A salt of an aromatic amino purine derivative and its preparation method and application

Abstract

The present invention provides a salt of an aromatic amino purine derivative shown in Formula 2, and a preparation method and application thereof. The salt obtained by the present invention has good crystallinity and significantly improved solubility relative to the free form. The salt and the crystal form preferably have low hygroscopicity and can exist stably, so it is easier to make medicine than the free form of aromatic amino purine derivatives or other salts. (2).

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry, and specifically relates to a salt of an aromatic amino purine derivative and a preparation method and application thereof. Background Art

[0002] Compound 1, chemical name: 9-isopropyl-2-(4-(4-methylpiperazin-1-yl)anilino)-8-(pyridin-3-amino)-9H-purine, is an aromatic amino purine derivative and a novel multi-target protein kinase inhibitor. Its main targets include FLT3, EGFR, Abl, Fyn, Hck, Lck, Lyn, Ret, Yes, etc. Preclinical pharmacological experiments show that it has a good inhibitory effect and good tolerance on a variety of tumors such as leukemia and non-small cell lung cancer, especially acute myeloid leukemia (AML) with positive FLT3 mutations such as FLT3-ITD (internal tandem duplication) and non-small cell lung cancer (NSCLC) with EGFR activation mutations. Its mechanism of action is to exert its anti-tumor effect by inhibiting multiple targets or signaling pathways, especially for AML, it mainly exerts its anti-leukemia effect by inhibiting the FLT3 signaling pathway, and for NSCLC, it mainly exerts its anti-tumor effect by inhibiting the EGFR signaling pathway. It has significant therapeutic effects on human leukemia (MV4-11, K562) and lung cancer (HCC827, PC-9) transplanted tumors in nude mice. Its activity against leukemia is better than that of sunitinib, and its activity against lung cancer is equivalent to that of gefitinib.

[0003]

[0004] WO 2011 / 147066 relates to the aromatic amino purine derivatives, and discloses the preparation method and medical use of the free form of a series of derivatives, but does not describe and prepare the salts of the general formula compounds and specific compounds.

[0005] The inventors have found that the compound of formula 1 is insoluble in water, which seriously affects its drugability. Therefore, it is necessary to improve the structure of the compound of formula 1 to meet the pharmaceutical requirements. Summary of the invention

[0006] In order to solve the above problems, the present inventors have conducted extensive research on the salts of the aromatic amino purine derivatives shown in Formula 1, in order to find a drug form that has good solubility, low hygroscopicity and good stability and meets pharmaceutical requirements.

[0007] Therefore, the present invention provides a salt of an aromatic amino purine derivative shown in Formula 2:

[0008]

[0009] in,

[0010] HA is an acid;

[0011] H2O is water of crystallization;

[0012] m is an integer or half integer of 1-4, that is, m=1, 1.5, 2, 2.5, 3, 3.5 or 4;

[0013] n is an integer or half integer of 0-5, that is, n=0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5.

[0014] Preferably, the acid is selected from: 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.

[0015] In one embodiment of the present invention, the salt of the aromatic amino purine derivative is characterized in that the salt is a hydrochloride salt represented by Formula 3:

[0016]

[0017] n is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5;

[0018] Preferably, the salt is a hydrochloride salt represented by formula 3':

[0019]

[0020] Preferably, the hydrochloride salts represented by Formula 3 and Formula 3' use CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 8.5±0.2°, 11.8±0.2°, 19.6±0.2°, 25.2±0.2°, and 27.2±0.2°; more preferably, the hydrochloride salts represented by Formula 3 and Formula 3' use CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 8.5±0.2°, 1 1.8±0.2°, 12.6±0.2°, 19.6±0.2°, 20.0±0.2°, 23.7±0.2°, 25.2±0.2°, and 27.2±0.2°; further preferably, the hydrochloride represented by Formula 3 and Formula 3' uses CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles is 7.3±0.2°, 8.5±0.2°, 9.0±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°, and 27.2±0.2°. 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° or 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° have characteristic peaks; further preferably, the hydrochloride represented by Formula 3 and Formula 3' uses CuKα radiation, having substantially Figure 1 or Figure 3 The X-ray powder diffraction spectrum is shown.

[0021] Preferably, the single crystal of the hydrochloride represented by Formula 3 and Formula 3' is triclinic when irradiated with CuKα. The space group, whose unit cell parameters are: α=93.2215(5)°, β=95.3039(6)°, γ=91.9554(6)°, }.

[0022] In one embodiment of the present invention, the salt of the aromatic amino purine derivative is a mesylate salt represented by Formula 4, Formula 5, or Formula 6:

[0023]

[0024] n is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5;

[0025] Preferably, the salt is a mesylate salt represented by Formula 4', Formula 5', or Formula 6':

[0026]

[0027] Preferably, the mesylate salts represented by Formula 4 and Formula 4' use CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 6.8±0.2°, 15.1±0.2°, 16.3±0.2°, 21.0±0.2°, and 25.0±0.2°; more preferably, the mesylate salts represented by Formula 4 and Formula 4' use CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 6.8±0.2°, 8.6±0.2°, and 25.0±0.2°. 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° have characteristic peaks; further preferably, the mesylate represented by Formula 4 and Formula 4' uses CuKα radiation, having substantially Figure 4 The X-ray powder diffraction spectrum is shown.

[0028] Or, the mesylate represented by Formula 5 and Formula 5' uses CuKα radiation, and the X-ray powder diffraction expressed in 2θ angle is 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° or 6.1±0.2°, 6.4±0.2°, 17.5±0.2°, 18.9±0.2°, 19. 3±0.2°, 24.4±0.2°, and 26.4±0.2°; preferably, the mesylate represented by Formula 5 and Formula 5' uses CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles is 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° or 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° have characteristic peaks; further preferably, the mesylate represented by Formula 5 and Formula 5' uses CuKα radiation, having substantially Figure 5 The X-ray powder diffraction spectrum is shown.

[0029] Or, the mesylate salts represented by Formula 6 and Formula 6' use CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.9±0.2°, 11.5±0.2°, 14.5±0.2°, 18.5±0.2°, and 18.9±0.2°; preferably, the mesylate salts represented by Formula 6 and Formula 6' use CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 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° have characteristic peaks; further preferably, the methanesulfonate represented by Formula 6 and Formula 6' uses CuKα radiation, having substantially Figure 6 The X-ray powder diffraction spectrum is shown.

[0030] In one embodiment of the present invention, the salt of the aromatic amino purine derivative is an L-malate salt as shown in Formula 7:

[0031]

[0032] n is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5;

[0033] Preferably, the salt is an L-malate salt of formula 7':

[0034]

[0035] Preferably, the L-malate salt represented by Formula 7 and Formula 7' uses CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 7.0±0.2°, 9.3±0.2°, 17.6±0.2°, 19.7±0.2°, and 25.9±0.2°; More preferably, the L-malate salt represented by Formula 7 and Formula 7' uses CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 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° or 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°; further preferably, the L-malate represented by Formula 7 and Formula 7' uses CuKα radiation and has a characteristic peak substantially as follows Figure 7 The X-ray powder diffraction spectrum is shown.

[0036] In one embodiment of the present invention, the salt of the aromatic amino purine derivative is an L-tartrate salt represented by Formula 8, Formula 9, or Formula 10:

[0037]

[0038] n is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5;

[0039] Preferably, the salt is an L-tartrate represented by Formula 8', Formula 9', or Formula 10':

[0040]

[0041] Preferably, the L-tartrate salts represented by Formula 8 and Formula 8' use CuKα radiation, and the X-ray powder diffraction represented by 2θ angles has characteristic peaks at 6.9±0.2°, 9.1±0.2°, 17.8±0.2°, 19.4±0.2°, and 25.5±0.2°; More preferably, the L-tartrate salts represented by Formula 8 and Formula 8' use CuKα radiation, and the X-ray powder diffraction represented by 2θ angles has characteristic peaks at 6.9±0.2°, 9.1±0.2°, 17.8±0.2°, 19.4±0.2°, and 25.5±0.2°. The radiation has characteristic peaks at 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°, and 26.9±0.2°; further preferably, the L-tartrate represented by Formula 8 and Formula 8' uses CuKα radiation and has substantially Figure 8 The X-ray powder diffraction spectrum is shown.

[0042] Or, the L-tartrate salts represented by Formula 9 and Formula 9' use CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 8.5±0.2°, 14.8±0.2°, 17.1±0.2°, 18.8±0.2°, 24.6±0.2°, and 26.1±0.2°; the L-tartrate salts represented by Formula 9 and Formula 9' use CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 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° have characteristic peaks; further preferably, the L-tartrate represented by Formula 9 and Formula 9' uses CuKα radiation, having substantially Fig. 9 The X-ray powder diffraction spectrum is shown.

[0043] Or, the L-tartrate salt represented by Formula 10 and Formula 10' uses CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 8.3±0.2°, 8.9±0.2°, 9.5±0.2°, 14.8±0.2°, 17.7±0.2°, 21.0±0.2°, and 24.0±0.2°; preferably, the L-tartrate salt represented by Formula 10 and Formula 10' uses CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 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° have characteristic peaks; further preferably, the L-tartrate represented by Formula 10 and Formula 10' uses CuKα radiation, having substantially Fig.10 The X-ray powder diffraction spectrum is shown.

[0044] In one embodiment of the present invention, the salt of the aromatic amino purine derivative is an oxalate represented by Formula 11 or Formula 12:

[0045]

[0046] n is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5;

[0047] Preferably, the salt is an oxalate represented by formula 11' or formula 12':

[0048]

[0049] Preferably, the oxalate represented by Formula 11 and Formula 11' uses CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 8.1±0.2°, 8.4±0.2°, 9.0±0.2°, 14.1±0.2°, 16.7±0.2°, and 25.6±0.2°; Preferably, the oxalate represented by Formula 11 and Formula 11' uses CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 8.1±0.2°, 8.4±0.2°, 9.0±0.2°, 14.1±0.2°, 16.7±0.2°, and 25.6±0.2°. There are characteristic peaks at 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°, and 25.6±0.2°; further preferably, the oxalates represented by Formula 11 and Formula 11' are irradiated with CuKα and have a peak substantially as follows Fig.11The X-ray powder diffraction spectrum is shown.

[0050] Or, the oxalates represented by Formula 12 and Formula 12' are radiated with CuKα, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 7.1±0.2°, 12.2±0.2°, 14.2±0.2°, 16.4±0.2°, 17.7±0.2°, 19.0±0.2°, and 24.4±0.2°; preferably, the oxalates represented by Formula 12 and Formula 12' are radiated with CuKα, The X-ray powder diffraction represented by 2θ angle has characteristic peaks at 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°, and 24.4±0.2°; further preferably, the oxalate represented by Formula 12 and Formula 12' uses CuKα radiation and has substantially Fig.12 The X-ray powder diffraction spectrum is shown.

[0051] In one embodiment of the present invention, the salt of the aromatic amino purine derivative is a succinate salt represented by Formula 13 or Formula 14:

[0052]

[0053] n is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5;

[0054] Preferably, the salt is a succinate salt represented by formula 13' or formula 14':

[0055]

[0056] Preferably, the succinates represented by Formula 13 and Formula 13' use CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 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° or 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°; Preferably, the succinates represented by Formula 13 and Formula 13' use CuKα radiation, The X-ray powder diffraction represented by 2θ angle has characteristic peaks at 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°, and 27.1±0.2°; further preferably, the succinate represented by Formula 13 and Formula 13' uses CuKα radiation and has substantially Fig.13 The X-ray powder diffraction spectrum is shown.

