SALT OF ARYLAMINOPURINE DERIVATIVE, PREPARATION METHOD THEREFOR AND USE THEREOF

Abstract

Provided in the present invention are a salt of an arylaminopurine derivative represented by Formula (2), a preparation method therefor and the use thereof. The salt obtained in the present invention has good crystallinity and significantly improved solubility relative to that in the free form, and the preferred salt and crystal form have low hygroscopicity and can exist stably. Therefore, compared with the free form of arylaminopurine derivatives or other salts, it is easier to prepare same into a medicine.

##STR00001##

Claims

1. A salt of the arylaminopurine derivative, wherein said salt is represented by Formula 2: ##STR00060## wherein, HA is an acid; H.sub.2O is the water of crystallization; m is an integer or half-integer from 1 to 4; n is an integer or half-integer from 0 to 5.

2. The salt of the arylaminopurine derivative according to claim 1, wherein the acid is selected from a group consisting of hydrochloric acid, methanesulfonic acid, L-malic acid, L-tartaric acid, oxalic acid, succinic acid, acetic acid, or sulfuric acid; preferably hydrochloric acid, L-malic acid, L-tartaric acid, oxalic acid, succinic acid, acetic acid, or sulfuric acid; more preferably hydrochloric acid, L-malic acid, L-tartaric acid, oxalic acid, succinic acid or acetic acid; further preferably hydrochloric acid.

3. The salt of the arylaminopurine derivative according to claim 1, wherein the salt is a hydrochloride represented by Formula 3: ##STR00061## n is 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5; preferably, the salt is a hydrochloride represented by Formula 3′: ##STR00062## more preferably, the hydrochloride represented by Formula 3 or Formula 3′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 8.5±0.2°, 11.8±0.2°, 19.6±0.2°, 25.2±0.2°, 27.2±0.2° as measured with CuKα radiation; Further more preferably, the hydrochloride represented by Formula 3 or Formula 3′ has an X-ray powder diffraction pattern substantially as shown in FIG. 1 or FIG. 3, as measured with CuKα radiation; or more preferably, the single crystal of the hydrochloride represented by Formula 3 or Formula 3′, as measured with CuKα radiation, belongs to the triclinic system, space group P.sup.1, and has the unit cell parameters: {a=7.04142(7) {acute over (Å)}, b=12.15291(7) {acute over (Å)}, c=18.13188(10) {acute over (Å)}, α=93.2215(5)°, β=95.3039(6)°, γ=91.9554(6)°, V=1541.32(2) {acute over (Å)}.sup.3}.

4. The salt of the arylaminopurine derivative according to claim 1, wherein the salt is a mesylate represented by Formula 4, Formula 5, or Formula 6: ##STR00063## n is 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5; preferably, the salt is a mesylate represented by Formula 4′, Formula 5′, or Formula 6′: ##STR00064## more preferably, the mesylate represented by Formula 4 or Formula 4′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 6.8±0.2°, 15.1±0.2°, 16.3±0.2°, 21.0±0.2°, 25.0±0.2° as measured with CuKα radiation; further more preferably, the mesylate represented by Formula 4 or Formula 4′ has an X-ray powder diffraction pattern substantially as shown in FIG. 4, as measured with CuKα radiation; or more preferably, the mesylate represented by Formula 5 or Formula 5′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 6.1±0.2°, 6.4±0.2°, 17.5±0.2°, 18.9±0.2°, 19.3±0.2°, 24.4±0.2°, 26.4±0.2° as measured with CuKα radiation; further more preferably, the mesylate represented by Formula 5 or Formula 5′ has an X-ray powder diffraction pattern substantially as shown in FIG. 5, as measured with CuKα radiation; or more preferably, the mesylate represented by Formula 6 or Formula 6′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 4.9±0.2°, 11.5±0.2°, 14.5±0.2°, 18.5±0.2°, 18.9±0.2° as measured with CuKα radiation; further more preferably, the mesylate represented by Formula 6 or Formula 6′ has an X-ray powder diffraction pattern substantially as shown in FIG. 6, as measured with CuKα radiation.

5. The salt of the arylaminopurine derivative according to claim 1, wherein the salt is an L-malate represented by Formula 7: ##STR00065## n is 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5; preferably, the salt is an L-malate represented by Formula 7′: ##STR00066## more preferably, the L-malate represented by Formula 7 or Formula 7′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 7.0±0.2°, 9.3±0.2°, 17.6±0.2°, 19.7±0.2°, 25.9±0.2° as measured with CuKα radiation; further more preferably, the L-malate represented by Formula 7 or Formula 7′ has an X-ray powder diffraction pattern substantially as shown in FIG. 7, as measured with CuKα radiation.

6. The salt of the arylaminopurine derivative according to claim 1, wherein the salt is an L-tartrate represented by Formula 8, Formula 9, or Formula 10: ##STR00067## n is 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5; preferably, the salt is an L-tartrate represented by Formula 8′, Formula 9′, or Formula 10′: ##STR00068## more preferably, the L-tartrate represented by Formula 8 or Formula 8′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 6.9±0.2°, 9.1±0.2°, 17.8±0.2°, 19.4±0.2°, 25.5±0.2° as measured with CuKα radiation; further more preferably, the L-tartrate represented by Formula 8 or Formula 8′ has an X-ray powder diffraction pattern substantially as shown in FIG. 8, as measured with CuKα radiation; or more preferably, the L-tartrate represented by Formula 9 or Formula 9′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 8.5±0.2°, 14.8±0.2°, 17.1±0.2°, 18.8±0.2°, 24.6±0.2°, 26.1±0.2° as measured with CuKα radiation; further more preferably, the L-tartrate represented by Formula 9 or Formula 9′ has an X-ray powder diffraction pattern substantially as shown in FIG. 9, as measured with CuKα radiation; or more preferably, the L-tartrate represented by Formula 10 or Formula 10′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 8.3±0.2°, 8.9±0.2°, 9.5±0.2°, 14.8±0.2°, 17.7±0.2°, 21.0±0.2°, 24.0±0.2° as measured with CuKα radiation; further more preferably, the L-tartrate represented by Formula 10 or Formula 10′ has an X-ray powder diffraction pattern substantially as shown in FIG. 10, as measured with CuKα radiation.

7. The salt of the arylaminopurine derivative according to claim 1, wherein the salt is an oxalate represented by Formula 11, or Formula 12: ##STR00069## n is 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5; preferably, the salt is an oxalate represented by Formula 11′, or Formula 12′: ##STR00070## more preferably, the oxalate represented by Formula 11 or Formula 11′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 8.1±0.2°, 8.4±0.2°, 9.0±0.2°, 14.1±0.2°, 16.7±0.2°, 25.6±0.2° as measured with CuKα radiation; further more preferably, the oxalate represented by Formula 11 or Formula 11′ has an X-ray powder diffraction pattern substantially as shown in FIG. 11, as measured with CuKα radiation; or more preferably, the oxalate represented by Formula 12 or Formula 12′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 7.1±0.2°, 12.2±0.2°, 14.2±0.2°, 16.4±0.2°, 17.7±0.2°, 19.0±0.2°, 24.4±0.2° as measured with CuKα radiation; further more preferably, the oxalate represented by Formula 12 or Formula 12′ has an X-ray powder diffraction pattern substantially as shown in FIG. 12, as measured with CuKα radiation.

8. The salt of the arylaminopurine derivative according to claim 1, wherein the salt is a succinate represented by Formula 13, or Formula 14: ##STR00071## n is 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5; preferably, the salt is a succinate represented by Formula 13′, or Formula 14′: ##STR00072## more preferably, the succinate represented by Formula 13 or Formula 13′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 7.0±0.2°, 9.1±0.2°, 18.5±0.2°, 20.4±0.2°, 21.0±0.2°, 22.4±0.2°, 27.1±0.2° as measured with CuKα radiation; further more preferably, the succinate represented by Formula 13 or Formula 13′ has an X-ray powder diffraction pattern substantially as shown in FIG. 13, as measured with CuKα radiation; or more preferably, the succinate represented by Formula 14 or Formula 14′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 7.0±0.2°, 9.2±0.2°, 17.6±0.2°, 18.4±0.2°, 19.7±0.2°, 25.8±0.2°, 27.3±0.2° as measured with CuKα radiation; further more preferably, the succinate represented by Formula 14 or Formula 14′ has an X-ray powder diffraction pattern substantially as shown in FIG. 14, as measured with CuKα radiation.

9. The salt of the arylaminopurine derivative according to claim 1, wherein the salt is an acetate represented by Formula 15, or Formula 16: ##STR00073## n is 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5; preferably, the salt is an acetate represented by Formula 15′, or Formula 16′: ##STR00074## more preferably, the acetate represented by Formula 15 or Formula 15′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 10.9±0.2°, 12.6±0.2°, 15.1±0.2°, 17.8±0.2°, 19.2±0.2°, 19.6±0.2°, 21.0±0.2°, 21.8±0.2°, 22.3±0.2°, 24.6±0.2°, 25.4±0.2° as measured with CuKα radiation; further more preferably, the acetate represented by Formula 15 or Formula 15′ has an X-ray powder diffraction pattern substantially as shown in FIG. 15, as measured with CuKα radiation; or more preferably, the acetate represented by Formula 16 or Formula 16′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 6.2±0.2°, 12.2±0.2°, 17.5±0.2°, 21.5±0.2°, 23.4±0.2°, 24.8±0.2° as measured with CuKα radiation; further more preferably, the acetate represented by Formula 16 or Formula 16′ has an X-ray powder diffraction pattern substantially as shown in FIG. 16, as measured with CuKα radiation.

10. The salt of the arylaminopurine derivative according to claim 1, wherein the salt is a sulfate represented by Formula 17, or Formula 18: ##STR00075## n is 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5; preferably, the salt is a sulfate represented by Formula 17′, or Formula 18′: ##STR00076## more preferably, the sulfate represented by Formula 17 or Formula 17′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 4.8±0.2°, 7.0±0.2°, 8.6±0.2°, 9.2±0.2°, 9.5±0.2°, 11.6±0.2°, 12.8±0.2°, 13.6±0.2°, 15.7±0.2°, 17.6±0.2°, 18.6±0.2°, 20.5±0.2°, 21.6±0.2°, 23.8±0.2°, 25.7±0.2° as measured with CuKα radiation; further more preferably, the sulfate represented by Formula 17 or Formula 17′ has an X-ray powder diffraction pattern substantially as shown in FIG. 17, as measured with CuKα radiation; or more preferably, the sulfate represented by Formula 18 or Formula 18′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 8.6±0.2°, 9.6±0.2°, 15.7±0.2°, 17.1±0.2°, 19.3±0.2°, 20.0±0.2°, 26.6±0.2° as measured with CuKα radiation; further more preferably, the sulfate represented by Formula 18 or Formula 18′ has an X-ray powder diffraction pattern substantially as shown in FIG. 18, as measured with CuKα radiation.

11. A pharmaceutical composition, comprising the salt represented by Formula 2 of the arylaminopurine derivative according to claim 1.

12. Use of the salt represented by Formula 2 of the arylaminopurine derivative according to claim 1 in manufacture of a medicament as the protein kinase inhibitor, wherein the kinase is selected from FLT3, EGFR, Abl, Fyn, Hck, Lck, Lyn, Ret, Yes, VEGFR2, ALK, BTK, c-KIT, c-SRC, FGFR1, KDR, MET and PDGFRα; preferably, the medicament as the protein kinase inhibitor is an antitumor drug, the tumor is selected from non-small cell lung cancer, acute myeloid leukemia, chronic myelocytic leukemia, chronic myeloid leukemia, squamous cell carcinoma, mammary cancer, colorectal cancer, liver cancer, stomach cancer, and malignant melanoma, more preferably leukemia or lung cancer, further more preferably acute myeloid leukemia or non-small cell lung cancer, further preferably FLT3 mutation-positive acute myeloid leukemia (such as FLT3-ITD acute myeloid leukemia), Ph-positive chronic myeloid leukemia, or non-small cell lung cancer with EGFR activating mutations.

13. A method for preparing the salt represented by Formula 2 of the arylaminopurine derivative according to claim 1, which comprises a reaction of an arylaminopurine derivative represented by Formula 1 and an acid is performed in the presence of water and an organic solvent to obtain the salt represented by Formula 2 of the arylaminopurine derivative: ##STR00077## wherein, HA is an acid; H.sub.2O is the water of crystallization; m is an integer or half-integer from 1 to 4; n is an integer or half-integer from 0 to 5.

14. The method for preparing the salt of the arylaminopurine derivative according to claim 13, wherein the molar ratio of the arylaminopurine derivative represented by Formula 1 to the acid is 1:1 to 1:4, preferably 1:1.2 to 1:3.5; the reaction temperature is 0-70° C., preferably 35-45° C.; the reaction is performed in the presence of the combination of water and one or more organic solvents selected from alcohols, ethers, esters, ketones, nitriles, and alkanes, preferably in the presence of C.sub.1-C.sub.3 lower alcohol and water, in the presence of a ketone and water, in the presence of a nitrile and water, or the presence of ether and water, and more preferably in the presence of methanol-water, ethanol-water, isopropanol-water, tetrahydrofuran-water, dioxane-water, acetone-water or acetonitrile-water; and the ratio of the use amounts by volume of the organic solvent to water is 1:10 to 10:1, for example, 1:1 to 10:1 or 1:10 to 1:1.

