generated, and after slow cooling to 20-25°C, stirring was continued for 1 hour. Filtration was performed through a Buchner funnel, and air blowing drying was performed at 40-45°C for 48-50 hours to obtain white solid (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenediamide dimaleate salt 64.3 g, with a yield of 90.2%.

[0079] Example 4

[0080] This example relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2- ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenediamide dimaleate salt, and the specific preparation process is as follows:

[0081] Under nitrogen protection, (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide (47.4 g, 103.2 mmol, 1 eq), acetonitrile (940 mL) were added into a 10 L three-necked flask, stirred, heated to 70 °C, maleic acid (23.9 g, 206.4 mmol, 2 eq) in acetonitrile (940 mL) was added dropwise, controlled to be completed within one hour, after dropwise addition, the temperature was controlled at 60-65 °C, and stirring was continued for 12-15 hours. White solid was generated. Slowly cooled to 20-25 °C and continued to stir for 1 hour. Filtered by Buchner funnel and air-dried at 40-45 °C for 48-50 hours to obtain white solid (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide dimaleate 66.8 g, yield 93.8%.

[0082] Example 5

[0083] This example relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide dimaleate, and the specific preparation process is as follows:

[0084] Under nitrogen protection, (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide (47.4 g, 103.2 mmol, 1 eq), tetrahydrofuran (600 mL) were added into a 10 L three-necked flask, stirred, heated to 70 °C, maleic acid (23.9 g, 206.4 mmol, 2 eq) in tetrahydrofuran (600 mL) was added dropwise, controlled to be completed within one hour, after dropwise addition, the temperature was controlled at 60-65 °C, and stirring was continued for 12-15 hours. White solid was generated. Slowly cooled to 20-25 °C and continued to stir for 1 hour. Filtered by Buchner funnel and air-dried at 40-45 °C for 48-50 hours to obtain white solid (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide dimaleate 62.9 g, yield 88.2%.

[0085] Example 6

[0086] This example relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide dimaleate, and the specific preparation process is as follows:

[0087] (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6- quinolinyl)-2-butenediamide (47.4 g, 103.2 mmol, 1 eq), methyl tert-butyl ether (1000 mL), was charged into a 10 L three-necked flask, stirred, heated to 70 °C, maleic acid (23.9 g, 206.4 mmol, 2 eq) in isopropyl alcohol (1000 mL) was added dropwise, controlled to be completed within one hour, after the dropwise addition, the temperature was controlled at 60-65 °C, and stirring was continued for 12-15 hours. White solid was generated, slowly cooled to 20-25 °C, and stirring was continued for 1 hour. Filtration was performed using a Buchner funnel, and air-drying was performed at 40-45 °C for 48-50 hours to obtain white solid (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinolinyl)-2-butenediamide dimaleate 65.0 g, with a yield of 91.3%.

[0088] Example 7

[0089] This example relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2- ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinolinyl)-2-butenediamide methanesulfonate, and the specific preparation process is as follows:

[0090] (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6- quinolinyl)-2-butenediamide (10 g, 0.021 mol, 1 eq), isopropyl alcohol (100 mL), was charged into a 10 L three-necked flask, stirred, heated to 70 °C, methanesulfonic acid (2.0 g, 0.021 mol, 1 eq) in isopropyl alcohol (20 mL) was added dropwise, controlled to be completed within one hour, after the dropwise addition, the temperature was controlled at 60-65 °C, and stirring was continued for 12-15 hours. White solid was generated, slowly cooled to 20-25 °C, and stirring was continued for 1 hour. Filtration was performed using a Buchner funnel, and air-drying was performed at 40-45 °C for 48-50 hours to obtain white solid (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinolinyl)-2-butenediamide methanesulfonate 6.1 g, with a yield of 50.1%.

[0091] Example 8

[0092] This example relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2- ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenediamide mesylate salt, and the specific preparation process is as follows:

[0093] Under nitrogen protection, (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenediamide (10 g, 0.021 mol, 1 eq), isopropanol (100 mL) were added into a 10 L three-necked flask, stirred, heated to 70°C, dropwise added methanesulfonic acid (4.1 g, 0.043 mol, 2 eq) in isopropanol (30 mL), controlled to be completed within one hour, after dropwise addition, the temperature was controlled at 60-65°C, continued to stir for 12-15 hours, a white solid was generated, slowly cooled to 20-25°C, continued to stir for 1 hour, suction filtered through a Buchner funnel, air-dried at 40-45°C for 48-50 hours to obtain a white solid (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenediamide mesylate salt 7.8 g, yield 55.2%.

[0094] Example 9

[0095] This example relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2- ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenediamide mesylate salt, and the specific preparation process is as follows:

[0096] Under nitrogen protection, (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenediamide (10 g, 0.021 mol, 1 eq), isopropanol (100 mL) were added into a 10 L three-necked flask, stirred, heated to 70°C, dropwise added methanesulfonic acid (4.1 g, 0.043 mol, 2 eq) in isopropanol (30 mL), controlled to be completed within one hour, after dropwise addition, the temperature was controlled at 60-65°C, continued to stir for 12-15 hours, a white solid was generated, slowly cooled to 20-25°C, continued to stir for 1 hour, suction filtered through a Buchner funnel, air-dried at 40-45°C for 48-50 hours to obtain a white solid (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenediamide mesylate salt 7.8 g, yield 55.2%.

[0097] Example 10

[0098] This example relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2- ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenediamide hydrochloride, and the specific preparation process is as follows:

[0099] (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6- quinazolinyl)-2-butenediamide (10 g, 0.021 mol, 1 eq), isopropanol (100 mL) were added into a 10 L three-necked flask, stirred, heated to 70 °C, and (E)-4-(dimethylamino)-N-(7-(2- ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenediamide (10 g, 0.021 mol, 1 eq), isopropanol (100 mL) were added into a 10 L three-necked flask, stirred, heated to 70 °C, and phosphoric acid (2.1 g, 0.021 mol, 1 eq) in isopropanol (10 mL) was added dropwise, and the dropwise addition was controlled to be completed within one hour, and after the dropwise addition was completed, the temperature was controlled at 60-65 °C, and stirring was continued for 12-15 hours, and a white solid was generated, and after slow cooling to 20-25 °C, stirring was continued for 1 hour, and suction filtration was performed with a Buchner funnel, and air-drying was performed at 40-45 °C for 48-50 hours to obtain white solid (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenediamide hydrochloride 7.4 g, and the yield was 42.3%.

[0100] Example 11

[0101] This example relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2- ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenediamide hydrochloride, and the specific preparation process is as follows:

[0102] (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6- quinazolinyl)-2-butenediamide (10 g, 0.021 mol, 1 eq), isopropanol (100 mL) were added into a 10 L three-necked flask, stirred, heated to 70 °C, and (E)-4-(dimethylamino)-N-(7-(2- ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenediamide (10 g, 0.021 mol, 1 eq), isopropanol (100 mL) were added into a 10 L three-necked flask, stirred, heated to 70 °C, and phosphoric acid (2.1 g, 0.021 mol, 1 eq) in isopropanol (10 mL) was added dropwise, and the dropwise addition was controlled to be completed within one hour, and after the dropwise addition was completed, the temperature was controlled at 60-65 °C, and stirring was continued for 12-15 hours, and a white solid was generated, and after slow cooling to 20-25 °C, stirring was continued for 1 hour, and suction filtration was performed with a Buchner funnel, and air-drying was performed at 40-45 °C for 48-50 hours to obtain white solid (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenediamide hydrochloride 7.4 g, and the yield was 42.3%.

