WO2021147996A1 - 一种芳胺基嘌呤衍生物的盐及其制备方法和应用 - Google Patents

一种芳胺基嘌呤衍生物的盐及其制备方法和应用 Download PDF

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WO2021147996A1
WO2021147996A1 PCT/CN2021/073285 CN2021073285W WO2021147996A1 WO 2021147996 A1 WO2021147996 A1 WO 2021147996A1 CN 2021073285 W CN2021073285 W CN 2021073285W WO 2021147996 A1 WO2021147996 A1 WO 2021147996A1
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formula
salt
ray powder
represented
powder diffraction
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PCT/CN2021/073285
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English (en)
French (fr)
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纪德华
杨胜勇
郭小丰
张臣
李琳丽
马玉秀
孙晓伟
崔巧利
郭凤
张豪豪
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石药集团中奇制药技术（石家庄）有限公司
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Priority to JP2022544790A priority Critical patent/JP2023511675A/ja
Priority to KR1020227029004A priority patent/KR20220130771A/ko
Priority to EP21743887.8A priority patent/EP4095139A1/en
Priority to US17/794,781 priority patent/US20230144619A1/en
Priority to CA3165784A priority patent/CA3165784A1/en
Priority to AU2021210477A priority patent/AU2021210477A1/en
Priority to CN202180010630.5A priority patent/CN115038702A/zh
Publication of WO2021147996A1 publication Critical patent/WO2021147996A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
    • C07C53/08—Acetic acid
    • C07C53/10—Salts thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/06—Oxalic acid
    • C07C55/07—Salts thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/10—Succinic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/255—Tartaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention belongs to the field of medicinal chemistry, and specifically relates to a salt of an arylamino purine derivative and a preparation method and application thereof.
  • Compound 1 chemical name: 9-isopropyl-2-(4-(4-methylpiperazin-1-yl)anilino)-8-(pyridin-3-amino)-9H-purine, which is Arylaminopurine derivatives are a new type of multi-target protein kinase inhibitors.
  • the main targets include FLT3, EGFR, Abl, Fyn, Hck, Lck, Lyn, Ret, Yes, etc.
  • WO 2011/147066 relates to the arylamino purine derivative, and discloses the preparation method and medical use of the free form of the series derivative, and does not describe and prepare the general formula compound and the salt of the specific compound.
  • the present inventors conducted a lot of research on the salt of the arylaminopurine derivative represented by formula 1 in order to find a pharmaceutical form that has good solubility, low hygroscopicity and good stability to meet the needs of pharmaceuticals.
  • one aspect of the present invention provides a salt of an arylamino purine derivative represented by formula 2:
  • HA is acid
  • H 2 O is crystal water
  • 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 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.
  • the salt of the arylaminopurine derivative is characterized in that the salt is the hydrochloride represented by formula 3:
  • n is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5;
  • the salt is the hydrochloride represented by formula 3':
  • the hydrochloride shown in formula 3 and formula 3' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is at 8.5 ⁇ 0.2°, 11.8 ⁇ 0.2°, 19.6 ⁇ 0.2°, 25.2 ⁇ 0.2° There is a characteristic peak at 27.2 ⁇ 0.2°; more preferably, the hydrochloride shown in formula 3 and formula 3′ uses CuK ⁇ radiation, and the X-ray powder diffraction expressed at an angle of 2 ⁇ is 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°, 27.2 ⁇ 0.2°, there are characteristic peaks; further preferably, the formula 3 and formula 3' The hydrochloride uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is 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 ⁇
  • the salt of the arylamino purine derivative is a methanesulfonate salt represented by formula 4, or formula 5, or formula 6:
  • n is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5;
  • the salt is a mesylate salt represented by formula 4', or formula 5', or formula 6':
  • the methanesulfonate represented by formula 4 and formula 4' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is at 6.8 ⁇ 0.2°, 15.1 ⁇ 0.2°, 16.3 ⁇ 0.2°, 21.0 ⁇ 0.2 °, 25.0 ⁇ 0.2°, there are characteristic peaks; more preferably, the methanesulfonate shown in formula 4 and formula 4′ uses CuK ⁇ radiation, and the X-ray powder diffraction expressed at an angle of 2 ⁇ is 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 There are characteristic peaks at ⁇ 0.2° and 25.0 ⁇ 0.2°; further preferably, the methanesulfonate shown in Formula 4 and Formula 4′ uses CuK ⁇ radiation, and has an X-ray powder diffraction
  • the methanesulfonate represented by formula 5 and formula 5' uses CuK ⁇ radiation
  • the X-ray powder diffraction represented by 2 ⁇ 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°, 26.4 ⁇ 0.2°
  • the methanesulfonate represented by formula 5 and formula 5′ uses CuK ⁇ radiation
  • the X-ray powder diffraction expressed by 2 ⁇ angle is 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 ⁇
  • the methanesulfonate shown in Formula 6 and Formula 6' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is 4.9 ⁇ 0.2°, 11.5 ⁇ 0.2°, 14.5 ⁇ 0.2°, 18.5 ⁇ 0.2° There is a characteristic peak at 18.9 ⁇ 0.2°; preferably, the methanesulfonate represented by formula 6 and formula 6′ uses CuK ⁇ radiation, and the X-ray powder diffraction expressed at an angle of 2 ⁇ is 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 salt of the arylaminopurine derivative is the L-malate salt represented by formula 7:
  • n is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5;
  • the salt is L-malate represented by formula 7':
  • the L-malate shown in Formula 7 and Formula 7' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is at 7.0 ⁇ 0.2°, 9.3 ⁇ 0.2°, 17.6 ⁇ 0.2°, 19.7 ⁇ There are characteristic peaks at 0.2° and 25.9 ⁇ 0.2°; more preferably, the L-malate shown in Formula 7 and Formula 7'uses CuK ⁇ radiation, and the X-ray powder diffraction expressed at an angle of 2 ⁇ is 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° , 19.3 ⁇ 0.2
  • the salt of the arylaminopurine derivative is an L-tartrate salt represented by formula 8, or formula 9, or formula 10:
  • n is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5;
  • the salt is an L-tartrate salt represented by formula 8', or formula 9', or formula 10':
  • the L-tartrate shown in Formula 8 and Formula 8' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is at 6.9 ⁇ 0.2°, 9.1 ⁇ 0.2°, 17.8 ⁇ 0.2°, 19.4 ⁇ 0.2 °, 25.5 ⁇ 0.2°, there are characteristic peaks; more preferably, the L-tartrate shown in Formula 8 and Formula 8′ uses CuK ⁇ radiation, and the X-ray powder diffraction expressed at an angle of 2 ⁇ is at 6.9 ⁇ 0.2°, 9.1 There are characteristic peaks at ⁇ 0.2°, 12.9 ⁇ 0.2°, 13.8 ⁇ 0.2°, 16.5 ⁇ 0.2°, 17.8 ⁇ 0.2°, 19.4 ⁇ 0.2°, 20.1 ⁇ 0.2°, 25.5 ⁇ 0.2°, 26.9 ⁇ 0.2°; further preferred Specifically, the L-tartrate shown in Formula 8 and Formula 8′ uses CuK ⁇ radiation, and has an X-ray powder diffraction spectrum substantially as shown in FIG. 8.
  • the L-tartrate shown in formula 9 and formula 9' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is at 8.5 ⁇ 0.2°, 14.8 ⁇ 0.2°, 17.1 ⁇ 0.2°, 18.8 ⁇ 0.2°
  • the X-ray powder diffraction expressed by 2 ⁇ angle is 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
  • the L-tartrate shown in formula 10 and formula 10' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is at 8.3 ⁇ 0.2°, 8.9 ⁇ 0.2°, 9.5 ⁇ 0.2°, 14.8 ⁇ 0.2° There are characteristic peaks at 17.7 ⁇ 0.2°, 21.0 ⁇ 0.2°, 24.0 ⁇ 0.2°; preferably, the L-tartrate shown in formula 10 and formula 10′ uses CuK ⁇ radiation and X-ray powder expressed in 2 ⁇ angles Diffraction 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°, there are characteristic peaks; further preferably, the formula 10 and formula 10' The L-tartrate salt uses CuK ⁇ radiation and has an X-
  • the salt of the arylaminopurine derivative is the oxalate represented by formula 11 or formula 12:
  • n is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5;
  • the salt is an oxalate salt represented by formula 11' or formula 12':
  • the oxalate shown in formula 11 and formula 11' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is 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° have characteristic peaks; preferably, the oxalate shown in formula 11 and formula 11' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed at an angle of 2 ⁇ is 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°, 25.6 ⁇ 0.2° It is further preferred that the oxalate shown in Formula 11 and Formula 11′ uses CuK ⁇ radiation, and has an X-ray powder diffraction spectrum substantially as shown in FIG. 11.
  • the oxalate shown in Formula 12 and Formula 12' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is at 7.1 ⁇ 0.2°, 12.2 ⁇ 0.2°, 14.2 ⁇ 0.2°, 16.4 ⁇ 0.2°, There are characteristic peaks at 17.7 ⁇ 0.2°, 19.0 ⁇ 0.2°, and 24.4 ⁇ 0.2°; preferably, the oxalate shown in Formula 12 and Formula 12' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed at 2 ⁇ angles is There are 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°, 24.4 ⁇ 0.2°; further Preferably, the oxalate shown in Formula 12 and Formula 12' uses CuK ⁇ radiation, and has an X-ray powder diffraction spectrum substantially as shown in FIG. 12.
  • the salt of the arylaminopurine derivative is a succinate salt represented by formula 13 or formula 14:
  • n is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5;
  • the salt is a succinate represented by formula 13' or formula 14':
  • the succinate shown in formula 13 and formula 13' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is 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°
  • the succinate shown in formula 13 and formula 13' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is 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° There are characteristic peaks at 24.2 ⁇ 0.2°, 25.9
  • the succinate shown in Formula 14 and Formula 14' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is at 7.0 ⁇ 0.2°, 9.2 ⁇ 0.2°, 17.6 ⁇ 0.2°, 18.4 ⁇ 0.2°, There are characteristic peaks at 19.7 ⁇ 0.2°, 25.8 ⁇ 0.2°, and 27.3 ⁇ 0.2°; preferably, the succinate shown in Formula 14 and Formula 14' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed at 2 ⁇ 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°, 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°, There are characteristic peaks at 23.0
  • the salt of the arylaminopurine derivative is the acetate salt represented by formula 15 or formula 16:
  • n is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5;
  • the salt is an acetate salt represented by formula 15' or formula 16':
  • the acetate shown in formula 15 and formula 15' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is at 10.9 ⁇ 0.2°, 12.6 ⁇ 0.2°, 15.1 ⁇ 0.2°, 17.8 ⁇ 0.2° There are characteristic peaks at, 19.2 ⁇ 0.2°, 19.6 ⁇ 0.2°, 21.0 ⁇ 0.2°, 21.8 ⁇ 0.2°, 22.3 ⁇ 0.2°, 24.6 ⁇ 0.2°, 25.4 ⁇ 0.2°; preferably, the formula 15 and formula 15 'The acetate salt shown uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is 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°, 25.4 ⁇ 0.2° have characteristic peaks; Further preferably, the acetate salt shown
  • the acetate shown in Formula 16 and Formula 16' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is at 6.2 ⁇ 0.2°, 12.2 ⁇ 0.2°, 16.1 ⁇ 0.2°, 17.5 ⁇ 0.2°, There are characteristic peaks at 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 formula The acetate shown in 16 and formula 16' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is 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°, 28.8 ⁇ 0.2° have characteristic peaks; further preferably, the The acetate salt shown in Formula 16 and Formula 16
  • the salt of the arylaminopurine derivative is a sulfate salt represented by formula 17 or formula 18:
  • n is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5;
  • the salt is a sulfate salt represented by formula 17' or formula 18':
  • the sulfate shown in formula 17 and formula 17' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is 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°, There are characteristic peaks at 18.6 ⁇ 0.2°, 21.6 ⁇ 0.2°, and 25.7 ⁇ 0.2°; preferably, the sulfate shown in formula 17 and formula 17' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed at an angle of 2 ⁇ is 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.
  • the sulfate shown in formula 18 and formula 18' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is 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° Characteristic peaks; the sulfate shown in formula 18 and formula 18' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is 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°, 26.6 ⁇ 0.2° have characteristic peaks; further preferably, the formula 18 and formula 18 The sulfate shown in
  • the present invention provides a pharmaceutical composition comprising the salt of the arylaminopurine derivative represented by formula 2 above.
  • the present invention provides a pharmaceutical composition, which comprises the salt of the arylaminopurine derivative represented by formula 2 and pharmaceutically acceptable excipients.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically effective amount of the salt of the arylaminopurine derivative represented by formula 2 above, and pharmaceutically acceptable excipients.
  • the pharmaceutically effective amount may be 0.1-99.9% by weight, such as 1-90% by weight, 5-80% by weight, 5-65% by weight, 5-55% by weight, 5-45% by weight, or 5-40% by weight, based on the total weight of the pharmaceutical composition .
  • the term "pharmaceutically acceptable excipients” includes: solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents Agents, osmotic pressure regulators, stabilizers, glidants, flavors, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, antioxidants, chelating agents, penetration enhancers, pH adjustment Agents, buffers, plasticizers, surfactants, foaming agents, defoamers, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculants, filter aids, release inhibitors Retardant etc.
  • the present invention provides a salt or pharmaceutical composition of the arylaminopurine derivative represented by formula 2 for inhibiting FLT3, EGFR, Abl, Fyn, Hck, Lck, Lyn, Ret, Yes, VEGFR2, ALK , BTK, c-KIT, c-SRC, FGFR1, KDR, MET and PDGFR ⁇ kinase activity.