15. Use of the pharmaceutical composition according to claim 11 in manufacture of a medicament as the protein kinase inhibitor, wherein the kinase is selected from FLT3, EGFR, Abl, Fyn, Hck, Lck, Lyn, Ret, Yes, VEGFR2, ALK, BTK, c-KIT, c-SRC, FGFR1, KDR, MET and PDGFRα; preferably, the medicament as the protein kinase inhibitor is an antitumor drug, the tumor is selected from non-small cell lung cancer, acute myeloid leukemia, chronic myelocytic leukemia, chronic myeloid leukemia, squamous cell carcinoma, mammary cancer, colorectal cancer, liver cancer, stomach cancer, and malignant melanoma, more preferably leukemia or lung cancer, further more preferably acute myeloid leukemia or non-small cell lung cancer, further preferably FLT3 mutation-positive acute myeloid leukemia (such as FLT3-ITD acute myeloid leukemia), Ph-positive chronic myeloid leukemia, or non-small cell lung cancer with EGFR activating mutations.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0105] FIG. 1 is the XRPD pattern of the hydrochloride of the arylaminopurine derivative obtained in Example 1.

[0106] FIG. 2 is the micrograph of a single crystal of the hydrochloride of the arylaminopurine derivative obtained in Example 2.

[0107] FIG. 3 is the XRPD pattern of the single crystal hydrochloride of the arylaminopurine derivative obtained in Example 2.

[0108] FIG. 4 is the XRPD pattern of the mesylate of the arylaminopurine derivative obtained in Example 3.

[0109] FIG. 5 is the XRPD pattern of the mesylate of the arylaminopurine derivative obtained in Example 3.

[0110] FIG. 6 is the XRPD pattern of the mesylate of the arylaminopurine derivative obtained in Example 5.

[0111] FIG. 7 is the XRPD pattern of the L-malate of the arylaminopurine derivative obtained in Example 6.

[0112] FIG. 8 is the XRPD pattern of the L-tartrate of the arylaminopurine derivative obtained in Example 7.

[0113] FIG. 9 is the XRPD pattern of the L-tartrate of the arylaminopurine derivative obtained in Example 8.

[0114] FIG. 10 is the XRPD pattern of the L-tartrate of the arylaminopurine derivative obtained in Example 9.

[0115] FIG. 11 is the XRPD pattern of the oxalate of the arylaminopurine derivative obtained in Example 10.

[0116] FIG. 12 is the XRPD pattern of the oxalate of the arylaminopurine derivative obtained in Example 11.

[0117] FIG. 13 is the XRPD pattern of the succinate of the arylaminopurine derivative obtained in Example 12.

[0118] FIG. 14 is the XRPD pattern of the succinate of the arylaminopurine derivative obtained in Example 13.

[0119] FIG. 15 is the XRPD pattern of the acetate of the arylaminopurine derivative obtained in Example 14.

[0120] FIG. 16 is the XRPD pattern of the acetate of the arylaminopurine derivative obtained in Example 15.

[0121] FIG. 17 is the XRPD pattern of the sulfate of the arylaminopurine derivative obtained in Example 16.

[0122] FIG. 18 is the XRPD pattern of the sulfate of the arylaminopurine derivative obtained in Example 17.

[0123] FIG. 19 is the differential scanning calorimetry-thermogravimetric analysis (DSC-TGA) diagram of the hydrochloride of the arylaminopurine derivative obtained in Example 1.

[0124] FIG. 20 is the differential scanning calorimetry (DSC) diagram of the mesylate of the arylaminopurine derivative obtained in Example 3.

[0125] FIG. 21 is the thermogravimetric analysis (TGA) diagram of the mesylate of the arylaminopurine derivative obtained in Example 3.

[0126] FIG. 22 is the differential scanning calorimetry (DSC) diagram of the mesylate of the arylaminopurine derivative obtained in Example 4.

[0127] FIG. 23 is the thermogravimetric analysis (TGA) diagram of the mesylate of the arylaminopurine derivative obtained in Example 4.

[0128] FIG. 24 is the differential scanning calorimetry (DSC) diagram of the mesylate of the arylaminopurine derivative obtained in Example 5.

[0129] FIG. 25 is the thermogravimetric analysis (TGA) diagram of the mesylate of the arylaminopurine derivative obtained in Example 5.

[0130] FIG. 26 is the differential scanning calorimetry-thermogravimetric analysis (DSC-TGA) diagram of the L-malate of the arylaminopurine derivative obtained in Example 6.

[0131] FIG. 27 is the differential scanning calorimetry-thermogravimetric analysis (DSC-TGA) diagram of the L-tartrate of the arylaminopurine derivative obtained in Example 7.

[0132] FIG. 28 is the differential scanning calorimetry-thermogravimetric analysis (DSC-TGA) diagram of the L-tartrate of the arylaminopurine derivative obtained in Example 8.

[0133] FIG. 29 is the differential scanning calorimetry-thermogravimetric analysis (DSC-TGA) diagram of the L-tartrate of the arylaminopurine derivative obtained in Example 9.

[0134] FIG. 30 is the differential scanning calorimetry-thermogravimetric analysis (DSC-TGA) diagram of the oxalate of the arylaminopurine derivative obtained in Example 10.

[0135] FIG. 31 is the differential scanning calorimetry-thermogravimetric analysis (DSC-TGA) diagram of the oxalate of the arylaminopurine derivative obtained in Example 11.

[0136] FIG. 32 is the differential scanning calorimetry (DSC) diagram of the succinate of the arylaminopurine derivative obtained in Example 12.

[0137] FIG. 33 is the thermogravimetric analysis (TGA) diagram of the succinate of the arylaminopurine derivative obtained in Example 12.

[0138] FIG. 34 is the differential scanning calorimetry (DSC) diagram of the succinate of the arylaminopurine derivative obtained in Example 13.

[0139] FIG. 35 is the thermogravimetric analysis (TGA) diagram of the succinate of the arylaminopurine derivative obtained in Example 13.

[0140] FIG. 36 is the differential scanning calorimetry (DSC) diagram of the acetate of the arylaminopurine derivative obtained in Example 14.

[0141] FIG. 37 is the thermogravimetric analysis (TGA) diagram of the acetate of the arylaminopurine derivative obtained in Example 14.

[0142] FIG. 38 is the differential scanning calorimetry (DSC) diagram of the acetate of the arylaminopurine derivative obtained in Example 15.

[0143] FIG. 39 is the thermogravimetric analysis (TGA) diagram of the acetate of the arylaminopurine derivative obtained in Example 15.

[0144] FIG. 40 is the differential scanning calorimetry-thermogravimetric analysis (DSC-TGA) diagram of the sulfate of the arylaminopurine derivative obtained in Example 16.

[0145] FIG. 41 is the differential scanning calorimetry-thermogravimetric analysis (DSC-TGA) diagram of the sulfate of the arylaminopurine derivative obtained in Example 17.

[0146] FIG. 42 is the differential scanning calorimetry-thermogravimetric analysis (DSC-TGA) diagram of the arylaminopurine derivative obtained in Preparation Example 1.

DETAILED DESCRIPTION

[0147] The technical solutions of the present invention will be further described in detail with reference to specific examples. The following examples are merely illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the techniques realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.

[0148] Unless otherwise specified, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known processes.

[0149] In the following examples, the analysis and detection conditions are as follows:

[0150] 1. Moisture

[0151] Detection instrument: Karl Fischer moisture titrator/915 KF Ti-Touch

[0152] Test method: After the instrument was balanced, a proper amount (about 200 mg) of the test sample was taken, precisely weighed, and added to a titration cup, absolute methanol was used as the solvent, and a moisture titration solution was used for the direct measurement, and an average value was obtained by measuring each test sample twice.

[0153] 2. Solubility

[0154] Detection instrument: Ultraviolet spectrophotometer/Evolution 300

[0155] Test Method:

[0156] The following solutions with pH=1.2, pH=4.5, and pH=6.8 and water were used as the solvent, and the solvent preparation process was as follows:

[0157] (1) pH=1.2 hydrochloric acid solution: To 7.65 mL of hydrochloric acid was added 1000 mL of water, and the mixture was shaken uniformly to obtain the target solution.

[0158] (2) pH=4.5 phosphate buffer solution: 6.8 g of potassium dihydrogen phosphate was taken and diluted with water to 1000 mL, and the mixture was shaken uniformly to obtain the target solution.

[0159] (2) pH=6.8 phosphate buffer solution: 6.8 g of potassium dihydrogen phosphate and 0.896 g of sodium hydroxide were taken and diluted with water to 1000 mL, and the mixture was shaken uniformly to obtain the target solution.

[0160] (4) Water: purified water

[0161] Sample Preparation:

[0162] Test tubes with stopper were taken, and 10 mL of dissolution media at various pH values were precisely added to the test tubes respectively, and excessive stock drugs were added until supersaturated solutions were formed. The adding amounts were recorded. The solutions were shaken uniformly, sealed with stoppers, and shaken for 24 hours in a shaker. 2 mL of solutions were taken out at different time points respectively, and centrifuged. The resulting supernatants were taken, filtered, and the subsequent filtrates were taken for later use.

[0163] The above-mentioned saturated solutions in different solvents were taken, and solvents were added to dilute the solutions to certain volumes. The absorbances were measured at a wavelength of 287 nm.

[0164] Preparation of a solution of the reference substance: an appropriate amount of the compound represented by Formula 1 was taken as the reference substance, and precisely weighed. A solvent was added to dissolve and dilute the reference compound to produce a solution containing about 10 μg of the compound represented by Formula 1 per 1 mL. The absorbance was measured at a wavelength of 287 nm to calculate the solubility.

[0165] 3. Hygroscopicity

[0166] Detection instrument: XPE105DR

[0167] Test Method:

[0168] (1) A dry stoppered glass weighing bottle was taken, placed in a suitable constant-temperature desiccator at 25° C. 1° C. (with a saturated solution of ammonium chloride or ammonium sulfate in the lower part) or an artificial climate box (with the set temperature of 25° C.±1° C. and the relative humidity of 80%±2%) on the day before the test, and precisely weighed and recorded as the weight (m1).

[0169] (2) An appropriate amount of the test sample was taken and spread in the above-mentioned weighing bottle. The thickness of the test sample was generally about 1 mm, and the bottle was precisely weighed and recorded as the weight (m2).

[0170] (3) The stopper was removed to open the weighing bottle, and the opened weighing bottle and the stopper were placed under the above-mentioned constant temperature and humidity conditions for 24 hours.

[0171] (4) The opened weighing bottle was stoppered, precisely weighed, and recorded as the weight (m3).

Percentage increase in mass=(m3−m2)/(m2−m1)×100%

[0172] (5) The description of hygroscopicity characteristics and the definition for the weight gain due to hygroscopicity:

[0173] Deliquescence: Sufficient water was absorbed to form a liquid.

[0174] Very hygroscopic: the weight gain due to hygroscopicity was not less than 15%.

[0175] Hygroscopic: the weight gain due to hygroscopicity was less than 15% but not less than 2%.

[0176] Slightly hygroscopic: the weight gain due to hygroscopicity was less than 2% but not less than 0.2%.

[0177] Not or nearly not hygroscopic: the weight gain due to hygroscopicity was less than 0.2%.

[0178] 4. Content

[0179] Detection Instrument: High performance liquid chromatograph/Waters e2695-2489

[0180] Analysis Method:

[0181] Octadecyl silane bonded to silica gel was used as a filler (the applicable range of the pH value should be greater than 10.0), 20 mmol/L of disodium hydrogen phosphate solution (the pH value was adjusted to 10.0 with sodium hydroxide)-acetonitrile (65:35) was used as the mobile phase; the detection wavelength was 287 nm, and the column temperature was 30° C. The number of theoretical plates should be not less than 3000.

[0182] Determination method: About 20 mg of the sample was taken and precisely weighed, put in a 100 mL volumetric flask. A diluent (50% methanol/water) was added to dissolve and dilute the sample to the scale. The content was shaken uniformly, and 10 μL was precisely metered and injected into a liquid chromatograph, and the chromatogram was recorded; another appropriate amount of the reference substance was taken, and the same method was used for determination. The result was obtained by calculating the peak area according to the external standard method.

[0183] 5. X-Ray Powder Diffraction (XRPD)

(1) Examples 1 and 2

[0184] Detection instrument: PANalytical Empyrean type powder X-ray diffractometer

[0185] Test Conditions:

[0186] Light tube type: Cu target, metal-ceramic X-ray tube;

[0187] X-ray wavelength: CuKα, Kα.sub.1 ({acute over (Å)}): 1.540598, Kα.sub.2 ({acute over (Å)}): 1.544426, Kα.sub.2/Kα.sub.1 intensity ratio: 0.5;

[0188] Voltage and current: 45 kV, 40 mA;

[0189] Scanning range: 3-40° 20;

[0190] Total scanning time: About 5 minutes.

(2) Examples 3-17

[0191] Detection instrument: BRUKER D2 PHASER powder X-ray diffractometer

[0192] Test Conditions:

[0193] Light tube type: Cu target, ceramic X-ray tube;

[0194] X-ray wavelength: CuKα, Kα.sub.1 ({acute over (Å)}): 1.540598, Kα.sub.2 ({acute over (Å)}): 1.544426, Kα.sub.2/Kα.sub.1 intensity ratio: 0.5;

[0195] Voltage and current: 30 kV, 10 mA;

[0196] Scanning range: 4-40° 20;

[0197] Total scanning time: 200.9 S.