[0057] Or, the succinates represented by Formula 14 and Formula 14' use CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles is 7.0±0.2°, 9.2±0.2°, 17.6±0.2°, 18.4±0.2°, 19.7±0.2°, 25.8±0.2°, and 27.3±0.2°. Preferably, the succinates represented by Formula 14 and Formula 14' use CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles is 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°. .2°, 23.0±0.2°, 24.1±0.2°, 25.2±0.2°, 25.8±0.2°, 27.3±0.2° or 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° have characteristic peaks; further preferably, the succinate represented by Formula 14 and Formula 14' uses CuKα radiation and has a characteristic peak substantially as follows Fig.14 The X-ray powder diffraction spectrum is shown.

[0058] In one embodiment of the present invention, the salt of the aromatic amino purine derivative is an acetate salt represented by Formula 15 or Formula 16:

[0059]

[0060] n is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5;

[0061] Preferably, the salt is an acetate represented by Formula 15' or Formula 16':

[0062]

[0063] Preferably, the acetates represented by Formula 15 and Formula 15' use CuKα radiation, and the X-ray powder diffraction represented by 2θ angles has characteristic peaks at 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°, and 25.4±0.2°; Preferably, the acetates represented by Formula 15 and Formula 15' use CuKα radiation, and the X-ray powder diffraction represented by 2θ angles has characteristic peaks at 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°, and 25.4±0.2°. X-ray powder diffraction has characteristic peaks at 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°, and 25.4±0.2°; further preferably, the acetates represented by Formula 15 and Formula 15' use CuKα radiation and have a substantially Fig.15 The X-ray powder diffraction spectrum is shown.

[0064] Or, the acetates represented by Formula 16 and Formula 16' use CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 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 6.2±0.2°, 12.2±0.2°, 17.5±0.2°, 21.5±0.2°, 23.4±0.2°, 24.8±0.2°; preferably, the acetates represented by Formula 16 and Formula 16' use Cu Kα radiation, X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 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°, and 28.8±0.2°; further preferably, the acetates represented by Formula 16 and Formula 16′ use CuKα radiation and have a characteristic peak substantially as follows: Fig.16 The X-ray powder diffraction spectrum is shown.

[0065] In one embodiment of the present invention, the salt of the aromatic amino purine derivative is a sulfate salt represented by Formula 17 or Formula 18:

[0066]

[0067] n is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5;

[0068] Preferably, the salt is a sulfate represented by Formula 17' or Formula 18':

[0069]

[0070] Preferably, the sulfates represented by Formula 17 and Formula 17' use CuKα radiation, and the X-ray powder diffraction represented by 2θ angle has characteristic peaks at 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° or 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°; Preferably, Formula 17 The sulfates represented by Formula 17' use CuKα radiation, and the X-ray powder diffraction represented by 2θ angles has characteristic peaks at 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°, and 25.7±0.2°; further preferably, the sulfates represented by Formula 17 and Formula 17' use CuKα radiation, and have characteristic peaks substantially as shown in Figure 17. Fig.17 The X-ray powder diffraction spectrum is shown.

[0071] Or, the sulfates represented by Formula 18 and Formula 18' have characteristic peaks at 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° or 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° when using CuKα radiation and expressed in 2θ angle; The sulfates represented by Formula 18 and Formula 18' use CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 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°, and 26.6±0.2°; further preferably, the sulfates represented by Formula 18 and Formula 18' use CuKα radiation, and have a characteristic peak substantially as shown in Figure 17. Fig.18 The X-ray powder diffraction spectrum is shown.

[0072] In another aspect, the present invention provides a pharmaceutical composition comprising a salt of the aromatic amino purine derivative represented by the aforementioned formula 2.

[0073] In another aspect, the present invention provides a pharmaceutical composition comprising a salt of an aromatic amino purine derivative represented by the aforementioned formula 2, and a pharmaceutically acceptable excipient.

[0074] On the other hand, the present invention provides a pharmaceutical composition comprising a pharmaceutically effective amount of a salt of an arylaminopurine derivative represented by the aforementioned formula 2, and a pharmaceutically acceptable excipient. The pharmaceutically effective amount may be 0.1-99.9wt%, such as 1-90wt%, 5-80wt%, 5-65wt%, 5-55wt%, 5-45wt% or 5-40wt%, based on the total weight of the pharmaceutical composition.

[0075] In the context of the present application, the term "pharmaceutically acceptable excipients" includes: solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, adhesives, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, antioxidants, chelating agents, penetration enhancers, pH regulators, buffers, plasticizers, surfactants, foaming agents, defoamers, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculating agents, filter aids, release retardants, etc. Those skilled in the art can select specific pharmaceutically acceptable excipients according to actual needs. The knowledge of the excipients is well known to those skilled in the art, for example, reference can be made to "Pharmaceutics" (edited by Cui Fude, 5th edition, People's Medical Publishing House, 2003).

[0076] On the other hand, the present invention provides a salt or pharmaceutical composition of an aromatic amino purine derivative represented by the aforementioned formula 2 for inhibiting the activity of one or more of FLT3, EGFR, Abl, Fyn, Hck, Lck, Lyn, Ret, Yes, VEGFR2, ALK, BTK, c-KIT, c-SRC, FGFR1, KDR, MET and PDGFRα kinases.

[0077] In another aspect, the present invention provides a salt or pharmaceutical composition of an aromatic amino purine derivative represented by the aforementioned formula 2 for use in preparing a protein kinase inhibitor drug, 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, for example, the kinase is selected from: FLT3, EGFR, Abl, Fyn, Hck, Lck, Lyn, Ret or Yes;

[0078] Preferably, the protein kinase inhibitor drug is an anti-tumor drug, and the tumor is preferably leukemia or lung cancer, more preferably acute myeloid leukemia such as FLT3 mutation-positive acute myeloid leukemia (further such as FLT3-ITD acute myeloid leukemia), chronic myeloid leukemia (such as Ph-positive chronic myeloid leukemia), or non-small cell lung cancer (such as non-small cell lung cancer with EGFR activating mutation).

[0079] On the other hand, the present invention provides a use of a salt or a pharmaceutical composition of an aromatic amino purine derivative represented by the aforementioned formula 2 in the preparation of a medicament for treating or preventing a disease; preferably, the disease is caused by one or more of FLT3, EGFR, Abl, Fyn, Hck, Lck, Lyn, Ret, Yes, VEGFR2, ALK, BTK, c-KIT, c-SRC, FGFR1, KDR, MET and PDGFRα kinases; more preferably, the disease is selected from non-small cell lung cancer, acute myeloid leukemia, chronic myeloid leukemia, chronic myeloid leukemia, epidermal squamous cell carcinoma, breast cancer, colorectal cancer, liver cancer, gastric cancer, and malignant melanoma; further preferably, the disease is selected from human non-small cell lung cancer, human acute myeloid leukemia, human chronic myeloid leukemia, human chronic myeloid leukemia, human epidermal squamous cell carcinoma, human breast cancer, human colorectal cancer, human liver cancer, human gastric cancer, and human malignant melanoma.

[0080] In another aspect, the present invention provides a use of a salt or a pharmaceutical composition of an aromatic amino purine derivative represented by the aforementioned formula 2 in the preparation of a medicament for treating or preventing acute myeloid leukemia; preferably, the acute myeloid leukemia is selected from relapsed and / or refractory acute myeloid leukemia, or the acute myeloid leukemia is selected from acute myeloid leukemia with FLT3-ITD mutation and / or TKD mutation, relapsed and / or refractory acute myeloid leukemia that has failed treatment with type II FLT3 inhibitors (e.g., sorafenib), or acute myeloid leukemia with both DEK-CAN positivity and FLT3-ITD mutation; more preferably, the acute myeloid leukemia is acute myeloid leukemia with FLT3-ITD high mutation; and / or the poor prognostic factors of the acute myeloid leukemia are 0 to 2; and / or the FAB classification of the acute myeloid leukemia is M2, M4, or M5, preferably M5. Furthermore, the aforementioned use in the preparation of drugs for the treatment or prevention of acute myeloid leukemia is described in detail in patent application PCT / CN2020 / 127449, and the disclosure of patent application PCT / CN2020 / 127449 is incorporated herein as disclosed in the present application.

[0081] On the other hand, the present invention provides a pharmaceutical composition for treating or preventing a disease, comprising a pharmaceutically effective amount of a salt of an aromatic amino purine derivative represented by the aforementioned formula 2, and a pharmaceutically acceptable excipient; preferably, the disease is caused by one or more of FLT3, EGFR, Abl, Fyn, Hck, Lck, Lyn, Ret, Yes, VEGFR2, ALK, BTK, c-KIT, c-SRC, FGFR1, KDR, MET and PDGFRα kinases; more preferably, the disease is selected from non-small cell lung cancer, acute myeloid leukemia, chronic myeloid leukemia, chronic myeloid leukemia, epidermal squamous cell carcinoma, breast cancer, colorectal cancer, liver cancer, gastric cancer, and malignant melanoma; further preferably, the disease is selected from human non-small cell lung cancer, human acute myeloid leukemia, human chronic myeloid leukemia, human chronic myeloid leukemia, human epidermal squamous cell carcinoma, human breast cancer, human colorectal cancer, human liver cancer, human gastric cancer, and human malignant melanoma. The pharmaceutically effective amount may be 0.1-99.9 wt%, such as 1-90 wt%, 5-80 wt%, 5-65 wt%, 5-55 wt%, 5-45 wt% or 5-40 wt%, based on the total weight of the pharmaceutical composition.

[0082] In another aspect, the present invention provides a method for preparing a salt of an arylamino purine derivative shown in Formula 2, comprising reacting an arylamino purine derivative shown in Formula 1 with an acid in the presence of water and an organic solvent to obtain a salt of an arylamino purine derivative shown in Formula 2:

[0083]

[0084] in,

[0085] HA is an acid;

[0086] H2O is water of crystallization;

[0087] m is an integer or half integer from 1 to 4;

[0088] n is an integer or half integer of 0-5.

[0089] According to the preparation method of the present invention, the molar ratio of the aromatic amino purine derivative represented by Formula 1 to the acid is 1:1 to 1:4, preferably 1:1.2 to 1:3.5.

[0090] According to the preparation method of the present invention, the molar ratio of the aromatic amino purine derivative represented by Formula 1 to water is not greater than 1:1 (ie, 1:1 to 1:∞), preferably 1:4 to 1:200.

[0091] According to the preparation method of the present invention, the reaction temperature is 0-70°C, preferably 35-45°C.

[0092] According to the preparation method of the present invention, the reaction time is 0.5-10 h, preferably 0.5-5 h.

[0093] According to the preparation method of the present invention, the reaction is carried out in the presence of water and one or more combinations of organic solvents selected from alcohols, ethers, esters, ketones, nitriles, and alkanes, preferably in the presence of C1-C3 lower alcohols and water, in the presence of ketones and water, in the presence of nitriles and water, or in the presence of ethers and water, more preferably in the presence of methanol-water, ethanol-water, isopropanol-water, tetrahydrofuran-water, dioxane-water, acetone-water or acetonitrile-water; the volume ratio 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, and the organic solvent is the aforementioned solvent other than water.