  • the present invention provides the use of the salt or pharmaceutical composition of the arylaminopurine derivative represented by formula 2 in the preparation of a drug as a protein kinase inhibitor, wherein the kinase is selected from: FLT3, EGFR, Abl, Fyn, Hck, Lck, Lyn, Ret, Yes, VEGFR2, ALK, BTK, c-KIT, c-SRC, FGFR1, KDR, MET or PDGFR ⁇ , for example, the kinase is selected from: FLT3, EGFR, Abl, Fyn, Hck , Lck, Lyn, Ret or Yes;
  • the protein kinase inhibitor drug is an anti-tumor drug
  • 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 mutations).
  • 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 mutations).
  • the present invention provides the use of the salt or pharmaceutical composition of the arylaminopurine derivative represented by formula 2 in the preparation of a medicament for the treatment or prevention of a disease; preferably, the disease is composed of FLT3, A disorder caused by one or more of EGFR, Abl, Fyn, Hck, Lck, Lyn, Ret, Yes, VEGFR2, ALK, BTK, c-KIT, c-SRC, FGFR1, KDR, MET and PDGFR ⁇ kinase; more
  • the condition is selected from non-small cell lung cancer, acute myeloid leukemia, chronic myeloid leukemia, chronic myelogenous leukemia, epidermal squamous cell carcinoma, breast cancer, colorectal cancer, liver cancer, gastric cancer, and malignant melanoma; further preferred
  • the condition is selected from human non-small cell lung cancer, human acute myeloid leukemia, human chronic myelogenous leukemia, human chronic my
  • the present invention provides the use of the salt or pharmaceutical composition of the arylaminopurine derivative represented by formula 2 in the preparation of a medicament for the treatment or prevention of acute myeloid leukemia; preferably, the acute myeloid leukemia
  • the 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, type II FLT3 inhibitor (such as Sola Fini) treatment failed relapsed and/or refractory acute myeloid leukemia, or, DEK-CAN positive and FLT3-ITD mutation coexisting acute myeloid leukemia; more preferably, the acute myeloid leukemia is FLT3- Acute myeloid leukemia with ITD high mutation; and/or the prognostic factors of the acute myeloid leukemia are 0 to 2 types; and/or the FAB classification of the acute myeloid leuk
  • the present invention provides a pharmaceutical composition for the treatment or prevention of diseases, which comprises a pharmaceutically effective amount of the salt of the arylaminopurine derivative represented by formula 2 above, and pharmaceutically acceptable excipients;
  • the disorder is caused by FLT3, EGFR, Abl, Fyn, Hck, Lck, Lyn, Ret, Yes, VEGFR2, ALK, BTK, c-KIT, c-SRC, FGFR1, KDR, MET and PDGFR ⁇ kinase
  • the disease is selected from non-small cell lung cancer, acute myeloid leukemia, chronic myelogenous leukemia, chronic myelogenous leukemia, epidermal squamous cell carcinoma, breast cancer, colorectal cancer, liver cancer , Gastric cancer, and malignant melanoma; further preferably, the disorder is selected from the group consisting of human non-small cell lung cancer, human acute myeloid leukemia, human
  • the pharmaceutically effective amount may be 0.1-99.9% by weight, such as 1-90% by weight, 5-80% by weight, 5-65% by weight, 5-55% by weight, 5-45% by weight, or 5-40% by weight, based on the total weight of the pharmaceutical composition .
  • the present invention provides a method for preparing the salt of the arylamino purine derivative represented by formula 2, which comprises combining the arylamino purine derivative represented by formula 1 with an acid in the presence of water and an organic solvent. The reaction is carried out to obtain the salt of the arylamino purine derivative represented by formula 2:
  • HA is acid
  • H 2 O is crystal water
  • n is an integer or half integer of 1-4;
  • n is an integer of 0-5 or a half integer.
  • the molar ratio of the arylamino purine derivative shown in Formula 1 to the acid is 1:1 to 1:4, preferably 1:1.2 to 1:3.5.
  • the molar ratio of the arylamino purine derivative represented by formula 1 to water is not more than 1:1 (ie, 1:1 to 1: ⁇ ), preferably 1:4 to 1: 200.
  • the reaction temperature is 0-70°C, preferably 35-45°C.
  • the reaction time is 0.5-10h, preferably 0.5-5h.
  • the reaction is carried out in the presence of a combination of water and one or more organic solvents selected from alcohols, ethers, esters, ketones, nitriles, and alkanes, preferably In the presence of C 1 -C 3 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 methanol-water , Ethanol-water, isopropanol-water, tetrahydrofuran-water, dioxane-water, acetone-water or acetonitrile-water; the volume ratio of organic solvent to water is 1:10-10:1, For example, 1:1-10:1 or 1:10-1:1, the organic solvent is the aforementioned solvents other than water.
  • organic solvents selected from alcohols, ethers, esters, ketones, nitriles, and alkanes
  • the temperature is lowered to 0-30° C., standing for 0.5-24 h to crystallize, the solid is separated, and dried to obtain the salt of the arylaminopurine derivative represented by formula 2.
  • the crystallization temperature is 5-15°C and the time is 1-10h.
  • the separation step includes separating the obtained salt of the arylaminopurine derivative represented by Formula 2 from the crystalline solution by filtering, such as suction filtration, centrifugation, and other suitable methods.
  • the drying method may adopt any suitable known method, preferably reduced pressure (vacuum) drying.
  • the specific drying conditions are, for example, the temperature is preferably 35-70°C, more preferably 40-65°C; the pressure is preferably vacuum>0.090Mpa; the drying time is preferably 5-50h, more preferably 5-10h. Regardless of the drying method used, it is advisable that the solvent residue in the product obtained meets the quality standard.
  • the present invention provides a method for preparing the salt of the arylamino purine derivative represented by formula 2, which comprises combining the arylamino purine derivative represented by formula 1 with an acid in the presence of water and an organic solvent. The reaction is carried out to obtain the salt of the arylamino purine derivative represented by formula 2:
  • HA is acid
  • H 2 O is crystal water
  • n is an integer or half integer of 1-4;
  • n is an integer or half integer of 0-5;
  • the molar ratio of the arylamino purine derivative and the acid shown in Formula 1 is 1:1 to 1:4, preferably 1:1.2 to 1:3.5;
  • the molar ratio of the arylaminopurine derivative shown in Formula 1 to water is not more than 1:1, preferably 1:4 to 1:200;
  • the reaction temperature is 0-70°C, preferably 35-45°C;
  • the reaction time is 0.5-10h, preferably 0.5-5h;
  • 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 C 1 -C 3
  • organic solvents selected from alcohols, ethers, esters, ketones, nitriles, and alkanes, preferably in the presence of C 1 -C 3
  • ketones 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, isopropyl
  • the reaction After the reaction is completed, cool to 0-30°C, preferably 5-15°C, crystallize for 0.5-24h, preferably 1-10h, separate the solid (for example, by filtration such as suction filtration, centrifugation, etc.), and optionally dry (For example, the drying temperature is 35-70°C, preferably 40-65°C; the drying pressure is vacuum>0.090MPa; the drying time is 5-50h, preferably 5-10h), the arylamine group shown in formula 2 is obtained. Salts of purine derivatives.
  • the salt of the arylaminopurine derivative is characterized in that the salt is the hydrochloride represented by formula 3':
  • the hydrochloride represented by the formula 3′ uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is 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°, 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 ⁇ There are characteristic peaks at 0.2°, 21.9 ⁇ 0.2°, 23.7 ⁇ 0.2°, 25.2 ⁇ 0.2°, 26.1 ⁇ 0.2°, 27.2 ⁇ 0.2°;
  • hydrochloride represented by formula 3' is prepared in the following manner:
  • the molar ratio of the arylamino purine derivative and hydrochloric acid represented by Formula 1 is 1:1 to 1:4, preferably 1:1.2 to 1:3.5;
  • the organic solvent is selected from acetone, isopropanol, tetrahydrofuran and acetonitrile, and the volume ratio is 1:10-10:1, for example, 1:1-10:1 or 1:10-1:1;
  • the molar ratio of the arylamino purine derivative shown in Formula 1 to water is not more than 1:1 (ie, 1:1 to 1: ⁇ ), preferably 1:4 to 1:200;
  • the reaction temperature is 35-45°C;
  • the reaction time is 0.5-10h, preferably 0.5-5h;
  • the arylamino purine derivative represented by 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, and the contents of the above documents are hereby incorporated by reference.
  • the present invention provides salts of arylaminopurine derivatives represented by formula 2, especially hydrochloride, methanesulfonate, L-malate, L-tartrate, oxalate, succinate, and acetate
  • These salts can be prepared into crystalline forms, and the solubility of the arylaminopurine derivatives shown in Formula 1 is significantly improved.
  • the salts and the crystalline forms have low hygroscopicity and can exist stably, so compared to Formula 1
  • the arylaminopurine derivatives or other salts shown are easier to prepare medicines.
  • Figure 1 is an XRPD spectrum of the hydrochloride salt of the arylaminopurine derivative obtained in Example 1.
  • FIG. 2 is a single crystal micrograph of the hydrochloride salt of the arylaminopurine derivative obtained in Example 2.
  • FIG. 2 is a single crystal micrograph of the hydrochloride salt of the arylaminopurine derivative obtained in Example 2.
  • FIG. 3 is the XRPD spectrum of the hydrochloride single crystal of the arylaminopurine derivative obtained in Example 2.
  • FIG. 4 is the XRPD spectrum of the methanesulfonate salt of the arylaminopurine derivative obtained in Example 3.
  • FIG. 4 is the XRPD spectrum of the methanesulfonate salt of the arylaminopurine derivative obtained in Example 3.
  • FIG. 5 is an XRPD spectrum of the methanesulfonate salt of the arylaminopurine derivative obtained in Example 4.
  • FIG. 5 is an XRPD spectrum of the methanesulfonate salt of the arylaminopurine derivative obtained in Example 4.
  • FIG. 6 is the XRPD spectrum of the methanesulfonate salt of the arylaminopurine derivative obtained in Example 5.
  • FIG. 7 is an XRPD spectrum of the L-malate salt of the arylaminopurine derivative obtained in Example 6.
  • Example 8 is the XRPD spectrum of the L-tartrate salt of the arylaminopurine derivative obtained in Example 7.
  • Example 10 is the XRPD spectrum of the L-tartrate salt of the arylaminopurine derivative obtained in Example 9.
  • Example 11 is the XRPD spectrum of the oxalate of the arylaminopurine derivative obtained in Example 10.
  • Example 12 is an XRPD spectrum of the oxalate of the arylaminopurine derivative obtained in Example 11.
  • FIG. 13 is an XRPD spectrum of the succinate of the arylaminopurine derivative obtained in Example 12.
  • Example 14 is the XRPD spectrum of the succinate of the arylaminopurine derivative obtained in Example 13.
  • Example 15 is the XRPD spectrum of the acetate salt of the arylaminopurine derivative obtained in Example 14.
  • Example 16 is an XRPD spectrum of the acetate salt of the arylaminopurine derivative obtained in Example 15.
  • FIG. 17 is an XRPD spectrum of the sulfate salt of the arylaminopurine derivative obtained in Example 16.
  • Example 18 is an XRPD spectrum of the sulfate salt of the arylaminopurine derivative obtained in Example 17.
  • Fig. 19 is a differential thermal-thermo-regeneration analysis (DSC-TGA) chart of the hydrochloride salt of the arylaminopurine derivative obtained in Example 1.
  • FIG. 20 is a differential scanning calorimetry (DSC) chart of the methanesulfonate salt of the arylaminopurine derivative obtained in Example 3.
  • DSC differential scanning calorimetry
  • thermogravimetric analysis (TGA) chart of the methanesulfonate salt of the arylaminopurine derivative obtained in Example 3.
  • FIG. 22 is a differential scanning calorimetry (DSC) chart of the methanesulfonate salt of the arylaminopurine derivative obtained in Example 4.
  • DSC differential scanning calorimetry
  • FIG. 23 is a thermogravimetric analysis (TGA) chart of the methanesulfonate salt of the arylaminopurine derivative obtained in Example 4.
  • TGA thermogravimetric analysis
  • FIG. 24 is a differential scanning calorimetry (DSC) chart of the methanesulfonate salt of the arylaminopurine derivative obtained in Example 5.
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • FIG. 26 is a differential thermal-thermogravimetric analysis (DSC-TGA) chart of the L-malate salt of the arylaminopurine derivative obtained in Example 6.
  • DSC-TGA differential thermal-thermogravimetric analysis
  • FIG. 27 is a differential thermal-thermogravimetric analysis (DSC-TGA) chart of the L-tartrate salt of the arylaminopurine derivative obtained in Example 7.
  • DSC-TGA differential thermal-thermogravimetric analysis
  • Fig. 28 is a differential thermal-thermogravimetric analysis (DSC-TGA) chart of the L-tartrate salt of the arylaminopurine derivative obtained in Example 8.
  • Fig. 29 is a differential thermal-thermogravimetric analysis (DSC-TGA) chart of the L-tartrate salt of the arylaminopurine derivative obtained in Example 9.
  • Fig. 30 is a DSC-TGA chart of the oxalate of the arylaminopurine derivative obtained in Example 10.
  • Fig. 31 is a DSC-TGA chart of the oxalate of the arylaminopurine derivative obtained in Example 11.
  • DSC differential scanning calorimetry
  • thermogravimetric analysis (TGA) chart of the succinate of the arylaminopurine derivative obtained in Example 12.
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • FIG. 36 is a differential scanning calorimetry (DSC) chart of the acetate salt of the arylaminopurine derivative obtained in Example 14.
  • DSC differential scanning calorimetry
  • FIG. 37 is a thermogravimetric analysis (TGA) chart of the acetate of the arylaminopurine derivative obtained in Example 14.
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • thermogravimetric analysis (TGA) chart of the acetate salt of the arylaminopurine derivative obtained in Example 15.
  • Example 40 is a DSC-TGA chart of the sulfate salt of the arylaminopurine derivative obtained in Example 16.
  • Example 41 is a DSC-TGA chart of the sulfate salt of the arylaminopurine derivative obtained in Example 17.
  • Fig. 42 is a DSC-TGA chart of the arylaminopurine derivative obtained in Preparation Example 1.