[0198] 6. Differential Scanning Calorimetry-Thermogravimetric Analysis (DSC-TGA)

[0199] Detection instrument: NETZSCH STA 449F3

[0200] Test Conditions:

[0201] Temperature range: 20° C.-350° C.;

[0202] Heating rate: 10.0 (K/min);

[0203] Sample holder/thermocouple: DSC/TG Cp S/S

[0204] Crucible: DSC/TG pan Al2O3

[0205] Atmosphere: N2, 20.0 ml/min/N2, 50.0 ml/min

[0206] Calibration/measurement range: 020/5000 μV

[0207] 7. Differential Scanning Calorimetry (DSC)

[0208] Detection instrument: NETZSCH DSC 214 Polyma

[0209] Test Conditions:

[0210] Temperature range: 20° C.-250° C.;

[0211] Heating rate: 5.0 (K/min);

[0212] Sample holder/thermocouple: DSC 214 Corona sensor/E

[0213] Crucible: Pan AI, pierced lid

[0214] Atmosphere: N2, 40.0 ml/min/N2, 60.0 ml/min

[0215] Calibration/measurement range: 000/5000 μV

[0216] 8. Thermogravimetric Analysis (TGA)

[0217] Detection instrument: METTLER and SDT Q600

[0218] Analysis Method:

[0219] Temperature range: 20° C.-250° C.;

[0220] Heating rate: 5.0 (K/min);

[0221] 9. Nuclear Magnetic Resonance Spectroscopy (NMRS)

[0222] Detection instrument: AVIII BRUKER 600 type superconducting nuclear magnetic resonance spectrometer

[0223] Contents and test solvent: .sup.1H-NMR, the test solvent was H.sub.2D.

[0224] 10. Single-Crystal

[0225] Single crystal diffraction data were collected using a Rigaka XtaLAB Synergy-R (Micro-Max007HF Cu mode, CuKα (λ=1.54184 {acute over (Å)}), Hypix 6000 HE detector) type single crystal diffractometer at a temperature of 120.00(10)K. The micrograph of the single crystal sample was taken by using a Shanghai CEWEI PXS9-T type stereoscopic microscope.

[0226] 11. Acidity Measurement

[0227] Detection instrument: Mettler Toledo S210-K pH meter

[0228] Test method: Based on the operation according to the pH value measurement method, 10 mg of a sample was precisely weighed, then 10 mL of freshly boiled and cooled purified water was added to dissolve the sample, and the mixture was shaken uniformly, and then the pH value was measured.

[0229] 12. Measurement of Related Substances

[0230] Detection instrument: High performance liquid chromatograph/Waters e2695-2489

[0231] Chromatographic Conditions:

[0232] Octadecylsilane bonded to silica gel was used as a filler (Model: Waters Xbridge C18 chromatographic column, with a length of 250 mm, an inner diameter of 4.6 mm, and a filler particle size of 5 μm), the detection wavelength was 250 nm, the column temperature was 35° C., and the flow rate was 1.0 mL/minute, the mobile phase A was 0.02 mol/L of a disodium hydrogen phosphate solution (the pH value was adjusted to 10.0 with a sodium hydroxide solution), the mobile phase B was acetonitrile, and the diluent was methanol, and the temperature of the sample plate was 4° C.

[0233] Test method: The system applicability test was performed according to the requirements, and the test sample solution, the control solution, and the sensitivity solution were prepared. Each 10 μL of the control solution and the test sample solution were precisely metered and injected into a liquid chromatograph, and the chromatogram was recorded. The result was obtained by calculating the peak area according to the self-dilution control method with the correction factor.

Preparation Example 1: Preparation of the Compound Represented by Formula 1

[0234] ##STR00024##

[0235] With reference to the method described in Example 90 of the patent document WO2011/147066, 100 g of the compound represented by Formula 1 was prepared.

Example 1: Preparation of a Hydrochloride of the Arylaminopurine Derivative

[0236] ##STR00025##

The arylaminopurine derivative (90 g, 0.203 mol) from Preparation Example 1, 800 mL of purified water, and 400 mL of acetone were added to the reactor. The mixture was heated to 40±5° C. under stirring, and a stream of concentrated hydrochloric acid (74 g, 0.731 mol) was added to the reactor. After completing the addition of concentrated hydrochloric acid, 2 L of acetone was added, and the reaction was continued for 1 hour while keeping the temperature at 40±5° C. Then the reaction mixture was cooled down to 10±5° C. under stirring and crystallized for 2 hours. Suction filtration was performed. The filter cake was washed with 300 mL of acetone to produce a yellow or pale yellow hydrochloride (74.7 g). .sup.1H-NMR (600 MHz, D.sub.2O) δ: 1.556 (d, 6H), δ: 2.896 (s, 3H), δ: 3.058 (t, 2H), δ: 3.187 (t, 2H), δ: 3.586 (d, 2H), δ: 3.749 (d, 2H), δ: 4.701 (s, 1H), δ: 7.062 (d, 2H), δ: 7.377 (d, 2H), δ: 7.968 (t, 1H), δ: 8.086 (s, 1H), δ: 8.431 (d, 1H), δ: 8.636 (d, 1H), δ: 9.171 (s, 1H). The obtained hydrochloride exhibited good crystallinity, and its XRPD characterization pattern was shown in FIG. 1. The main diffraction peak data were as follows:

TABLE-US-00001 Peak Relative position peak 2θ angle intensity (°) % 7.300 20.96 8.504 40.4 9.052 14.65 11.814 34.65 12.579 13.44 14.300 15.86 18.136 18.09 19.641 29.87 20.027 26.40 21.140 22.06 21.913 14.4 23.701 25.54 25.162 62.26 26.137 15.54 27.165 100

[0237] It could be inferred from the calculation of the free base content by HPLC, the determination of the water content, and the hydrogen ratio in .sup.1H-NMR of the nuclear magnetic resonances (see the table below) that the base/acid/H.sub.2O of the hydrochloride was 1:3:5.

TABLE-US-00002 Acid:base Theoretical Theoretical Theoretical Theoretical Measured Measured hydrogen atom ratio water content acid content base content water content base content number ratio Name (base/acid/H.sub.2O) (%) (%) (%) (%) (%, HPLC) (.sup.1H-NMR) Example 1 1:3:5 14.0% 17.0% 69.0% 13.9% 69.0% N/A hydrochloride

[0238] The process of Example 1 was repeated except for changing the amount of concentrated hydrochloric acid used in Example 1, and still, only the arylaminopurine derivative.trihydrochloride.pentahydrate obtained in Example 1 could be obtained. The process of Example 1 was repeated except for replacing acetone in Example 1 with isopropanol or tetrahydrofuran, and the arylaminopurine derivative-trihydrochloride-pentahydrate obtained in Example 1 could also be obtained.

Example 2: Preparation of Single Crystal Hydrochloride of the Arylaminopurine Derivative

[0239] 14.9 mg of the hydrochloride obtained in Example 1 was weighed and placed in a 3 mL glass bottle. 0.6 mL of acetonitrile/water (4:1, v/v) mixed solvent was added. The mixture was stirred to dissolve the hydrochloride and then placed in a 25 mL hydrothermal reaction vessel. The hydrothermal reaction vessel was sealed and placed in a temperature-controlled oven for the programmed temperature up and down. The temperature program was:

##STR00026##

[0240] After the completion of the experiment, it was found that a long and platy single crystal sample was precipitated in the system. A micrograph of the single crystal sample was shown in FIG. 2. The single crystal X-ray diffraction characterization result showed that the crystal belonged to the triclinic system, space group P 1, and had the unit cell parameters: {a=7.04142(7) {acute over (Å)}, b=12.15291(7) {acute over (Å)}, c=18.13188(10) {acute over (Å)}, α=93.2215(5)°, β3=95.3039(6)°, γ=91.9554(6)°, V=1541.32(2) {acute over (Å)}.sup.3}. The asymmetric unit of the crystal consists of a cation of the compound represented by Formula 1, three chloride ions, and five water molecules. The single crystal was subjected to the XRPD measurement, and the obtained pattern was shown in FIG. 3, and the main diffraction peak data were as follows:

TABLE-US-00003 Peak Relative position peak 2θ angle intensity (°) % 7.292 26.96 8.507 66.86 9.041 12.81 11.815 51.74 12.558 11.89 14.281 16.05 18.109 14.25 19.633 41.79 20.033 30.29 21.125 11.68 21.919 22.19 23.727 28.37 25.166 42.06 26.131 15.26 27.177 100

[0241] It could be seen from the result of the comparison between FIG. 1 and FIG. 3 that the single crystal obtained in Example 2 was the same crystal form as that obtained in Example 1.

Example 3: Preparation of a Mesylate of the Arylaminopurine Derivative

[0242] ##STR00027##

[0243] The arylaminopurine derivative (7 g, 15.8 mmol) from Preparation Example 1, 7 mL of purified water, and 28 mL of acetone were added to the reactor. The mixture was heated to 40±5° C. under stirring, and methanesulfonic acid (1.82 g, 18.9 mmol) was added to the reactor. After completing the addition, 147 mL of acetone was added, and the reaction was continued for 1 hour while keeping the temperature at 40±5° C. Then the reaction mixture was cooled down to 10±5° C. under stirring and crystallized for 2 hours. Suction filtration was performed. The filter cake was washed with 45 mL of acetone to produce a yellow or pale yellow mesylate (7.8 g). .sup.1H-NMR (600 MHz, D.sub.2O) δ: 1.500 (d, 6H), δ: 2.783 (s, 4H), δ: 2.888 (m, 5H), δ: 3.085 (m, 2H), δ: 3.511 (m, 4H), δ: 4.489 (m, 1H), δ: 6.817 (d, 2H), δ: 7.200 (d, 2H), δ: 7.404 (m, 1H), δ: 7.906 (m, 2H), δ: 8.122 (d, 1H), δ: 8.567 (s, 1H). The obtained mesylate exhibited good crystallinity, and its XRPD characterization pattern was shown in FIG. 4. The main diffraction peak data were as follows:

TABLE-US-00004 Peak Relative position peak 2θ angle intensity (°) % 6.803 36.6 8.599 20.2 10.679 16.0 12.633 19.7 13.112 36.1 13.434 26.1 15.136 47.0 16.271 55.4 17.734 34.4 19.009 40.7 19.913 41.3 20.967 100 25.008 55.5

[0244] It could be inferred from the calculation of the free base content by HPLC, the determination of the water content, and the hydrogen ratio in .sup.1H-NMR of the nuclear magnetic resonances (see the table below) that the base/acid/H.sub.2O of the mesylate was 1:1.5:1.

TABLE-US-00005 Acid:base Theoretical Theoretical Theoretical Theoretical Measured Measured hydrogen atom ratio water content acid content base content water content base content number ratio Name (base/acid/H.sub.2O) (%) (%) (%) (%) (%, HPLC) (.sup.1H-NMR) Example 3 1:1.5:1 3.0% 23.8% 73.2% 4.1% 77.5% 1:1.5 mesylate

Example 4: Preparation of a Mesylate of the Arylaminopurine Derivative

[0245] ##STR00028##

[0246] The preparation process of Example 3 was repeated except for changing the amount of methanesulfonic acid to (5.2 g, 54.1 mmol), and a yellow or pale yellow mesylate (8.8 g) was obtained. .sup.1H-NMR (600 MHz, D.sub.2O) δ: 1.621 (d, 6H), δ: 2.770 (s, 8H), δ: 2.962 (s, 3H), δ: 3.120 (m, 2H), δ: 3.242 (m, 2H), δ: 3.643 (d, 2H), δ: 3.808 (d, 2H), δ: 4.747 (m, 1H), δ: 7.139 (d, 2H), δ: 7.450 (d, 2H), δ: 7.972 (m, 1H), δ: 8.125 (s, 1H), δ: 8.457 (d, 1H), δ: 8.608 (m, 1H), δ: 9.158 (d, 1H). The obtained mesylate exhibited good crystallinity, and its XRPD characterization pattern was shown in FIG. 5. The main diffraction peak data were as follows:

TABLE-US-00006 Peak Relative position peak 2θ angle intensity (°) % 6.058 100 6.394 83.4 11.664 21.5 12.380 15.1 16.027 21.7 16.569 33.2 16.915 29.1 17.450 55.4 18.033 33.2 18.911 55.7 19.271 58.6 19.896 26.4 20.219 29.9 23.368 26.5 24.382 47.7 26.375 38.7 27.339 26.2

[0247] It could be inferred from the calculation of the free base content by HPLC, the determination of the water content, and the hydrogen ratio in .sup.1H-NMR of the nuclear magnetic resonances (see the table below) that the base/acid/H.sub.2O of the mesylate was 1:2.5:1.