[0094] According to the preparation method of the present invention, after the reaction is completed, the temperature is lowered to 0-30°C, and the mixture is allowed to stand for crystallization for 0.5-24 hours, and the solid is separated and dried to obtain the salt of the aromatic amino purine derivative shown in Formula 2. Preferably, the crystallization temperature is 5-15°C and the crystallization time is 1-10 hours.

[0095] According to the preparation method of the present invention, the separation step comprises separating the obtained salt of the aromatic amino purine derivative represented by formula 2 from the crystal solution by a suitable method such as filtration, suction filtration, centrifugation, etc.

[0096] According to the preparation method of the present invention, the drying method can adopt any suitable known method, preferably reduced pressure (vacuum) drying. Specific drying conditions are, for example, preferably 35 to 70°C, more preferably 40 to 65°C; preferably vacuum degree> 0.090Mpa; preferably 5 to 50h, more preferably 5 to 10h for the drying time. Regardless of the drying method, it is preferred that the residual solvent in the obtained product meets the quality standards.

[0097] In another aspect, the present invention provides a method for preparing a salt of an arylamino purine derivative shown in Formula 2, comprising reacting an arylamino purine derivative shown in Formula 1 with an acid in the presence of water and an organic solvent to obtain a salt of an arylamino purine derivative shown in Formula 2:

[0098]

[0099] in,

[0100] HA is an acid;

[0101] H2O is water of crystallization;

[0102] m is an integer or half integer from 1 to 4;

[0103] n is an integer or half integer from 0 to 5;

[0104] in:

[0105] The molar ratio of the arylamino purine derivative represented by Formula 1 to the acid is 1:1 to 1:4, preferably 1:1.2 to 1:3.5;

[0106] The molar ratio of the aromatic amino purine derivative represented by Formula 1 to water is not greater than 1:1, preferably 1:4 to 1:200;

[0107] The reaction temperature is 0-70°C, preferably 35-45°C;

[0108] The reaction time is 0.5-10h, preferably 0.5-5h;

[0109] The reaction is carried out in the presence of water and one or more combinations of organic solvents selected from alcohols, ethers, esters, ketones, nitriles, and alkanes, preferably in the presence of C1-C3 lower alcohols and water, in the presence of ketones and water, in the presence of nitriles and water, or in the presence of ethers and water, more preferably in the presence of methanol-water, ethanol-water, isopropanol-water, tetrahydrofuran-water, dioxane-water, acetone-water or acetonitrile-water; the volume ratio 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, and the organic solvent is the aforementioned solvent other than water;

[0110] After the reaction is completed, the temperature is lowered to 0-30°C, preferably 5-15°C, and crystallization is carried out for 0.5-24h, preferably 1-10h. The solid is separated (for example, by filtration such as suction filtration, centrifugation, etc.), and optionally dried (for example, the drying temperature is 35-70°C, preferably 40-65°C; the drying pressure is vacuum degree>0.090MPa; the drying time is 5-50h, preferably 5-10h), to obtain the salt of the aromatic amino purine derivative shown in Formula 2.

[0111] In a preferred method for preparing the salt of the aromatic amino purine derivative shown in formula 2, the aromatic amino purine derivative shown in formula 1 and purified water (molar multiple of 4-200), and an appropriate amount of organic solvent (any one of methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, acetone or acetonitrile) are added to a reactor, stirred and heated to 35-45°C, and then an acid (molar multiple of 1.2-3.5) is added to the reactor. After the acid is added, an appropriate amount of organic solvent is added, the temperature is maintained at 35-45°C, and the reaction is continued for 0.5-5h, and then stirred and cooled to 5-15°C for crystallization for 1-10h, filtered or centrifuged to obtain the salt of the aromatic amino purine derivative shown in formula 2.

[0112] In one embodiment of the present invention, the salt of the aromatic amino purine derivative is characterized in that the salt is a hydrochloride represented by formula 3':

[0113]

[0114] Preferably, the hydrochloride represented by Formula 3' uses CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles is 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. Characteristic peaks are present at 1±0.2°, 27.2±0.2° or 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°, and 27.2±0.2°;

[0115] The hydrochloride shown in formula 3' is prepared by the following method:

[0116] (1) reacting the arylamino purine derivative represented by formula 1 with hydrochloric acid in the presence of water and an organic solvent,

[0117]

[0118] The molar ratio of the arylamino purine derivative represented by Formula 1 to hydrochloric acid is 1:1 to 1:4, preferably 1:1.2 to 1:3.5;

[0119] Preferably, the organic solvent is selected from acetone, isopropanol, tetrahydrofuran and acetonitrile, and the volume ratio is 1:10 to 10:1, such as 1:1 to 10:1 or 1:10 to 1:1;

[0120] The molar ratio of the aromatic amino purine derivative represented by Formula 1 to water is not greater than 1:1 (i.e., 1:1 to 1:∞), preferably 1:4 to 1:200;

[0121] The reaction temperature is 35-45°C;

[0122] The reaction time is 0.5-10h, preferably 0.5-5h;

[0123] (2) After the reaction is completed, the temperature is lowered to 5-15° C., crystallization is carried out for 0.5 to 24 hours, and the solid is separated (by filtration such as suction filtration, centrifugation, etc.), washed, and dried to obtain the hydrochloride represented by formula 3′.

[0124] The aromatic amino purine derivatives shown in Formula 1 can be prepared by referring to the methods disclosed in the prior art, such as the method described in patent document WO2011 / 147066, the contents of which are incorporated herein by reference.

[0125] Beneficial Effects

[0126] The present invention provides salts of arylamino purine derivatives shown in Formula 2, especially hydrochloride, methanesulfonate, L-malate, L-tartrate, oxalate, succinate, acetate and sulfate. These salts can be prepared into crystal forms, and the solubility is significantly improved compared with the arylamino purine derivatives shown in Formula 1. Preferably, the salts and crystal forms have low hygroscopicity and can exist stably, so they are easier to make into medicines than the arylamino purine derivatives shown in Formula 1 or other salts. BRIEF DESCRIPTION OF THE DRAWINGS

[0127] Figure 1 This is the XRPD spectrum of the hydrochloride of the aromatic amino purine derivative obtained in Example 1.

[0128] Figure 2 This is a single crystal micrograph of the hydrochloride salt of the aromatic amino purine derivative obtained in Example 2.

[0129] Figure 3 This is the XRPD spectrum of the hydrochloride single crystal of the aromatic amino purine derivative obtained in Example 2.

[0130] Figure 4 This is the XRPD spectrum of the mesylate of the aromatic amino purine derivative obtained in Example 3.

[0131] Figure 5 This is the XRPD spectrum of the mesylate of the aromatic amino purine derivative obtained in Example 4.

[0132] Figure 6 This is the XRPD spectrum of the mesylate of the aromatic amino purine derivative obtained in Example 5.

[0133] Figure 7 This is the XRPD spectrum of the L-malate of the aromatic amino purine derivative obtained in Example 6.

[0134] Figure 8 This is the XRPD spectrum of the L-tartrate salt of the aromatic amino purine derivative obtained in Example 7.

[0135] Fig. 9 This is the XRPD spectrum of the L-tartrate salt of the aromatic amino purine derivative obtained in Example 8.

[0136] Fig.10 This is the XRPD spectrum of the L-tartrate salt of the aromatic amino purine derivative obtained in Example 9.

[0137] Fig.11This is the XRPD spectrum of the oxalate of the aromatic amino purine derivative obtained in Example 10.

[0138] Fig.12 This is the XRPD spectrum of the oxalate of the aromatic amino purine derivative obtained in Example 11.

[0139] Fig.13 This is the XRPD spectrum of the succinate of the aromatic amino purine derivative obtained in Example 12.

[0140] Fig.14 This is the XRPD spectrum of the succinate of the aromatic amino purine derivative obtained in Example 13.

[0141] Fig.15 This is the XRPD spectrum of the acetate salt of the aromatic amino purine derivative obtained in Example 14.

[0142] Fig.16 This is the XRPD spectrum of the acetate salt of the aromatic amino purine derivative obtained in Example 15.

[0143] Fig.17 This is the XRPD spectrum of the sulfate salt of the aromatic amino purine derivative obtained in Example 16.

[0144] Fig.18 This is the XRPD spectrum of the sulfate salt of the aromatic amino purine derivative obtained in Example 17.

[0145] Fig.19 This is a differential thermal scanning-thermogravimetric analysis (DSC-TGA) chart of the hydrochloride of the aromatic amino purine derivative obtained in Example 1.

[0146] Fig. 20 The differential scanning calorimetry (DSC) diagram of the mesylate of the aromatic amino purine derivative obtained in Example 3 is shown in FIG.

[0147] Fig.21 This is the thermogravimetric analysis (TGA) diagram of the mesylate of the aromatic amino purine derivative obtained in Example 3.

[0148] Fig. 22 The differential scanning calorimetry (DSC) diagram of the mesylate of the aromatic amino purine derivative obtained in Example 4 is shown in FIG.

[0149] Fig.23 This is the thermogravimetric analysis (TGA) diagram of the mesylate of the aromatic amino purine derivative obtained in Example 4.

[0150] Fig.24 This is the differential scanning calorimetry (DSC) diagram of the mesylate of the aromatic amino purine derivative obtained in Example 5.

[0151] Fig.25This is the thermogravimetric analysis (TGA) chart of the mesylate of the aromatic amino purine derivative obtained in Example 5.

[0152] Fig.26 This is a differential thermal scanning-thermogravimetric analysis (DSC-TGA) chart of the L-malate of the aromatic amino purine derivative obtained in Example 6.

[0153] Fig. 27 This is the differential thermal scanning-thermogravimetric analysis (DSC-TGA) diagram of the L-tartrate salt of the aromatic amino purine derivative obtained in Example 7.

[0154] Fig.28 This is the differential thermal scanning-thermogravimetric analysis (DSC-TGA) diagram of the L-tartrate salt of the aromatic amino purine derivative obtained in Example 8.

[0155] Fig.29 This is the differential thermal analysis-thermogravimetric analysis (DSC-TGA) chart of the L-tartrate salt of the aromatic amino purine derivative obtained in Example 9.

[0156] Fig.30 This is the differential thermal scanning-thermogravimetric analysis (DSC-TGA) chart of the oxalate of the aromatic amino purine derivative obtained in Example 10.

[0157] Fig.31 This is the differential thermal scanning-thermogravimetric analysis (DSC-TGA) chart of the oxalate of the aromatic amino purine derivative obtained in Example 11.

[0158] Fig.32 This is the differential scanning calorimetry (DSC) diagram of the succinate of the aromatic amino purine derivative obtained in Example 12.

[0159] Fig.33 This is the thermogravimetric analysis (TGA) chart of the succinate of the aromatic amino purine derivative obtained in Example 12.

[0160] Fig.34 This is the differential scanning calorimetry (DSC) diagram of the succinate of the aromatic amino purine derivative obtained in Example 13.

[0161] Fig.35 This is the thermogravimetric analysis (TGA) chart of the succinate of the aromatic amino purine derivative obtained in Example 13.

[0162] Fig.36 This is the differential scanning calorimetry (DSC) diagram of the acetate salt of the aromatic amino purine derivative obtained in Example 14.