  • Test method After the instrument is equilibrated, take an appropriate amount (about 200 mg) of the test product, accurately weigh it, add it to the titration cup, use anhydrous methanol as the solvent, and directly measure with the moisture titrant, and take the average of the two measurements for each test product. value.
  • pH1.2 hydrochloric acid solution 7.65ml hydrochloric acid, add 1000ml water, shake well, and get it.
  • pH 4.5 phosphate buffer Take 6.8 g of potassium dihydrogen phosphate, dilute to 1000 ml with water, and shake well to obtain.
  • 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 to obtain.
  • Preparation of reference solution take an appropriate amount of the reference substance of formula 1 and accurately weigh it, add a solvent to dissolve and dilute to prepare a solution containing about 10 ⁇ g of the compound of formula 1 per 1 ml, measure the absorbance at a wavelength of 287 nm, and calculate it.
  • the thickness of the test product is generally about 1 mm, and the weight is accurately weighed (m2).
  • Weight gain percentage (m3-m2)/(m2-m1) ⁇ 100%
  • Deliquescence Absorb enough water to form a liquid.
  • moisture-absorbing weight gain is not less than 15%.
  • moisture absorption weight gain is less than 15% but not less than 2%.
  • moisture absorption weight gain is less than 2% but not less than 0.2%.
  • octadecyl silane bonded silica gel as filler (the applicable range of pH value should be greater than 10.0), and use 20mmol/L disodium hydrogen phosphate solution (adjust the pH value to 10.0 with sodium hydroxide)-acetonitrile (65:35) Mobile phase; detection wavelength is 287nm, column temperature is 30°C. The number of theoretical boards should not be less than 3000.
  • Determination method Take about 20 mg of sample, accurately weigh it, put it in a 100ml measuring flask, add diluent (50% methanol water) to dissolve and dilute to the mark, shake well, accurately measure 10 ⁇ l, inject it into the liquid chromatograph, and record the chromatogram ; Take another appropriate amount of reference substance and measure it in the same way. Calculate the peak area according to the external standard method to obtain.
  • diluent 50% methanol water
  • Light tube type Cu target, metal ceramic X-ray tube;
  • Scan range: 3-40°2 ⁇ ;
  • Total scanning time about 5min.
  • Light tube type Cu target, ceramic X-ray tube
  • DSC-TGA Differential thermal-thermo-regeneration analysis
  • Heating rate 10.0 (K/min);
  • Atmosphere N2, 20.0ml/min/N2, 50.0ml/min
  • Heating rate 5.0 (K/min);
  • Atmosphere N2, 40.0ml/min/N2, 60.0ml/min
  • Heating rate 5.0 (K/min);
  • test solvent 1 H-NMR, the test solvent is H 2 D.
  • Test method According to the pH value measurement method, accurately weigh 10 mg of the sample, add 10 ml of freshly boiled and cooled purified water to dissolve it, shake it well, and determine the pH value.
  • octadecylsilane-bonded silica gel as filler (model: Waters Xbridge C18 chromatographic column, length 250mm, inner diameter 4.6mm, filler particle size 5 ⁇ m), detection wavelength is 250nm, column temperature is 35°C, flow rate is 1.0 per minute ml, the mobile phase A is 0.02mol/L disodium hydrogen phosphate solution (sodium hydroxide solution adjusts the pH to 10.0), the mobile phase B is acetonitrile, the diluent is methanol, and the sample pan temperature is 4°C.
  • the assay method is required to conduct system suitability tests, prepare test solution, control solution, and sensitivity solution. Precisely measure 10 ⁇ l each of the control solution and the test solution, inject it into the liquid chromatograph, record the chromatogram, and calculate the peak area according to the self-dilution control method with correction factor.
  • Example 1 Changing the amount of concentrated hydrochloric acid used in Example 1 and repeating the process of Example 1, still only the arylaminopurine derivative ⁇ trihydrochloride ⁇ pentahydrate obtained in Example 1 can be obtained. Substituting isopropanol and tetrahydrofuran for the acetone in Example 1, and repeating the process of Example 1, the arylaminopurine derivative ⁇ trihydrochloride ⁇ pentahydrate obtained in Example 1 can also be obtained.
  • Example 2 Weigh 14.9 mg of the hydrochloride obtained in Example 1 into 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 thermal reaction kettle is sealed, it is placed in a temperature-controlled oven to perform the temperature rise and fall program.
  • the temperature program is:
  • Example 2 is the same crystal type as the crystal form obtained in Example.
  • Peak position 2 ⁇ angle (°) Relative peak intensity% 25.353 39.4 26.675 27.2 27.264 20.9
  • Example 8 L-tartrate salt of arylaminopurine derivative
  • the free alkali content is calculated by HPLC, moisture determination, the proportion of hydrogen 1 H-NMR (see table below) NMR talk can be extrapolated to the tartrate base / acid / H 2 O 1: 1 1/2 :4.
  • Example 14 Acetate salt of arylaminopurine derivative
  • Example 15 Acetate salt of arylaminopurine derivative
  • Peak position 2 ⁇ 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
  • Example 17 Sulfates of arylaminopurine derivatives
  • Peak position 2 ⁇ 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
  • Test case 1 DSC and TGA test
  • Test case 3 accelerated stability test
  • Test example 4 Hygroscopicity test
  • Test case 5 Long-term stability test
  • the inner package is a medicinal low-density polyethylene bag
  • the outer package is a polyester/aluminum/polyethylene compound bag for pharmaceutical packaging, at a temperature of 25 ⁇ 2°C and a relative humidity of 60% ⁇ 5%, respectively
  • Example 1 According to the evaluation of kinase inhibitory activity 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 FLT3, EGFR, Abl, Fyn, Hck, Lck, Lyn, Ret, Yes, VEGFR2, ALK, BTK, c-KIT, c-SRC, FGFR1, KDR, MET and PDGFR ⁇ kinase See the table below for the activity and the test results of some kinases.
  • Example 1 According to the in vivo anti-tumor experiment described in the biological evaluation of patent application WO 2011/147066, the salt samples obtained in Example 1 were tested (specifically for acute myeloid leukemia of FLT3-ITD and non-small cell lung cancer with EGFR activating mutations, respectively) , Or Ph-positive chronic myeloid leukemia).
  • the test results show that in the MV4-11 (FLT3-ITD mutation) subcutaneous tumor model experiment (refer to WO 2011/147066 Example 4 to establish the model), the sample (orally once a day for 21 days) was administered at a dose of At 5mg/kg, tumor growth can be completely inhibited, and at doses of 10mg/kg and 20mg/kg, it can cause complete tumor regression.
  • the sample can inhibit the growth of human non-small cell lung cancer HCC827 in a dose-dependent manner, at 7.5 mg/kg, 15 mg/kg, and 30 mg/kg.
  • the sample (orally once a day for 18 days) was administered at a dose of 70 mg/kg It can effectively inhibit tumor growth, and the tumor inhibition rate reaches 71.3%.
  • HA is acid
  • H 2 O is crystal water
  • n is an integer or half integer of 1-4;
  • n is an integer of 0-5 or a half integer.
  • n is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5;
  • the salt is the hydrochloride represented by formula 3':
  • the hydrochloride shown in formula 3 and formula 3' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is at 8.5 ⁇ 0.2°, 11.8 ⁇ 0.2°, 19.6 ⁇ 0.2°, 25.2 ⁇ 0.2°, 27.2 ⁇ There is a characteristic peak at 0.2°;
  • the hydrochloride shown in formula 3 and formula 3' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is at 8.5 ⁇ 0.2°, 11.8 ⁇ 0.2°, 12.6 ⁇ 0.2°, 19.6 ⁇ 0.2°, There are characteristic peaks at 20.0 ⁇ 0.2°, 23.7 ⁇ 0.2°, 25.2 ⁇ 0.2°, 27.2 ⁇ 0.2°;
  • the hydrochloride shown in formula 3 and formula 3' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is 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°, There is a characteristic peak at 27.2 ⁇ 0.2°;
  • the hydrochloride shown in Formula 3 and Formula 3' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is 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°, There is a characteristic peak at 27.2 ⁇ 0.2°;
  • the hydrochloride salt represented by formula 3 and formula 3' uses CuK ⁇ radiation, and has an X-ray powder diffraction spectrum substantially as shown in FIG. 1 or FIG. 3;
  • n is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5;
  • the salt is a mesylate salt represented by formula 4', or formula 5', or formula 6':
  • the methanesulfonate shown in formula 4 and formula 4' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is at 6.8 ⁇ 0.2°, 15.1 ⁇ 0.2°, 16.3 ⁇ 0.2°, 21.0 ⁇ 0.2°, 25.0 There is a characteristic peak at ⁇ 0.2°;
  • the methanesulfonate represented by formula 4 and formula 4' uses CuK ⁇ radiation
  • the X-ray powder diffraction represented by the angle of 2 ⁇ is 6.8 ⁇ 0.2°, 8.6 ⁇ 0.2°, 10.7 ⁇ 0.2°, 12.6 ⁇ 0.2° , 13.1 ⁇ 0.2°, 13.4 ⁇ 0.2°, 15.1 ⁇ 0.2°, 16.3 ⁇ 0.2°, 17.7 ⁇ 0.2°, 19.0 ⁇ 0.2°, 19.9 ⁇ 0.2°, 21.0 ⁇ 0.2°, 25.0 ⁇ 0.2° with characteristic peaks;
  • the methanesulfonate salt represented by formula 4 and formula 4′ uses CuK ⁇ radiation and has an X-ray powder diffraction spectrum substantially as shown in FIG. 4;
  • the methanesulfonate represented by the formula 5 and formula 5' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed by the angle of 2 ⁇ is 6.1 ⁇ 0.2°, 6.4 ⁇ 0.2°, 17.4 ⁇ 0.2°, 18.9 ⁇ 0.2°, 19.3 There are characteristic peaks at ⁇ 0.2°, 24.4 ⁇ 0.2°, and 26.4 ⁇ 0.2°;
  • the methanesulfonate represented by formula 5 and formula 5' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is 6.1 ⁇ 0.2°, 6.4 ⁇ 0.2°, 17.5 ⁇ 0.2°, 18.9 ⁇ 0.2° , 19.3 ⁇ 0.2°, 24.4 ⁇ 0.2°, 26.4 ⁇ 0.2° have characteristic peaks;
  • the methanesulfonate represented by the formula 5 and formula 5' uses CuK ⁇ radiation
  • the X-ray powder diffraction represented by the angle of 2 ⁇ 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° have characteristic peaks;
  • the methanesulfonate represented by the formula 5 and formula 5' uses CuK ⁇ radiation
  • the X-ray powder diffraction represented by the angle of 2 ⁇ 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°, 17.5 ⁇ 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;
  • the methanesulfonate salt represented by formula 5 and formula 5′ uses CuK ⁇ radiation and has an X-ray powder diffraction spectrum substantially as shown in FIG. 5;
  • the methanesulfonate represented by the formula 6 and formula 6' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed by the angle of 2 ⁇ is 4.9 ⁇ 0.2°, 11.5 ⁇ 0.2°, 14.5 ⁇ 0.2°, 18.5 ⁇ 0.2°, 18.9 There is a characteristic peak at ⁇ 0.2°;
  • the methanesulfonate shown in Formula 6 and Formula 6' uses CuK ⁇ radiation, and the X-ray powder diffraction represented by the angle of 2 ⁇ is 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°, there are characteristic peaks;
  • the methanesulfonate salt represented by Formula 6 and Formula 6′ uses CuK ⁇ radiation, and has an X-ray powder diffraction spectrum substantially as shown in FIG. 6.
  • n is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5;
  • the salt is L-malate represented by formula 7':
  • the L-malate shown in Formula 7 and Formula 7' uses CuK ⁇ radiation, and the X-ray powder diffraction represented by 2 ⁇ angles is at 7.0 ⁇ 0.2°, 9.3 ⁇ 0.2°, 17.6 ⁇ 0.2°, 19.7 ⁇ 0.2°, There is a characteristic peak at 25.9 ⁇ 0.2°;
  • the L-malate shown in Formula 7 and Formula 7' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed at 2 ⁇ angles is 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° with characteristic peaks ;
  • the L-malate shown in Formula 7 and Formula 7' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed at 2 ⁇ angles is 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°, 27.5 ⁇ 0.2 ° has a characteristic peak;
  • the L-malate shown in Formula 7 and Formula 7' uses CuK ⁇ radiation, and has an X-ray powder diffraction spectrum substantially as shown in FIG. 7.
  • n is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5;
  • the salt is an L-tartrate salt represented by formula 8', or formula 9', or formula 10':
  • the L-tartrate shown in Formula 8 and Formula 8' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is 6.9 ⁇ 0.2°, 9.1 ⁇ 0.2°, 17.8 ⁇ 0.2°, 19.4 ⁇ 0.2°, 25.5 There is a characteristic peak at ⁇ 0.2°;
  • the L-tartrate shown in Formula 8 and Formula 8' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is 6.9 ⁇ 0.2°, 9.1 ⁇ 0.2°, 12.9 ⁇ 0.2°, 13.8 ⁇ 0.2° , 16.5 ⁇ 0.2°, 17.8 ⁇ 0.2°, 19.4 ⁇ 0.2°, 20.1 ⁇ 0.2°, 25.5 ⁇ 0.2°, 26.9 ⁇ 0.2° with characteristic peaks;
  • the L-tartrate salt shown in Formula 8 and Formula 8' uses CuK ⁇ radiation, and has an X-ray powder diffraction spectrum substantially as shown in FIG. 8;
  • the L-tartrate shown in Formula 9 and Formula 9' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is at 8.5 ⁇ 0.2°, 14.8 ⁇ 0.2°, 17.1 ⁇ 0.2°, 18.8 ⁇ 0.2°, 24.6 There are characteristic peaks at ⁇ 0.2° and 26.1 ⁇ 0.2°;
  • the L-tartrate shown in Formula 9 and Formula 9' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is 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° , There is a characteristic peak at 26.1 ⁇ 0.2°;
  • the L-tartrate shown in Formula 9 and Formula 9' uses CuK ⁇ radiation, and has an X-ray powder diffraction spectrum substantially as shown in FIG. 9;
  • the L-tartrate shown in formula 10 and formula 10' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is at 8.3 ⁇ 0.2°, 8.9 ⁇ 0.2°, 9.5 ⁇ 0.2°, 14.8 ⁇ 0.2°, 17.7 There are characteristic peaks at ⁇ 0.2°, 21.0 ⁇ 0.2°, 24.0 ⁇ 0.2°;
  • the L-tartrate shown in formula 10 and formula 10' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is 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° There are characteristic peaks at 25.3 ⁇ 0.2° and 26.7 ⁇ 0.2°;
  • the L-tartrate shown in Formula 10 and Formula 10' uses CuK ⁇ radiation, and has an X-ray powder diffraction spectrum substantially as shown in FIG. 10.