[0103] Example 12

[0104] This example relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2- ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenediamide L- malate, and the preparation is carried out as follows:

[0105] (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6- quinazolinyl)-2-butenediamide (10 g, 0.021 mol, 1 eq), isopropanol (100 mL) were charged into a 10 L three-necked flask under nitrogen protection, stirred, heated to 70 °C, dropwise added L-malic acid (5.8 g, 0.044 mmol, 2 eq) in isopropanol (20 mL), controlled to dropwise complete within one hour, after dropwise complete, controlled the temperature at 60-65 °C, continued to stir for 12-15 hours, generated a white solid, slowly cooled to 20-25 °C, continued to stir for 1 hour, filtered by Buchner funnel, air-dried at 40-45 °C for 48-50 hours to obtain white solid (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenediamide L-malate 6.7 g, yield 42.7%. The DSC, TGA test results of the product are shown in Figures 1, 2 respectively, as shown in the figures, the sample has an endothermic peak at 86 °C, which is speculated to be a water loss process, and has an irregular endothermic peak starting from 120 °C, which is speculated to be a sample decomposition process.

[0106] Example 13

[0107] This example relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2- ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenediamide L- malate, and the preparation is carried out as follows:

[0108] (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6- quinolinyl)-2-butenediamide (10 g, 0.021 mol, 1 eq), isopropanol (100 mL) was charged into a 10 L three-necked flask, stirred, heated to 70 °C, and succinic acid (2.1 g, 0.022 mmol, 1 eq) in isopropanol (20 mL) was added dropwise, and the dropwise addition was controlled to be completed within one hour. After the dropwise addition was completed, the temperature was controlled at 60-65 °C, and stirring was continued for 12-15 hours. A white solid was generated, and after slow cooling to 20-25 °C, stirring was continued for 1 hour. Filtration was performed using a Buchner funnel, and air-drying was performed at 40-45 °C for 48-50 hours to obtain (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinolinyl)-2-butenediamide succinate as a white solid 9.4 g, with a yield of 62.3%. Melting point: 77.5-97.5 °C.

[0109] 1 H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 1H), 9.67 (s, 1H), 8.92 (s, 1H), 8.54 (s, 1H), 8.01 (s, 1H), 7.92-7.85 (m, 1H), 7.39 (t, J = 7.9 Hz, 1H), 7.34 (s, 1H), 7.24-7.17 (m, 1H), 6.89-6.77 (m, 1H), 6.70-6.61 (m, 1H), 4.40-4.33 (m, 2H), 4.21 (s, 5H), 3.87-3.80 (m, 2H), 3.59-3.40 (m, 4H), 2.48 (s, 5H), 1.13 (t, J = 7.0 Hz, 3H).

[0110] Example 14

[0111] This example relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinolinyl)-2-butenediamide sulfate, and the preparation process is as follows:

[0112] (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide (10 g, 0.021 mol, 1 eq), isopropanol (100 mL) was taken in a 10 L three necked flask, stirred, heated to 70 °C, hydrogen chloride in ethanol (2 M, 21 mL, 0.042 mol, 2 eq) was added drop wise, controlled to complete the addition in one hour, after completion of addition, temperature was controlled between 60-65 °C, stirring was continued for 12-15 hours, off white solid was formed, slow cooling was done to 20-25 °C, stirring was continued for 1 hour, filtered through bushing funnel, air dried at 40-45 °C for 48-50 hours to get off white solid (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide dihydrochloride 10.5 g, yield 100 %.

[0113] Example 15

[0114] This example relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide dihydrochloride, the specific preparation process is as follows:

[0115] (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide (10 g, 0.021 mol, 1 eq), isopropanol (100 mL) was taken in a 10 L three necked flask, stirred, heated to 70 °C, hydrogen chloride in ethanol (2 M, 21 mL, 0.042 mol, 2 eq) was added drop wise, controlled to complete the addition in one hour, after completion of addition, temperature was controlled between 60-65 °C, stirring was continued for 12-15 hours, off white solid was formed, slow cooling was done to 20-25 °C, stirring was continued for 1 hour, filtered through bushing funnel, air dried at 40-45 °C for 48-50 hours to get off white solid (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide dihydrochloride 10.5 g, yield 100 %.

[0116] Example 16

[0117] This example relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide dihydrochloride, the specific preparation process is as follows:

[0118] (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6- quinolinyl)-2-butenediamide (10 g, 0.021 mol, 1 eq), isopropanol (100 mL) were charged into a 10 L three-necked flask, stirred, heated to 70 °C, and a solution of tartaric acid (3.26 g, 0.022 mol, 1 eq) in isopropanol was added dropwise, controlling the dropwise addition to be completed within one hour. After the dropwise addition was completed, the temperature was controlled at 60-65 °C, and stirring was continued for 12-15 hours. A white solid was generated, and the temperature was slowly lowered to 20-25 °C, and stirring was continued for 1 hour. Filtration was performed using a Buchner funnel, and air-drying was performed at 40-45 °C for 48-50 hours to obtain (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinolinyl)-2-butenediamide di-tartrate 6.1 g, with a yield of 42.7%. Melting point: 96.0-130.5 °C.

[0119] 1 H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 9.65 (s, 1H), 8.92 (s, 1H), 8.54 (s, 1H), 8.04-7.99 (m, 1H), 7.92-7.85 (m, 1H), 7.39 (t, J = 7.9 Hz, 1H), 7.33 (s, 1H), 7.24-7.17 (m, 1H), 6.88-6.77 (m, 1H), 6.64 (d, J = 15.3 Hz, 1H), 4.36 (dd, J = 5.7, 3.6 Hz, 2H), 4.20 (d, J = 9.6 Hz, 4H), 3.87-3.71 (m, 3H), 3.55 (q, J = 7.0 Hz, 2H), 3.45 (d, J = 6.5 Hz, 2H), 3.17 (s, 4H), 1.14 (t, J = 7.0 Hz, 3H).

[0120] Example 17

[0121] This example relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinolinyl)-2-butenediamide di-acetate, which was prepared according to the following procedure:

[0122] (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide (10 g, 0.021 mol, 1 eq), isopropanol (100 mL) was taken in a 10 L three necked flask, stirred, heated to 70 °C, trifluoroacetic acid (5.0 g, 0.043 mol, 2 eq) was added drop wise, controlled to complete the addition in one hour, after completion of addition, temperature was controlled between 60-65 °C, stirring was continued for 12-15 hours, white solid was formed, slow cooling was done to 20-25 °C, stirring was continued for 1 hour, filtered through bushing funnel, air dried at 40-45 °C for 48-50 hours to get (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide di(trifluoroacetate) salt 5.7 g, yield 37.9 %.