TABLE-US-00007 Acid:base Theoretical Theoretical Theoretical Theoretical Measured Measured hydrogen atom ratio water content acid content base content water content base content number ratio Name (base/acid/H.sub.2O) (%) (%) (%) (%) (%, HPLC) (.sup.1H-NMR) Example 4 1:2.5:1 2.6% 34.2% 63.2% 3.2% 64.1% 1:2.5 mesylate

Example 5: Preparation of a Mesylate of the Arylaminopurine Derivative

[0248] ##STR00029##

[0249] The preparation process of Example 3 was repeated except for changing the amount of methanesulfonic acid to (7.58 g, 78.9 mmol), and a yellow or pale yellow mesylate (11.2 g) was obtained. .sup.1H-NMR (600 MHz, D.sub.2O) δ: 1.602 (d, 6H), δ: 2.736 (s, 1H), δ: 2.951 (s, 3H), δ: 3.177 (m, 2H), δ: 3.263 (m, 2H), δ: 3.655 (d, 2H), δ: 3.837 (d, 2H), δ: 4.745 (m, 1H), δ: 7.188 (d, 2H), δ: 7.473 (d, 2H), δ: 8.015 (m, 1H), δ: 8.131 (s, 1H), δ: 8.486 (d, 1H), δ: 8.678 (m, 1H), δ: 9.210 (d, 1H). The obtained mesylate exhibited good crystallinity, and its XRPD characterization pattern was shown in FIG. 6. The main diffraction peak data were as follows:

TABLE-US-00008 Peak Relative position peak 2θ angle intensity (°) % 4.887 55.7 6.038 15.3 9.733 12.7 10.514 14.1 11.471 70.2 12.306 15.4 14.492 76.5 15.055 35.4 16.808 33.2 18.487 47.2 18.871 100 21.557 27.5 22.023 19.5 22.316 17.2 22.767 39.4 23.372 22.8 24.260 43.2 25.353 39.4 26.675 27.2 27.264 20.9

[0250] It could be inferred from the calculation of the free base content by HPLC, the determination of the water content, and the hydrogen ratio in .sup.1H-NMR of the nuclear magnetic resonances (see the table below) that the base/acid/H.sub.2O of the mesylate was 1:3.5:1.

TABLE-US-00009 Acid:base Theoretical Theoretical Theoretical Theoretical Measured Measured hydrogen atom ratio water content acid content base content water content base content number ratio Name (base/acid/H.sub.2O) (%) (%) (%) (%) (%, HPLC) (.sup.1H-NMR) Example 5 1:3.5:1 2.3% 42.2% 55.6% 3.0% 57.1% 1:3.5 mesylate

Example 6: Preparation of an L-Malate of the Arylaminopurine Derivative

[0251] ##STR00030##

[0252] The arylaminopurine derivative (8 g, 18 mmol) from Preparation Example 1, 64 mL of purified water, and 32 mL of acetone were added to the reactor. The mixture was heated to 40±5° C. under stirring, and L-malic acid (2.902 g, 21.6 mmol) was added to the reactor. After completing the addition, 168 mL of acetone was added, and the reaction was continued for 1 hour while keeping the temperature at 40±5° C. Then the reaction mixture was cooled down to 10±5° C. under stirring and crystallized for 2 hours. Suction filtration was performed. The filter cake was washed with 30 mL of acetone to produce a yellow L-malate (8.63 g). .sup.1H-NMR (600 MHz, D.sub.2O) δ: 1.590 (d, 6H), δ: 2.527 (q, 1H), δ: 2.749 (q, 1H), δ: 2.929 (s, 3H), δ: 3.010 (t, 2H), δ: 3.184 (t, 2H), δ: 3.587 (d, 4H), δ: 4.328 (d, 1H), δ: 4.606 (d, 1H), δ: 6.983 (d, 2H), δ: 7.370 (d, 2H), δ: 7.538 (q, 1H), δ: 8.052 (d, 2H), δ: 8.254 (d, 1H), δ: 8.690 (d, 1H). The obtained malate exhibited good crystallinity, and its XRPD characterization pattern was shown in FIG. 7. The main diffraction peak data were as follows:

TABLE-US-00010 Peak Relative position peak 2θ angle intensity (°) % 7.039 100 9.340 83.6 11.953 14.5 12.945 19.3 13.976 11.3 16.648 15.0 17.646 31.3 18.518 22.7 19.651 30.9 22.995 10.7 24.198 13.9 25.190 20.7 25.937 73.4 27.535 22.5

[0253] It could be inferred from the calculation of the free base content by HPLC, the determination of the water content, and the hydrogen ratio in .sup.1H-NMR of the nuclear magnetic resonances (see the table below) that the base/acid/H.sub.2O of the malate was 1:1:4.

TABLE-US-00011 Acid:base Theoretical Theoretical Theoretical Theoretical Measured Measured hydrogen atom ratio water content acid content base content water content base content number ratio Name (base/acid/H.sub.2O) (%) (%) (%) (%) (%, HPLC) (.sup.1H-NMR) Example 6 1:1:4 11.1% 20.6% 68.3% 11.0% 69.1% 1:1 L-malate

Example 7: Preparation of an L-Tartrate of the Arylaminopurine Derivative

[0254] ##STR00031##

[0255] The arylaminopurine derivative (8 g, 18 mmol) from Preparation Example 1, 64 mL of purified water, and 32 mL of acetone were added to the reactor. The mixture was heated to 40±5° C. under stirring, and L-tartaric acid (3.248 g, 21.6 mmol) was added to the reactor. After completing the addition, 168 mL of acetone was added, and the reaction was continued for 1 hour while keeping the temperature at 40±5° C. Then the reaction mixture was cooled down to 10±5° C. under stirring and crystallized for 2 hours. Suction filtration was performed. The filter cake was washed with 30 mL of acetone to produce a yellow L-tartrate (10.06 g). .sup.1H-NMR (600 MHz, D.sub.2O) δ: 1.626 (d, 6H), δ: 2.954 (s, 3H), δ: 3.086 (t, 2H), δ: 3.242 (t, 2H), δ: 3.629 (d, 2H), δ: 3.747 (d, 2H), δ: 4.414 (s, 2H), δ: 4.683 (m, 1H), δ: 7.098 (d, 2H), δ: 7.453 (d, 2H), δ: 7.705 (m, 1H), δ: 8.109 (s, 1H), δ: 8.255 (d, 1H), δ: 8.349 (d, 1H), δ: 8.857 (s, 1H). The obtained tartrate exhibited good crystallinity, and its XRPD characterization pattern was shown in FIG. 8. The main diffraction peak data were as follows:

TABLE-US-00012 Peak Relative position peak 2θ angle intensity (°) % 6.895 61.5 9.058 100 12.884 27.6 13.810 25.9 16.470 29.0 17.773 40.2 19.419 42.8 20.087 21.6 25.503 95.3 26.920 26.6

[0256] It could be inferred from the calculation of the free base content by HPLC, the determination of the water content, and the hydrogen ratio in .sup.1H-NMR of the nuclear magnetic resonances (see the table below) that the base/acid/H.sub.2O of the tartrate was 1:1:4.

TABLE-US-00013 Acid:base Theoretical Theoretical Theoretical Theoretical Measured Measured hydrogen atom ratio water content acid content base content water content base content number ratio Name (base/acid/H.sub.2O) (%) (%) (%) (%) (%, HPLC) (.sup.1H-NMR) Example 7 1:1:4 10.8% 22.6% 66.7% 11.0% 68.0% 1:1 L-tartrate

Example 8: Preparation of an L-Tartrate of the Arylaminopurine Derivative

[0257] ##STR00032##

[0258] The arylaminopurine derivative (7 g, 15.8 mmol) from Preparation Example 1, 56 mL of purified water, and 28 mL of acetone were added to the reactor. The mixture was heated to 40±5° C. under stirring, and L-tartaric acid (5.685 g, 37.9 mmol) was added to the reactor. After completing the addition, 147 mL of acetone was added, and the reaction was continued for 1 hour while keeping the temperature at 40±5° C. Then the reaction mixture was cooled down to 10±5° C. under stirring and crystallized for 2 hours. Suction filtration was performed. The filter cake was washed with 30 mL of acetone to produce a pale yellow L-tartrate (11.3 g). .sup.1H-NMR (600 MHz, D.sub.2O) δ: 1.610 (d, 6H), δ: 2.948 (s, 3H), δ: 3.067 (s, 2H), δ: 3.229 (s, 2H), δ: 3.630 (s, 2H), δ: 3.755 (s, 2H), δ: 4.469 (s, 3H), δ: 4.697 (m, 1H), δ: 7.085 (d, 2H), δ: 7.431 (d, 2H), δ: 7.798 (m, 1H), δ: 8.094 (s, 1H), δ: 8.366 (m, 2H), δ: 8.978 (s, 1H). The obtained tartrate exhibited good crystallinity, and its XRPD characterization pattern was shown in FIG. 9. The main diffraction peak data were as follows:

TABLE-US-00014 Peak Relative position peak 2θ angle intensity (°) % 8.531 64.5 9.754 30.4 10.144 28.7 11.267 21.1 13.722 18.5 14.831 46.5 15.447 26.4 16.345 32.4 17.081 57.1 17.648 23.4 18.837 87.3 20.461 33.8 22.316 33.4 24.578 80.1 26.075 100

[0259] It could be inferred from the calculation of the free base content by HPLC, the determination of the water content, and the hydrogen ratio in .sup.1H-NMR of the nuclear magnetic resonances (see the table below) that the base/acid/H.sub.2O of the tartrate was 1:1.5:4.

TABLE-US-00015 Acid:base Theoretical Theoretical Theoretical Theoretical Measured Measured hydrogen atom ratio water content acid content base content water content base content number ratio Name (base/acid/H.sub.2O) (%) (%) (%) (%) (%, HPLC) (.sup.1H-NMR) Example 8 1:1.5:4 9.7% 30.4% 59.9% 14.4% 61.0% 1:1.5 L-tartrate

Example 9: Preparation of an L-Tartrate of the Arylaminopurine Derivative

[0260] ##STR00033##

[0261] The preparation process of Example 8 was repeated except for changing the amount of L-tartaric acid to (8.29 g, 55.2 mmol), and a pale yellow L-tartrate (11.59 g) was obtained. .sup.1H-NMR (600 MHz, D.sub.2O) δ: 1.646 (d, 6H), δ: 2.983 (s, 3H), δ: 3.100 (s, 2H), δ: 3.276 (s, 2H), δ: 3.674 (s, 2H), δ: 3.817 (s, 2H), δ: 4.528 (s, 4H), δ: 7.148 (s, 2H), δ: 7.489 (s, 2H), δ: 7.896 (m, 1H), δ: 8.148 (s, 1H), δ: 8.440 (d, 1H), δ: 8.502 (d, 1H), δ: 9.072 (s, 1H). The obtained tartrate exhibited good crystallinity, and its XRPD characterization pattern was shown in FIG. 10. The main diffraction peak data were as follows:

TABLE-US-00016 Peak position 2θ angle (°) Relative peak intensity % 7.011 16.1 8.253 54.4 8.912 63.3 9.531 100 12.455 33.3 13.132 26.4 14.794 56.0 16.034 23.0 17.670 71.7 18.129 21.9 19.184 32.4 21.005 67.6 23.571 39.5 24.023 55.1 25.251 42.6 26.727 35.9

[0262] It could be inferred from the calculation of the free base content by HPLC, the determination of the water content, and the hydrogen ratio in .sup.1H-NMR of the nuclear magnetic resonances (see the table below) that the base/acid/H.sub.2O of the tartrate was 1:2:4.

TABLE-US-00017 Acid:base Theoretical Theoretical Theoretical Theoretical Measured Measured hydrogen atom ratio water content acid content base content water content base content number ratio Name (base/acid/H.sub.2O) (%) (%) (%) (%) (%, HPLC) (.sup.1H-NMR) Example 9 1:2:4 8.8% 36.8% 54.4% 8.3% 55.8% 1:2 L-tartrate

Example 10: Preparation of an Oxalate of the Arylaminopurine Derivative

[0263] ##STR00034##

[0264] The arylaminopurine derivative (7 g, 15.8 mmol) from Preparation Example 1, 28 mL of purified water, and 28 mL of acetone were added to the reactor. The mixture was heated to 40±5° C. under stirring, and oxalic acid dihydrate (2.388 g, 18.9 mmol) was added to the reactor. After completing the addition, 147 mL of acetone was added, and the reaction was continued for 1 hour while keeping the temperature at 40±5° C. Then the reaction mixture was cooled down to 10±5° C. under stirring and crystallized for 2 hours. Suction filtration was performed. The filter cake was washed with 30 mL of acetone to produce a yellow oxalate (8.01 g). .sup.1H-NMR (600 MHz, D.sub.2O) δ: 1.637 (d, 6H), δ: 2.974 (s, 3H), δ: 3.158 (m, 2H), δ: 3.276 (m, 2H), δ: 3.663 (d, 2H), δ: 3.848 (d, 2H), δ: 4.790 (m, 1H), δ: 7.192 (d, 2H), δ: 7.505 (d, 2H), δ: 7.972 (m, 1H), δ: 8.139 (s, 1H), δ: 8.491 (d, 1H), δ: 8.601 (d, 1H), δ: 9.127 (s, 1H). The obtained oxalate exhibited good crystallinity, and its XRPD characterization pattern was shown in FIG. 11. The main diffraction peak data were as follows:

TABLE-US-00018 Peak position 2θ angle (°) Relative peak intensity % 8.063 59.5 8.353 91.6 8.983 29.0 14.103 35.0 14.799 28.1 16.712 28.2 17.884 19.3 18.510 14.4 19.560 19.6 23.634 14.4 25.622 100

[0265] It could be inferred from the calculation of the free base content by HPLC, the determination of the water content, and the hydrogen ratio in .sup.1H-NMR of the nuclear magnetic resonances (see the table below) that the base/acid/H.sub.2O of the oxalate was 1:1:1.