  • n is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5;
  • the salt is an oxalate salt represented by formula 11' or formula 12':
  • the oxalate shown in formula 11 and formula 11' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is at 8.1 ⁇ 0.2°, 8.4 ⁇ 0.2°, 9.0 ⁇ 0.2°, 14.1 ⁇ 0.2°, 16.7 ⁇ There are characteristic peaks at 0.2°, 25.6 ⁇ 0.2°;
  • the oxalate shown in Formula 11 and Formula 11' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is at 8.1 ⁇ 0.2°, 8.4 ⁇ 0.2°, 9.0 ⁇ 0.2°, 14.1 ⁇ 0.2°, There are characteristic peaks at 14.8 ⁇ 0.2°, 16.7 ⁇ 0.2°, 17.9 ⁇ 0.2°, 18.5 ⁇ 0.2°, 19.6 ⁇ 0.2°, 23.6 ⁇ 0.2°, 25.6 ⁇ 0.2°;
  • the oxalate shown in Formula 11 and Formula 11' uses CuK ⁇ radiation, and has an X-ray powder diffraction spectrum substantially as shown in FIG. 11;
  • the oxalate shown in formula 12 and formula 12' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is at 7.1 ⁇ 0.2°, 12.2 ⁇ 0.2°, 14.2 ⁇ 0.2°, 16.4 ⁇ 0.2°, 17.7 ⁇ There are characteristic peaks at 0.2°, 19.0 ⁇ 0.2°, 24.4 ⁇ 0.2°;
  • the oxalate shown in Formula 12 and Formula 12' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is at 7.1 ⁇ 0.2°, 8.3 ⁇ 0.2°, 12.2 ⁇ 0.2°, 14.2 ⁇ 0.2°, There are characteristic peaks at 16.4 ⁇ 0.2°, 17.7 ⁇ 0.2°, 18.6 ⁇ 0.2°, 19.0 ⁇ 0.2°, 24.4 ⁇ 0.2°;
  • the oxalate shown in Formula 12 and Formula 12' uses CuK ⁇ radiation, and has an X-ray powder diffraction spectrum substantially as shown in FIG. 12.
  • n is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5;
  • the salt is a succinate represented by formula 13' or formula 14':
  • the succinate shown in formula 13 and formula 13' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is at 7.0 ⁇ 0.2°, 9.1 ⁇ 0.2°, 11.3 ⁇ 0.2°, 16.8 ⁇ 0.2°, 20.4 ⁇ There are characteristic peaks at 0.2°, 21.0 ⁇ 0.2°, and 22.4 ⁇ 0.2°;
  • the succinate shown in formula 13 and formula 13' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is at 7.0 ⁇ 0.2°, 9.1 ⁇ 0.2°, 18.5 ⁇ 0.2°, 20.4 ⁇ 0.2°, There are characteristic peaks at 21.0 ⁇ 0.2°, 22.4 ⁇ 0.2°, 27.1 ⁇ 0.2°;
  • the succinate shown in formula 13 and formula 13' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is 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°, There are characteristic peaks at 25.9 ⁇ 0.2° and 27.1 ⁇ 0.2°;
  • succinates represented by formula 13 and formula 13' use CuK ⁇ radiation and have an X-ray powder diffraction spectrum substantially as shown in FIG. 13;
  • the succinate shown in formula 14 and formula 14' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is at 7.0 ⁇ 0.2°, 9.2 ⁇ 0.2°, 17.6 ⁇ 0.2°, 18.4 ⁇ 0.2°, 19.7 ⁇ There are characteristic peaks at 0.2°, 25.8 ⁇ 0.2°, and 27.3 ⁇ 0.2°;
  • the succinate shown in formula 14 and formula 14' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is at 7.0 ⁇ 0.2°, 9.2 ⁇ 0.2°, 11.9 ⁇ 0.2°, 16.7 ⁇ 0.2°, There are characteristic peaks at 17.6 ⁇ 0.2°, 18.4 ⁇ 0.2°, 19.7 ⁇ 0.2°, 23.0 ⁇ 0.2°, 24.1 ⁇ 0.2°, 25.2 ⁇ 0.2°, 25.8 ⁇ 0.2°, 27.3 ⁇ 0.2°;
  • the succinate shown in formula 14 and formula 14' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is at 7.0 ⁇ 0.2°, 9.2 ⁇ 0.2°, 11.9 ⁇ 0.2°, 16.7 ⁇ 0.2°, There are characteristic peaks at 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°;
  • the succinates represented by Formula 14 and Formula 14' use CuK ⁇ radiation, and have an X-ray powder diffraction spectrum substantially as shown in FIG. 14.
  • n is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5;
  • the salt is an acetate salt represented by formula 15' or formula 16':
  • the acetate shown in formula 15 and formula 15' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is at 10.9 ⁇ 0.2°, 12.6 ⁇ 0.2°, 15.1 ⁇ 0.2°, 17.8 ⁇ 0.2°, 19.2 ⁇ There are characteristic peaks at 0.2°, 19.6 ⁇ 0.2°, 21.0 ⁇ 0.2°, 21.8 ⁇ 0.2°, 22.3 ⁇ 0.2°, 24.6 ⁇ 0.2°, 25.4 ⁇ 0.2°;
  • the acetate shown in Formula 15 and Formula 15' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is 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°, There is a characteristic peak at 25.4 ⁇ 0.2°;
  • the acetate salt shown in Formula 15 and Formula 15' uses CuK ⁇ radiation, and has an X-ray powder diffraction spectrum substantially as shown in FIG. 15;
  • the acetate shown in Formula 16 and Formula 16' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is at 6.2 ⁇ 0.2°, 12.2 ⁇ 0.2°, 16.1 ⁇ 0.2°, 17.5 ⁇ 0.2°, 23.4 ⁇ There are characteristic peaks at 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°;
  • the acetate shown in Formula 16 and Formula 16' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is at 6.2 ⁇ 0.2°, 8.1 ⁇ 0.2°, 9.1 ⁇ 0.2°, 12.2 ⁇ 0.2°, There are characteristic peaks at 15.0 ⁇ 0.2°, 16.1 ⁇ 0.2°, 17.5 ⁇ 0.2°, 18.2 ⁇ 0.2°, 20.7 ⁇ 0.2°, 21.5 ⁇ 0.2°, 23.4 ⁇ 0.2°, 24.8 ⁇ 0.2°, 28.8 ⁇ 0.2°;
  • the acetate salt shown in Formula 16 and Formula 16' uses CuK ⁇ radiation, and has an X-ray powder diffraction spectrum substantially as shown in FIG. 16.
  • n is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5;
  • the salt is a sulfate salt represented by formula 17' or formula 18':
  • the sulfate shown in formula 17 and formula 17' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is at 4.8 ⁇ 0.2°, 7.0 ⁇ 0.2°, 9.5 ⁇ 0.2°, 13.6 ⁇ 0.2°, There are characteristic peaks at 15.7 ⁇ 0.2°, 18.6 ⁇ 0.2°, 21.6 ⁇ 0.2°, 25.7 ⁇ 0.2°;
  • the sulfate shown in formula 17 and formula 17' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is at 4.8 ⁇ 0.2°, 7.0 ⁇ 0.2°, 9.2 ⁇ 0.2°, 9.5 ⁇ 0.2°, 13.6 There are characteristic peaks at ⁇ 0.2°, 15.7 ⁇ 0.2°, 18.6 ⁇ 0.2°, 21.6 ⁇ 0.2°, 25.7 ⁇ 0.2°;
  • the sulfate represented by formula 17 and formula 17' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is 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°, 25.7 There is a characteristic peak at ⁇ 0.2°;
  • the sulfates represented by Formula 17 and Formula 17' use CuK ⁇ radiation, and have an X-ray powder diffraction spectrum substantially as shown in FIG. 17;
  • the sulfate shown in the formula 18 and formula 18' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is 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° have characteristic peaks;
  • the sulfate shown in formula 18 and formula 18' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is at 8.6 ⁇ 0.2°, 9.6 ⁇ 0.2°, 15.7 ⁇ 0.2°, 17.1 ⁇ 0.2°, 19.3 There are characteristic peaks at ⁇ 0.2°, 20.0 ⁇ 0.2°, 26.6 ⁇ 0.2°;
  • the sulfate shown in Formula 18 and Formula 18' uses CuK ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is at 8.6 ⁇ 0.2°, 9.6 ⁇ 0.2°, 15.7 ⁇ 0.2°, 16.5 ⁇ 0.2°, 17.1 There are characteristic peaks at ⁇ 0.2°, 19.3 ⁇ 0.2°, 20.0 ⁇ 0.2°, 21.9 ⁇ 0.2°, 23.5 ⁇ 0.2°, 24.4 ⁇ 0.2°, 26.6 ⁇ 0.2°;
  • the sulfates represented by Formula 18 and Formula 18' use CuK ⁇ radiation, and have an X-ray powder diffraction spectrum substantially as shown in FIG. 18.
  • a pharmaceutical composition comprising the salt of the arylaminopurine derivative represented by Formula 2 of any one of the technical solutions 1-10.
  • kinase is selected from: FLT3, EGFR, Abl, Fyn, Hck, Lck, Lyn, Ret, Yes, VEGFR2, ALK, BTK, c-KIT, c-SRC, FGFR1, KDR, MET or PDGFR ⁇ ;
  • the protein kinase inhibitor drug is an anti-tumor drug
  • the tumor is selected from the group consisting of non-small cell lung cancer, acute myeloid leukemia, chronic myeloid leukemia, chronic myelogenous leukemia, epidermal squamous cell carcinoma, breast cancer, colorectal cancer , Liver cancer, gastric cancer, and malignant melanoma, more preferably leukemia or lung cancer, still more preferably acute myeloid leukemia or non-small cell lung cancer, still more preferably FLT3 mutation-positive acute myeloid leukemia (such as acute myeloid leukemia of FLT3-ITD Leukemia), Ph-positive chronic myeloid leukemia, or non-small cell lung cancer with EGFR activating mutations.
  • non-small cell lung cancer acute myeloid leukemia, chronic myeloid leukemia, chronic myelogenous leukemia, epidermal squamous cell carcinoma, breast cancer, colorectal cancer , Liver cancer, gas
  • HA is acid
  • H 2 O is crystal water
  • n is an integer or half integer of 1-4;
  • n is an integer of 0-5 or a half integer.