[0123] Example 18

[0124] This example relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide di(lactic acid) salt, the specific preparation process is as follows:

[0125] (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide (10 g, 0.021 mol, 1 eq), isopropanol (100 mL) was taken in a 10 L three necked flask, stirred, heated to 70 °C, trifluoroacetic acid (5.0 g, 0.043 mol, 2 eq) was added drop wise, controlled to complete the addition in one hour, after completion of addition, temperature was controlled between 60-65 °C, stirring was continued for 12-15 hours, white solid was formed, slow cooling was done to 20-25 °C, stirring was continued for 1 hour, filtered through bushing funnel, air dried at 40-45 °C for 48-50 hours to get (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide di(trifluoroacetate) salt 5.7 g, yield 37.9 %.

[0126] Example 19

[0127] This example relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide di(lactic acid) salt, the specific preparation process is as follows:

[0128] (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6- quinolinyl)-2-butenediamide (10 g, 0.021 mol, 1 eq), isopropanol (100 mL) were charged into a 10 L three-necked flask, stirred, heated to 70 °C, citric acid (8.3 g, 0.043 mol, 1 eq) was added dropwise, controlled to be added within one hour, after dropwise addition, the temperature was controlled at 60-65 °C, and stirring was continued for 12-15 hours, a white solid was generated, slowly cooled to 20-25 °C, and stirring was continued for 1 hour, filtered through a Buchner funnel, and air-dried at 40-45 °C for 48-50 hours to obtain white solid (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6- quinolinyl)-2-butenediamide citrate 6.4 g, yield 46.7%. Melting point: 59.0-69.0 °C.

[0129] 1 H NMR (400 MHz, DMSO-d6) δ 9.74 (d, J = 16.1 Hz, 2H), 8.91 (d, J = 5.6 Hz, 1H), 8.55 (s, 1H), 8.00 (s, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H), 7.34 (s, 1H), 7.21 (d, J = 7.5 Hz, 1H), 6.80 (dt, J = 13.7, 6.5 Hz, 1H), 6.68 (d, J = 15.4 Hz, 1H), 4.40 - 4.34 (m, 2H), 4.19 (s, 1H), 3.86 - 3.70 (m, 3H), 3.67 (d, J = 6.5 Hz, 2H), 3.55 (q, J = 7.0 Hz, 2H), 2.72 - 2.61 (m, 4H), 2.59 (s, 6H), 1.13 (t, J = 7.0 Hz, 3H).

[0130] Example 20

[0131] This example relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2- ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinolinyl)-2-butenediamide dihydrobromide, and the specific preparation process is as follows:

[0132] (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide (10 g, 0.021 mol, 1 eq), isopropanol (100 mL) were added into a 10 L three-necked flask, stirred, heated to 70 °C, dropwise added fumaric acid (5.1 g, 2.06 mmol, 2 eq) in isopropanol (100 mL), controlled to dropwise added within one hour, after dropwise added, controlled the temperature at 60-65 °C, continued to stir for 12-15 hours, there was a white solid generated, slowly cooled to 20-25 °C, continued to stir for 1 hour, suction filtered through a Buchner funnel, air-dried at 40-45 °C for 48-50 hours to get a white solid (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide di-fumarate 11.8 g, yield 77.9%.

[0133] Example 21

[0134] This example relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide di-fumarate, the specific preparation process is as follows:

[0135] (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide (10 g, 0.021 mol, 1 eq), isopropanol (100 mL) were added into a 10 L three-necked flask, stirred, heated to 70 °C, dropwise added fumaric acid (5.1 g, 2.06 mmol, 2 eq) in isopropanol (100 mL), controlled to dropwise added within one hour, after dropwise added, controlled the temperature at 60-65 °C, continued to stir for 12-15 hours, there was a white solid generated, slowly cooled to 20-25 °C, continued to stir for 1 hour, suction filtered through a Buchner funnel, air-dried at 40-45 °C for 48-50 hours to get a white solid (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide di-fumarate 11.8 g, yield 77.9%.

[0136] Example 22

[0137] This example relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide di-fumarate, the specific preparation process is as follows:

[0138] AMX3009 and 20 g of maleic acid were added into 400 mL of isopropanol, heated to 70 °C, reacted for 5 hours, slowly reduced to room temperature, stirred for 2 hours, stood for 16 hours, suction filtered, and dried at 50 °C. The X-ray powder diffraction pattern of this crystalline sample is shown in Figure 3. After correction with silicon powder, the crystalline form has characteristic peaks at about 4.98 ± 0.2°, 5.98 ± 0.2°, 6.62 ± 0.2°, 8.27 ± 0.2°, 10.41 ± 0.2°, 11.09 ± 0.2°, 11.89 ± 0.2°, 13.99 ± 0.2°, 14.76 ± 0.2°, 15.16 ± 0.2°, 16.21 ± 0.2°, 16.53 ± 0.2°, 18.95 ± 0.2°, 19.72 ± 0.2°, 20.55 ± 0.2°, 20.82 ± 0.2°, 21.43 ± 0.2°, 22.09 ± 0.2°, 23.72 ± 0.2°, 24.42 ± 0.2°, 24.71 ± 0.2°, 25.29 ± 0.2°, 25.8 ± 0.2°, 26.18 ± 0.2°, 26.53 ± 0.2°, 27.05 ± 0.2°, 27.4 ± 0.2°, 28.53 ± 0.2°, 29.71 ± 0.2°, 29.93 ± 0.2°, 31.43 ± 0.2°, 32.56 ± 0.2°, 34.15 ± 0.2°, 34.81 ± 0.2°, 36.28 ± 0.2°, 37.3 ± 0.2°, 38.55 ± 0.2°, 39.6 ± 0.2°. The DSC spectrum is shown in Figure 4, and has a sharp melting endothermic peak at 144 °C. The TGA spectrum is shown in Figure 5, and has a weight loss of 0.8% at 120 °C. The NMR result (HNMR) is shown in Figure 6, and shows that the molar ratio of free base to maleic acid is about 1.0:1.9, and there is no residual solvent. This crystalline form is defined as Form A. 1 HNMR) is shown in Figure 6, and shows that the molar ratio of free base to maleic acid is about 1.0:1.9, and there is no residual solvent. This crystalline form is defined as Form A.

[0139] The AMX3009 L-malate prepared in Example 12 and the AMX3009 dimaleate Form A prepared in this example were left standing in air for the same time. The AMX3009 L-malate absorbed moisture and turned into a sticky solid, while the AMX3009 dimaleate Form A remained as a powder. Thus, it can be seen that the AMX3009 dimaleate Form A has lower hygroscopicity than the AMX3009 L-malate.

[0140] In addition, from the DSC graph of AMX3009 L-malate, an endothermic peak at 86°C was observed, combined with the obvious weight loss phenomenon in the TGA graph, it was speculated that the process was the dehydration of AMX3009 L-malate. When heated to 120°C, a continuous irregular endothermic peak was observed, indicating that the sample had begun to decompose. From the TGA graph of AMX3009 dimaleate Form A, it can be seen that the weight loss of AMX3009 dimaleate Form A when heated to 120°C was only 0.76%, which further indicated that the salt had low hygroscopicity. From the DSC graph, a sharp endothermic peak at 140°C was observed, which was the melting temperature of the salt. No other endothermic or exothermic peaks were observed before the melting temperature. Therefore, it can be concluded that the melting point of AMX3009 dimaleate Form A is high, and the salt maintains good thermal stability before melting.

[0141] Therefore, compared with AMX3009 L-malate, AMX3009 dimaleate has better drug properties.