TABLE-US-00019 Acid:base Theoretical Theoretical Theoretical Theoretical Measured Measured hydrogen atom ratio water content acid content base content water content base content number ratio Name (base/acid/H.sub.2O) (%) (%) (%) (%) (%, HPLC) (.sup.1H-NMR) Example 10 1:1:1 3.3% 16.3% 80.4% 5.1% 80.9% N/A oxalate

Example 11: Preparation of an Oxalate of the Arylaminopurine Derivative

[0266] ##STR00035##

[0267] The preparation process of Example 10 was repeated except for changing the amount of oxalic acid dihydrate to (4.755 g, 37.9 mmol), and a yellow oxalate (8.01 g) was obtained. .sup.1H-NMR (600 MHz, D.sub.2O) δ: 1.621 (d, 6H), δ: 2.963 (s, 3H), δ: 3.126 (m, 2H), δ: 3.257 (m, 2H), δ: 3.650 (d, 2H), δ: 3.833 (d, 2H), δ: 4.757 (m, 1H), δ: 7.167 (d, 2H), δ: 7.474 (d, 2H), δ: 8.013 (m, 1H), δ: 8.127 (s, 1H), δ: 8.496 (d, 1H), δ: 8.665 (d, 1H), δ: 9.191 (s, 1H). The obtained oxalate exhibited good crystallinity, and its XRPD characterization pattern was shown in FIG. 12. The main diffraction peak data were as follows:

TABLE-US-00020 Peak position 2θ angle (°) Relative peak intensity % 7.108 100 8.272 14.7 12.195 49.8 14.202 28.6 16.442 35.7 17.690 31.3 18.599 25.6 19.047 36.5 24.385 56.4

[0268] It could be inferred from the calculation of the free base content by HPLC, the determination of the water content, and the hydrogen ratio in .sup.1H-NMR of the nuclear magnetic resonances (see the table below) that the base/acid/H.sub.2O of the oxalate was 1:2:1.

TABLE-US-00021 Acid:base Theoretical Theoretical Theoretical Theoretical Measured Measured hydrogen atom ratio water content acid content base content water content base content number ratio Name (base/acid/H.sub.2O) (%) (%) (%) (%) (%, HPLC) (.sup.1H-NMR) Example 11 1:2:1 2.8% 28.1% 69.2% 2.9% 70.1% N/A oxalate

Example 12: Preparation of a Succinate of the Arylaminopurine Derivative

[0269] ##STR00036##

[0270] The arylaminopurine derivative (7 g, 15.8 mmol) from Preparation Example 1, 28 mL of purified water, and 28 mL of acetone were added to the reactor. The mixture was heated to 40±5° C. under stirring, and succinic acid (2.236 g, 18.9 mmol) was added to the reactor. After completing the addition, 147 mL of acetone was added, and the reaction was continued for 1 hour while keeping the temperature at 40±5° C. Then the reaction mixture was cooled down to 10±5° C. under stirring and crystallized for 2 hours. Suction filtration was performed. The filter cake was washed with 30 mL of acetone to produce a pale yellow succinate (7.51 g). .sup.1H-NMR (600 MHz, D.sub.2O) δ: 1.584 (d, 6H), δ: 2.482 (s, 4H), δ: 2.923 (s, 3H), δ: 2.992 (m, 2H), δ: 3.174 (m, 2H), δ: 3.594 (m, 4H), δ: 4.584 (m, 1H), δ: 6.959 (d, 2H), δ: 7.365 (d, 2H), δ: 7.440 (m, 1H), δ: 7.929 (d, 1H), δ: 8.058 (s, 1H), δ: 8.227 (d, 1H), δ: 8.579 (s, 1H). The obtained succinate exhibited good crystallinity, and its XRPD characterization pattern was shown in FIG. 13. The main diffraction peak data were as follows:

TABLE-US-00022 Peak position 2θ angle (°) Relative peak intensity % 7.024 80.2 9.128 55.0 11.323 46.7 13.065 23.9 13.849 36.0 14.399 46.2 15.969 18.2 16.769 40.5 17.744 33.6 18.476 52.3 20.351 53.8 21.017 48.7 22.437 100 24.204 35.9 25.889 46.9 27.115 50.9

[0271] It could be inferred from the calculation of the free base content by HPLC, the determination of the water content, and the hydrogen ratio in .sup.1H-NMR of the nuclear magnetic resonances (see the table below) that the base/acid/H.sub.2O of the succinate was 1:1:4.

TABLE-US-00023 Acid:base Theoretical Theoretical Theoretical Theoretical Measured Measured hydrogen atom ratio water content acid content base content water content base content number ratio Name (base/acid/H.sub.2O) (%) (%) (%) (%) (%, HPLC) (.sup.1H-NMR) Example 12 1:1:4 11.4% 18.6% 70.0% 12.6% 69.3% 1:1 succinate

Example 13: Preparation of a Succinate of the Arylaminopurine Derivative

[0272] ##STR00037##

[0273] The preparation process of Example 12 was repeated except for changing the amount of succinic acid to (4.473 g, 37.9 mmol), and a pale yellow succinate (8.14 g) was obtained. .sup.1H-NMR (600 MHz, D.sub.2O) δ: 1.643 (d, 6H), δ: 2.548 (s, 9H), δ: 2.961 (s, 3H), δ: 3.080 (m, 2H), δ: 3.246 (m, 2H), δ: 3.639 (d, 2H), δ: 3.762 (d, 2H), δ: 4.695 (m, 1H), δ: 7.114 (d, 2H), δ: 7.497 (d, 2H), δ: 7.638 (m, 1H), δ: 8.138 (s, 1H), δ: 8.159 (d, 1H), δ: 8.347 (d, 1H), δ: 8.769 (s, 1H). The obtained succinate exhibited good crystallinity, and its XRPD characterization pattern was shown in FIG. 14. The main diffraction peak data were as follows:

TABLE-US-00024 Peak position 2θ angle (°) Relative peak intensity % 6.965 100 9.193 47.5 11.919 15.0 16.657 19.6 17.626 32.2 18.410 30.6 19.661 31.0 20.273 10.7 22.953 11.9 24.149 11.9 25.171 19.1 25.816 58.1 27.263 28.5

[0274] It could be inferred from the calculation of the free base content by HPLC, the determination of the water content, and the hydrogen ratio in .sup.1H-NMR of the nuclear magnetic resonances (see the table below) that the base/acid/H.sub.2O of the succinate was 1:2:4.

TABLE-US-00025 Acid:base Theoretical Theoretical Theoretical Theoretical Measured Measured hydrogen atom ratio water content acid content base content water content base content number ratio Name (base/acid/H.sub.2O) (%) (%) (%) (%) (%, HPLC) (.sup.1H-NMR) Example 13 1:2:4 9.6% 31.4% 59.0% 12.7% 58.9% 1:2 succinate

Example 14: Preparation of an Acetate of the Arylaminopurine Derivative

[0275] ##STR00038##

[0276] The arylaminopurine derivative (7 g, 15.8 mmol) from Preparation Example 1, 28 mL of purified water, and 28 mL of acetone were added to the reactor. The mixture was heated to 40±5° C. under stirring, and acetic acid (1.13 g, 18.9 mmol) was added to the reactor. After completing the addition, 147 mL of acetone was added, and the reaction was continued for 1 hour while keeping the temperature at 40±5° C. Then the reaction mixture was cooled down to 10±5° C. under stirring and crystallized for 2 hours. Suction filtration was performed. The filter cake was washed with 30 mL of acetone to produce an off-white acetate (7.51 g). .sup.1H-NMR (600 MHz, DMSO) δ: 1.676 (d, 6H), δ: 2.216 (s, 3H), δ: 2.442 (m, 2H), δ: 2.497 (m, 2H), δ: 3.038 (m, 4H), δ: 4.846 (m, 1H), δ: 6.868 (d, 2H), δ: 7.350 (q, 1H), δ: 7.622 (d, 2H), δ: 8.188 (q, 1H), δ: 8.324 (q, 1H), δ: 8.379 (s, 1H), δ: 8.931 (d, 1H), δ: 9.029 (s, 1H), δ: 9.204 (s, 1H). The obtained acetate exhibited good crystallinity, and its XRPD characterization pattern was shown in FIG. 15. The main diffraction peak data were as follows:

TABLE-US-00026 Peak position 2θ angle (°) Relative peak intensity % 6.319 18.9 8.867 21.5 10.861 62.7 11.498 19.6 12.164 32.7 12.622 83.6 15.148 66.2 17.754 91.8 19.221 81.2 19.645 75.1 20.988 55.0 21.767 57.8 22.268 62.3 24.595 100 25.405 57.7

[0277] It could be inferred from the calculation of the free base content by HPLC, the determination of the water content, and the hydrogen ratio in .sup.1H-NMR of the nuclear magnetic resonances (see the table below) that the base/acid/H.sub.2O of the acetate was 1:1:1.

TABLE-US-00027 Acid:base Theoretical Theoretical Theoretical Theoretical Measured Measured hydrogen atom ratio water content acid content base content water content base content number ratio Name (base/acid/H.sub.2O) (%) (%) (%) (%) (%, HPLC) (.sup.1H-NMR) Example 14 1:1:1 3.5% 11.5% 85.0% 3.7% 86.2% 1:1 acetate

Example 15: Preparation of an Acetate of the Arylaminopurine Derivative

[0278] ##STR00039##

[0279] The arylaminopurine derivative (10 g, 22.5 mmol) from Preparation Example 1, 10 mL of purified water, and 40 mL of acetone were added to the reactor. The mixture was heated to 40±5° C. under stirring, and acetic acid (4.74 g, 78.9 mmol) was added to the reactor. After completing the addition, 210 mL of acetone was added, and the reaction was continued for 1 hour while keeping the temperature at 40±5° C. Then the reaction mixture was cooled down to 10±5° C. under stirring and crystallized for 2 hours. Suction filtration was performed. The filter cake was washed with 40 mL of acetone to produce an off-white acetate (9.04 g). .sup.1H-NMR (600 MHz, D.sub.2O) δ: 1.542 (d, 6H), δ: 1.951 (s, 6H), δ: 2.902 (s, 1H), δ: 2.934 (m, 4H), δ: 3.126 (m, 2H), δ: 3.553 (m, 4H), δ: 4.541 (m, 1H), δ: 6.885 (m, 2H), δ: 7.284 (m, 2H), δ: 7.417 (m, 1H), δ: 7.899 (m, 1H), δ: 7.997 (s, 1H), δ: 8.181 (s, 1H), δ: 8.552 (s, 1H). The obtained acetate exhibited good crystallinity, and its XRPD characterization pattern was shown in FIG. 16. The main diffraction peak data were as follows:

TABLE-US-00028 Peak position 2θ angle (°) Relative peak intensity % 6.174 100 8.109 29.6 9.097 33.4 12.231 92.9 15.024 16.9 16.074 29.9 17.496 63.6 18.193 31.4 20.676 35.7 21.453 38.7 23.399 41.6 24.766 48.4 28.820 21.1

[0280] It could be inferred from the calculation of the free base content by HPLC, the determination of the water content, and the hydrogen ratio in .sup.1H-NMR of the nuclear magnetic resonances (see the table below) that the base/acid/H.sub.2O of the acetate was 1:2:1.

TABLE-US-00029 Acid:base Theoretical Theoretical Theoretical Theoretical Measured Measured hydrogen atom ratio water content acid content base content water content base content number ratio Name (base/acid/H.sub.2O) (%) (%) (%) (%) (%, HPLC) (.sup.1H-NMR) Example 15 1:2:1 3.1% 20.7% 76.3% 3.5% 77.1% 1:2 acetate

Example 16: Preparation of a Sulfate of the Arylaminopurine Derivative

[0281] ##STR00040##

[0282] The arylaminopurine derivative (7 g, 15.8 mmol) from Preparation Example 1, 7 mL of purified water, and 28 mL of acetone were added to the reactor. The mixture was heated to 40±5° C. under stirring, and sulfuric acid (1.86 g, 18.9 mmol) was added to the reactor. After completing the addition, 147 mL of acetone was added, and the reaction was continued for 1 hour while keeping the temperature at 40±5° C. Then the reaction mixture was cooled down to 10±5° C. under stirring and crystallized for 2 hours. Suction filtration was performed. The filter cake was washed with 30 mL of acetone to produce a pale yellow sulfate (7.5 g). .sup.1H-NMR (600 MHz, D.sub.2O) δ: 1.533 (d, 6H), δ: 2.894 (s, 3H), δ: 3.009 (m, 2H), δ: 3.086 (m, 2H), δ: 3.547 (d, 2H), δ: 3.634 (d, 2H), δ: 4.699 (m, 1H), δ: 6.936 (d, 2H), δ: 7.291 (d, 2H), δ: 7.929 (m, 1H), δ: 8.114 (s, 1H), δ: 8.387 (d, 1H), δ: 8.640 (m, 1H), δ: 9.217 (d, 1H). The obtained sulfate exhibited good crystallinity, and its XRPD characterization pattern was shown in FIG. 17. The main diffraction peak data were as follows:

TABLE-US-00030 Peak position 2θ angle (°) Relative peak intensity % 4.825 59.1 7.010 89.3 8.553 46.5 9.183 64.5 9.528 96.8 11.644 33.4 12.785 43.3 13.556 82.2 15.743 72.1 17.576 45.9 18.612 100 20.504 61.7 21.565 77.2 23.753 42.9 25.697 98.8

[0283] It could be inferred from the calculation of the free base content by HPLC, the determination of the water content, and the hydrogen ratio in .sup.1H-NMR of the nuclear magnetic resonances (see the table below) that the base/acid/H.sub.2O of the sulfate was 1:1:1.