[0163] Fig.37 This is the thermogravimetric analysis (TGA) chart of the acetate salt of the aromatic amino purine derivative obtained in Example 14.

[0164] Fig.38This is the differential scanning calorimetry (DSC) diagram of the acetic acid of the aromatic amino purine derivative obtained in Example 15.

[0165] Fig.39 This is the thermogravimetric analysis (TGA) chart of the acetate salt of the aromatic amino purine derivative obtained in Example 15.

[0166] Fig.40 This is the differential thermal scanning-thermogravimetric analysis (DSC-TGA) chart of the sulfate salt of the aromatic amino purine derivative obtained in Example 16.

[0167] Fig.41 This is the differential thermal scanning-thermogravimetric analysis (DSC-TGA) chart of the sulfate salt of the aromatic amino purine derivative obtained in Example 17.

[0168] Fig.42 This is the differential thermal scanning-thermogravimetric analysis (DSC-TGA) diagram of the aromatic amino purine derivative obtained in Preparation Example 1. DETAILED DESCRIPTION

[0169] The technical scheme of the present invention will be further described in detail below in conjunction with specific embodiments. The following embodiments are only exemplary to illustrate and explain the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.

[0170] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0171] In the following examples, the analysis and detection conditions are as follows:

[0172] 1. Moisture

[0173] Testing instrument: Karl Fischer titrator / 915KF Ti-Touch

[0174] Test method: After the instrument is balanced, take an appropriate amount of the test sample (about 200 mg), accurately weigh it, add it to the titration cup, use anhydrous methanol as the solvent, and directly measure it with the water titration solution. Each test sample is measured twice and the average value is taken.

[0175] 2. Solubility

[0176] Testing instrument: UV spectrophotometer / Evolution 300

[0177] Test method:

[0178] Select pH 1.2, pH 4.5, pH 6.8 and water as solvents. The solvent preparation method is as follows:

[0179] (1) pH 1.2 hydrochloric acid solution: add 7.65 ml of hydrochloric acid to 1000 ml of water and shake well.

[0180] (2) pH 4.5 phosphate buffer: Take 6.8 g of potassium dihydrogen phosphate, dilute to 1000 ml with water, and shake well.

[0181] (3) pH 6.8 phosphate buffer: Take 6.8 g of potassium dihydrogen phosphate and 0.896 g of sodium hydroxide, dilute to 1000 ml with water, and shake well.

[0182] (4) Water: Purified water

[0183] Sample preparation:

[0184] Take a stoppered test tube, accurately add 10 ml of dissolution medium of each pH value, add excess raw material drug until a supersaturated solution is formed, record the amount added, shake well, seal, and shake in a shaker for 24 hours. Take out 2 ml of solution at different time points, centrifuge, take the supernatant, filter, take the filtrate, and set aside.

[0185] Take the saturated solutions in the above different solvents, add solvent to dilute a certain volume, and measure the absorbance at a wavelength of 287nm.

[0186] Preparation of reference solution: Take an appropriate amount of reference compound of formula 1, weigh accurately, add solvent to dissolve and dilute to make a solution containing about 10 μg of compound of formula 1 per 1 ml, measure the absorbance at a wavelength of 287 nm, and calculate the result.

[0187] 3. Moisture absorption

[0188] Testing instrument: XPE105DR

[0189] Test method:

[0190] (1) Take a dry stoppered glass weighing bottle and place it in a suitable 25℃±1℃ constant temperature desiccator (with ammonium chloride or ammonium sulfate saturated solution placed at the bottom) or an artificial climate box (set temperature at 25℃±1℃, relative humidity at 80%±2%) one day before the test, and accurately weigh the weight (m1).

[0191] (2) Take an appropriate amount of the test sample and spread it evenly in the above-mentioned weighing bottle. The thickness of the test sample is generally about 1 mm. Accurately weigh the weight (m2).

[0192] (3) Open the weighing bottle and place it with the bottle cap under the above constant temperature and humidity conditions for 24 hours.

[0193] (4) Cover the weighing bottle and accurately weigh the weight (m3).

[0194] Weight gain percentage = (m3-m2) / (m2-m1)×100%

[0195] (5) Description of hygroscopic characteristics and definition of hygroscopic weight gain:

[0196] Deliquescent: Absorbs sufficient water to form a liquid.

[0197] Highly hygroscopic: weight gain due to moisture absorption is not less than 15%.

[0198] Hygroscopic: Weight gain due to moisture absorption is less than 15% but not less than 2%.

[0199] Slightly hygroscopic: weight gain due to moisture absorption is less than 2% but not less than 0.2%.

[0200] No or almost no hygroscopicity: moisture gain is less than 0.2%.

[0201] 4. Content

[0202] Detection instrument: High performance liquid chromatograph / Waters e2695-2489

[0203] Analytical methods:

[0204] Octadecylsilane bonded silica gel was used as filler (pH value should be greater than 10.0), 20mmol / L disodium hydrogen phosphate solution (adjust pH value to 10.0 with sodium hydroxide)-acetonitrile (65:35) was used as mobile phase; detection wavelength was 287nm, column temperature was 30℃. The number of theoretical plates should be no less than 3000.

[0205] Determination method: Take about 20 mg of sample, weigh accurately, place in a 100 ml volumetric flask, add diluent (50% methanol water) to dissolve and dilute to scale, shake well, accurately measure 10 μl, inject into liquid chromatograph, record chromatogram; take appropriate amount of reference substance, determine in the same way. Calculate by peak area according to external standard method.

[0206] 5. X-Ray Powder Diffraction (XRPD)

[0207] (1) Examples 1 and 2

[0208] Testing instrument: PANalytical Empyrean powder X-ray diffractometer

[0209] Test conditions:

[0210] Light tube type: Cu target, metal ceramic X-ray tube;

[0211] X-ray wavelength: CuKα, 1.540598, 1.544426, Kα2 / Kα1 intensity ratio: 0.5;

[0212] Voltage and current: 45kV, 40mA;

[0213] Scanning range: 3-40°2θ;

[0214] Total scanning time: about 5 minutes.

[0215] (2) Example 3-17

[0216] Testing instrument: BRUKER D2 PHASER powder X-ray diffractometer

[0217] Test conditions:

[0218] Light tube type: Cu target, ceramic X-ray tube;

[0219] X-ray wavelength: CuKα, 1.540598, 1.544426, Kα2 / Kα1 intensity ratio: 0.5;

[0220] Voltage and current: 30kV, 10mA;

[0221] Scanning range: 4-40°2θ;

[0222] Total scanning time: 200.9S.

[0223] 6. Differential thermal analysis-thermogravimetric analysis (DSC-TGA)

[0224] Testing instrument: NETZSCH STA 449F3

[0225] Test conditions:

[0226] Temperature range: 20℃-350℃;

[0227] Heating rate: 10.0 (K / min);

[0228] Sample holder / thermocouple: DSC / TG Cp S / S

[0229] Crucible: DSC / TG pan Al2O3

[0230] Atmosphere: N2, 20.0ml / min / N2, 50.0ml / min

[0231] Calibration / measurement range: 020 / 5000μV

[0232] 7. Differential scanning calorimetry (DSC)

[0233] Testing instrument: NETZSCH DSC 214 Polyma

[0234] Test conditions:

[0235] Temperature range: 20℃-250℃;

[0236] Heating rate: 5.0 (K / min);

[0237] Sample holder / thermocouple: DSC 214 Corona sensor / E

[0238] Crucible: Pan AI, pierced lid

[0239] Atmosphere: N2, 40.0ml / min / N2, 60.0ml / min

[0240] Calibration / measurement range: 000 / 5000μV

[0241] 8. Thermogravimetric Analysis (TGA)

[0242] Testing instruments: METTLER and SDT Q600

[0243] Analytical methods:

[0244] Temperature range: 20℃-250℃;

[0245] Heating rate: 5.0 (K / min);

[0246] 9. Nuclear Magnetic Resonance spectroscopy (NMRS)

[0247] Testing instrument: AVⅢ BRUKER 600 superconducting nuclear magnetic resonance spectrometer

[0248] Content and test solvent: 1 H-NMR, the test solvent was H2D.

[0249] 10. Single crystal

[0250] Single crystal diffraction data were obtained using Rigaka XtaLAB Synergy-R (Micro-Max007HF Cu mode, CuKαλ=1.54184) The single crystal diffractometer was Hypix 6000HE detector) and collected at 120.00(10) K. The micrographs of single crystal samples were taken using a Shanghai Cewei PXS9-T stereo microscope.

[0251] 11. Measurement of acidity

[0252] Testing instrument: Mettler Toledo S210-K pH meter

[0253] Test method: Follow the pH value determination method, accurately weigh 10 mg of sample, add 10 ml of freshly boiled and cooled purified water to dissolve, shake well, and determine the pH value.

[0254] 12. Measurement of related substances

[0255] Detection instrument: High performance liquid chromatograph / Waters e2695-2489

[0256] Chromatographic conditions:

[0257] Octadecylsilane bonded silica gel was used as filler (model: Waters Xbridge C18 chromatographic column, 250 mm in length, 4.6 mm in inner diameter, 5 μm in filler particle size), the detection wavelength was 250 nm, the column temperature was 35°C, the flow rate was 1.0 ml per minute, the mobile phase A was 0.02 mol / L disodium hydrogen phosphate solution (the pH value was adjusted to 10.0 with sodium hydroxide solution), the mobile phase B was acetonitrile, the diluent was methanol, and the sample plate temperature was 4°C.

[0258] Determination method: Carry out system suitability test as required, prepare test solution, control solution and sensitivity solution. Accurately measure 10μl of control solution and test solution, inject into liquid chromatograph, record chromatogram, and calculate by peak area according to self-dilution control method with correction factor.

[0259] Preparation Example 1: Preparation of the compound of formula 1

[0260]

[0261] With reference to the method described in Example 90 of patent document WO 2011 / 147066, 100 g of the compound represented by formula 1 was prepared.

[0262] Example 1: Preparation of hydrochloride salts of arylaminopurine derivatives

[0263]

[0264] The aromatic amino purine derivative (90 g, 0.203 mol) obtained in Preparation Example 1, 800 ml of purified water and 400 ml of acetone were added into the reactor. After stirring and heating to 40±5°C, (74 g, 0.731 mol) of concentrated hydrochloric acid was added into the reactor. After the concentrated hydrochloric acid was added, 2 L of acetone was added, and the temperature was maintained at 40±5°C. The reaction was continued for 1 h, and then stirred and cooled to 10±5°C for crystallization for 2 h. The filter cake was washed with 300 ml of acetone to obtain 74.7 g of yellow or light yellow hydrochloride. 1 H-NMR (600MHz, D2O) 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 exhibits good crystallinity, and its XRPD characterization spectrum is shown in Figure 1 As shown, the main diffraction peak data are as follows:

[0265] Peak position 2θ angle (°) Relative peak 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

[0266] The free base content and water content were calculated by HPLC and then compared with NMR. 1 From the hydrogen ratio in H-NMR (see table below), it can be inferred that the base / acid / H2O of the hydrochloride is 1:3:5.