[0142] Example 23

[0143] This example relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide dimaleate Form A, and the specific preparation process is as follows:

[0144] AMX3009 dimaleate (Form A) 15 mg was placed in a 3 mL vial, 1.0-3.0 mL of acetonitrile was added, and after shaking and filtering, the supernatant was taken. The vial containing the clear solution was sealed with a sealing film and four small holes were made on it, and it was placed in a 50°C environment for slow evaporation. When the solvent was completely evaporated, the obtained solid was collected, and its X-ray powder diffraction pattern and DSC spectrum were studied and compared to determine that the product was Form A.

[0145] Example 24

[0146] This example relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide dimaleate Form A, and the specific preparation process is as follows:

[0147] AMX3009 dimaleate (Form A) 30 mg was added to a 20 mL vial, dissolved with 0.2-3.4 mL of methanol, and then an antisolvent was added to the clear solution while stirring. The precipitated solid was centrifuged and separated, and its X-ray powder diffraction pattern and DSC spectrum were studied and compared to determine that the product was Form A. The types of antisolvents are shown in the following table:

[0148] Example 25

[0149] This example relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2- ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenediamide dimaleate salt Form A, which is prepared according to the following procedure:

[0150] AMX3009 dimaleate salt (Form A) 20 mg was placed in a 3 mL vial, 1.0-2.5 mL solvent (acetone or acetonitrile) was added, and after stirring at 50 °C for about 2 hours, the supernatant was filtered, and the obtained supernatant was placed in a biochemical incubator, and cooled from 50 °C to 5 °C at a cooling rate of 0.1 °C / min. The precipitated solid was collected, and the X-ray powder diffraction pattern and DSC spectrum of the product were determined by comparison to be Form A.

[0151] Example 26

[0152] This example relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2- ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenediamide dimaleate salt Form B, which is prepared according to the following procedure:

[0153] 10 g AMX3009 and 5 g maleic acid were added to 100 mL isopropanol, heated to 38 °C, reacted for 5 hours, quickly cooled to room temperature, stirred for 2 hours, and allowed to stand for 16 hours. The product was filtered and dried. The X-ray powder diffraction pattern of the crystalline sample is shown in Figure 7. The crystalline sample has characteristic peaks at about 4.68 ± 0.2°, 5.67 ± 0.2°, 6.99 ± 0.2°, 7.75 ± 0.2°, 9.9 ± 0.2°, 12.15 ± 0.2°, 13.4 ± 0.2°, 14.03 ± 0.2°, 14.41 ± 0.2°, 16.18 ± 0.2°, 16.7 ± 0.2°, 17.64 ± 0.2°, 18.73 ± 0.2°, 19.59 ± 0.2°, 20.04 ± 0.2°, 20.56 ± 0.2°, 20.95 ± 0.2°, 21.33 ± 0.2°, 21.76 ± 0.2°, 22.98 ± 0.2°, 24.54 ± 0.2°, 25.52 ± 0.2°, 26.38 ± 0.2°, 27.35 ± 0.2°, 28.24 ± 0.2°, 29.95 ± 0.2°, 30.8 ± 0.2°, 33.07 ± 0.2°, 35.69 ± 0.2°, 36.95 ± 0.2°, 37.97 ± 0.2°, 39.2 ± 0.2°.

[0154] Example 27

[0155] This example relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2- ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenediamide dimaleate salt Form C, which is prepared according to the following procedure:

[0156] AMX3009 dimaleate salt (Form A) 20 mg was placed in a 1.5 mL vial, 0.5 mL of ethanol was added, and the sample was stirred magnetically at room temperature for about 5 days. The solid was centrifuged and dried in a fume hood at room temperature. The X-ray powder diffraction pattern of this crystalline sample is shown in Figure 8, which has characteristic peaks at about 4.82 ± 0.2°, 9.56 ± 0.2°, 14.12 ± 0.2°, 14.41 ± 0.2°, 15.41 ± 0.2°, 17.91 ± 0.2°, 19.24 ± 0.2°, 19.69 ± 0.2°, 21.84 ± 0.2°, 25.72 ± 0.2°, 34.04 ± 0.2°. This crystalline form is defined as Form C.

[0157] Example 28

[0158] This example relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2- ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenediamide dimaleate salt Form F, which is prepared according to the following procedure:

[0159] AMX3009 dimaleate salt (Form A) 20 mg was placed in a 1.5 mL vial, 0.5 mL of methanol / ethyl acetate (1 :4, v / v) was added, and the sample was stirred magnetically at 50 °C for about 4 days. The sample was clarified, and about 20 mg of sample was added and stirred magnetically at 50 °C for about 1 day. The solid was centrifuged and dried in a fume hood at room temperature. The X-ray powder diffraction pattern of this crystalline sample is shown in Figure 9, which has characteristic peaks at about 3.52 ± 0.2°, 4.57 ± 0.2°, 7.06 ± 0.2°, 8.51 ± 0.2°, 9.29 ± 0.2°, 12.93 ± 0.2°, 14.39 ± 0.2°, 15.5 ± 0.2°, 17.61 ± 0.2°, 18.44 ± 0.2°, 19.33 ± 0.2°, 20.23 ± 0.2°, 20.94 ± 0.2°, 21.92 ± 0.2°, 23.57 ± 0.2°, 25.58 ± 0.2°, 25.85 ± 0.2°, 26.31 ± 0.2°, 27.85 ± 0.2°, 32.75 ± 0.2°. This crystalline form is defined as Form F.

[0160] Example 29

[0161] This example relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2- ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenediamide dimaleate salt Form D, which was prepared according to the following procedure:

[0162] AMX3009 dimaleate salt (Form A) 30 mg was placed in a 20 mL glass vial, 0.2 mL dimethylacetamide was added, and anti-solvent 2-methyltetrahydrofuran was added dropwise with stirring, for a total of 8 mL. The precipitated solid was centrifuged and dried at room temperature. The resulting solid was weighed into a 1.5 mL vial, 0.5 mL 2-methyltetrahydrofuran was added, and the mixture was stirred magnetically at room temperature for 19 hours. The solid was isolated and dried at room temperature. The X-ray powder diffraction pattern of this crystalline sample is shown in Figure 10, and this crystalline form was defined as Form D, having characteristic peaks at about 3.37 ± 0.2°, 3.96 ± 0.2°, 5.93 ± 0.2°, 7.91 ± 0.2°, 14.86 ± 0.2°, 16.06 ± 0.2°, 17.64 ± 0.2°, 19.2 ± 0.2°, 19.5 ± 0.2°, 20.33 ± 0.2°, 21.81 ± 0.2°, 24.02 ± 0.2°, 25.36 ± 0.2°, 26.05 ± 0.2°, 27.28 ± 0.2°.