TABLE-US-00031 Acid:base Theoretical Theoretical Theoretical Theoretical Measured Measured hydrogen atom ratio water content acid content base content water content base content number ratio Name (base/acid/H.sub.2O) (%) (%) (%) (%) (%, HPLC) (.sup.1H-NMR) Example 16 1:1:1 3.2% 17.5% 79.3% 3.4% 74.1% N/A sulfate

Example 17: Preparation of a Sulfate of the Arylaminopurine Derivative

[0284] ##STR00041##

[0285] The preparation process of Example 16 was repeated except for changing the amount of succinic acid to (3.71 g, 37.9 mmol), and a pale yellow succinate (10.0 g) was obtained. .sup.1H-NMR (600 MHz, D.sub.2O) δ: 1.600 (d, 6H), δ: 2.957 (s, 3H), δ: 3.243 (m, 4H), δ: 3.644 (d, 2H), δ: 3.829 (d, 2H), δ: 4.757 (m, 1H), δ: 7.208 (d, 2H), δ: 7.294 (d, 2H), δ: 8.014 (m, 1H), δ: 8.155 (s, 1H), δ: 8.485 (d, 1H), δ: 8.685 (m, 1H), δ: 9.217 (d, 1H). The obtained sulfate exhibited good crystallinity, and its XRPD characterization pattern was shown in FIG. 18. The main diffraction peak data were as follows:

TABLE-US-00032 Peak position 2θ angle (°) Relative peak intensity % 8.622 33.2 9.588 78.1 15.681 44.6 16.519 14.5 17.129 31.1 19.269 50.0 20.033 49.8 21.862 29.5 23.467 21.6 24.352 16.5 26.649 100

[0286] It could be inferred from the calculation of the free base content by HPLC, the determination of the water content, and the hydrogen ratio in .sup.1H-NMR of the nuclear magnetic resonances (see the table below) that the base/acid/H.sub.2O of the sulfate was 1:2:1.

TABLE-US-00033 Acid:base Theoretical Theoretical Theoretical Theoretical Measured Measured hydrogen atom ratio water content acid content base content water content base content number ratio Name (base/acid/H.sub.2O) (%) (%) (%) (%) (%, HPLC) (.sup.1H-NMR) Example 17 1:2:1 2.7% 29.8% 67.5% 3.5% 68.0% N/A sulfate

Test Example 1: DSC and TGA Tests

[0287] The salts obtained in Examples 1 and 3-17 and the compound represented by Formula 1 were subjected to the DSC and TGA tests in media, and the test results were shown in the following table:

TABLE-US-00034 Example Salt DSC TGA Example 1 Hydrochloride Easy to lose the water of Starting to lose the water of crystallization and the acid, no crystallization at about 40° C.; obvious melting point (see FIG. starting to lose the acid at about 19) 140° C. (see FIG. 19) Example 3 Mesylate Easy to lose the water of Starting to lose the water of crystallization and the acid, no crystallization at about 40° C.; obvious melting point (see FIG. starting to lose the acid at about 20) 120° C. (see FIG. 21) Example 4 Mesylate Easy to lose the water of Starting to lose the water of crystallization and the acid, no crystallization at about 40° C.; obvious melting point (see FIG. starting to lose the acid at about 22) 220° C. (see FIG. 23) Example 5 Mesylate Easy to lose the water of Starting to lose the water of crystallization and the acid, no crystallization at about 40° C.; obvious melting point (see FIG. starting to lose the acid at about 24) 190° C. (see FIG. 25) Example 6 L-Malate Easy to lose the water of Starting to lose the water of crystallization and the acid, no crystallization at about 40° C.; obvious melting point (see FIG. starting to lose the acid at about 26) 170° C. (see FIG. 26) Example 7 L-Tartrate Easy to lose the water of Starting to lose the water of crystallization and the acid, no crystallization at about 40° C.; obvious melting point (see FIG. starting to lose the acid at about 27) 180° C. (see FIG. 27) Example 8 L-Tartrate Easy to lose the water of Starting to lose the water of crystallization and the acid, no crystallization at about 40° C.; obvious melting point (see FIG. starting to lose the acid at about 28) 180° C. (see FIG. 28) Example 9 L-Tartrate Easy to lose the water of Starting to lose the water of crystallization and the acid, no crystallization at about 40° C.; obvious melting point (see FIG. starting to lose the acid at about 29) 170° C. (see FIG. 29) Example 10 Oxalate Easy to lose the water of Starting to lose the water of crystallization and the acid, no crystallization at about 40° C.; obvious melting point (see FIG. starting to lose the acid at about 30) 170° C. (see FIG. 30) Example 11 Oxalate Easy to lose the water of Starting to lose the water of crystallization and the acid, no crystallization at about 40° C.; obvious melting point (see FIG. starting to lose the acid at about 31) 220° C. (see FIG. 31) Example 12 Succinate Easy to lose the water of Starting to lose the water of crystallization and the acid, no crystallization at about 40° C.; obvious melting point (see FIG. starting to lose the acid at about 32) 140° C. (see FIG. 33) Example 13 Succinate Easy to lose the water of Starting to lose the water of crystallization and the acid, no crystallization at about 40° C.; obvious melting point (see FIG. starting to lose the acid at about 34) 140° C. (see FIG. 35) Example 14 Acetate Easy to lose the water of Starting to lose the water of crystallization and the acid, no crystallization at about 40° C.; obvious melting point (see FIG. starting to lose the acid at about 36) 80° C. (see FIG. 37) Example 15 Acetate Easy to lose the water of Starting to lose the water of crystallization and the acid, no crystallization at about 40° C.; obvious melting point (see FIG. starting to lose the acid at about 38) 80° C. (see FIG. 39) Example 16 Sulfate Easy to lose the water of Starting to lose the water of crystallization and the acid, no crystallization at about 40° C.; obvious melting point (see FIG. starting to lose the acid at about 40) 240° C. (See FIG. 40) Example 17 Sulfate Easy to lose the water of Starting to lose the water of crystallization and the acid, no crystallization at about 40° C.; obvious melting point (see FIG. starting to lose the acid at about 41) 210° C. (see FIG. 41) The compound represented Starting to melt at about 150° C. Starting to decompose at about by Formula 1 and decompose at about 155° C. 155° C. (see FIG. 42) (see FIG. 42)

Test Example 2: Solubility Test

[0288] The salts obtained in Examples 1 and 3-17 and the compound represented by Formula 1 were subjected to the solubility test in media and the test results were shown in the following table:

TABLE-US-00035 Solubility (25° C., mg/mL) Water Water medium Water medium Water medium Example Salt medium pH = 1.2 pH = 4.5 pH = 6.8 Example 1 Hydrochloride 40.41 33.89 47.27 50.62 Example 3 Mesylate 212.73 360.00 207.53 153.30 Example 4 Mesylate >1000 >1000 >1000 >1000 Example 5 Mesylate >1000 >1000 >1000 >1000 Example 6 L-Malate 9.68 54.70 14.59 12.05 Example 7 L-Tartrate 6.91 43.07 6.51 12.24 Example 8 L-Tartrate 9.74 36.41 14.36 10.46 Example 9 L-Tartrate 10.50 44.51 15.17 11.48 Example 10 Oxalate 2.49 66.52 13.98 6.36 Example 11 Oxalate 27.78 87.38 16.13 8.61 Example 12 Succinate 3.09 42.39 2.70 0.14 Example 13 Succinate 5.06 59.71 8.42 1.12 Example 14 Acetate 0.04 41.47 0.72 0.03 Example 15 Acetate 63.57 96.58 45.67 27.84 Example 16 Sulfate 76.59 129.50 90.03 90.09 Example 17 Sulfate 16.51 33.29 21.64 31.39 The compound represented 0.05 12.60 0.57 0.04 by Formula 1

Test Example 3: Accelerated Stability Test

[0289] Appropriate amounts of the salt samples obtained from Examples 1 and 3-17 were placed at a temperature of 25±2° C. under 0%±5% RH in an open environment for 10 days and at a temperature of 40±2° C. under 75%±5% RH in an open environment for 10 days respectively to perform the accelerated tests, and the results were as follows:

TABLE-US-00036 Placed at 25 ± 2° C. under Placed at 40 ± 2° C. under 0% ± 5% RH in an open 75% ± 5% RH in an open environment for 10 days environment for 10 days Example Salt Appearance Crystal Form Appearance Crystal Form Example Hydrochloride Pale yellow or Keeping consistent Pale yellow or Keeping 1 yellow solid before and after yellow solid consistent before being placed and after being placed Example Mesylate Pale yellow or Keeping consistent Pale yellow or Keeping 3 yellow solid before and after yellow solid consistent before being placed and after being placed Example Mesylate Liquid N/a Liquid N/A 4 Example Mesylate Liquid N/a Liquid N/A 5 Example L-Malate Yellow solid Keeping consistent Yellow solid Keeping 6 before and after consistent before being placed and after being placed Example L-Tartrate Yellow solid Keeping consistent Yellow solid Keeping 7 before and after consistent before being placed and after being placed Example L-Tartrate Pale yellow Keeping consistent Pale yellow Keeping 8 solid before and after solid consistent before being placed and after being placed Example L-Tartrate Pale yellow Keeping consistent Pale yellow Keeping 9 solid before and after solid consistent before being placed and after being placed Example Oxalate Yellow solid Keeping consistent Yellow solid Keeping 10 before and after consistent before being placed and after being placed Example Oxalate Yellow solid Keeping consistent Yellow solid Keeping 11 before and after consistent before being placed and after being placed Example Succinate Pale yellow Keeping consistent Pale yellow Keeping 12 solid before and after solid consistent before being placed and after being placed Example Succinate Pale yellow Keeping consistent Pale yellow Keeping 13 solid before and after solid consistent before being placed and after being placed Example Acetate Off-white solid Keeping consistent Off-white solid Keeping 14 before and after consistent before being placed and after being placed Example Acetate Off-white solid Keeping consistent Off-white solid Keeping 15 before and after consistent before being placed and after being placed Example Sulfate Pale yellow Keeping consistent Pale yellow Keeping 16 solid before and after solid consistent before being placed and after being placed Example Sulfate Pale yellow Keeping consistent Pale yellow Keeping 17 solid before and after solid consistent before being placed and after being placed

Test Example 4: Hygroscopicity Test

[0290] Appropriate amounts of the salt samples obtained from Examples 1 and 3-17 were subjected to the hygroscopicity test at a temperature of 25±1° C. under a relative humidity of 80%±2%, and the results were as follows:

TABLE-US-00037 Result of hygroscopicity test (DVS, 80% RH) Weight gain due Example Salt to hygroscopicity Hygroscopicity Example 1 Hydrochloride 0.7% Slightly hygroscopic Example 3 Mesylate 5.86% Hygroscopic Example 4 Mesylate 6.94% Hygroscopic Example 5 Mesylate 19.62% Very hygroscopic Example 6 L-Malate 1.02% Slightly hygroscopic Example 7 L-Tartrate 1.19% Slightly hygroscopic Example 8 L-Tartrate 1.43% Slightly hygroscopic Example 9 L-Tartrate 1.43% Slightly hygroscopic Example 10 Oxalate 0.54% Slightly hygroscopic Example 11 Oxalate 0.68% Slightly hygroscopic Example 12 Succinate 0.11% Not or nearly not hygroscopic Example 13 Succinate 0.05% Not or nearly not hygroscopic Example 14 Acetate 1.59% Slightly hygroscopic Example 15 Acetate 2.59% Hygroscopic Example 16 Sulfate 7.67% Hygroscopic Example 17 Sulfate 1.34% Slightly hygroscopic The compound represented 0.45% Slightly hygroscopic by Formula 1

Test Example 5: Long-Term Stability Test

[0291] An appropriate amount of the salt sample obtained from Example 1 was taken, a medicinal low-density polyethylene sack was used as the internal packaging, and a polyester/aluminum/polyethylene composite bag for medicine packaging was used as the external packaging. Samples were taken respectively at the end of the 3rd, 6th, 9th, 12th, and 18th months after being stored at a temperature of 25±2° C. under a relative humidity of 60%±5%. The appearances were compared, followed by measuring other investigation indexes. The results were compared with those measured in the 0th month. The test results were shown in the following table:

TABLE-US-00038 Related Moisture substances Content Time Character (%) Acidity (%) (%) 0 Month Yellow crystalline 13.9 3.1 0.33 100.9 powder 3 Month Yellow crystalline 13.9 3.3 0.34 100.4 powder 6 Month Yellow crystalline 14.3 3.3 0.34 100.8 powder 9 Month Yellow crystalline 14.3 3.3 0.31 101.7 powder 12 Month Yellow crystalline 13.9 3.3 0.34 99.6 powder 18 Month Yellow crystalline 14.2 3.3 0.26 100.2 powder

Test Example 6: Biological Activity Test

[0292] The salt sample obtained from Example 1 was tested according to the kinase inhibitory activity test described in the biological assessment of the patent application WO2011/147066. The test results showed that the sample could inhibit the activities of FLT3, EGFR, Abl, Fyn, Hck, Lck, Lyn, Ret, Yes, VEGFR2, ALK, BTK, c-KIT, c-SRC, FGFR1, KDR, MET and PDGFRα kinases, and the test results for some kinases were shown in the following table.