[0267]

[0268] Changing the amount of concentrated hydrochloric acid used in Example 1 and repeating the process of Example 1 still only yielded the arylaminopurine derivative trihydrochloride pentahydrate obtained in Example 1. Replacing the acetone in Example 1 with isopropanol and tetrahydrofuran and repeating the process of Example 1 also yielded the arylaminopurine derivative trihydrochloride pentahydrate obtained in Example 1.

[0269] Example 2: Preparation of single crystals of hydrochloride salt of arylaminopurine derivatives

[0270] Weigh 14.9 mg of the hydrochloride obtained in Example 1 and place it in a 3 mL glass bottle, add 0.6 mL of acetonitrile / water (4:1, v / v) mixed solvent, stir to dissolve, and place it in a 25 mL hydrothermal reactor. After the hydrothermal reactor is sealed, place it in a temperature-controlled oven for programmed heating and cooling. The temperature program is:

[0271]

[0272] After the experiment, it was found that long single crystal samples were precipitated in the system. The microscopic photo of the single crystal sample is as follows: Figure 2 As shown. The single crystal X-ray diffraction characterization results show that the crystal belongs to the triclinic system. The space group, whose unit cell parameters are: α=93.2215(5)°, β=95.3039(6)°, γ=91.9554(6)°, The asymmetric unit of the crystal is composed of a cation of the compound of formula 1, three chloride ions and five water molecules. The single crystal was subjected to XRPD measurement, and the obtained spectrum is shown in Figure 3 , the main diffraction peak data are as follows:

[0273] Peak position 2θ angle (°) Relative peak 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

[0274] Depend on Figure 1 and Figure 3 From the comparison results, it can be seen that the single crystal obtained in Example 2 is the same crystal form as the crystal form obtained in Example 4.

[0275] Example 3: Preparation of Mesylate Salts of Arylaminopurine Derivatives

[0276]

[0277] The aromatic amino purine derivative (7 g, 15.8 mmol) obtained in Preparation Example 1, 7 ml of purified water and 28 ml of acetone were added to the reactor. After stirring and heating to 40±5°C, methanesulfonic acid (1.82 g, 18.9 mmol) was added to the reactor. After the addition was completed, 147 ml of acetone was added, and the temperature was maintained at 40±5°C. The reaction was continued for 1 h, and then stirred and cooled to 10±5°C for crystallization for 2 h. The filter cake was washed with 45 ml of acetone to obtain 7.8 g of yellow or light yellow methanesulfonate. 1 H-NMR (600MHz, D2O) 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 exhibits good crystallinity, and its XRPD characterization spectrum is shown in the following figure. Figure 4 As shown, the main diffraction peak data are as follows:

[0278] Peak position 2θ angle (°) Relative peak 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

[0279] The free base content and water content were calculated by HPLC and then compared with NMR.1 The ratio of hydrogen in H-NMR (see the table below) indicates that the base / acid / H2O of the mesylate is 1:1. 1 / 2:1.

[0280]

[0281] Example 4: Preparation of Mesylate Salts of Arylaminopurine Derivatives

[0282]

[0283] The preparation method was prepared by referring to Example 3, except that the amount of methanesulfonic acid added was changed to (5.2 g, 54.1 mmol), to obtain 8.8 g of yellow or light yellow methanesulfonate. 1 H-NMR (600MHz, D2O) 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 exhibits good crystallinity, and its XRPD characterization spectrum is shown in Figure 5 As shown, the main diffraction peak data are as follows:

[0284] Peak position 2θ angle (°) Relative peak 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

[0285] The free base content and water content were calculated by HPLC and then compared with NMR. 1 The ratio of hydrogen in H-NMR (see the table below) indicates that the base / acid / H2O of the mesylate is 1:2. 1 / 2:1.

[0286]

[0287] Example 5: Preparation of Mesylate Salts of Arylaminopurine Derivatives

[0288]

[0289] The preparation method was prepared by referring to Example 3, except that the amount of methanesulfonic acid added was changed to (7.58 g, 78.9 mmol), to obtain 11.2 g of yellow or light yellow methanesulfonate. 1H-NMR (600MHz, D2O) δ: 1.602 (d, 6H), δ: 2.736 (s, 11H), 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 exhibits good crystallinity, and its XRPD characterization spectrum is shown in Figure 6 As shown, the main diffraction peak data are as follows:

[0290] Peak position 2θ angle (°) Relative peak 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

[0291] Peak position 2θ angle (°) Relative peak intensity % 25.353 39.4 26.675 27.2 27.264 20.9

[0292] The free base content and water content were calculated by HPLC and then compared with NMR. 1 The ratio of hydrogen in H-NMR (see the table below) indicates that the base / acid / H2O of the mesylate is 1:3. 1 / 2:1.

[0293]

[0294] Example 6: Preparation of L-malate salts of arylaminopurine derivatives

[0295]

[0296] The aromatic amino purine derivative (8 g, 18 mmol) obtained in Preparation Example 1, 64 ml of purified water and 32 ml of acetone were added to the reactor. After stirring and heating to 40±5°C, (2.902 g, 21.6 mmol) of L-malic acid was added to the reactor. After the addition was completed, 168 ml of acetone was added, and the temperature was maintained at 40±5°C. The reaction was continued for 1 hour, and then stirred and cooled to 10±5°C for crystallization for 2 hours. The filter cake was washed with 30 ml of acetone to obtain 8.63 g of yellow L-malate. 1H-NMR (600MHz, D2O) 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 exhibits good crystallinity, and its XRPD characterization spectrum is shown in Figure 7 As shown, the main diffraction peak data are as follows:

[0297] Peak position 2θ angle (°) Relative peak 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

[0298] Peak position 2θ angle (°) Relative peak intensity % 22.995 10.7 24.198 13.9 25.190 20.7 25.937 73.4 27.535 22.5

[0299] The free base content and water content were calculated by HPLC and then compared with NMR. 1 From the hydrogen ratio in H-NMR (see table below), it can be inferred that the base / acid / H2O of the malate is 1:1:4.

[0300]

[0301] Example 7: L-Tartrate of Arylaminopurine Derivatives

[0302]

[0303] The aromatic amino purine derivative (8 g, 18 mmol) obtained in Preparation Example 1, 64 ml of purified water and 32 ml of acetone were added to the reactor. After stirring and heating to 40±5°C, L-tartaric acid (3.248 g, 21.6 mmol) was added to the reactor. After the addition was completed, 168 ml of acetone was added, and the temperature was maintained at 40±5°C. The reaction was continued for 1 h, and then stirred and cooled to 10±5°C for crystallization for 2 h. The filter cake was washed with 30 ml of acetone to obtain 10.06 g of yellow L-tartrate. 1H-NMR (600MHz, D2O) 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 exhibits good crystallinity, and its XRPD characterization spectrum is shown in Figure 8 As shown, the main diffraction peak data are as follows:

[0304] Peak position 2θ angle (°) Relative peak 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

[0305] Peak position 2θ angle (°) Relative peak intensity % 20.087 21.6 25.503 95.3 26.920 26.6

[0306] The free base content and water content were calculated by HPLC and then compared with NMR. 1 From the hydrogen ratio in H-NMR (see table below), it can be inferred that the base / acid / H2O of the tartrate salt is 1:1:4.

[0307]

[0308] Example 8: L-Tartrate of Arylaminopurine Derivatives

[0309]

[0310] The aromatic amino purine derivative (7 g, 15.8 mmol) obtained in Preparation Example 1, 56 ml of purified water and 28 ml of acetone were added to the reactor. After stirring and heating to 40±5°C, (5.685 g, 37.9 mmol) of L-tartaric acid was added to the reactor. After the addition was completed, 147 ml of acetone was added, and the temperature was maintained at 40±5°C. The reaction was continued for 1 hour, and then stirred and cooled to 10±5°C for crystallization for 2 hours. The filter cake was washed with 30 ml of acetone to obtain 11.3 g of light yellow L-tartaric acid salt. 1H-NMR (600MHz, D2O) 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 exhibits good crystallinity, and its XRPD characterization spectrum is shown in Fig. 9 As shown, the main diffraction peak data are as follows:

[0311] Peak position 2θ angle (°) Relative peak 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

[0312] Peak position 2θ angle (°) Relative peak intensity % 17.648 23.4 18.837 87.3 20.461 33.8 22.316 33.4 24.578 80.1 26.075 100

[0313] The free base content and water content were calculated by HPLC and then compared with NMR. 1 The ratio of hydrogen in H-NMR (see the table below) indicates that the base / acid / H2O of the tartrate is 1:1. 1 / 2:4.

[0314]

[0315] Example 9: L-Tartrate of Arylaminopurine Derivatives

[0316]

[0317] The preparation method of Example 8 was followed, except that the amount of L-tartaric acid added was changed to (8.29 g, 55.2 mmol), to obtain 11.59 g of light yellow L-tartaric acid salt. 1 H-NMR (600MHz, D2O) 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 exhibits good crystallinity, and its XRPD characterization spectrum is shown in Fig.10 As shown, the main diffraction peak data are as follows:

[0318] 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

[0319] Peak position 2θ angle (°) Relative peak intensity % 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

[0320] The free base content and water content were calculated by HPLC and then compared with NMR. 1 From the hydrogen ratio in H-NMR (see table below), it can be inferred that the base / acid / H2O of the tartrate salt is 1:2:4.

[0321]

[0322] Example 10: Oxalates of Arylaminopurine Derivatives

[0323]

[0324] The aromatic amino purine derivative (7 g, 15.8 mmol) obtained in Preparation Example 1, 28 ml of purified water and 28 ml of acetone were added to the reactor. After stirring and heating to 40±5°C, oxalic acid dihydrate (2.388 g, 18.9 mmol) was added to the reactor. After the addition was completed, 147 ml of acetone was added, and the temperature was maintained at 40±5°C. The reaction was continued for 1 h, and then stirred and cooled to 10±5°C for crystallization for 2 h. The filter cake was washed with 30 ml of acetone to obtain 8.01 g of yellow oxalate. 1 H-NMR (600MHz, D2O) 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 exhibits good crystallinity, and its XRPD characterization spectrum is shown in the following figure. Fig.11 As shown, the main diffraction peak data are as follows:

[0325] Peak position 2θ angle (°) Relative peak intensity % 8.063 59.5 8.353 91.6 8.983 29.0 14.103 35.0

[0326] Peak position 2θ angle (°) Relative peak intensity % 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

[0327] The free base content and water content were calculated by HPLC and then compared with NMR. 1 From the hydrogen ratio in H-NMR (see table below), it can be inferred that the base / acid / H2O of the oxalate is 1:1:1.

[0328]

[0329] Example 11: Oxalates of Arylaminopurine Derivatives

[0330]

[0331] The preparation method was prepared by referring to Example 10, except that the amount of oxalic acid dihydrate added was changed to (4.755 g, 37.9 mmol), to obtain 8.01 g of yellow oxalate. 1 H-NMR (600MHz, D2O) 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 exhibits good crystallinity, and its XRPD characterization spectrum is shown in the following figure. Fig.12 As shown, the main diffraction peak data are as follows:

[0332] 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

[0333] Peak position 2θ angle (°) Relative peak intensity % 19.047 36.5 24.385 56.4

[0334] The free base content and water content were calculated by HPLC and then compared with NMR. 1 From the hydrogen ratio in H-NMR (see table below), it can be inferred that the base / acid / H2O of the oxalate is 1:1:1.