[0163] Example 30

[0164] This example relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2- ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenediamide dimaleate salt Form E, which was prepared according to the following procedure:

[0165] Approximately 20 mg of AMX3009 dimaleate (crystal form A) was placed in a vial, and 0.05 mL of acetone / water (19:1, v / v) was added. The mixture was magnetically stirred at room temperature for 42 h to obtain a white solid. X-ray powder diffraction (XPD) was performed on the white solid, and the pattern is shown in Figure 11. After silicon powder correction, the crystals were observed at approximately 5.13±0.2°, 6.71±0.2°, 11.37±0.2°, 12.7±0.2°, 14.19±0.2°, 14.55±0.2°, 15.61±0.2°, 15.85±0.2°, 16.33±0.2°, 16.62±0.2°, 17.79±0.2°, 18.06±0.2°, 18.85±0.2°, 19.42±0.2°, 20.07±0.2°, and 20.26±0.2°. Characteristic peaks are observed at 20.68±0.2°, 21.25±0.2°, 22.02±0.2°, 22.54±0.2°, 23.4±0.2°, 24.7±0.2°, 25.02±0.2°, 25.21±0.2°, 26.09±0.2°, 26.65±0.2°, 27.5±0.2°, 27.92±0.2°, 29.19±0.2°, 30.54±0.2°, 32.92±0.2°, 34.03±0.2°, 34.64±0.2°, 35.18±0.2°, and 39.07±0.2°. This crystal form is defined as the E crystal form.

[0166] In addition, at water activity a w A solvent system of ~0.3 (water:isopropanol volume ratio 3:97), water activity a w A solvent system of ~0.4 (water:1,4-dioxane volume ratio of 5:95) and water activity a w The above stirring experiment was carried out in a solvent system of ~0.8 (water:isopropanol volume ratio of 15:85), with all other conditions being the same, and the X-ray powder diffraction pattern showed that all crystals were of the E crystal form.

[0167] Example 31

[0168] This embodiment relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazolin)-2-butenamide dimaleate crystal form H, and the specific preparation process is as follows:

[0169] AMX3009 dimaleate Form A 69 mg was placed in a 3 mL vial and open to a 20 mL glass vial with 4 mL water. The sample was collected after 19 days of vapor-solid permeation. The X-ray powder diffraction pattern of the crystalline sample is shown in Figure 12. The crystalline form has characteristic peaks at about 3.67±0.2°, 5.51±0.2°, 7.15±0.2°, 7.36±0.2°, 9.31±0.2°, 11.04±0.2°, 11.45±0.2°, 13.21±0.2°, 16.69±0.2°, 19.73±0.2°, 20.48±0.2°, 21.66±0.2°, 22.9±0.2°, 24.01±0.2°, 25.79±0.2°, 26.48±0.2°, 27.86±0.2°, 30.23±0.2°. This crystalline form is defined as Form H.

[0170] Example 32

[0171] This example relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2- ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenediamide dimaleate Form K, and is specifically prepared as follows:

[0172] AMX3009 dimaleate Form E was heated to 75 °C at a heating rate of 10 °C / min, held isothermally for 2 min, and then cooled to 30 °C at a rate of 20 °C / min and left at ambient conditions. The X-ray powder diffraction pattern of the crystalline sample is shown in Figure 13. The crystalline form has characteristic peaks at about 5.16±0.2°, 6.96±0.2°, 7.74±0.2°, 13.14±0.2°, 13.86±0.2°, 15.54±0.2°, 16.15±0.2°, 17.67±0.2°, 18.19±0.2°, 18.57±0.2°, 19.62±0.2°, 20.52±0.2°, 20.92±0.2°, 21.92±0.2°, 23.34±0.2°, 23.79±0.2°, 24.34±0.2°, 25.43±0.2°, 27.5±0.2°, 27.91±0.2°, 30.59±0.2°, 36.74±0.2°. This crystalline form is defined as Form K.

[0173] Example 33

[0174] This example relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2- ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenediamide dimaleate Form R, and is specifically prepared as follows:

[0175] Dynamic moisture sorption test was performed on AMX3009 dimaleate salt Form A at 25 °C, humidity from 0% RH to 95% RH to 0% RH, the solid was collected after the test, Form R was obtained. The X-ray powder diffraction pattern of this crystalline sample is shown in Figure 14, this crystalline has characteristic peaks at about 4.67±0.2°, 4.93±0.2°, 7.53±0.2°, 8.52±0.2°, 9.21±0.2°, 10.8±0.2°, 11.63±0.2°, 12.49±0.2°, 13.94±0.2°, 15.13±0.2°, 15.82±0.2°, 16.28±0.2°, 16.98±0.2°, 17.69±0.2°, 18.6±0.2°, 19.69±0.2°, 21.08±0.2°, 22.48±0.2°, 23.43±0.2°, 24.2±0.2°, 25.89±0.2°, 26.47±0.2°, 27.34±0.2°, 27.78±0.2°, 31.25±0.2°. This form was defined as Form R.

[0176] Example 34

[0177] This example relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2- ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenediamide dimaleate salt Form V, the preparation process is as follows:

[0178] AMX3009 dimaleate salt (Form A) was stirred in isopropanol / water (98 / 2 by volume) at room temperature with magnetic stirring, the solid was collected by centrifugation and dried in the fume hood at room temperature. The X-ray powder diffraction pattern of this crystalline sample is shown in Figure 15, this crystalline has characteristic peaks at about 4.65±0.2°, 8.56±0.2°, 10.1±0.2°, 10.73±0.2°, 13.48±0.2°, 14.16±0.2°, 15.35±0.2°, 16.58±0.2°, 16.83±0.2°, 18.2±0.2°, 18.4±0.2°, 19.19±0.2°, 20.28±0.2°, 21.31±0.2°, 21.74±0.2°, 22.28±0.2°, 23.33±0.2°, 23.77±0.2°, 26.03±0.2°, 27.19±0.2°, 27.73±0.2°, 28.91±0.2°, 29.29±0.2°, 30.73±0.2°, 32.23±0.2°, 35.43±0.2°, 36.81±0.2°. This form was defined as Form V.

[0179] Test Example 1 In vitro cell inhibition rate test

[0180] The EGFR-resistant mutant lung cancer cell inhibition rate test of the (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide pharmaceutically acceptable salt prepared by the present application was carried out, and the specific operation was as follows:

[0181] Compound preparation: the compound was prepared into a dilute solution with a final concentration of 1000 times by using dimethyl sulfoxide. The final concentration of the compound for testing was 1000, 250, 62.5, 15.63, 3.91, 0.98, 0.25, 0.06, 0.02 nM. The compound was diluted with culture medium to prepare a 20-fold final concentration of the compound.

[0182] Cell culture: the suspension cells were spun down, resuspended in growth medium, and then counted using a cell counter. The cell suspension was diluted in growth medium to the desired density. 95 μL of cells were added to each well, followed by the addition of 5 μL of 20-fold final concentration of the compound, and incubated at 37°C for 72 hours in a 5% CO2 incubator.

[0183] Detection: the cell plate was equilibrated to room temperature. 50 μL of reagent was added to each well, mixed and shaken for 2 minutes, and incubated at room temperature for 10 minutes. The SpectraMax Paradigm was used for detection.

[0184] Data analysis: IC50 was calculated using GraphPad Prism 8.0.

[0185] %Inh = 100-(RLU compound-RLU blank) / (RLU control-RLU blank) x 100%

[0186] RLU control: only cells and DMSO were added, without drugs.

[0187] RLU blank: only medium and DMSO were added, without cells.

[0188] The test results are shown in the following table:

[0189] As can be seen from the in vitro cell inhibition rate test results in the above table, the AMX3009 dimaleate salt has better inhibitory activity than drugs such as osimertinib and afatinib on the two EGFR mutant lung cancer cells.

[0190] Test Example 2: in vivo pharmacodynamic test

[0191] To study the efficacy of AMX3009 dimaleate in the form of crystalline form A on Ba / F3-FL-EGFR-S768I cell subcutaneous xenograft tumor in BALB / c nude mouse model in vivo.