  • the reaction temperature is 0-70°C, preferably 35-45°C;
  • 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 C 1 -C 3
  • organic solvents selected from alcohols, ethers, esters, ketones, nitriles, and alkanes, preferably in the presence of C 1 -C 3
  • ketones 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, isopropyl

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Abstract

本发明提供一种式2所示的芳胺基嘌呤衍生物的盐及其制备方法和应用。本发明所得盐结晶性好，相对于游离形式的溶解度有显著改善，优选盐及晶型吸湿性小且能够稳定存在，因此相对于游离形式的芳胺基嘌呤衍生物或其他盐更易于成药。

Description

一种芳胺基嘌呤衍生物的盐及其制备方法和应用 技术领域
本发明属于药物化学领域，具体涉及到一种芳胺基嘌呤衍生物的盐及其制备方法和应用。
背景技术
化合物1，化学名为：9-异丙基-2-(4-(4-甲基哌嗪-1-基)苯胺基)-8-(吡啶-3-胺基)-9H-嘌呤，为芳胺基嘌呤衍生物，是一种新型多靶点蛋白激酶抑制剂，主要作用靶标包括FLT3、EGFR、Abl、Fyn、Hck、Lck、Lyn、Ret、Yes等。临床前药理实验显示其对白血病、非小细胞肺癌等多种肿瘤，特别是FLT3突变阳性如FLT3-ITD(internal tandem duplication,内部串联突变)的急性髓性白血病(AML)和EGFR激活突变的非小细胞肺癌(NSCLC)，具有很好的抑制作用且有良好的耐受性，其作用机制是通过抑制多个靶标或信号通路发挥其抗肿瘤作用，特别是针对AML主要通过抑制FLT3信号通路发挥其抗白血病作用，针对NSCLC主要通过抑制EGFR信号通路发挥其抗肿瘤作用。对人白血病(MV4-11、K562)和肺癌(HCC827、PC-9)裸小鼠移植瘤有明显疗效，在抗白血病方面，活性优于舒尼替尼，在抗肺癌方面，活性与吉非替尼相当。
Figure PCTCN2021073285-appb-000001
WO 2011/147066涉及该芳胺基嘌呤衍生物，对系列衍生物游离形式的制备方法及医药用途进行了公开，并未对通式化合物及具体化合物的盐进行阐述和制备。
本发明人发现，式1化合物不溶于水，这严重影响了其成药性。因此，有必要对式1化合物结构进行改进，使其满足制药需求。
发明内容
为解决上述问题，本发明人对式1所示的芳胺基嘌呤衍生物的盐进行了大量研究，以期找到溶解性好、吸湿性低且稳定性好的满足制药需求的药物形式。
因此，本发明一方面提供了一种式2所示的芳胺基嘌呤衍生物的盐：
Figure PCTCN2021073285-appb-000002
其中，
HA是酸；
H 2O为结晶水；
m为1-4的整数或半整数，即，m＝1、1.5、2、2.5、3、3.5或4；
n为0-5的整数或半整数，即，n＝0、0.5、1、1.5、2、2.5、3、3.5、4、4.5或5。
优选地，所述酸选自：盐酸、甲磺酸、L-苹果酸、L-酒石酸、草酸、琥珀酸、醋酸或硫酸；优选为：盐酸、L-苹果酸、L-酒石酸、草酸、琥珀酸、醋酸或硫酸；更优选为：盐酸、L-苹果酸、L-酒石酸、草酸、琥珀酸或醋酸；进一步优选为：盐酸。
在本发明一种实施方案中，所述芳胺基嘌呤衍生物的盐，其特征在于，所述盐为式3所示的盐酸盐：
Figure PCTCN2021073285-appb-000003
n选自0、0.5、1、1.5、2、2.5、3、3.5、4、4.5或5；
优选地，所述盐为式3'所示的盐酸盐：
Figure PCTCN2021073285-appb-000004
优选地，所述式3和式3'所示的盐酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在8.5±0.2°、11.8±0.2°、19.6±0.2°、25.2±0.2°、27.2±0.2°处具有特征峰；更优选地，所述式3和式3'所示的盐酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在8.5±0.2°、11.8±0.2°、12.6±0.2°、19.6±0.2°、20.0±0.2°、23.7±0.2°、25.2±0.2°、27.2±0.2°处具有特征峰；进一步优选地，所述式3和式3'所示的盐酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在7.3±0.2°、8.5±0.2°、9.0±0.2°、11.8±0.2°、12.6±0.2°、14.3±0.2°、18.1±0.2°、19.6±0.2°、20.0±0.2°、21.1±0.2°、21.9±0.2°、23.7±0.2°、25.2±0.2°、26.1±0.2°、27.2±0.2°或者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°处具有特征峰；更进一步优选地，所述式3和式3'所示的盐酸盐使用CuKα辐射，具有基本上如图1或图3所示的X射线粉末衍射谱图。
优选地，所述式3和式3'所示的盐酸盐的单晶使用CuKα辐射，属三斜晶系，
Figure PCTCN2021073285-appb-000005
空间群，其单胞参数为：{
Figure PCTCN2021073285-appb-000006
α＝93.2215(5)°,β＝95.3039(6)°,γ＝91.9554(6)°,
Figure PCTCN2021073285-appb-000007
}。
在本发明一种实施方案中，所述芳胺基嘌呤衍生物的盐为式4、或式5、或式6所示的甲磺酸盐：
Figure PCTCN2021073285-appb-000008
n选自0、0.5、1、1.5、2、2.5、3、3.5、4、4.5或5；
优选地，所述盐为式4'、或式5'、或式6'所示的甲磺酸盐：
Figure PCTCN2021073285-appb-000009
优选地，所述式4和式4'所示的甲磺酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在6.8±0.2°、15.1±0.2°、16.3±0.2°、21.0±0.2°、25.0±0.2°处具有特征峰；更优选地，所述式4和式4'所示的甲磺酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在6.8±0.2°、8.6±0.2°、10.7±0.2°、12.6±0.2°、13.1±0.2°、13.4±0.2°、15.1±0.2°、16.3±0.2°、17.7±0.2°、19.0±0.2°、19.9±0.2°、21.0±0.2°、25.0±0.2°处具有特征峰；进一步优选地，所述式4和式4'所示的甲磺酸盐使用CuKα辐射，具有基本上如图4所示的X射线粉末衍射谱图。
或，所述式5和式5'所示的甲磺酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在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°或者6.1±0.2°、6.4±0.2°、17.5±0.2°、18.9±0.2°、19.3±0.2°、24.4±0.2°、26.4±0.2°处具有特征峰；优选地，所述式5和式5'所示的甲磺酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在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°或者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°处具有特征峰；进一步优选地，所述式5和式5'所示的甲磺酸盐使用CuKα辐射，具有基本上如图5所示的X射线粉末衍射谱图。
或，所述式6和式6'所示的甲磺酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在4.9±0.2°、11.5±0.2°、14.5±0.2°、18.5±0.2°、18.9±0.2°处具有特征峰；优选地，所述式6和式6'所示的甲磺酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在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°处具有特征峰；进一步优选地，所述式6和式6'所示的甲磺酸盐使用CuKα辐射，具有基本上如图6所示的X射线粉末衍射谱图。
在本发明一种实施方案中，所述芳胺基嘌呤衍生物的盐为式7所示的L-苹果 酸盐：
Figure PCTCN2021073285-appb-000010
n选自0、0.5、1、1.5、2、2.5、3、3.5、4、4.5或5；
优选地，所述盐为式7'所示的L-苹果酸盐：
Figure PCTCN2021073285-appb-000011
优选地，所述式7和式7'所示的L-苹果酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在7.0±0.2°、9.3±0.2°、17.6±0.2°、19.7±0.2°、25.9±0.2°处具有特征峰；更优选地，所述式7和式7'所示的L-苹果酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在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°或者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°处具有特征峰；进一步优选地，所述式7和式7'所示的L-苹果酸盐使用CuKα辐射，具有基本上如图7所示的X射线粉末衍射谱图。
在本发明一种实施方案中，所述芳胺基嘌呤衍生物的盐为式8、或式9、或式10所示的L-酒石酸盐：
Figure PCTCN2021073285-appb-000012
n选自0、0.5、1、1.5、2、2.5、3、3.5、4、4.5或5；
优选地，所述盐为式8'、或式9'、或式10'所示的L-酒石酸盐：
Figure PCTCN2021073285-appb-000013
优选地，所述式8和式8'所示的L-酒石酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在6.9±0.2°、9.1±0.2°、17.8±0.2°、19.4±0.2°、25.5±0.2°处具有特征峰；更优选地，所述式8和式8'所示的L-酒石酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在6.9±0.2°、9.1±0.2°、12.9±0.2°、13.8±0.2°、16.5±0.2°、17.8±0.2°、19.4±0.2°、20.1±0.2°、25.5±0.2°、26.9±0.2°处具有特征峰；进一步优选地，所述式8和式8'所示的L-酒石酸盐使用CuKα辐射，具有基本上如图8所示的X射线粉末衍射谱图。
或，所述式9和式9'所示的L-酒石酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在8.5±0.2°、14.8±0.2°、17.1±0.2°、18.8±0.2°、24.6±0.2°、26.1±0.2°处具有特征峰；所述式9和式9'所示的L-酒石酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在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°处具有特征峰；进一步优选地，所述式9和式9'所示的L-酒石酸盐使用CuKα辐射，具有基本上如图9所示的X射线粉末衍射谱图。
或，所述式10和式10'所示的L-酒石酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在8.3±0.2°、8.9±0.2°、9.5±0.2°、14.8±0.2°、17.7±0.2°、21.0±0.2°、24.0±0.2°处具有特征峰；优选地，所述式10和式10'所示的L-酒石酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在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°处具有特征峰；进一步优选地，所述式10和式10'所示的L-酒石酸盐使用CuKα辐射，具有基本上如图10所示的X射线粉末衍射谱图。
在本发明一种实施方案中，所述芳胺基嘌呤衍生物的盐为式11、或式12所示的草酸盐：
Figure PCTCN2021073285-appb-000014
n选自0、0.5、1、1.5、2、2.5、3、3.5、4、4.5或5；
优选地，所述盐为式11'、或式12'所示的草酸盐：
Figure PCTCN2021073285-appb-000015
优选地，所述式11和式11'所示的草酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在8.1±0.2°、8.4±0.2°、9.0±0.2°、14.1±0.2°、16.7±0.2°、25.6±0.2°处具有特征峰；优选地，所述式11和式11'所示的草酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在8.1±0.2°、8.4±0.2°、9.0±0.2°、14.1±0.2°、14.8±0.2°、16.7±0.2°、17.9±0.2°、18.5±0.2°、19.6±0.2°、23.6±0.2°、25.6±0.2°处具有特征峰；进一步优选地，所述式11和式11'所示的草酸盐使用CuKα辐射，具有基本上如图11所示的X射线粉末衍射谱图。
或，所述式12和式12'所示的草酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在7.1±0.2°、12.2±0.2°、14.2±0.2°、16.4±0.2°、17.7±0.2°、19.0±0.2°、24.4±0.2°处具有特征峰；优选地，所述式12和式12'所示的草酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在7.1±0.2°、8.3±0.2°、12.2±0.2°、14.2±0.2°、16.4±0.2°、17.7±0.2°、18.6±0.2°、19.0±0.2°、24.4±0.2°处具有特征峰；进一步优选地，所述式12和式12'所示的草酸盐使用CuKα辐射，具有基本上如图12所示的X射线粉末衍射谱图。
在本发明一种实施方案中，所述芳胺基嘌呤衍生物的盐为式13、或式14所示的琥珀酸盐：
Figure PCTCN2021073285-appb-000016
n选自0、0.5、1、1.5、2、2.5、3、3.5、4、4.5或5；
优选地，所述盐为式13'、或式14'所示的琥珀酸盐：
Figure PCTCN2021073285-appb-000017