[0335]

[0336] Example 12: Succinate of Arylaminopurine Derivatives

[0337]

[0338] The aromatic amino purine derivative (7 g, 15.8 mmol) obtained in Preparation Example 1, 28 ml of purified water and 28 ml of acetone were added to the reactor. After stirring and heating to 40±5°C, succinic acid (2.236 g, 18.9 mmol) was added to the reactor. After the addition was completed, 147 ml of acetone was added, and the temperature was maintained at 40±5°C. The reaction was continued for 1 h, and then stirred and cooled to 10±5°C for crystallization for 2 h. The filter cake was washed with 30 ml of acetone to obtain 7.51 g of light yellow succinate. 1H-NMR (600MHz, D2O) 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 exhibits good crystallinity, and its XRPD characterization spectrum is shown in the following figure. Fig.13 As shown, the main diffraction peak data are as follows:

[0339] 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

[0340] Peak position 2θ angle (°) Relative peak intensity % 20.351 53.8 21.017 48.7 22.437 100 24.204 35.9 25.889 46.9 27.115 50.9

[0341] The free base content and water content were calculated by HPLC and then compared with NMR. 1 From the hydrogen ratio in H-NMR (see table below), it can be inferred that the base / acid / H2O of the succinate is 1:1:4.

[0342]

[0343] Example 13: Succinate of Arylaminopurine Derivatives

[0344]

[0345] The preparation method was prepared by referring to Example 12, except that the amount of succinic acid added was changed to (4.473 g, 37.9 mmol), and 8.14 g of light yellow succinate was obtained. 1 H-NMR (600MHz, D2O) 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 exhibits good crystallinity, and its XRPD characterization spectrum is shown in the following figure. Fig.14 As shown, the main diffraction peak data are as follows:

[0346] 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

[0347] Peak position 2θ angle (°) Relative peak intensity % 24.149 11.9 25.171 19.1 25.816 58.1 27.263 28.5

[0348] The free base content and water content were calculated by HPLC and then compared with NMR. 1 From the hydrogen ratio in H-NMR (see table below), it can be inferred that the base / acid / H2O of the succinate is 1:2:4.

[0349]

[0350] Example 14: Acetate salts of arylaminopurine derivatives

[0351]

[0352] The aromatic amino purine derivative (7 g, 15.8 mmol) obtained in Preparation Example 1, 28 ml of purified water and 28 ml of acetone were added to the reactor. After stirring and heating to 40±5°C, acetic acid (1.13 g, 18.9 mmol) was added to the reactor. After the addition was completed, 147 ml of acetone was added, and the temperature was maintained at 40±5°C. The reaction was continued for 1 h, and then stirred and cooled to 10±5°C for crystallization for 2 h. The filter cake was washed with 30 ml of acetone to obtain 7.51 g of off-white acetate. 1 H-NMR (600MHz, 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 acetate obtained showed good crystallinity, and its XRPD characterization spectrum was as follows Fig.15 As shown, the main diffraction peak data are as follows:

[0353] 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

[0354] Peak position 2θ angle (°) Relative peak intensity % 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

[0355] The free base content and water content were calculated by HPLC and then compared with NMR. 1 From the hydrogen ratio in H-NMR (see table below), it can be inferred that the base / acid / H2O of the acetate is 1:1:1.

[0356]

[0357] Example 15: Acetate salts of arylaminopurine derivatives

[0358]

[0359] The aromatic amino purine derivative (10 g, 22.5 mmol) obtained in Preparation Example 1, 10 ml of purified water and 40 ml of acetone were added to the reactor. After stirring and heating to 40±5°C, acetic acid (4.74 g, 78.9 mmol) was added to the reactor. After the addition was completed, 210 ml of acetone was added, and the temperature was maintained at 40±5°C. The reaction was continued for 1 h, and then stirred and cooled to 10±5°C for crystallization for 2 h. The filter cake was washed with 40 ml of acetone to obtain 9.04 g of off-white acetate. 1 H-NMR (600MHz, D2O) 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 acetate obtained showed good crystallinity, and its XRPD characterization spectrum was as follows Fig.16 As shown, the main diffraction peak data are as follows:

[0360] 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

[0361] Peak position 2θ angle (°) Relative peak intensity % 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

[0362] The free base content and water content were calculated by HPLC and then compared with NMR. 1 From the hydrogen ratio in H-NMR (see table below), it can be inferred that the base / acid / H2O of the acetate is 1:2:1.

[0363]

[0364] Example 16: Sulfate salts of arylaminopurine derivatives

[0365]

[0366] The aromatic amino purine derivative (7 g, 15.8 mmol) obtained in Preparation Example 1, 7 ml of purified water and 28 ml of acetone were added to the reactor. After stirring and heating to 40±5°C, sulfuric acid (1.86 g, 18.9 mmol) was added to the reactor. After the addition was completed, 147 ml of acetone was added, and the temperature was maintained at 40±5°C. The reaction was continued for 1 hour, and then stirred and cooled to 10±5°C for crystallization for 2 hours. The filter cake was washed with 30 ml of acetone to obtain 7.5 g of light yellow sulfate.1 H-NMR (600MHz, D2O) 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 exhibits good crystallinity, and its XRPD characterization spectrum is shown in the following figure. Fig.17 As shown, the main diffraction peak data are as follows:

[0367] Peak position 2θ angle (°) Relative peak intensity % 4.825 59.1 7.010 89.3 8.553 46.5 9.183 64.5

[0368] Peak position 2θ angle (°) Relative peak intensity % 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

[0369] The free base content and water content were calculated by HPLC and then compared with NMR. 1 From the hydrogen ratio in H-NMR (see table below), it can be inferred that the base / acid / H2O of the sulfate is 1:1:1.

[0370]

[0371] Example 17: Sulfate salts of arylaminopurine derivatives

[0372]

[0373] The preparation method was followed by referring to Example 16, except that the amount of sulfuric acid added was changed to (3.71 g, 37.9 mmol) to obtain 10.0 g of light yellow sulfate. 1 H-NMR (600MHz, D2O) 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 exhibits good crystallinity, and its XRPD characterization spectrum is shown in the following figure. Fig.18 As shown, the main diffraction peak data are as follows:

[0374] Peak position 2θ angle (°) Relative peak intensity % 8.622 33.2 9.588 78.1 15.681 44.6

[0375] Peak position 2θ angle (°) Relative peak intensity % 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

[0376] The free base content and water content were calculated by HPLC and then compared with NMR. 1 From the hydrogen ratio in H-NMR (see table below), it can be inferred that the base / acid / H2O of the sulfate is 1:2:1.

[0377]

[0378] Test Example 1: DSC and TGA Test

[0379] The salts obtained in Examples 1, 3-17 and the compound of Formula 1 were subjected to DSC and TGA tests in a medium. The test results are shown in the following table:

[0380]

[0381]

[0382]

[0383] Test Example 2: Solubility Test

[0384] The salts obtained in Examples 1, 3-17 and the compound of Formula 1 were subjected to solubility tests in a medium. The test results are shown in the following table:

[0385]

[0386] Test Example 3: Accelerated Stability Test

[0387] Take appropriate amount of salt samples obtained in Examples 1, 3-17, and place them in an open environment for 10 days at 25±2°C, 0%±5%RH and 40±2°C, 75%±5%RH, and place them in an open environment for 10 days, respectively, and conduct accelerated tests. The results are as follows:

[0388]

[0389]

[0390] Test Example 4: Hygroscopicity test

[0391] Take appropriate amount of salt samples obtained in Examples 1, 3-17 and conduct hygroscopicity tests at 25±1°C and relative humidity of 80%±2%. The results are as follows:

[0392]

[0393] Test Example 5: Long-term stability test

[0394] Take an appropriate amount of the salt sample obtained in Example 1, pack it in a medicinal low-density polyethylene bag, and pack it in a polyester / aluminum / polyethylene composite bag for drug packaging. At a temperature of 25±2°C and a relative humidity of 60%±5%, take samples at the end of the 3rd, 6th, 9th, 12th and 18th month, respectively, compare the appearance and test other inspection indicators. The results are compared with those at 0 month. The experimental results are shown in the following table:

[0395] time Characteristics Moisture (%) acidity Related substances (%) content(%) 0 month Yellow crystalline powder 13.9 3.1 0.33 100.9 March Yellow crystalline powder 13.9 3.3 0.34 100.4 June Yellow crystalline powder 14.3 3.3 0.34 100.8 September Yellow crystalline powder 14.3 3.3 0.31 101.7 December Yellow crystalline powder 13.9 3.3 0.34 99.6 18 months Yellow crystalline powder 14.2 3.3 0.26 100.2

[0396] Test Example 6: Biological Activity Test

[0397] According to the kinase inhibitory activity evaluation described in the biological evaluation of patent application WO 2011 / 147066, the salt sample obtained in Example 1 was tested. The test results show that the sample can inhibit the activity 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 of some kinases are shown in the table below.

[0398] Kinase <![CDATA[IC 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 FGFR1(h) 247 KDR(h) 323

[0399] According to the in vivo anti-tumor experiment described in the biological evaluation of patent application WO 2011 / 147066, the salt sample obtained in Example 1 was tested (specifically for acute myeloid leukemia of FLT3-ITD, non-small cell lung cancer with EGFR activating mutation, or Ph-positive chronic myeloid leukemia). The test results show that in the MV4-11 (FLT3-ITD mutation) subcutaneous tumor model experiment (model established with reference to Example 4 of WO 2011 / 147066), the sample (orally administered once a day for 21 days) can completely inhibit tumor growth at a dosage of 5 mg / kg, and can cause complete regression of the tumor at a dosage of 10 mg / kg and 20 mg / kg. In a non-small cell lung cancer model (model established with reference to Example 3 of WO 2011 / 147066), the sample can inhibit the growth of human non-small cell lung cancer HCC827 in a dose-dependent manner, and all three dose groups of 7.5 mg / kg, 15 mg / kg, and 30 mg / kg (orally administered once a day for 30 days) cause tumor shrinkage (compared with the initial tumor), wherein the 30 mg / kg group can cause nearly complete regression of the tumor. In a K562 (BCR-Abl gene rearrangement) subcutaneous tumor model experiment (model established similar to the MV4-11 subcutaneous tumor model), the sample (orally administered once a day for 18 days) can effectively inhibit tumor growth at a dose of 70 mg / kg, with a tumor inhibition rate of 71.3%.

[0400] The present invention provides the following technical solutions, but the present invention is not limited thereto. The protection scope of the present invention is determined by the scope defined by the claims:

[0401] [Technical Solution 1]. Salt of an aromatic amino purine derivative shown in Formula 2:

[0402]

[0403] in,

[0404] HA is an acid;

[0405] H2O is water of crystallization;

[0406] m is an integer or half integer from 1 to 4;

[0407] n is an integer or half integer of 0-5.

[0408] [Technical Solution 2]. The salt of the aromatic amino purine derivative according to Technical Solution 1, characterized in that the acid is selected from: 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.