[0192] Experimental drug: AMX3009 dimaleate in the form of crystalline form A.

[0193] Test animals: 6-8 weeks old female mice, 18-22 g, a total of 40.

[0194] Drug preparation: weigh an appropriate amount of experimental drug, and prepare 1, 0.5, 0.25 mg / mL of pure water solution of crystalline form A for oral control drug afatinib 1 mg / mL solution.

[0195] Dosing: free drinking water, free feeding, oral administration, dose 10 μL / g (different concentrations in different groups).

[0196] Operation: culture Ba / F3-FL-EGFR-S768I cell strain, collect, prepare and dilute into cell suspension with a viable cell concentration of 1×10^7 / mL, inoculate in mice in the right axillary subcutaneously, and when the average tumor volume reaches about 124.44 mm 3 When the average tumor volume reaches about 124.44 mm 2 , the mice were randomly divided into 5 groups according to the tumor volume, and the mice were dosed according to their body weight: 10 μL / g. If the body weight decreases by more than 15%, the dosing regimen is adjusted accordingly. The health status and death of the animals were detected every day, and the routine examination included the tumor growth of the animals, the activity, diet, body weight, eyes, hair and other abnormal behaviors. The body weight was measured every day, and the tumor volume was measured three times a week (Monday, Wednesday and Friday). The tumor volume was measured by vernier caliper, and the formula was TV = 0.5a x b 2 , where a is the long diameter of the tumor and b is the short diameter of the tumor. The results were analyzed.

[0197] The results of the evaluation of the antitumor efficacy of AMX3009 and Afatinib on Ba / F3-FL-EGFR-S768I cell xenograft tumor model (based on the tumor volume on day 13 after administration) are shown in the following table:

[0198] The average tumor volume of animals in the AMX3009 and Afatinib efficacy experiment changed with time, as shown in Figure 16. As can be seen from the figure, AMX3009 dimaleate also showed strong efficacy in animals.

[0199] Test Example 3: Results of single-dose pharmacokinetic test in SD rats

[0200] The single pharmacokinetic test result of the test drug A crystalline form of AMX3009 dimaleate in SD rats in vivo was studied.

[0201] Experimental drug: AMX3009 dimaleate in the form of a crystalline form A.

[0202] Test animals: 4 female and 4 male 6-week-old SD rats in each group, a total of 16.

[0203] Drug preparation: An appropriate amount of test product AMX3009 maleate was accurately weighed and dissolved in physiological saline to obtain a colorless and clear liquid (pH ~ 6) with a concentration of 1 mg / mL for intravenous injection and oral administration.

[0204] Dosing: The oral group was fasted for about 13-14 hours before dosing. The feed was restored about 4 hours after dosing.

[0205] Sample collection and processing: Intravenous injection group, before dosing, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h and 24 h after dosing.

[0206] The blood sampling time points of the oral PO group were: before dosing, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h and 24 h after dosing. The single pharmacokinetic test results of SD rats are shown in the following table:

[0207] Intravenous injection group, dose 5 mg / kg (n=8)

[0208] Oral group (PO), dose 10 mg / kg (n=8)

[0209] AUC(0-t)—t is 48 h; MRT(0-t)—t is 48 h

[0210] The single pharmacokinetic test results of SD rats show that the exposure of AMX3009 dimaleate in animals is high, and the bioavailability is high.

[0211] Test Example 4 Solubility and Stability Test

[0212] The crystalline form of the dimaleate salt of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide prepared by the present application and (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide (AMX3009 free base) were subjected to solubility and stability tests, and the specific results are as follows:

[0213] (1) Solubility test

[0214] a. Solubility comparison of AMX3009 dimaleate Form A and AMX3009 free base

[0215] AMX3009 free base and AMX3009 dimaleate Form A were prepared into supersaturated solution in water, pH 1.2 hydrochloric acid solution, FaSSIF (simulated intestinal fluid), respectively, and dissolved by oscillation. After 24 h, the supernatant after centrifugation was taken, and the solubility was determined by high performance liquid chromatography according to the external standard method. The results are as follows:

[0216] From the above table, it can be seen that the solubility of AMX3009 free base in water and FaSSIF (simulated intestinal fluid) is low, and AMX3009 dimaleate Form A is significantly improved.

[0217] b. Solubility comparison of AMX3009 dimaleate Form E and AMX3009 free base

[0218] AMX3009 free base and AMX3009 dimaleate Form E were taken in an appropriate amount in water, pH 1.2 hydrochloric acid solution, FaSSIF (simulated intestinal fluid), and the solubility was tested according to the method of solubility test in the General Rules of Chinese Pharmacopoeia. The results are as follows:

[0219] From the above table, it can be seen that the solubility of AMX3009 free base in water and FaSSIF (simulated intestinal fluid) is low, and AMX3009 dimaleate Form E is significantly improved.

[0220] (2) Stability test

[0221] Short-term stability study of Form A:

[0222] AMX3009 dimaleate Form A was weighed into a glass vial, and the vial containing the sample was covered with a sealing film, then about 10-20 small pinholes were punched, and then placed in a 25℃ / 60% RH environment for 1 week, and placed in a closed environment at 80℃ for 1 day. The purity and XRPD were tested to evaluate the physicochemical stability. The results are as follows:

[0223] The stability test results show that the purity and crystal form of Form A crystal basically do not change when placed in a 25℃ / 60% RH environment for 1 week, at 80℃ for 1 day, and in a 25℃ / 60% RH environment for 1 week.

[0224] Long-term stability study of Form A:

[0225] AMX3009 dimaleate Form A crystals were packed in PE bags, with an aluminum foil bag outside, and placed in 25℃ / 60%RH and 40℃ / 75%RH conditions for 6 months, and 5℃ conditions for 36 months, and X-ray powder diffraction was used to test the stability. The test results are shown in the following table:

[0226] As shown in the above table, Form A has good long-term stability under different temperature and humidity conditions in simulated market packaging conditions.

[0227] Short-term stability study of Form E:

[0228] AMX3009 dimaleate Form E crystals were weighed into a glass vial, the sample vial was capped with sealing film, and then about 10-20 small pinholes were punched, and then placed in 25℃ / 60%RH and 40℃ / 75%RH conditions for 1 week, and purity and XRPD were tested to evaluate the physicochemical stability. The results are shown in the following table:

[0229] The results show that Form E crystals placed in 25℃ / 60%RH and 40℃ / 75%RH conditions for 1 week have no change in purity and crystal form, and have good stability.

[0230] In summary, AMX3009 dimaleate Form A and Form E have high solubility in water, pH 1.2 hydrochloric acid solution, and simulated intestinal fluid, and have good stability, and are suitable for pharmaceutical preparation applications.

[0231] The above-described examples are only preferred examples for fully illustrating the present application, and the protection scope of the present application is not limited thereto. Equivalent substitutions or transformations made by those skilled in the art based on the present application are within the protection scope of the present application. The protection scope of the present application is subject to the claims.

Claims

1. A pharmaceutically acceptable salt of (E)-4-(dimethylamino)-N-(7-(2- ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenoic amide, characterized in that, The pharmaceutically acceptable salt is a maleate salt, a mesylate salt, a p-toluenesulfonate salt, a phosphate salt, an L-malate salt, a succinate salt, a sulfate salt, a hydrochloride salt, a tartrate salt, an acetate salt, a trifluoroacetate salt, a citrate salt, a hydrobromide salt, or a fumarate salt.