优选地，所述式13和式13'所示的琥珀酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在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°或者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°处具有特征峰；优选地，所述式13和式13'所示的琥珀酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在7.0±0.2°、9.1±0.2°、11.3±0.2°、13.1±0.2°、13.8±0.2°、14.4±0.2°、16.0±0.2°、16.8±0.2°、17.7±0.2°、18.5±0.2°、20.4±0.2°、21.0±0.2°、22.4±0.2°、24.2±0.2°、25.9±0.2°、27.1±0.2°处具有特征峰；进一步优选地，所述式13和式13'所示的琥珀酸盐使用CuKα辐射，具有基本上如图13所示的X射线粉末衍射谱图。
或，所述式14和式14'所示的琥珀酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在7.0±0.2°、9.2±0.2°、17.6±0.2°、18.4±0.2°、19.7±0.2°、25.8±0.2°、27.3±0.2°处具有特征峰；优选地，所述式14和式14'所示的琥珀酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在7.0±0.2°、9.2±0.2°、11.9±0.2°、16.7±0.2°、17.6±0.2°、18.4±0.2°、19.7±0.2°、23.0±0.2°、24.1±0.2°、25.2±0.2°、25.8±0.2°、27.3±0.2°或者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°处具有特征峰；进一步优选地，所述式14和式14'所示的琥珀酸盐使用CuKα辐射，具有基本上如图14所示的X射线粉末衍射谱图。
在本发明一种实施方案中，所述芳胺基嘌呤衍生物的盐为式15、或式16所 示的醋酸盐：
Figure PCTCN2021073285-appb-000018
n选自0、0.5、1、1.5、2、2.5、3、3.5、4、4.5或5；
优选地，所述盐为式15'、或式16'所示的醋酸盐：
Figure PCTCN2021073285-appb-000019
优选地，所述式15和式15'所示的醋酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在10.9±0.2°、12.6±0.2°、15.1±0.2°、17.8±0.2°、19.2±0.2°、19.6±0.2°、21.0±0.2°、21.8±0.2°、22.3±0.2°、24.6±0.2°、25.4±0.2°处具有特征峰；优选地，所述式15和式15'所示的醋酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在6.3±0.2°、8.9±0.2°、10.9±0.2°、11.5±0.2°、12.2±0.2°、12.6±0.2°、15.1±0.2°、17.8±0.2°、19.2±0.2°、19.6±0.2°、21.0±0.2°、21.8±0.2°、22.3±0.2°、24.6±0.2°、25.4±0.2°处具有特征峰；进一步优选地，所述式15和式15'所示的醋酸盐使用CuKα辐射，具有基本上如图15所示的X射线粉末衍射谱图。
或，所述式16和式16'所示的醋酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在6.2±0.2°、12.2±0.2°、16.1±0.2°、17.5±0.2°、23.4±0.2°、24.8±0.2°或者6.2±0.2°、12.2±0.2°、17.5±0.2°、21.5±0.2°、23.4±0.2°、24.8±0.2°处具有特征峰；优选地，所述式16和式16'所示的醋酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在6.2±0.2°、8.1±0.2°、9.1±0.2°、12.2±0.2°、15.0±0.2°、16.1±0.2°、17.5±0.2°、18.2±0.2°、20.7±0.2°、21.5±0.2°、23.4±0.2°、24.8±0.2°、28.8±0.2°处具有特征峰；进一步优选地，所述式16和式16'所示的醋酸盐使用CuKα辐射，具有基本上如图16所示的X射线粉末衍射谱图。
在本发明一种实施方案中，所述芳胺基嘌呤衍生物的盐为式17、或式18所 示的硫酸盐：
Figure PCTCN2021073285-appb-000020
n选自0、0.5、1、1.5、2、2.5、3、3.5、4、4.5或5；
优选地，所述盐为式17'、或式18'所示的硫酸盐：
Figure PCTCN2021073285-appb-000021
优选地，所述式17和式17'所示的硫酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在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°或者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°处具有特征峰；优选地，所述式17和式17'所示的硫酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在4.8±0.2°、7.0±0.2°、8.6±0.2°、9.2±0.2°、9.5±0.2°、11.6±0.2°、12.8±0.2°、13.6±0.2°、15.7±0.2°、17.6±0.2°、18.6±0.2°、20.5±0.2°、21.6±0.2°、23.8±0.2°、25.7±0.2°处具有特征峰；进一步优选地，所述式17和式17'所示的硫酸盐使用CuKα辐射，具有基本上如图17所示的X射线粉末衍射谱图。
或，所述式18和式18'所示的硫酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在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°或者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°处具有特征峰；所述式18和式18'所示的硫酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在8.6±0.2°、9.6±0.2°、15.7±0.2°、16.5±0.2°、17.1±0.2°、19.3±0.2°、20.0±0.2°、21.9±0.2°、23.5±0.2°、24.4±0.2°、26.6±0.2°处具有特征峰；进一步优选地，所述式18和式18'所示的硫酸盐使用CuKα辐射，具有基本上如图18所示的X射线粉末衍射谱图。
另一方面，本发明提供一种药物组合物，其包含前述式2所示的芳胺基嘌呤衍生物的盐。
另一方面，本发明提供一种药物组合物，其包含前述式2所示的芳胺基嘌呤衍生物的盐，以及药用可接受的辅料。
另一方面，本发明提供一种药物组合物，其包含药用有效量的前述式2所示的芳胺基嘌呤衍生物的盐，以及药用可接受的辅料。药用有效量可以是0.1-99.9wt％，例如1-90wt％、5-80wt％、5-65wt％、5-55wt％、5-45wt％或5-40wt％，基于药物组合物的总重量。
在本申请的上下文中，术语“药用可接受的辅料”包括：溶剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏着剂、抗氧剂、螯合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、助滤剂、释放阻滞剂等。本领域技术人员可根据实际需要选择具体的药用可接受的辅料。有关辅料的知识是本领域技术人员众所周知的，例如可以参考《药剂学》(崔福德主编，第5版，人民卫生出版社，2003)。
又一方面，本发明提供了前述式2所示的芳胺基嘌呤衍生物的盐或药物组合物用于抑制FLT3、EGFR、Abl、Fyn、Hck、Lck、Lyn、Ret、Yes、VEGFR2、ALK、BTK、c-KIT、c-SRC、FGFR1、KDR、MET和PDGFRα激酶中一个或多个的活性的用途。
又一方面，本发明提供了前述式2所示的芳胺基嘌呤衍生物的盐或药物组合物用于制备作为蛋白激酶抑制剂药物的用途，所述激酶选自：FLT3、EGFR、Abl、Fyn、Hck、Lck、Lyn、Ret、Yes、VEGFR2、ALK、BTK、c-KIT、c-SRC、FGFR1、KDR、MET或PDGFRα，例如所述激酶选自：FLT3、EGFR、Abl、Fyn、Hck、Lck、Lyn、Ret或Yes；
优选地，所述蛋白激酶抑制剂药物为抗肿瘤药物，所述肿瘤优选白血病或肺癌，更优选为急性髓性白血病如FLT3突变阳性的急性髓性白血病(进一步如FLT3-ITD的急性髓性白血病)、慢性髓性白血病(如Ph阳性的慢性髓性白血病)、或非小细胞肺癌(如EGFR激活突变的非小细胞肺癌)。
再一方面，本发明提供了前述式2所示的芳胺基嘌呤衍生物的盐或药物组合物在制备用于治疗或预防病症的药物中的用途；优选地，所述病症是由FLT3、EGFR、Abl、Fyn、Hck、Lck、Lyn、Ret、Yes、VEGFR2、ALK、BTK、c-KIT、c-SRC、FGFR1、KDR、MET和PDGFRα激酶中的一个或多于一个导致的病症； 更优选地，所述病症选自非小细胞肺癌、急性髓性白血病、慢性粒细胞白血病、慢性髓性白血病、表皮鳞癌、乳腺癌、结直肠癌、肝癌、胃癌、和恶性黑色素瘤；进一步优选地，所述病症选自人非小细胞肺癌、人急性髓性白血病、人慢性粒细胞白血病、人慢性髓性白血病、人表皮鳞癌、人乳腺癌、人结直肠癌、人肝癌、人胃癌、和人恶性黑色素瘤。
再一方面，本发明提供了前述式2所示的芳胺基嘌呤衍生物的盐或药物组合物在制备用于治疗或预防急性髓性白血病的药物中的用途；优选地，所述急性髓性白血病选自复发和/或难治性急性髓性白血病，或者，所述急性髓性白血病选自FLT3-ITD突变和/或TKD突变的急性髓性白血病，II型FLT3抑制剂(例如索拉非尼)治疗失败的复发和/或难治性急性髓性白血病，或者，DEK-CAN阳性与FLT3-ITD突变同时存在的急性髓性白血病；更优选地，所述急性髓性白血病为FLT3-ITD high突变的急性髓性白血病；和/或所述急性髓性白血病的预后不良因素为0～2种；和/或所述急性髓性白血病的FAB分型为M2、M4、M5型，优选M5型。更进一步地，前述在制备用于治疗或预防急性髓性白血病的药物中的用途详述于专利申请PCT/CN2020/127449中，在此将该专利申请PCT/CN2020/127449的公开内容并入这里，如同在本申请中公开的一样。
另一方面，本发明提供一种用于治疗或预防病症的药物组合物，其包含药用有效量的前述式2所示的芳胺基嘌呤衍生物的盐，以及药用可接受的辅料；优选地，所述病症是由FLT3、EGFR、Abl、Fyn、Hck、Lck、Lyn、Ret、Yes、VEGFR2、ALK、BTK、c-KIT、c-SRC、FGFR1、KDR、MET和PDGFRα激酶中的一个或多于一个导致的病症；更优选地，所述病症选自非小细胞肺癌、急性髓性白血病、慢性粒细胞白血病、慢性髓性白血病、表皮鳞癌、乳腺癌、结直肠癌、肝癌、胃癌、和恶性黑色素瘤；进一步优选地，所述病症选自人非小细胞肺癌、人急性髓性白血病、人慢性粒细胞白血病、人慢性髓性白血病、人表皮鳞癌、人乳腺癌、人结直肠癌、人肝癌、人胃癌、和人恶性黑色素瘤。药用有效量可以是0.1-99.9wt％，例如1-90wt％、5-80wt％、5-65wt％、5-55wt％、5-45wt％或5-40wt％，基于药物组合物的总重量。
又一方面，本发明提供了一种式2所示的芳胺基嘌呤衍生物的盐的制备方法，包括将式1所示的芳胺基嘌呤衍生物与酸在水和有机溶剂的存在下进行反应，得到式2所示的芳胺基嘌呤衍生物的盐：
Figure PCTCN2021073285-appb-000022
其中，
HA是酸；
H 2O为结晶水；
m为1-4的整数或半整数；
n为0-5的整数或半整数。
根据本发明的制备方法，所述式1所示的芳胺基嘌呤衍生物与酸的摩尔比为1:1～1:4，优选为1:1.2～1:3.5。
根据本发明的制备方法，所述式1所示的芳胺基嘌呤衍生物与水的摩尔比例不大于1:1(即，1:1～1:∞)，优选为1:4～1:200。
根据本发明的制备方法，反应温度为0-70℃，优选35-45℃。
根据本发明的制备方法，反应时间为0.5-10h，优选0.5-5h。
根据本发明的制备方法，反应在水和选自醇类、醚类、酯类、酮类、腈类、和烷烃类的有机溶剂中的一种或者多种的组合的存在下进行，优选地在C 1-C 3的低级醇和水的存在下、在酮类和水的存在下，在腈类和水的存在下，或者在醚类和水的存在下进行，更优选地在甲醇-水、乙醇-水、异丙醇-水、四氢呋喃-水、二氧六环-水、丙酮-水或乙腈-水的存在下进行；有机溶剂与水用量体积比为1:10～10:1，例如1:1～10:1或1:10～1:1，所述有机溶剂为前述除水之外的其它溶剂。
根据本发明的制备方法，所述反应进行完毕，降温至0-30℃，静置析晶0.5～24h，分离固体，干燥，得式2所示的芳胺基嘌呤衍生物的盐。优选地，析晶温度为5-15℃，时间为1-10h。
根据本发明的制备方法，所述分离步骤包括采用过滤如抽滤、离心等适宜的方法将所得式2所示的芳胺基嘌呤衍生物的盐从结晶液中分离出来。
根据本发明的制备方法，所述干燥方法可采用任何适宜的已知方法，优选为减压(真空)干燥。具体的干燥条件是，例如，温度优选35～70℃，更优选为40～65℃；压力优选为真空度＞0.090Mpa；干燥时间优选为5～50h，更优选为5～10h。无论采用何种干燥手段，都以所得产品中溶剂残留量符合质量标准为宜。
再一方面，本发明提供了一种式2所示的芳胺基嘌呤衍生物的盐的制备方法，包括将式1所示的芳胺基嘌呤衍生物与酸在水和有机溶剂的存在下进行反应，得到式2所示的芳胺基嘌呤衍生物的盐：
Figure PCTCN2021073285-appb-000023
其中，
HA是酸；
H 2O为结晶水；
m为1-4的整数或半整数；
n为0-5的整数或半整数；
其中：
所述式1所示的芳胺基嘌呤衍生物与酸的摩尔比为1:1～1:4，优选为1:1.2～1:3.5；
所述式1所示的芳胺基嘌呤衍生物与水的摩尔比例不大于1:1，优选为1:4～1:200；
反应温度为0-70℃，优选35-45℃；
反应时间为0.5-10h，优选0.5-5h；
反应在水和选自醇类、醚类、酯类、酮类、腈类、和烷烃类的有机溶剂中的一种或者多种的组合的存在下进行，优选地在C 1-C 3的低级醇和水的存在下、在酮类和水的存在下，在腈类和水的存在下，或者在醚类和水的存在下进行，更优选地在甲醇-水、乙醇-水、异丙醇-水、四氢呋喃-水、二氧六环-水、丙酮-水或乙腈-水的存在下进行；有机溶剂与水用量体积比为1:10～10:1，例如1:1～10:1或1:10～1:1，所述有机溶剂为前述除水之外的其它溶剂；
所述反应进行完毕，降温至0-30℃，优选地5-15℃，析晶0.5～24h，优选地1-10h，分离固体(例如通过过滤如抽滤、离心等)，任选地干燥(例如，干燥温度为35～70℃，优选为40～65℃；干燥压力为真空度＞0.090MPa；干燥时间为5～50h，优选为5～10h)，得式2所示的芳胺基嘌呤衍生物的盐。
在一种优选的制备式2所示的芳胺基嘌呤衍生物的盐的方法中，将式1所示的芳胺基嘌呤衍生物和纯化水(摩尔倍数为4-200)、适量有机溶剂(甲醇、乙 醇、异丙醇、四氢呋喃、二氧六环、丙酮或乙腈中任意一种)加入反应器中，搅拌升温至35-45℃后，向反应器中流加入酸(摩尔倍数为1.2-3.5)，加完酸后，再加入适量有机溶剂，保持温度35-45℃，继续反应0.5-5h，然后搅拌降温至5-15℃析晶1-10h，过滤或离心，得式2所示的芳胺基嘌呤衍生物的盐。
在本发明一种实施方案中，所述芳胺基嘌呤衍生物的盐，其特征在于，所述盐为式3'所示的盐酸盐：