[0409] [Technical Solution 3] The salt of the aromatic amino purine derivative according to Technical Solution 1, characterized in that the salt is a hydrochloride shown in Formula 3:

[0410]

[0411] n is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5;

[0412] Preferably, the salt is a hydrochloride salt represented by formula 3':

[0413]

[0414] Preferably,

[0415] The hydrochloride represented by Formula 3 and Formula 3' uses CuKα radiation, and the X-ray powder diffraction expressed in 2θ angle has characteristic peaks at 8.5±0.2°, 11.8±0.2°, 19.6±0.2°, 25.2±0.2°, and 27.2±0.2°;

[0416] Alternatively, the hydrochloride represented by Formula 3 and Formula 3' uses CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 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°, and 27.2±0.2°;

[0417] Alternatively, the hydrochloride represented by Formula 3 and Formula 3' uses CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 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°, and 27.2±0.2°;

[0418] Alternatively, the hydrochloride represented by Formula 3 and Formula 3' uses CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 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°, and 27.2±0.2°;

[0419] Alternatively, the hydrochloride salts represented by Formula 3 and Formula 3' are irradiated with CuKα and have a substantially Figure 1 or Figure 3 The X-ray powder diffraction spectrum shown;

[0420] Alternatively, the single crystal of the hydrochloride represented by Formula 3 and Formula 3' is triclinic when irradiated with CuKα. The space group, whose unit cell parameters are: α=93.2215(5)°, β=95.3039(6)°, γ=91.9554(6)°, }.

[0421] [Technical Solution 4] The salt of the aromatic amino purine derivative according to Technical Solution 1, characterized in that the salt is a mesylate represented by Formula 4, Formula 5, or Formula 6:

[0422]

[0423] n is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5;

[0424] Preferably, the salt is a mesylate salt represented by Formula 4', Formula 5', or Formula 6':

[0425]

[0426] Preferably,

[0427] The mesylate salts represented by Formula 4 and Formula 4' use CuKα radiation, and X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 6.8±0.2°, 15.1±0.2°, 16.3±0.2°, 21.0±0.2°, and 25.0±0.2°;

[0428] Alternatively, the mesylate represented by Formula 4 and Formula 4' uses CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 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°, and 25.0±0.2°;

[0429] Alternatively, the mesylate salts of Formula 4 and Formula 4' are irradiated with CuKα and have a substantially Figure 4 The X-ray powder diffraction spectrum shown;

[0430] Or preferably,

[0431] The mesylate represented by Formula 5 and Formula 5' uses CuKα radiation, and the X-ray powder diffraction expressed in 2θ angle has characteristic peaks at 6.1±0.2°, 6.4±0.2°, 17.4±0.2°, 18.9±0.2°, 19.3±0.2°, 24.4±0.2°, and 26.4±0.2°;

[0432] Alternatively, the mesylate represented by Formula 5 and Formula 5' uses CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 6.1±0.2°, 6.4±0.2°, 17.5±0.2°, 18.9±0.2°, 19.3±0.2°, 24.4±0.2°, and 26.4±0.2°;

[0433] Alternatively, the mesylate represented by Formula 5 and Formula 5' uses CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 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°, and 27.3±0.2°;

[0434] Alternatively, the mesylate represented by Formula 5 and Formula 5' uses CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 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°, and 27.3±0.2°;

[0435] Alternatively, the mesylate salts of Formula 5 and Formula 5' are irradiated with CuKα and have a substantially Figure 5 The X-ray powder diffraction spectrum shown;

[0436] Or preferably,

[0437] The mesylate salts represented by Formula 6 and Formula 6' use CuKα radiation, and X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.9±0.2°, 11.5±0.2°, 14.5±0.2°, 18.5±0.2°, and 18.9±0.2°;

[0438] Alternatively, the mesylate represented by Formula 6 and Formula 6' uses CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 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°, and 27.3±0.2°;

[0439] Alternatively, the mesylate salts represented by Formula 6 and Formula 6' are irradiated with CuKα and have a substantially Figure 6 The X-ray powder diffraction spectrum is shown.

[0440] [Technical Solution 5]. The salt of the aromatic amino purine derivative according to Technical Solution 1, characterized in that the salt is an L-malate salt represented by Formula 7:

[0441]

[0442] n is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5;

[0443] Preferably, the salt is an L-malate salt of formula 7':

[0444]

[0445] Preferably,

[0446] The L-malate represented by Formula 7 and Formula 7' has characteristic peaks at 7.0±0.2°, 9.3±0.2°, 17.6±0.2°, 19.7±0.2°, and 25.9±0.2° using CuKα radiation and X-ray powder diffraction expressed in 2θ angles;

[0447] Alternatively, the L-malate represented by Formula 7 and Formula 7' uses CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 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°, and 27.5±0.2°;

[0448] Alternatively, the L-malate represented by Formula 7 and Formula 7' uses CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 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°, and 27.5±0.2°;

[0449] Alternatively, the L-malate salts of Formula 7 and Formula 7' are irradiated with CuKα and have a substantially Figure 7 The X-ray powder diffraction spectrum is shown.

[0450] [Technical Solution 6]. The salt of the aromatic amino purine derivative according to Technical Solution 1, characterized in that the salt is an L-tartrate salt represented by Formula 8, Formula 9, or Formula 10:

[0451]

[0452] n is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5;

[0453] Preferably, the salt is an L-tartrate represented by Formula 8', Formula 9', or Formula 10':

[0454]

[0455] Preferably,

[0456] The L-tartrate represented by Formula 8 and Formula 8' has characteristic peaks at 6.9±0.2°, 9.1±0.2°, 17.8±0.2°, 19.4±0.2°, and 25.5±0.2° in X-ray powder diffraction expressed in 2θ angle using CuKα radiation;

[0457] Alternatively, the L-tartrate represented by Formula 8 and Formula 8' uses CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 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°, and 26.9±0.2°;

[0458] Alternatively, the L-tartrate salts of Formula 8 and Formula 8' are irradiated with CuKα and have a substantially Figure 8 The X-ray powder diffraction spectrum shown;

[0459] Or preferably,

[0460] The L-tartrate represented by Formula 9 and Formula 9' has characteristic peaks at 8.5±0.2°, 14.8±0.2°, 17.1±0.2°, 18.8±0.2°, 24.6±0.2°, and 26.1±0.2° using CuKα radiation and X-ray powder diffraction expressed in 2θ angles;

[0461] Alternatively, the L-tartrate represented by Formula 9 and Formula 9' uses CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 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°, and 26.1±0.2°;

[0462] Alternatively, the L-tartrate salts of Formula 9 and Formula 9' are irradiated with CuKα and have a substantially Fig. 9 The X-ray powder diffraction spectrum shown;

[0463] Or preferably,

[0464] The L-tartrate represented by Formula 10 and Formula 10' has characteristic peaks at 8.3±0.2°, 8.9±0.2°, 9.5±0.2°, 14.8±0.2°, 17.7±0.2°, 21.0±0.2°, and 24.0±0.2° using CuKα radiation and X-ray powder diffraction expressed in 2θ angles;

[0465] Alternatively, the L-tartrate represented by Formula 10 and Formula 10' uses CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 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°, and 26.7±0.2°;

[0466] Alternatively, the L-tartrate salts of Formula 10 and Formula 10' are irradiated with CuKα and have a substantially Fig.10 The X-ray powder diffraction spectrum is shown.

[0467] [Technical Solution 7]. The salt of the aromatic amino purine derivative according to Technical Solution 1, characterized in that the salt is an oxalate represented by Formula 11 or Formula 12:

[0468]

[0469] n is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5;

[0470] Preferably, the salt is an oxalate represented by formula 11' or formula 12':

[0471]

[0472] Preferably,

[0473] The oxalate represented by Formula 11 and Formula 11' has characteristic peaks at 8.1±0.2°, 8.4±0.2°, 9.0±0.2°, 14.1±0.2°, 16.7±0.2°, and 25.6±0.2° in X-ray powder diffraction expressed in 2θ angle using CuKα radiation;

[0474] Alternatively, the oxalate represented by Formula 11 and Formula 11' uses CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 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°, and 25.6±0.2°;

[0475] Alternatively, the oxalates represented by Formula 11 and Formula 11' are irradiated with CuKα and have a substantially Fig.11 The X-ray powder diffraction spectrum shown;

[0476] Or preferably,

[0477] The oxalate represented by Formula 12 and Formula 12' has characteristic peaks at 7.1±0.2°, 12.2±0.2°, 14.2±0.2°, 16.4±0.2°, 17.7±0.2°, 19.0±0.2°, and 24.4±0.2° in X-ray powder diffraction expressed in 2θ angle using CuKα radiation;

[0478] Alternatively, the oxalate represented by Formula 12 and Formula 12' uses CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 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°, and 24.4±0.2°;

[0479] Alternatively, the oxalates represented by Formula 12 and Formula 12' are irradiated with CuKα and have a substantially Fig.12 The X-ray powder diffraction spectrum is shown.

[0480] [Technical Solution 8] The salt of the aromatic amino purine derivative according to Technical Solution 1, characterized in that the salt is a succinate represented by Formula 13 or Formula 14:

[0481]

[0482] n is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5;

[0483] Preferably, the salt is a succinate salt represented by formula 13' or formula 14':

[0484]

[0485] Preferably,

[0486] The succinates represented by Formula 13 and Formula 13' have characteristic peaks at 7.0±0.2°, 9.1±0.2°, 11.3±0.2°, 16.8±0.2°, 20.4±0.2°, 21.0±0.2°, and 22.4±0.2° in X-ray powder diffraction expressed in 2θ angle using CuKα radiation;

[0487] Alternatively, the succinate represented by Formula 13 and Formula 13' uses CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 7.0±0.2°, 9.1±0.2°, 18.5±0.2°, 20.4±0.2°, 21.0±0.2°, 22.4±0.2°, and 27.1±0.2°;

[0488] Alternatively, the succinate represented by Formula 13 and Formula 13' uses CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 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°, and 27.1±0.2°;

[0489] Alternatively, the succinates represented by Formula 13 and Formula 13' are irradiated with CuKα and have a substantially Fig.13 The X-ray powder diffraction spectrum shown;

[0490] Or preferably,

[0491] The succinates represented by Formula 14 and Formula 14' have characteristic peaks at 7.0±0.2°, 9.2±0.2°, 17.6±0.2°, 18.4±0.2°, 19.7±0.2°, 25.8±0.2°, and 27.3±0.2° in X-ray powder diffraction expressed in 2θ angle using CuKα radiation;

[0492] Alternatively, the succinate represented by Formula 14 and Formula 14' uses CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 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°, and 27.3±0.2°;

[0493] Alternatively, the succinate represented by Formula 14 and Formula 14' uses CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 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°, and 27.3±0.2°;

[0494] Alternatively, the succinates represented by Formula 14 and Formula 14' are irradiated with CuKα and have a substantially Fig.14 The X-ray powder diffraction spectrum is shown.

[0495] [Technical Solution 9]. The salt of the aromatic amino purine derivative according to Technical Solution 1, characterized in that the salt is an acetate represented by Formula 15 or Formula 16:

[0496]

[0497] n is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5;

[0498] Preferably, the salt is an acetate represented by Formula 15' or Formula 16':

[0499]

[0500] Preferably,

[0501] The acetates represented by Formula 15 and Formula 15' have characteristic peaks at 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°, and 25.4±0.2° using CuKα radiation and X-ray powder diffraction expressed in 2θ angles;

[0502] Alternatively, the acetates represented by Formula 15 and Formula 15' use CuKα radiation, and X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 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°, and 25.4±0.2°;

[0503] Alternatively, the acetates represented by Formula 15 and Formula 15' are irradiated with CuKα and have a substantially Fig.15 The X-ray powder diffraction spectrum shown;

[0504] Or preferably,

[0505] The acetates represented by Formula 16 and Formula 16' use CuKα radiation, and X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 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 6.2±0.2°, 12.2±0.2°, 17.5±0.2°, 21.5±0.2°, 23.4±0.2°, 24.8±0.2°;

[0506] Alternatively, the acetates represented by Formula 16 and Formula 16' use CuKα radiation, and X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 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°, and 28.8±0.2°;

[0507] Alternatively, the acetates represented by Formula 16 and Formula 16' are irradiated with CuKα and have a substantially Fig.16 The X-ray powder diffraction spectrum is shown.