TABLE-US-00039 Kinase IC.sub.50 (nM) FLT3(h) 26 FLT3-ITD(h) 3-10 EGFR(h) 42 Abl(h) 25 Fyn(h) 34 Hck(h) 93 Lck(h) 37 Lyn(h) 7 Ret(h) 10 Yes 4 c-SRC(h) 176 FGFRl(h) 247 KDR(h) 323

[0293] The salt sample obtained from Example 1 was tested (specifically for FLT3-ITD acute myeloid leukemia, non-small cell lung cancer with EGFR activating mutations, or Ph-positive chronic myeloid leukemia) according to the in-vivo anti-tumor test described in the biological assessment of the patent application WO2011/147066. The test result showed that, in the MV4-11 (FLT3-ITD mutation) subcutaneous tumor model test (with reference to the model established in Assay 4 of WO2011/147066), the sample (once daily oral administration for 21 days) could completely inhibit the tumor growth at the administration dose of 5 mg/kg, and could cause the complete regression of the tumor at the administration doses of 10 mg/kg and 20 mg/kg. In the non-small cell lung cancer model (with reference to the model established in Assay 3 of WO2011/147066), the sample could dose-dependently inhibit the growth of human non-small cell lung cancer HCC827: the tumor shrinkage (compared with the initial tumor) was caused in three dose groups of 7.5 mg/kg, 15 mg/kg and 30 mg/kg (once daily oral administration for 30 days), wherein the 30 mg/kg group could cause the nearly complete regression of the tumor. In the K562 (BCR-Abl gene rearrangement) subcutaneous tumor model test (a model established similarly to the MV4-11 subcutaneous tumor model), the sample (once daily oral administration for 18 days) could effectively inhibit the tumor growth at the administration dose of 70 mg/kg, and the tumor inhibition rate reached 71.3%.

[0294] The present disclosure provides the following technical solutions, but the present invention is not limited thereto, and the protection scope of the present invention is determined according to the scope defined by the claims:

Technical Solution 1

[0295] A salt of the arylaminopurine derivative, wherein said salt is represented by Formula 2:

##STR00042##

[0296] wherein,

[0297] HA is an acid;

[0298] H.sub.2O is the water of crystallization;

[0299] m is an integer or half-integer from 1 to 4;

[0300] n is an integer or half-integer from 0 to 5.

Technical Solution 2

[0301] The salt of the arylaminopurine derivative according to technical solution 1, wherein the acid is selected from a group consisting of hydrochloric acid, methanesulfonic acid, L-malic acid, L-tartaric acid, oxalic acid, succinic acid, acetic acid, or sulfuric acid; preferably hydrochloric acid, L-malic acid, L-tartaric acid, oxalic acid, succinic acid, acetic acid, or sulfuric acid; more preferably hydrochloric acid, L-malic acid, L-tartaric acid, oxalic acid, succinic acid or acetic acid; further preferably hydrochloric acid.

Technical Solution 3

[0302] The salt of the arylaminopurine derivative according to technical solution 1, wherein the salt is a hydrochloride represented by Formula 3:

##STR00043##

[0303] n is 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5;

[0304] preferably, the salt is a hydrochloride represented by Formula 3′:

##STR00044##

[0305] preferably,

[0306] the hydrochloride represented by Formula 3 or Formula 3′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 8.5±0.2°, 11.8±0.2°, 19.6±0.2°, 25.2±0.2°, 27.2±0.2° as measured with CuKα radiation;

[0307] or, the hydrochloride represented by Formula 3 or Formula 3′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 8.5±0.2°, 11.8±0.2°, 12.6±0.2°, 19.6±0.2°, 20.0±0.2°, 23.7±0.2°, 25.2±0.2°, 27.2±0.2° as measured with CuKα radiation;

[0308] or, the hydrochloride represented by Formula 3 or Formula 3′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 7.3±0.2°, 8.5±0.2°, 9.0±0.2°, 11.8±0.2°, 12.6±0.2°, 14.3±0.2°, 18.1±0.2°, 19.6±0.2°, 20.0±0.2°, 21.1±0.2°, 21.9±0.2°, 23.7±0.2°, 25.2±0.2°, 26.1±0.2°, 27.2±0.2° as measured with CuKα radiation;

[0309] or, the hydrochloride represented by Formula 3 or Formula 3′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 7.3±0.2°, 8.5±0.2°, 9.1±0.2°, 11.8±0.2°, 12.6±0.2°, 14.3±0.2°, 18.1±0.2°, 19.6±0.2°, 20.0±0.2°, 21.1±0.2°, 21.9±0.2°, 23.7±0.2°, 25.2±0.2°, 26.1±0.2°, 27.2±0.2° as measured with CuKα radiation;

[0310] or, the hydrochloride represented by Formula 3 or Formula 3′ has an X-ray powder diffraction pattern substantially as shown in FIG. 1 or FIG. 3, as measured with CuKα radiation;

[0311] or, the single crystal of the hydrochloride represented by Formula 3 or Formula 3′, as measured with CuKα radiation, belongs to the triclinic system, space group P1, and has the unit cell parameters: {a=7.04142(7) {acute over (Å)}, b=12.15291(7) {acute over (Å)}, c=18.13188(10) {acute over (Å)}, α=93.2215(5)°, β=95.3039(6)°, γ=91.9554(6)°, V=1541.32(2) {acute over (Å)}.sup.3}.

Technical Solution 4

[0312] The salt of the arylaminopurine derivative according to technical solution 1, wherein the salt is a mesylate represented by Formula 4, Formula 5, or Formula 6:

##STR00045##

[0313] n is 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5;

[0314] preferably, the salt is a mesylate represented by Formula 4′, Formula 5′, or Formula 6′:

##STR00046##

[0315] preferably,

[0316] the mesylate represented by Formula 4 or Formula 4′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 6.8±0.2°, 15.1±0.2°, 16.3±0.2°, 21.0±0.2°, 25.0±0.2° as measured with CuKα radiation;

[0317] or, the mesylate represented by Formula 4 or Formula 4′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 6.8±0.2°, 8.6±0.2°, 10.7±0.2°, 12.6±0.2°, 13.1±0.2°, 13.4±0.2°, 15.1±0.2°, 16.3±0.2°, 17.7±0.2°, 19.0±0.2°, 19.9±0.2°, 21.0±0.2°, 25.0±0.2° as measured with CuKα radiation;

[0318] or, the mesylate represented by Formula 4 or Formula 4′ has an X-ray powder diffraction pattern substantially as shown in FIG. 4, as measured with CuKα radiation;

[0319] or preferably,

[0320] the mesylate represented by Formula 5 or Formula 5′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 6.1±0.2°, 6.4±0.2°, 17.4±0.2°, 18.9±0.2°, 19.3±0.2°, 24.4±0.2°, 26.4±0.2° as measured with CuKα radiation;

[0321] or, the mesylate represented by Formula 5 or Formula 5′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 6.1±0.2°, 6.4±0.2°, 17.5±0.2°, 18.9±0.2°, 19.3±0.2°, 24.4±0.2°, 26.4±0.2° as measured with CuKα radiation;

[0322] or, the mesylate represented by Formula 5 or Formula 5′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 6.1±0.2°, 6.4±0.2°, 11.7±0.2°, 12.4±0.2°, 16.0±0.2°, 16.6±0.2°, 16.9±0.2°, 17.4±0.2°, 18.0±0.2°, 18.9±0.2°, 19.3±0.2°, 19.9±0.2°, 20.2±0.2°, 23.4±0.2°, 24.4±0.2°, 26.4±0.2°, 27.3±0.2° as measured with CuKα radiation;

[0323] or, the mesylate represented by Formula 5 or Formula 5′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 6.1±0.2°, 6.4±0.2°, 11.7±0.2°, 12.4±0.2°, 16.0±0.2°, 16.6±0.2°, 16.9±0.2°, 17.5±0.2°, 18.0±0.2°, 18.9±0.2°, 19.3±0.2°, 19.9±0.2°, 20.2±0.2°, 23.4±0.2°, 24.4±0.2°, 26.4±0.2°, 27.3±0.2° as measured with CuKα radiation;

[0324] or, the mesylate represented by Formula 5 or Formula 5′ has an X-ray powder diffraction pattern substantially as shown in FIG. 5, as measured with CuKα radiation;

[0325] or preferably,

[0326] the mesylate represented by Formula 6 or Formula 6′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 4.9±0.2°, 11.5±0.2°, 14.5±0.2°, 18.5±0.2°, 18.9±0.2° as measured with CuKα radiation;

[0327] or, the mesylate represented by Formula 6 or Formula 6′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 4.9±0.2°, 6.0±0.2°, 9.7±0.2°, 10.5±0.2°, 11.5±0.2°, 12.3±0.2°, 14.5±0.2°, 15.1±0.2°, 16.8±0.2°, 18.5±0.2°, 18.9±0.2°, 21.6±0.2°, 22.0±0.2°, 22.3±0.2°, 22.8±0.2°, 23.4±0.2°, 24.3±0.2°, 25.4±0.2°, 26.7±0.2°, 27.3±0.2° as measured with CuKα radiation;

[0328] or, the mesylate represented by Formula 6 or Formula 6′ has an X-ray powder diffraction pattern substantially as shown in FIG. 6, as measured with CuKα radiation.

Technical Solution 5

[0329] The salt of the arylaminopurine derivative according to technical solution 1, wherein the salt is an L-malate represented by Formula 7:

##STR00047##

[0330] n is 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5;

[0331] preferably, the salt is an L-malate represented by Formula 7′:

##STR00048##

[0332] preferably,

[0333] the L-malate represented by Formula 7 or Formula 7′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 7.0±0.2°, 9.3±0.2°, 17.6±0.2°, 19.7±0.2°, 25.9±0.2° as measured with CuKα radiation;

[0334] or, the L-malate represented by Formula 7 or Formula 7′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 7.0±0.2°, 9.3±0.2°, 12.0±0.2°, 12.9±0.2°, 14.0±0.2°, 16.6±0.2°, 17.6±0.2°, 18.5±0.2°, 19.7±0.2°, 24.2±0.2°, 25.2±0.2°, 25.9±0.2°, 27.5±0.2° as measured with CuKα radiation;

[0335] or, the L-malate represented by Formula 7 or Formula 7′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 7.0±0.2°, 9.3±0.2°, 12.0±0.2°, 12.9±0.2°, 14.0±0.2°, 16.6±0.2°, 17.6±0.2°, 18.5±0.2°, 19.7±0.2°, 23.0±0.2°, 24.2±0.2°, 25.2±0.2°, 25.9±0.2°, 27.5±0.2° as measured with CuKα radiation;

[0336] or, the L-malate represented by Formula 7 or Formula 7′ has an X-ray powder diffraction pattern substantially as shown in FIG. 7, as measured with CuKα radiation.

Technical Solution 6

[0337] The salt of the arylaminopurine derivative according to technical solution 1, wherein the salt is an L-tartrate represented by Formula 8, Formula 9, or Formula 10:

##STR00049##

[0338] n is 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5;

[0339] preferably, the salt is an L-tartrate represented by Formula 8′, Formula 9′, or Formula 10′:

##STR00050##

[0340] preferably,

[0341] the L-tartrate represented by Formula 8 or Formula 8′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 6.9±0.2°, 9.1±0.2°, 17.8±0.2°, 19.4±0.2°, 25.5±0.2° as measured with CuKα radiation;

[0342] or, the L-tartrate represented by Formula 8 or Formula 8′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 6.9±0.2°, 9.1±0.2°, 12.9±0.2°, 13.8±0.2°, 16.5±0.2°, 17.8±0.2°, 19.4±0.2°, 20.1±0.2°, 25.5±0.2°, 26.9±0.2° as measured with CuKα radiation;

[0343] or, the L-tartrate represented by Formula 8 or Formula 8′ has an X-ray powder diffraction pattern substantially as shown in FIG. 8, as measured with CuKα radiation;

[0344] or preferably,

[0345] the L-tartrate represented by Formula 9 or Formula 9′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 8.5±0.2°, 14.8±0.2°, 17.1±0.2°, 18.8±0.2°, 24.6±0.2°, 26.1±0.2° as measured with CuKα radiation;

[0346] or, the L-tartrate represented by Formula 9 or Formula 9′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 8.5±0.2°, 9.8±0.2°, 10.1±0.2°, 11.3±0.2°, 13.7±0.2°, 14.8±0.2°, 15.4±0.2°, 16.3±0.2°, 17.1±0.2°, 17.6±0.2°, 18.8±0.2°, 20.5±0.2°, 22.3±0.2°, 24.6±0.2°, 26.1±0.2° as measured with CuKα radiation;

[0347] or, the L-tartrate represented by Formula 9 or Formula 9′ has an X-ray powder diffraction pattern substantially as shown in FIG. 9, as measured with CuKα radiation;

[0348] or preferably,

[0349] the L-tartrate represented by Formula 10 or Formula 10′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 8.3±0.2°, 8.9±0.2°, 9.5±0.2°, 14.8±0.2°, 17.7±0.2°, 21.0±0.2°, 24.0±0.2° as measured with CuKα radiation;

[0350] or, the L-tartrate represented by Formula 10 or Formula 10′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 7.0±0.2°, 8.3±0.2°, 8.9±0.2°, 9.5±0.2°, 12.5±0.2°, 13.1±0.2°, 14.8±0.2°, 16.0±0.2°, 17.7±0.2°, 18.1±0.2°, 19.2±0.2°, 21.0±0.2°, 23.6±0.2°, 24.0±0.2°, 25.3±0.2°, 26.7±0.2° as measured with CuKα radiation;

[0351] or, the L-tartrate represented by Formula 10 or Formula 10′ has an X-ray powder diffraction pattern substantially as shown in FIG. 10, as measured with CuKα radiation.