Figure PCTCN2021073285-appb-000024
优选地，所述式3'所示的盐酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在7.3±0.2°、8.5±0.2°、9.0±0.2°、11.8±0.2°、12.6±0.2°、14.3±0.2°、18.1±0.2°、19.6±0.2°、20.0±0.2°、21.1±0.2°、21.9±0.2°、23.7±0.2°、25.2±0.2°、26.1±0.2°、27.2±0.2°或者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°处具有特征峰；
式3'所示的盐酸盐是通过下述方式制备的：
(1)将式1所示的芳胺基嘌呤衍生物与盐酸在水和有机溶剂的存在下进行反应，
Figure PCTCN2021073285-appb-000025
所述式1所示的芳胺基嘌呤衍生物与盐酸的摩尔比为1:1～1:4，优选为1:1.2～1:3.5；
优选地，有机溶剂选自丙酮、异丙醇、四氢呋喃和乙腈，体积比为1:10～10:1，例如1:1～10:1或1:10～1:1；
所述式1所示的芳胺基嘌呤衍生物与水的摩尔比例不大于1:1(即，1:1～1: ∞)，优选为1:4～1:200；
反应温度为35-45℃；
反应时间为0.5-10h，优选0.5-5h；
(2)所述反应进行完毕后，降温至5-15℃，析晶0.5～24h，分离固体(通过过滤如抽滤、离心等)，洗涤，干燥而得到式3'所示的盐酸盐。
式1所示的芳胺基嘌呤衍生物可参照现有技术公开方法，如专利文献WO2011/147066记载方法进行制备，上述文献内容在此引入作为参考。
有益效果
本发明提供式2所示的芳胺基嘌呤衍生物的盐，尤其是盐酸盐、甲磺酸盐、L-苹果酸盐、L-酒石酸盐、草酸盐、琥珀酸盐、醋酸盐和硫酸盐，该些盐可以制备成晶型，相对于式1所示的芳胺基嘌呤衍生物的溶解度有显著改善，优选盐及晶型吸湿性小且能够稳定存在，因此相对于式1所示的芳胺基嘌呤衍生物或其他盐更易于成药。
附图说明
图1为实施例1所得芳胺基嘌呤衍生物的盐酸盐的XRPD谱图。
图2为实施例2所得芳胺基嘌呤衍生物的盐酸盐的单晶显微照片。
图3为实施例2所得芳胺基嘌呤衍生物的盐酸盐单晶的XRPD谱图。
图4为实施例3所得芳胺基嘌呤衍生物的甲磺酸盐的XRPD谱图。
图5为实施例4所得芳胺基嘌呤衍生物的甲磺酸盐的XRPD谱图。
图6为实施例5所得芳胺基嘌呤衍生物的甲磺酸盐的XRPD谱图。
图7为实施例6所得芳胺基嘌呤衍生物的L-苹果酸盐的XRPD谱图。
图8为实施例7所得芳胺基嘌呤衍生物的L-酒石酸盐的XRPD谱图。
图9为实施例8所得芳胺基嘌呤衍生物的L-酒石酸盐的XRPD谱图。
图10为实施例9所得芳胺基嘌呤衍生物的L-酒石酸盐的XRPD谱图。
图11为实施例10所得芳胺基嘌呤衍生物的草酸盐的XRPD谱图。
图12为实施例11所得芳胺基嘌呤衍生物的草酸盐的XRPD谱图。
图13为实施例12所得芳胺基嘌呤衍生物的琥珀酸盐的XRPD谱图。
图14为实施例13所得芳胺基嘌呤衍生物的琥珀酸盐的XRPD谱图。
图15为实施例14所得芳胺基嘌呤衍生物的醋酸盐的XRPD谱图。
图16为实施例15所得芳胺基嘌呤衍生物的醋酸盐的XRPD谱图。
图17为实施例16所得芳胺基嘌呤衍生物的硫酸盐的XRPD谱图。
图18为实施例17所得芳胺基嘌呤衍生物的硫酸盐的XRPD谱图。
图19为实施例1所得芳胺基嘌呤衍生物的盐酸盐的差热-热重联用分析(DSC-TGA)图。
图20为实施例3所得芳胺基嘌呤衍生物的甲磺酸盐的差示扫描量热(DSC)图。
图21为实施例3所得芳胺基嘌呤衍生物的甲磺酸盐的热重分析(TGA)图。
图22为实施例4所得芳胺基嘌呤衍生物的甲磺酸盐的差示扫描量热(DSC)图。
图23为实施例4所得芳胺基嘌呤衍生物的甲磺酸盐的热重分析(TGA)图。
图24为实施例5所得芳胺基嘌呤衍生物的甲磺酸盐的差示扫描量热(DSC)图。
图25为实施例5所得芳胺基嘌呤衍生物的甲磺酸盐的热重分析(TGA)图。
图26为实施例6所得芳胺基嘌呤衍生物的L-苹果酸盐的差热-热重联用分析(DSC-TGA)图。
图27为实施例7所得芳胺基嘌呤衍生物的L-酒石酸盐的差热-热重联用分析(DSC-TGA)图。
图28为实施例8所得芳胺基嘌呤衍生物的L-酒石酸盐的差热-热重联用分析(DSC-TGA)图。
图29为实施例9所得芳胺基嘌呤衍生物的L-酒石酸盐的差热-热重联用分析(DSC-TGA)图。
图30为实施例10所得芳胺基嘌呤衍生物的草酸盐的差热-热重联用分析(DSC-TGA)图。
图31为实施例11所得芳胺基嘌呤衍生物的草酸盐的差热-热重联用分析(DSC-TGA)图。
图32为实施例12所得芳胺基嘌呤衍生物的琥珀酸盐的差示扫描量热(DSC)图。
图33为实施例12所得芳胺基嘌呤衍生物的琥珀酸盐的热重分析(TGA)图。
图34为实施例13所得芳胺基嘌呤衍生物的琥珀酸盐的差示扫描量热(DSC)图。
图35为实施例13所得芳胺基嘌呤衍生物的琥珀酸盐的热重分析(TGA)图。
图36为实施例14所得芳胺基嘌呤衍生物的醋酸盐的差示扫描量热(DSC)图。
图37为实施例14所得芳胺基嘌呤衍生物的醋酸盐的热重分析(TGA)图。
图38为实施例15所得芳胺基嘌呤衍生物的醋酸的差示扫描量热(DSC)图。
图39为实施例15所得芳胺基嘌呤衍生物的醋酸盐的热重分析(TGA)图。
图40为实施例16所得芳胺基嘌呤衍生物的硫酸盐的差热-热重联用分析(DSC-TGA)图。
图41为实施例17所得芳胺基嘌呤衍生物的硫酸盐的差热-热重联用分析(DSC-TGA)图。
图42为制备例1所得芳胺基嘌呤衍生物的差热-热重联用分析(DSC-TGA)图。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
以下实施例中，分析检测条件如下：
1、水分
检测仪器：卡式水分滴定仪/915KF Ti-Touch
测试方法：仪器平衡后，取供试品适量(约200mg)，精密称定，加入滴定杯中，以无水甲醇为溶剂，用水分滴定液直接测定，每个供试品测定两次取平均值。
2、溶解度
检测仪器：紫外分光光度计/Evolution 300
测试方法：
选择pH1.2、pH4.5、pH6.8和水做为溶剂，溶剂配制方法具体如下：
(1)pH1.2盐酸溶液：盐酸7.65ml，加水1000ml，摇匀，即得。
(2)pH4.5磷酸盐缓冲液：取磷酸二氢钾6.8g，用水稀释至1000ml，摇匀即得。
(3)pH6.8磷酸盐缓冲液：取磷酸二氢钾6.8g，氢氧化钠0.896g，用水稀释至1000ml，摇匀即得。
(4)水：纯化水
样品制备：
取具塞试管，分别精密加入10ml各pH值溶出介质，加入过量原料药，直至形成过饱和溶液，记录加入量，摇匀，密塞，于摇床中振摇24小时，分别于不同时间点取出2ml溶液，离心，取上清液，滤过，取续滤液，待用。
取上述不同溶剂下饱和溶液，加溶剂稀释一定体积，于287nm波长处测定吸光度。
对照品溶液制备：取式1化合物对照品适量，精密称定，加溶剂使溶解并稀释制成每1ml中约含式1化合物10μg的溶液，于287nm波长处测定吸光度，计算得到。
3、引湿性
检测仪器：XPE105DR
测试方法：
(1)取干燥的具塞玻璃称量瓶，于试验前一天置于适宜的25℃±1℃恒温干燥器(下部放置氯化铵或硫酸铵饱和溶液)或人工气候箱(设定温度为25℃±1℃，相对湿度为80％士2％)内，精密称定重量(m1)。
(2)取供试品适量，平铺于上述称量瓶中，供试品厚度一般约为lmm，精密称定重量(m2)。
(3)将称量瓶敞口，并与瓶盖同置于上述恒温恒湿条件下24小时。
(4)盖好称量瓶盖子，精密称定重量(m3)。
增重百分率＝(m3-m2)/(m2-m1)×100％
(5)引湿性特征描述与引湿性增重的界定：
潮解：吸收足量水分形成液体。
极具引湿性：引湿增重不小于15％。
有引湿性：引湿增重小于15％但不小于2％。
略有引湿性：引湿增重小于2％但不小于0.2％。
无或几乎无引湿性：引湿增重小于0.2％。
4、含量
检测仪器：高效液相色谱仪/Waters e2695-2489
分析方法：
用十八烷基硅烷键合硅胶为填充剂(pH值适用范围应大于10.0)，以20mmol/L磷酸氢二钠溶液(用氢氧化钠调pH值至10.0)-乙腈(65∶35)为流动相；检测波长为287nm，柱温为30℃。理论板数应不低于3000。
测定法取样品约20mg，精密称定，置100ml量瓶中，加稀释剂(50％甲醇水)使溶解并稀释至刻度，摇匀，精密量取10μl，注入液相色谱仪，记录色谱图；另取对照品适量，同法测定。按外标法以峰面积计算，即得。
5、X-射线粉末衍射(X-Ray Powder Diffraction，XRPD)
(1)实施例1和2
检测仪器：PANalytical Empyrean型粉末X-射线衍射仪
测试条件：
光管类型：Cu靶，金属陶瓷X光管；
X-射线波长：CuKα，
Figure PCTCN2021073285-appb-000026
1.540598,
Figure PCTCN2021073285-appb-000027
1.544426,Kα 2/Kα 1强度比例：0.5；
电压电流：45kV，40mA；
扫描范围：3-40°2θ；
扫描总时间：约5min。
(2)实施例3-17
检测仪器：BRUKER D2 PHASER粉末X射线衍射仪
测试条件：
光管类型：Cu靶，陶瓷X光管；
X-射线波长：CuKα，
Figure PCTCN2021073285-appb-000028
1.540598,
Figure PCTCN2021073285-appb-000029
1.544426,Kα 2/Kα 1强度比例：0.5；
电压电流：30kV，10mA；
扫描范围：4-40°2θ；
扫描总时间：200.9S。
6、差热-热重联用分析(DSC-TGA)
检测仪器：NETZSCH STA 449F3
测试条件：
温度范围：20℃-350℃；
升温速率：10.0(K/min)；
样品支架/热电偶：DSC/TG Cp S/S
坩埚：DSC/TG pan Al2O3
气氛：N2,20.0ml/min/N2,50.0ml/min
校正/测量范围：020/5000μV
7、差示扫描量热分析(differential scanning calorimetry，DSC)
检测仪器：NETZSCH DSC 214 Polyma
测试条件：
温度范围：20℃-250℃；
升温速率：5.0(K/min)；
样品支架/热电偶：DSC 214 Corona sensor/E
坩埚：Pan AI，pierced lid
气氛：N2,40.0ml/min/N2,60.0ml/min
校正/测量范围：000/5000μV
8、热重分析(Thermogravimetric Analysis，TGA)
检测仪器：METTLER和SDT Q600
分析方法：
温度范围：20℃-250℃；
升温速率：5.0(K/min)；
9、核磁共振波谱(Nuclear Magnetic Resonance spectroscopy，NMRS)
检测仪器：AVⅢ BRUKER 600型超导核磁共振谱仪
内容及测试溶剂： 1H-NMR，测试溶剂为H 2D。
10、单晶
单晶衍射数据使用Rigaka XtaLAB Synergy-R(Micro-Max007HF Cu mode,CuKαλ＝1.54184)
Figure PCTCN2021073285-appb-000030
Hypix 6000HE detector)型单晶衍射仪在120.00(10)K温度下收集。单晶样品的显微照片使用上海测维PXS9-T型体视显微镜拍摄。
11、酸度的测量
检测仪器：Mettler Toledo S210-K pH计
测试方法：照pH值测定法操作，精密称取样品10mg，加新沸放冷的纯化水10ml使溶解后，摇匀，测定pH值。
12、有关物质的测量
检测仪器：高效液相色谱仪/Waters e2695-2489
色谱条件：
用十八烷基硅烷键合硅胶为填充剂(型号：Waters Xbridge C18色谱柱，长250mm，内径4.6mm，填料粒径5μm)，检测波长为250nm，柱温为35℃，流速为每分钟1.0ml，流动相A为0.02mol/L磷酸氢二钠溶液(氢氧化钠溶液调节pH值至10.0)，流动相B为乙腈，稀释剂为甲醇，样品盘温度为4℃。
测定法按要求进行系统适用性试验，配制供试品溶液、对照溶液、灵敏度溶液。精密量取对照溶液及供试品溶液各10μl，注入液相色谱仪，记录色谱图，按加校正因子的自身稀释对照法以峰面积计算，即得。
制备例1：式1化合物的制备
Figure PCTCN2021073285-appb-000031
参考专利文献WO 2011/147066中实施例90所记载的方法，制备得到式1所示化合物100g。
实施例1：芳胺基嘌呤衍生物的盐酸盐的制备
Figure PCTCN2021073285-appb-000032
将制备例1所得芳胺基嘌呤衍生物(90g,0.203mol)和800ml纯化水、400ml丙酮加入反应器中，搅拌升温至40±5℃后，向反应器中流加(74g,0.731mol)浓盐酸，加完浓盐酸后，再加入2L丙酮，保持温度40±5℃，继续反应1h，然后搅拌降温至10±5℃析晶2h，抽滤，滤饼用300ml丙酮洗涤，得黄色或淡黄色盐酸盐74.7g。 1H-NMR(600MHz,D 2O)δ:1.556(d,6H),δ:2.896(s,3H),δ:3.058(t,2H),δ:3.187(t,2H),δ:3.586(d,2H),δ:3.749(d,2H),δ:4.701(s,1H),δ:7.062(d,2H),δ:7.377(d,2H),δ:7.968(t,1H),δ:8.086(s,1H),δ:8.431(d,1H),δ:8.636(d,1H),δ:9.171(s,1H)。所得盐酸盐呈现良好的结晶性，其XRPD表征谱图如图1所示，主要衍射峰数据如下：
峰位置2θ角(°) 相对峰强度％
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
通过HPLC计算自由碱含量、水分测定，再跟核磁共振中 1H-NMR中氢的比例(见下表)，可以推断得到该盐酸盐的碱/酸/H 2O为1:3:5。
Figure PCTCN2021073285-appb-000033
改变实施例1中使用的浓盐酸的用量，重复实施例1的过程，仍然只能得到实施例1所得芳胺基嘌呤衍生物·三盐酸盐·五水合物。用异丙醇、四氢呋喃替换实施例1中的丙酮，重复实施例1的过程，同样可得到实施例1所得芳胺基嘌呤衍生物·三盐酸盐·五水合物。
实施例2：芳胺基嘌呤衍生物的盐酸盐单晶的制备
称取实施例1所得盐酸盐14.9mg置于一3mL玻璃瓶内，加入0.6mL乙腈/水(4:1,v/v)混合溶剂，搅拌溶解，置于25mL水热反应釜中，水热反应釜密封后置于控温烘箱内进行程序升降温、温度程序为：
Figure PCTCN2021073285-appb-000034
实验结束后发现体系中析出长片状单晶样品。单晶样品的显微照片如图2所示。单晶X-射线衍射表征结果显示：该晶体属于三斜晶系，
Figure PCTCN2021073285-appb-000035
空间群，其单胞参数为：{
Figure PCTCN2021073285-appb-000036
α＝93.2215(5)°,β＝95.3039(6)°,γ＝91.9554(6)°,
Figure PCTCN2021073285-appb-000037
}。该晶体的不对称单元由式1化合物阳离子、三个氯离子和五个水分子组成。将该单晶进行XRPD测定，所得谱图见图3，主要衍射峰数据如下：
峰位置2θ角(°) 相对峰强度％
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
由图1和图3的对比结果可知，实施例2所得单晶与为实施例所得晶型为同一晶型。
实施例3：芳胺基嘌呤衍生物的甲磺酸盐的制备
Figure PCTCN2021073285-appb-000038