[0508] [Technical Solution 10] The salt of the aromatic amino purine derivative according to Technical Solution 1, characterized in that the salt is a sulfate represented by Formula 17 or Formula 18:

[0509]

[0510] n is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5;

[0511] Preferably, the salt is a sulfate represented by Formula 17' or Formula 18':

[0512]

[0513] Preferably, the sulfates represented by Formula 17 and Formula 17' use CuKα radiation, and X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 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°, and 25.7±0.2°;

[0514] Alternatively, the sulfates represented by Formula 17 and Formula 17' have characteristic peaks at 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°, and 25.7±0.2° in X-ray powder diffraction expressed in 2θ angle using CuKα radiation;

[0515] Alternatively, the sulfates represented by Formula 17 and Formula 17' have characteristic peaks at 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°, and 25.7±0.2° in X-ray powder diffraction expressed in 2θ angle using CuKα radiation;

[0516] Alternatively, the sulfates represented by Formula 17 and Formula 17' are irradiated with CuKα and have a substantially Fig.17 The X-ray powder diffraction spectrum shown;

[0517] Or preferably,

[0518] The sulfates represented by Formula 18 and Formula 18' have characteristic peaks at 8.6±0.2°, 9.6±0.2°, 15.7±0.2°, 19.3±0.2°, 20.0±0.2°, 21.9±0.2°, and 26.6±0.2° using CuKα radiation and X-ray powder diffraction expressed in 2θ angles;

[0519] Alternatively, the sulfates represented by Formula 18 and Formula 18' have characteristic peaks at 8.6±0.2°, 9.6±0.2°, 15.7±0.2°, 17.1±0.2°, 19.3±0.2°, 20.0±0.2°, and 26.6±0.2° in X-ray powder diffraction expressed in 2θ angle using CuKα radiation;

[0520] Alternatively, the sulfates represented by Formula 18 and Formula 18' have characteristic peaks at 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°, and 26.6±0.2° in X-ray powder diffraction expressed in 2θ angle using CuKα radiation;

[0521] Alternatively, the sulfates represented by Formula 18 and Formula 18' are irradiated with CuKα and have a substantially Fig.18 The X-ray powder diffraction spectrum is shown.

[0522] [Technical Solution 11]. A pharmaceutical composition comprising a salt of an aromatic amino purine derivative represented by formula 2 as described in any one of Technical Solutions 1-10.

[0523] [Technical Solution 12]. The use of the salt of the aromatic amino purine derivative represented by Formula 2 according to any one of Technical Solutions 1 to 10 or the pharmaceutical composition according to Technical Solution 11 for preparing a protein kinase inhibitor drug, 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;

[0524] Preferably, the protein kinase inhibitor drug is an anti-tumor drug, and the tumor is selected from non-small cell lung cancer, acute myeloid leukemia, chronic myeloid leukemia, chronic myeloid leukemia, epidermal squamous cell carcinoma, breast cancer, colorectal cancer, liver cancer, gastric 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 mutation.

[0525] [Technical Solution 13]. A method for preparing a salt of an arylamino purine derivative shown in Formula 2 according to Technical Solution 1, comprising reacting an arylamino purine derivative shown in Formula 1 with an acid in the presence of water and an organic solvent to obtain a salt of an arylamino purine derivative shown in Formula 2:

[0526]

[0527] in,

[0528] HA is an acid;

[0529] H2O is water of crystallization;

[0530] m is an integer or half integer from 1 to 4;

[0531] n is an integer or half integer of 0-5.

[0532] [Technical Solution 14]. A method for preparing a salt of an aromatic amino purine derivative as described in Technical Solution 13, characterized in that the molar ratio of the aromatic amino purine derivative represented by Formula 1 to the acid is 1:1 to 1:4, preferably 1:1.2 to 1:3.5;

[0533] The reaction temperature is 0-70°C, preferably 35-45°C;

[0534] The reaction is carried out in the presence of water and one or more combinations of organic solvents selected from alcohols, ethers, esters, ketones, nitriles, and alkanes, preferably in the presence of C1-C3 lower alcohols and water, in the presence of ketones and water, in the presence of nitriles and water, or in the presence of ethers and water, more preferably in the presence of methanol-water, ethanol-water, isopropanol-water, tetrahydrofuran-water, dioxane-water, acetone-water or acetonitrile-water; the volume ratio 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.

Claims

1. A salt of an aromatic amino purine derivative as shown in the following formula: It is characterized in that The salt uses CuKα radiation, and X-ray powder diffraction represented by 2θ angle has characteristic peaks at 8.5±0.2°, 11.8±0.2°, 19.6±0.2°, 25.2±0.2°, and 27.2±0.2°.

2. The salt of the arylamino purine derivative according to claim 1, characterized in that The salt uses CuKα radiation, and X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 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°, and 27.2±0.2°.

3. The salt of the arylamino purine derivative according to claim 1, characterized in that The salt uses CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 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°, and 27.2±0.2°.

4. The salt of the arylamino purine derivative according to claim 1, characterized in that The salt uses CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 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°, and 27.2±0.2°.

5. The salt of the arylamino purine derivative according to claim 1, characterized in that The salt has an X-ray powder diffraction pattern substantially as shown in FIG. 1 or FIG. 3 using CuKα radiation.

6. The salt of the arylamino purine derivative according to any one of claims 1 to 5, characterized in that The single crystal of the salt is irradiated with CuKα and belongs to the triclinic system. The space group, whose unit cell parameters are: α=93.2215(5)°,β=95.3039(6)°,γ=91.9554(6)°, }。 7. A salt of an aromatic amino purine derivative represented by the following formula: It is characterized in that The salt uses CuKα radiation, and X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 7.0±0.2°, 9.1±0.2°, 18.5±0.2°, 20.4±0.2°, 21.0±0.2°, 22.4±0.2°, and 27.1±0.2°.

8. A salt of an aromatic amino purine derivative represented by the following formula: It is characterized in that The salt uses CuKα radiation, and X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 7.0±0.2°, 9.1±0.2°, 11.3±0.2°, 16.8±0.2°, 20.4±0.2°, 21.0±0.2°, and 22.4±0.2°.

9. The salt of the arylamino purine derivative according to claim 7 or 8, characterized in that The salt uses CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 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°, and 27.1±0.2°.

10. The salt of the arylaminopurine derivative according to claim 7 or 8, characterized in that The salt has an X-ray powder diffraction pattern substantially as shown in FIG13 using CuKα radiation.

11. A salt of an aromatic amino purine derivative represented by the following formula: It is characterized in that The salt uses CuKα radiation, and X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 7.0±0.2°, 9.2±0.2°, 17.6±0.2°, 18.4±0.2°, 19.7±0.2°, 25.8±0.2°, and 27.3±0.2°.

12. The salt of the arylamino purine derivative according to claim 11, characterized in that The salt uses CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 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°, and 27.3±0.2°.

13. The salt of the arylamino purine derivative according to claim 11, characterized in that The salt uses CuKα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 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°, and 27.3±0.2°.

14. The salt of the arylamino purine derivative according to claim 11, characterized in that The salt has an X-ray powder diffraction pattern substantially as shown in FIG. 14 using CuKα radiation.

15. A pharmaceutical composition comprising the salt of the arylaminopurine derivative according to any one of claims 1 to 14.

16. Use of the salt of the aromatic amino purine derivative according to any one of claims 1 to 14 or the pharmaceutical composition according to claim 15 for the preparation of a protein kinase inhibitor drug, wherein the kinase is selected from the group consisting of: FLT3, EGFR, Abl, Fyn, Hck, Lck, Lyn, Ret, Yes, VEGFR2, ALK, BTK, c-KIT, c-SRC, FGFR1, KDR, MET and PDGFRα.

17. Use of the salt of the arylaminopurine derivative according to any one of claims 1 to 14 or the pharmaceutical composition according to claim 15 in the preparation of a medicament for treating a disease, wherein the disease is a tumor.

18. Use of the salt of the aromatic amino purine derivative according to any one of claims 1 to 14 or the pharmaceutical composition according to claim 15 in the preparation of a medicament for treating a disease, wherein the disease is selected from non-small cell lung cancer, acute myeloid leukemia, chronic myeloid leukemia, chronic myeloid leukemia, epidermal squamous cell carcinoma, breast cancer, colorectal cancer, liver cancer, gastric cancer, and malignant melanoma.

19. Use of the salt of the arylaminopurine derivative according to any one of claims 1 to 14 or the pharmaceutical composition according to claim 15 in the preparation of a medicament for treating a disease selected from leukemia or lung cancer.

20. Use of the salt of the arylaminopurine derivative according to any one of claims 1 to 14 or the pharmaceutical composition according to claim 15 in the preparation of a medicament for treating a disease selected from acute myeloid leukemia or non-small cell lung cancer.

21. Use of the salt of the aromatic amino purine derivative according to any one of claims 1 to 14 or the pharmaceutical composition according to claim 15 in the preparation of a medicament for treating a disease, wherein the disease is selected from FLT3 mutation-positive acute myeloid leukemia, Ph-positive chronic myeloid leukemia, or non-small cell lung cancer with EGFR activating mutation.

22. Use of the salt of the arylaminopurine derivative according to any one of claims 1 to 14 or the pharmaceutical composition according to claim 15 in the preparation of a medicament for treating a disease, wherein the disease is acute myeloid leukemia of FLT3-ITD.

23. A method for preparing a salt of an arylamino purine derivative according to any one of claims 1 to 14, comprising reacting the arylamino purine derivative represented by formula 1 with an acid selected from hydrochloric acid and succinic acid in the presence of water and an organic solvent to obtain the corresponding salt of the arylamino purine derivative:

24. The method for preparing a salt of an arylamino purine derivative according to claim 23, characterized in that: The molar ratio of the aromatic amino purine derivative represented by Formula 1 to the acid is 1:1 to 1:4; The reaction temperature is 0-70°C; The reaction is carried out in the presence of water and one or more organic solvents selected from ketones and nitriles; the volume ratio of the organic solvent to water is 1:10 to 10:

1.

25. The method for preparing a salt of an arylamino purine derivative according to claim 23, characterized in that: The molar ratio of the aromatic amino purine derivative represented by Formula 1 to the acid is 1:1.2 to 1:3.5; The reaction temperature is 35-45°C; The reaction is carried out in the presence of ketones and water, or in the presence of nitriles and water; the volume ratio of the organic solvent to water is 1:1-10:1 or 1:10-1:

1.

26. The method for preparing a salt of an arylamino purine derivative according to claim 23 or 24, characterized in that: The reaction is carried out in the presence of acetone-water or acetonitrile-water.

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