Technical Solution 7

[0352] The salt of the arylaminopurine derivative according to technical solution 1, wherein the salt is an oxalate represented by Formula 11, or Formula 12:

##STR00051##

[0353] n is 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5;

[0354] preferably, the salt is an oxalate represented by Formula 11′, or Formula 12′:

##STR00052##

[0355] preferably,

[0356] the oxalate represented by Formula 11 or Formula 11′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 8.1±0.2°, 8.4±0.2°, 9.0±0.2°, 14.1±0.2°, 16.7±0.2°, 25.6±0.2° as measured with CuKα radiation;

[0357] or, the oxalate represented by Formula 11 or Formula 11′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 8.1±0.2°, 8.4±0.2°, 9.0±0.2°, 14.1±0.2°, 14.8±0.2°, 16.7±0.2°, 17.9±0.2°, 18.5±0.2°, 19.6±0.2°, 23.6±0.2°, 25.6±0.2° as measured with CuKα radiation; or, the oxalate represented by Formula 11 or Formula 11′ has an X-ray powder diffraction pattern substantially as shown in FIG. 11, as measured with CuKα radiation;

[0358] or preferably,

[0359] the oxalate represented by Formula 12 or Formula 12′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 7.1±0.2°, 12.2±0.2°, 14.2±0.2°, 16.4±0.2°, 17.7±0.2°, 19.0±0.2°, 24.4±0.2° as measured with CuKα radiation;

[0360] or, the oxalate represented by Formula 12 or Formula 12′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 7.1±0.2°, 8.3±0.2°, 12.2±0.2°, 14.2±0.2°, 16.4±0.2°, 17.7±0.2°, 18.6±0.2°, 19.0±0.2°, 24.4±0.2° as measured with CuKα radiation;

[0361] or, the oxalate represented by Formula 12 or Formula 12′ has an X-ray powder diffraction pattern substantially as shown in FIG. 12, as measured with CuKα radiation.

Technical Solution 8

[0362] The salt of the arylaminopurine derivative according to technical solution 1, wherein the salt is a succinate represented by Formula 13, or Formula 14:

##STR00053##

[0363] n is 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5;

[0364] preferably, the salt is a succinate represented by Formula 13′, or Formula 14′:

##STR00054##

[0365] preferably,

[0366] the succinate represented by Formula 13 or Formula 13′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 7.0±0.2°, 9.1±0.2°, 11.3±0.2°, 16.8±0.2°, 20.4±0.2°, 21.0±0.2°, 22.4±0.2° as measured with CuKα radiation;

[0367] or, the succinate represented by Formula 13 or Formula 13′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 7.0±0.2°, 9.1±0.2°, 18.5±0.2°, 20.4±0.2°, 21.0±0.2°, 22.4±0.2°, 27.1±0.2° as measured with CuKα radiation;

[0368] or, the succinate represented by Formula 13 or Formula 13′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 7.0±0.2°, 9.1±0.2°, 11.3±0.2°, 13.1±0.2°, 13.8±0.2°, 14.4±0.2°, 16.0±0.2°, 16.8±0.2°, 17.7±0.2°, 18.5±0.2°, 20.4±0.2°, 21.0±0.2°, 22.4±0.2°, 24.2±0.2°, 25.9±0.2°, 27.1±0.2° as measured with CuKα radiation;

[0369] or, the succinate represented by Formula 13 or Formula 13′ has an X-ray powder diffraction pattern substantially as shown in FIG. 13, as measured with CuKα radiation;

[0370] or preferably,

[0371] the succinate represented by Formula 14 or Formula 14′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 7.0±0.2°, 9.2±0.2°, 17.6±0.2°, 18.4±0.2°, 19.7±0.2°, 25.8±0.2°, 27.3±0.2° as measured with CuKα radiation;

[0372] or, the succinate represented by Formula 14 or Formula 14′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 7.0±0.2°, 9.2±0.2°, 11.9±0.2°, 16.7±0.2°, 17.6±0.2°, 18.4±0.2°, 19.7±0.2°, 23.0±0.2°, 24.1±0.2°, 25.2±0.2°, 25.8±0.2°, 27.3±0.2° as measured with CuKα radiation;

[0373] or, the succinate represented by Formula 14 or Formula 14′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 7.0±0.2°, 9.2±0.2°, 11.9±0.2°, 16.7±0.2°, 17.6±0.2°, 18.4±0.2°, 19.7±0.2°, 20.3±0.2°, 23.0±0.2°, 24.1±0.2°, 25.2±0.2°, 25.8±0.2°, 27.3±0.2° as measured with CuKα radiation;

[0374] or, the succinate represented by Formula 14 or Formula 14′ has an X-ray powder diffraction pattern substantially as shown in FIG. 14, as measured with CuKα radiation.

Technical Solution 9

[0375] The salt of the arylaminopurine derivative according to technical solution 1, wherein the salt is an acetate represented by Formula 15, or Formula 16:

##STR00055##

[0376] n is 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5;

[0377] preferably, the salt is an acetate represented by Formula 15′, or Formula 16′:

##STR00056##

[0378] preferably,

[0379] the acetate represented by Formula 15 or Formula 15′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 10.9±0.2°, 12.6±0.2°, 15.1±0.2°, 17.8±0.2°, 19.2±0.2°, 19.6±0.2°, 21.0±0.2°, 21.8±0.2°, 22.3±0.2°, 24.6±0.2°, 25.4±0.2° as measured with CuKα radiation;

[0380] or, the acetate represented by Formula 15 or Formula 15′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 6.3±0.2°, 8.9±0.2°, 10.9±0.2°, 11.5±0.2°, 12.2±0.2°, 12.6±0.2°, 15.1±0.2°, 17.8±0.2°, 19.2±0.2°, 19.6±0.2°, 21.0±0.2°, 21.8±0.2°, 22.3±0.2°, 24.6±0.2°, 25.4±0.2° as measured with CuKα radiation;

[0381] or, the acetate represented by Formula 15 or Formula 15′ has an X-ray powder diffraction pattern substantially as shown in FIG. 15, as measured with CuKα radiation;

[0382] or preferably,

[0383] the acetate represented by Formula 16 or Formula 16′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 6.2±0.2°, 12.2±0.2°, 16.1±0.2°, 17.5±0.2°, 23.4±0.2°, 24.8±0.2° or at 2θ values of 6.2±0.2°, 12.2±0.2°, 17.5±0.2°, 21.5±0.2°, 23.4±0.2°, 24.8±0.2° as measured with CuKα radiation;

[0384] or, the acetate represented by Formula 16 or Formula 16′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 6.2±0.2°, 8.1±0.2°, 9.1±0.2°, 12.2±0.2°, 15.0±0.2°, 16.1±0.2°, 17.5±0.2°, 18.2±0.2°, 20.7±0.2°, 21.5±0.2°, 23.4±0.2°, 24.8±0.2°, 28.8±0.2° as measured with CuKα radiation;

[0385] or, the acetate represented by Formula 16 or Formula 16′ has an X-ray powder diffraction pattern substantially as shown in FIG. 16, as measured with CuKα radiation.

Technical Solution 10

[0386] The salt of the arylaminopurine derivative according to technical solution 1, wherein the salt is a sulfate represented by Formula 17, or Formula 18:

##STR00057##

[0387] n is 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5;

[0388] preferably, the salt is a sulfate represented by Formula 17′, or Formula 18′:

##STR00058##

[0389] preferably, the sulfate represented by Formula 17 or Formula 17′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 4.8±0.2°, 7.0±0.2°, 9.5±0.2°, 13.6±0.2°, 15.7±0.2°, 18.6±0.2°, 21.6±0.2°, 25.7±0.2° as measured with CuKα radiation;

[0390] or, the sulfate represented by Formula 17 or Formula 17′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 4.8±0.2°, 7.0±0.2°, 9.2±0.2°, 9.5±0.2°, 13.6±0.2°, 15.7±0.2°, 18.6±0.2°, 21.6±0.2°, 25.7±0.2° as measured with CuKα radiation;

[0391] or, the sulfate represented by Formula 17 or Formula 17′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 4.8±0.2°, 7.0±0.2°, 8.6±0.2°, 9.2±0.2°, 9.5±0.2°, 11.6±0.2°, 12.8±0.2°, 13.6±0.2°, 15.7±0.2°, 17.6±0.2°, 18.6±0.2°, 20.5±0.2°, 21.6±0.2°, 23.8±0.2°, 25.7±0.2° as measured with CuKα radiation;

[0392] or, the sulfate represented by Formula 17 or Formula 17′ has an X-ray powder diffraction pattern substantially as shown in FIG. 17, as measured with CuKα radiation;

[0393] or preferably,

[0394] the sulfate represented by Formula 18 or Formula 18′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 8.6±0.2°, 9.6±0.2°, 15.7±0.2°, 19.3±0.2°, 20.0±0.2°, 21.9±0.2°, 26.6±0.2° as measured with CuKα radiation;

[0395] or, the sulfate represented by Formula 18 or Formula 18′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 8.6±0.2°, 9.6±0.2°, 15.7±0.2°, 17.1±0.2°, 19.3±0.2°, 20.0±0.2°, 26.6±0.2° as measured with CuKα radiation;

[0396] or, the sulfate represented by Formula 18 or Formula 18′ has an X-ray powder diffraction pattern comprising peaks at 2θ values of 8.6±0.2°, 9.6±0.2°, 15.7±0.2°, 16.5±0.2°, 17.1±0.2°, 19.3±0.2°, 20.0±0.2°, 21.9±0.2°, 23.5±0.2°, 24.4±0.2°, 26.6±0.2° as measured with CuKα radiation;

[0397] or, the sulfate represented by Formula 18 or Formula 18′ has an X-ray powder diffraction pattern substantially as shown in FIG. 18, as measured with CuKα radiation.

Technical Solution 11

[0398] A pharmaceutical composition, comprising the salt represented by Formula 2 of the arylaminopurine derivative according to any of technical solutions 1-10.

Technical Solution 12

[0399] Use of the salt represented by Formula 2 of the arylaminopurine derivative according to any of technical solutions 1-10 or the pharmaceutical composition according to technical solution 11 in manufacture of a medicament as the protein kinase inhibitor, wherein the kinase is selected from FLT3, EGFR, Abl, Fyn, Hck, Lck, Lyn, Ret, Yes, VEGFR2, ALK, BTK, c-KIT, c-SRC, FGFR1, KDR, MET or PDGFRα;

[0400] preferably, the medicament as the protein kinase inhibitor is an antitumor drug, the tumor is selected from non-small cell lung cancer, acute myeloid leukemia, chronic myelocytic leukemia, chronic myeloid leukemia, squamous cell carcinoma, mammary cancer, colorectal cancer, liver cancer, stomach cancer, and malignant melanoma, more preferably leukemia or lung cancer, further more preferably acute myeloid leukemia or non-small cell lung cancer, further preferably FLT3 mutation-positive acute myeloid leukemia (such as FLT3-ITD acute myeloid leukemia), Ph-positive chronic myeloid leukemia or non-small cell lung cancer with EGFR activating mutations.

Technical Solution 13

[0401] A method for preparing the salt represented by Formula 2 of the arylaminopurine derivative according to technical solution 1, which comprises a reaction of an arylaminopurine derivative represented by Formula 1 and an acid is performed in the presence of water and an organic solvent to obtain the salt represented by Formula 2 of the arylaminopurine derivative:

##STR00059##

[0402] wherein,

[0403] HA is an acid;

[0404] H.sub.2O is the water of crystallization;

[0405] m is an integer or half-integer from 1 to 4;

[0406] n is an integer or half-integer from 0 to 5.

Technical Solution 14

[0407] The method for preparing the salt of the arylaminopurine derivative according to technical solution 13, wherein the molar ratio of the arylaminopurine derivative represented by Formula 1 to the acid is 1:1 to 1:4, preferably 1:1.2 to 1:3.5;

[0408] the reaction temperature is 0-70° C., preferably 35-45° C.;

[0409] the reaction is performed in the presence of the combination of water and one or more organic solvents selected from alcohols, ethers, esters, ketones, nitriles, and alkanes, preferably in the presence of C.sub.1-C.sub.3 lower alcohol and water, in the presence of a ketone and water, in the presence of a nitrile and water, or the presence of ether and water, and more preferably in the presence of methanol-water, ethanol-water, isopropanol-water, tetrahydrofuran-water, dioxane-water, acetone-water or acetonitrile-water; and the ratio of the use amounts by volume of the organic solvent to water is 1:10 to 10:1, for example, 1:1 to 10:1 or 1:10 to 1:1.

SALT OF ARYLAMINOPURINE DERIVATIVE, PREPARATION METHOD THEREFOR AND USE THEREOF

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Abstract

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