2. The pharmaceutically acceptable salt of claim 1, wherein, The pharmaceutically acceptable salts have the following general structure: n is 1, 2, or 3; A is maleic acid, methanesulfonic acid, p-toluenesulfonic acid, phosphoric acid, L-malic acid, succinic acid, sulfuric acid, hydrochloric acid, tartaric acid, acetic acid, trifluoroacetic acid, citric acid, hydrobromic acid, or fumaric acid.

3. The pharmaceutically acceptable salt of claim 2, wherein, n is 2, and A is maleic acid.

4. A crystalline form A of the dimaleate salt of (E)-4-(dimethylamino)-N-(7-(2- ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenoic amide characterized by, The X-ray powder diffraction pattern of the crystal form A has characteristic peaks at 4.98±0.2°, 10.41±0.2°, 15.16±0.2°, and 19.72±0.2° in terms of a 2θ angle using Cu-Kα as a radiation source.

5. The dimaleate salt Form A of claim 4, characterized by, The X-ray powder diffraction pattern of the crystal form A has characteristic peaks at 4.98±0.2°, 5.98±0.2°, 10.41±0.2°, 14.76±0.2°, 15.16±0.2°, 16.21±0.2°, 19.72±0.2°, 22.09±0.2°, 25.80±0.2°, and 34.81±0.2°.

6. A process for preparing the crystalline Form A of dimaleate salt according to claim 4 or 5, characterized in that, The preparation method comprises: (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide is dissolved in a first organic solvent selected from one or more of isopropyl alcohol, acetonitrile, tetrahydrofuran, methyl isobutyl ketone, chloroform, acetone, ethyl acetate, 1,4-dioxane, isopropyl acetate, methyl tert-butyl ether, 2-methyl tetrahydrofuran, and toluene, crystals are stirred out, and the crystal form A is separated. (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide di-maleate salt is dissolved in acetonitrile, and solid is volatilized and separated out to obtain the crystal form A. (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide di-maleate salt is dissolved in methanol, an anti-solvent is added, and solid is stirred out to obtain the crystal form A; the anti-solvent is methyl tert-butyl ether, 2-methyl tetrahydrofuran, or toluene. (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide di-maleate salt is dissolved in acetone or acetonitrile, and solid is separated out by cooling treatment to obtain the crystal form A.

7. A crystalline form B of the dimaleate salt of (E)-4-(dimethylamino)-N-(7-(2- ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenoic amide characterized by, The X-ray powder diffraction pattern of the crystal form B has characteristic peaks at 4.68±0.2°, 14.41±0.2°, 16.70±0.2°, and 18.73±0.2° in terms of a 2θ angle using Cu-Kα as a radiation source.

8. The dimaleate salt Form B according to claim 7, characterized by, The X-ray powder diffraction pattern of the crystal form B has characteristic peaks at 4.68±0.2°, 7.75±0.2°, 9.90±0.2°, 13.40±0.2°, 14.03±0.2°, 14.41±0.2°, 16.70±0.2°, 17.64±0.2°, 18.73±0.2°, 25.52±0.2°, 26.38±0.2°, 33.07±0.2°.

9. A crystalline Form C of the dimaleate salt of (E)-4-(dimethylamino)-N-(7-(2- ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenoic amide, characterized by an X-ray powder diffraction pattern having a peak at 7.2 ± 0.2 degrees two-theta. The X-ray powder diffraction pattern of the crystal form C has characteristic peaks at 4.82±0.2°, 14.41±0.2°, 15.41±0.2°, 19.24±0.2°, using Cu-Kα as the radiation source, expressed in degrees 2θ.

10. The dimaleate salt Form C of claim 9, characterized by, The X-ray powder diffraction pattern of the crystal form C has characteristic peaks at 4.82±0.2°, 9.56±0.2°, 14.12±0.2°, 14.41±0.2°, 15.41±0.2°, 19.24±0.2°, 19.69±0.2°, 25.72±0.2°.

11. A crystalline Form D of the dimaleate salt of (E)-4-(dimethylamino)-N-(7-(2- ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenoic amide, characterized by an X-ray powder diffraction pattern having a peak at 7.2 ± 0.2 degrees two-theta. The X-ray powder diffraction pattern of the crystal form D has characteristic peaks at 5.93±0.2°, 7.91±0.2°, 14.86±0.2°, 20.33±0.2°, 25.36±0.2°, 26.05±0.2°, using Cu-Kα as the radiation source, expressed in degrees 2θ.

12. The dimaleate salt Form D of claim 11, characterized by, The X-ray powder diffraction pattern of the crystal form D has characteristic peaks at 3.37±0.2°, 3.96±0.2°, 5.93±0.2°, 7.91±0.2°, 14.86±0.2°, 16.06±0.2°, 19.20±0.2°, 20.33±0.2°, 21.81±0.2°, 25.36±0.2°, 26.05±0.2°, 27.28±0.2°.

13. A crystalline form E of the dimaleate salt of (E)-4-(dimethylamino)-N-(7-(2- ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenoic amide, characterized by an X-ray powder diffraction pattern comprising a peak at 7.2 ± 0.2 degrees two-theta. The X-ray powder diffraction pattern of the crystal form E has characteristic peaks at 5.16±0.2°, 6.75±0.2°, 15.65±0.2°, 16.67±0.2°, 17.84±0.2°, 23.45±0.2°, 25.07±0.2°, using Cu-Kα as the radiation source, expressed in degrees 2θ.

14. The dimaleate salt Form E of claim 13, characterized by, The X-ray powder diffraction pattern of the crystal form E has characteristic peaks at 5.16±0.2°, 6.75±0.2°, 15.65±0.2°, 16.67±0.2°, 17.84±0.2°, 18.09±0.2°, 18.90±0.2°, 23.45±0.2°, 25.07±0.2°, 26.12±0.2°, 26.74±0.2°, 27.98±0.2°.

15. The dimaleate salt Form E of claim 13, characterized by, The X-ray powder diffraction pattern of the crystal form E has characteristic peaks at 5.13±0.2°, 6.71±0.2°, 15.61±0.2°, 16.62±0.2°, 17.79±0.2°, 23.4±0.2°, 25.02±0.2° after silicon powder correction.

16. The dimaleate salt Form E of claim 15, characterized by, The X-ray powder diffraction pattern of the crystal form E has characteristic peaks at 5.13±0.2°, 6.71±0.2°, 15.61±0.2°, 16.62±0.2°, 17.79±0.2°, 18.06±0.2°, 18.85±0.2°, 23.4±0.2°, 25.02±0.2°, 26.09±0.2°, 26.65±0.2°, 27.92±0.2° after silicon powder correction.

17. The dimaleate salt Form E of any one of claims 13-16, characterized by, The preparation method of the crystal form E of the dimaleate salt comprises the following steps: The dimaleate salt of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenediamide is stirred in an aqueous system, and the solid is separated by centrifugation to obtain the crystal form E; the aqueous system is a mixed system of water and an organic solvent, the organic solvent is acetone, isopropanol or 1,4 dioxane, and the volume percentage of water in the aqueous system is not less than 3%.

18. A crystalline Form F of the dimaleate salt of (E)-4-(dimethylamino)-N-(7-(2- ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenoic amide, characterized by an X-ray powder diffraction pattern having a peak at 7.2 ± 0.2 degrees two-theta. The X-ray powder diffraction pattern of the crystal form F has characteristic peaks at 4.57±0.2°, 12.93±0.2°, 15.5±0.2°, 18.44±0.2° using Cu-Kα as the radiation source and expressed in terms of 2θ angle.

19. The dimaleate salt Form F of claim 18, characterized by, The X-ray powder diffraction pattern of the crystal form F has characteristic peaks at 4.57±0.2°, 7.06±0.2°, 8.51±0.2°, 12.93±0.2°, 15.5±0.2°, 18.44±0.2°, 19.33±0.2°, 20.23±0.2°, 20.94±0.2°, 25.58±0.2°, 25.85±0.2°, 26.31±0.2°.

20. A dimaleate crystal form H of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazolin)-2-butenamide, characterized in that, The X-ray powder diffraction pattern of the crystal form H has characteristic peaks at 3.67±0.2°, 5.51±0.2°, 11.04±0.2°, 19.73±0.2°, 26.48±0.2°, 27.86±0.2° using Cu-Kα as the radiation source and expressed in terms of 2θ angle.

21. The dimaleate salt Form H of claim 20, characterized by: The X-ray powder diffraction pattern of the crystal form H has characteristic peaks at 3.67±0.2°, 5.51±0.2°, 7.15±0.2°, 7.36±0.2°, 11.04±0.2°, 11.45±0.2°, 19.73±0.2°, 20.48±0.2°, 21.66±0.2°, 25.79±0.2°, 26.48±0.2°, 27.86±0.2°.

22. A crystalline Form K of the dimaleate salt of (E)-4-(dimethylamino)-N-(7-(2- ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenoic amide, characterized by an X-ray powder diffraction pattern comprising a peak at 7.2 ± 0.2 degrees two-theta. X-ray powder diffraction pattern, expressed in terms of the 2 theta angle, using Cu-Ka as the radiation source, of the crystalline form K has characteristic peaks at 5.16 ± 0.2°, 6.96 ± 0.2°, 15.54 ± 0.2°, 23.34 ± 0.2°, 25.43 ± 0.2°, 27.91 ± 0.2°.

23. The dimaleate salt Form K of claim 22, characterized by: X-ray powder diffraction pattern, expressed in terms of the 2 theta angle, using Cu-Ka as the radiation source, of the crystalline form K has characteristic peaks at 5.16 ± 0.2°, 6.96 ± 0.2°, 13.86 ± 0.2°, 15.54 ± 0.2°, 17.67 ± 0.2°, 19.62 ± 0.2°, 23.34 ± 0.2°, 23.79 ± 0.2°, 24.34 ± 0.2°, 25.43 ± 0.2°, 27.50 ± 0.2°, 27.91 ± 0.2°.

24. A crystalline polymorph Form R of the dimaleate salt of (E)-4-(dimethylamino)-N-(7-(2- ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenoic amide, characterized by an X-ray powder diffraction pattern having a peak at 7.2 ± 0.2 degrees two-theta. X-ray powder diffraction pattern, expressed in terms of the 2 theta angle, using Cu-Ka as the radiation source, of the crystalline form R has characteristic peaks at 4.67 ± 0.2°, 8.52 ± 0.2°, 9.21 ± 0.2°, 15.13 ± 0.2°, 18.60 ± 0.2°, 19.69 ± 0.2°.

25. The dimaleate salt Form R of claim 24, characterized by: X-ray powder diffraction pattern, expressed in terms of the 2 theta angle, using Cu-Ka as the radiation source, of the crystalline form R has characteristic peaks at 4.67 ± 0.2°, 4.93 ± 0.2°, 7.53 ± 0.2°, 8.52 ± 0.2°, 9.21 ± 0.2°, 12.49 ± 0.2°, 15.13 ± 0.2°, 16.28 ± 0.2°, 16.98 ± 0.2°, 18.60 ± 0.2°, 19.69 ± 0.2°, 27.34 ± 0.2°.

26. A dimaleate crystal form V of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazolin)-2-butenamide, characterized in that, X-ray powder diffraction pattern, expressed in terms of the 2 theta angle, using Cu-Ka as the radiation source, of the crystalline form V has characteristic peaks at 8.56 ± 0.2°, 10.10 ± 0.2°, 14.16 ± 0.2°, 16.58 ± 0.2°, 18.20 ± 0.2°, 19.19 ± 0.2°, 20.28 ± 0.2°, 23.77 ± 0.2°, 26.03 ± 0.2°.

27. The dimaleate salt Form V of claim 26, characterized by: X-ray powder diffraction pattern, expressed in terms of the 2 theta angle, using Cu-Ka as the radiation source, of the crystalline form V has characteristic peaks at 8.56 ± 0.2°, 10.10 ± 0.2°, 13.48 ± 0.2°, 14.16 ± 0.2°, 16.58 ± 0.2°, 18.20 ± 0.2°, 18.40 ± 0.2°, 19.19 ± 0.2°, 20.28 ± 0.2°, 22.28 ± 0.2°, 23.77 ± 0.2°, 26.03 ± 0.2°.

28. A pharmaceutical composition comprising, A pharmaceutical composition comprising a pharmaceutically acceptable salt of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenoic amide of any one of claims 1-3, and / or a dimaleate salt crystalline form of any one of claims 4-27, and a pharmaceutically acceptable carrier.

29. Use of a pharmaceutically acceptable salt of (E)-4-(dimethylamino)-N-(7-(2- ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenamide of any one of claims 1-3, a dimaleate salt crystalline form of any one of claims 4-27, or a pharmaceutical composition of claim 28 for the manufacture of a medicament for the treatment of a disease associated with a protein kinase, said protein kinase being an EGFR receptor tyrosine kinase or a HER-2 receptor tyrosine kinase.

30. Use of a pharmaceutically acceptable salt of (E)-4-(dimethylamino)-N-(7-(2- ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenamide of any one of claims 1-3, a dimaleate salt crystalline form of any one of claims 4-27, or a pharmaceutical composition of claim 28 for the manufacture of a medicament for the treatment of a cancer, said cancer including EGFR resistance mutation lung cancer, head and neck cancer, Her2 positive gastric cancer, breast cancer, or colorectal cancer.

31. Use according to claim 29 or 30, characterised in that, The medicament is administered alone or in combination with other therapeutic agents.

31. A method of treating a disease associated with a protein kinase, said protein kinase being an EGFR receptor tyrosine kinase or a HER-2 receptor tyrosine kinase, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of (E)-4-(dimethylamino)-N-(7-(2- ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenamide of any one of claims 1-3, a dimaleate salt crystalline form of any one of claims 4-27, or a pharmaceutical composition of claim 28.

32. A method of treating a cancer, said cancer including EGFR resistance mutation lung cancer, head and neck cancer, Her2 positive gastric cancer, breast cancer, or colorectal cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of (E)-4-(dimethylamino)-N-(7-(2- ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazolinyl)-2-butenamide of any one of claims 1-3, a dimaleate salt crystalline form of any one of claims 4-27, or a pharmaceutical composition of claim 28. The medicament is administered alone or in combination with other therapeutic agents.

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