将制备例1所得芳胺基嘌呤衍生物(7g,15.8mmol)和7ml纯化水、28ml丙酮加入反应器中，搅拌升温至40±5℃后，向反应器中加入甲磺酸(1.82g,18.9mmol)，加毕，再加入147ml丙酮，保持温度40±5℃，继续反应1h，然后搅拌降温至10±5℃析晶2h，抽滤，滤饼用45ml丙酮洗涤，得黄色或淡黄色甲磺酸盐7.8g。 1H-NMR(600MHz,D 2O)δ:1.500(d,6H),δ:2.783(s,4H),δ:2.888(m,5H),δ:3.085(m,2H),δ:3.511(m,4H),δ:4.489(m,1H),δ:6.817(d,2H),δ:7.200(d,2H),δ:7.404(m,1H),δ:7.906(m,2H),δ:8.122(d,1H),δ:8.567(s,1H)。所得甲磺酸盐呈现良好的结晶性，其XRPD表征谱图如图4所示，主要衍射峰数据如下：
峰位置2θ角(°) 相对峰强度％
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
通过HPLC计算自由碱含量、水分测定，再跟核磁共振中 1H-NMR中氢的比例(见下表)，可以推断得到该甲磺酸盐的碱/酸/H 2O为1:1 1/ 2:1。
Figure PCTCN2021073285-appb-000039
实施例4：芳胺基嘌呤衍生物的甲磺酸盐的制备
Figure PCTCN2021073285-appb-000040
参照实施例3制备方法，只是将甲磺酸加入量改为(5.2g,54.1mmol)，得黄色或淡黄色甲磺酸盐8.8g。 1H-NMR(600MHz,D 2O)δ:1.621(d,6H),δ:2.770(s，8H),δ:2.962(s,3H),δ:3.120(m,2H),δ:3.242(m,2H),δ:3.643(d,2H),δ:3.808(d,2H),δ:4.747(m,1H),δ:7.139(d,2H),δ:7.450(d,2H),δ:7.972(m,1H),δ:8.125(s,1H),δ:8.457(d,1H),δ:8.608(m,1H),δ:9.158(d,1H)。所得甲磺酸盐呈现良好的结晶性，其XRPD表征谱图如图5所示，主要衍射峰数据如下：
峰位置2θ角(°) 相对峰强度％
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
通过HPLC计算自由碱含量、水分测定，再跟核磁共振中 1H-NMR中氢的 比例(见下表)，可以推断得到该甲磺酸盐的碱/酸/H 2O为1:2 1/ 2:1。
Figure PCTCN2021073285-appb-000041
实施例5：芳胺基嘌呤衍生物的甲磺酸盐的制备
Figure PCTCN2021073285-appb-000042
参照实施例3制备方法，只是将甲磺酸加入量改为(7.58g,78.9mmol)，得黄色或淡黄色甲磺酸盐11.2g。 1H-NMR(600MHz,D 2O)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)。所得甲磺酸盐呈现良好的结晶性，其XRPD表征谱图如图6所示，主要衍射峰数据如下：
峰位置2θ角(°) 相对峰强度％
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
峰位置2θ角(°) 相对峰强度％
25.353 39.4
26.675 27.2
27.264 20.9
通过HPLC计算自由碱含量、水分测定，再跟核磁共振中 1H-NMR中氢的比例(见下表)，可以推断得到该甲磺酸盐的碱/酸/H 2O为1:3 1/ 2:1。
Figure PCTCN2021073285-appb-000043
实施例6：芳胺基嘌呤衍生物的L-苹果酸盐的制备
Figure PCTCN2021073285-appb-000044
将制备例1所得芳胺基嘌呤衍生物(8g,18mmol)和64ml纯化水、32ml丙酮加入反应器中，搅拌升温至40±5℃后，向反应器中加入(2.902g,21.6mmol)L-苹果酸，加毕，再加入168ml丙酮，保持温度40±5℃，继续反应1h，然后搅拌降温至10±5℃析晶2h，抽滤，滤饼用30ml丙酮洗涤，得黄色L-苹果酸盐8.63g。 1H-NMR(600MHz,D 2O)δ:1.590(d,6H),δ:2.527(q,1H),δ:2.749(q,1H),δ:2.929(s,3H),δ:3.010(t,2H),δ:3.184(t,2H),δ:3.587(d,4H),δ:4.328(d,1H),δ:4.606(d,1H),δ:6.983(d,2H),δ:7.370(d,2H),δ:7.538(q,1H),δ:8.052(d,2H),δ:8.254(d,1H),δ:8.690(d,1H)。所得苹果酸盐呈现良好的结晶性，其XRPD表征谱图如图7所示，主要衍射峰数据如下：
峰位置2θ角(°) 相对峰强度％
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
峰位置2θ角(°) 相对峰强度％
22.995 10.7
24.198 13.9
25.190 20.7
25.937 73.4
27.535 22.5
通过HPLC计算自由碱含量、水分测定，再跟核磁共振中 1H-NMR中氢的比例(见下表)，可以推断得到该苹果酸盐的碱/酸/H 2O为1:1:4。
Figure PCTCN2021073285-appb-000045
实施例7：芳胺基嘌呤衍生物的L-酒石酸盐
Figure PCTCN2021073285-appb-000046
将制备例1所得芳胺基嘌呤衍生物(8g,18mmol)和64ml纯化水、32ml丙酮加入反应器中，搅拌升温至40±5℃后，向反应器中加入L-酒石酸(3.248g,21.6mmol)，加毕，再加入168ml丙酮，保持温度40±5℃，继续反应1h，然后搅拌降温至10±5℃析晶2h，抽滤，滤饼用30ml丙酮洗涤，得黄色L-酒石酸盐10.06g。 1H-NMR(600MHz,D 2O)δ:1.626(d,6H),δ:2.954(s,3H),δ:3.086(t,2H),δ:3.242(t,2H),δ:3.629(d,2H),δ:3.747(d,2H),δ:4.414(s,2H),δ:4.683(m,1H),δ:7.098(d,2H),δ:7.453(d,2H),δ:7.705(m,1H),δ:8.109(s,1H),δ:8.255(d,1H),δ:8.349(d,1H),δ:8.857(s,1H)。所得酒石酸盐呈现良好的结晶性，其XRPD表征谱图如图8所示，主要衍射峰数据如下：
峰位置2θ角(°) 相对峰强度％
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
峰位置2θ角(°) 相对峰强度％
20.087 21.6
25.503 95.3
26.920 26.6
通过HPLC计算自由碱含量、水分测定，再跟核磁共振中 1H-NMR中氢的比例(见下表)，可以推断得到该酒石酸盐的碱/酸/H 2O为1:1:4。
Figure PCTCN2021073285-appb-000047
实施例8：芳胺基嘌呤衍生物的L-酒石酸盐
Figure PCTCN2021073285-appb-000048
将制备例1所得芳胺基嘌呤衍生物(7g,15.8mmol)和56ml纯化水、28ml丙酮加入反应器中，搅拌升温至40±5℃后，向反应器中加入(5.685g,37.9mmol)L-酒石酸，加毕，再加入147ml丙酮，保持温度40±5℃，继续反应1h，然后搅拌降温至10±5℃析晶2h，抽滤，滤饼用30ml丙酮洗涤，得淡黄色L-酒石酸盐11.3g。 1H-NMR(600MHz,D 2O)δ:1.610(d,6H),δ:2.948(s,3H),δ:3.067(s,2H),δ:3.229(s,2H),δ:3.630(s,2H),δ:3.755(s,2H),δ:4.469(s,3H),δ:4.697(m,1H),δ:7.085(d,2H),δ:7.431(d,2H),δ:7.798(m,1H),δ:8.094(s,1H),δ:8.366(m,2H),δ:8.978(s,1H)。所得酒石酸盐呈现良好的结晶性，其XRPD表征谱图如图9所示，主要衍射峰数据如下：
峰位置2θ角(°) 相对峰强度％
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
峰位置2θ角(°) 相对峰强度％
17.648 23.4
18.837 87.3
20.461 33.8
22.316 33.4
24.578 80.1
26.075 100
通过HPLC计算自由碱含量、水分测定，再跟核磁共振中 1H-NMR中氢的比例(见下表)，可以推断得到该酒石酸盐的碱/酸/H 2O为1:1 1/ 2:4。
Figure PCTCN2021073285-appb-000049
实施例9：芳胺基嘌呤衍生物的L-酒石酸盐
Figure PCTCN2021073285-appb-000050
参照实施例8制备方法，只是将L-酒石酸加入量改为(8.29g,55.2mmol)，得淡黄色L-酒石酸盐11.59g。 1H-NMR(600MHz,D 2O)δ:1.646(d,6H),δ:2.983(s,3H),δ:3.100(s,2H),δ:3.276(s,2H),δ:3.674(s,2H),δ:3.817(s,2H),δ:4.528(s,4H),δ:7.148(s,2H),δ:7.489(s,2H),δ:7.896(m,1H),δ:8.148(s,1H),δ:8.440(d,1H),δ:8.502(d,1H),δ:9.072(s,1H)。所得酒石酸盐呈现良好的结晶性，其XRPD表征谱图如图10所示，主要衍射峰数据如下：
峰位置2θ角(°) 相对峰强度％
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
峰位置2θ角(°) 相对峰强度％
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
通过HPLC计算自由碱含量、水分测定，再跟核磁共振中 1H-NMR中氢的比例(见下表)，可以推断得到该酒石酸盐的碱/酸/H 2O为1:2:4。
Figure PCTCN2021073285-appb-000051
实施例10：芳胺基嘌呤衍生物的草酸盐
Figure PCTCN2021073285-appb-000052
将制备例1所得芳胺基嘌呤衍生物(7g,15.8mmol)和28ml纯化水、28ml丙酮加入反应器中，搅拌升温至40±5℃后，向反应器中加入草酸二水合物(2.388g,18.9mmol)，加毕，再加入147ml丙酮，保持温度40±5℃，继续反应1h，然后搅拌降温至10±5℃析晶2h，抽滤，滤饼用30ml丙酮洗涤，得黄色草酸盐8.01g。 1H-NMR(600MHz,D 2O)δ:1.637(d,6H),δ:2.974(s,3H),δ:3.158(m,2H),δ:3.276(m,2H),δ:3.663(d,2H),δ:3.848(d,2H)，,δ:4.790(m,1H),δ:7.192(d,2H),δ:7.505(d,2H),δ:7.972(m,1H),δ:8.139(s,1H),δ:8.491(d,1H),δ:8.601(d,1H),δ:9.127(s,1H)。所得草酸盐呈现良好的结晶性，其XRPD表征谱图如图11所示，主要衍射峰数据如下：
峰位置2θ角(°) 相对峰强度％
8.063 59.5
8.353 91.6
8.983 29.0
14.103 35.0
峰位置2θ角(°) 相对峰强度％
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
通过HPLC计算自由碱含量、水分测定，再跟核磁共振中 1H-NMR中氢的比例(见下表)，可以推断得到该草酸盐的碱/酸/H 2O为1:1:1。
Figure PCTCN2021073285-appb-000053
实施例11：芳胺基嘌呤衍生物的草酸盐
Figure PCTCN2021073285-appb-000054
参照实施例10制备方法，只是将草酸二水合物加入量改为(4.755g,37.9mmol)，得黄色草酸盐8.01g。 1H-NMR(600MHz,D 2O)δ:1.621(d,6H),δ:2.963(s,3H),δ:3.126(m,2H),δ:3.257(m,2H),δ:3.650(d,2H),δ:3.833(d,2H),δ:4.757(m,1H),δ:7.167(d,2H),δ:7.474(d,2H),δ:8.013(m,1H),δ:8.127(s,1H),δ:8.496(d,1H),δ:8.665(d,1H),δ:9.191(s,1H)。所得草酸盐呈现良好的结晶性，其XRPD表征谱图如图12所示，主要衍射峰数据如下：
峰位置2θ角(°) 相对峰强度％
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
峰位置2θ角(°) 相对峰强度％
19.047 36.5
24.385 56.4
通过HPLC计算自由碱含量、水分测定，再跟核磁共振中 1H-NMR中氢的比例(见下表)，可以推断得到该草酸盐的碱/酸/H 2O为1:1:1。
Figure PCTCN2021073285-appb-000055
实施例12：芳胺基嘌呤衍生物的琥珀酸盐
Figure PCTCN2021073285-appb-000056
将制备例1所得芳胺基嘌呤衍生物(7g,15.8mmol)和28ml纯化水、28ml丙酮加入反应器中，搅拌升温至40±5℃后，向反应器中加入(2.236g,18.9mmol)琥珀酸，加毕，再加入147ml丙酮，保持温度40±5℃，继续反应1h，然后搅拌降温至10±5℃析晶2h，抽滤，滤饼用30ml丙酮洗涤，得淡黄色琥珀酸盐7.51g。 1H-NMR(600MHz,D 2O)δ:1.584(d,6H),δ:2.482(s,4H),δ:2.923(s,3H),δ:2.992(m,2H),δ:3.174(m,2H),δ:3.594(m,4H),δ:4.584(m,1H),δ:6.959(d,2H),δ:7.365(d,2H),δ:7.440(m,1H),δ:7.929(d,1H),δ:8.058(s,1H),δ:8.227(d,1H),δ:8.579(s,1H)。所得琥珀酸盐呈现良好的结晶性，其XRPD表征谱图如图13所示，主要衍射峰数据如下：
峰位置2θ角(°) 相对峰强度％
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
峰位置2θ角(°) 相对峰强度％
20.351 53.8
21.017 48.7
22.437 100
24.204 35.9
25.889 46.9
27.115 50.9
通过HPLC计算自由碱含量、水分测定，再跟核磁共振中 1H-NMR中氢的比例(见下表)，可以推断得到该琥珀酸盐的碱/酸/H 2O为1:1:4。
Figure PCTCN2021073285-appb-000057
实施例13：芳胺基嘌呤衍生物的琥珀酸盐
Figure PCTCN2021073285-appb-000058
参照实施例12制备方法，只是将琥珀酸加入量改为(4.473g,37.9mmol)，得淡黄色琥珀酸盐8.14g。 1H-NMR(600MHz,D 2O)δ:1.643(d,6H),δ:2.548(s,9H),δ:2.961(s,3H),δ:3.080(m,2H),δ:3.246(m,2H),δ:3.639(d,2H),δ:3.762(d,2H),δ:4.695(m,1H),δ:7.114(d,2H),δ:7.497(d,2H),δ:7.638(m,1H),δ:8.138(s,1H),δ:8.159(d,1H),δ:8.347(d,1H),δ:8.769(s,1H)。所得琥珀酸盐呈现良好的结晶性，其XRPD表征谱图如图14所示，主要衍射峰数据如下：
峰位置2θ角(°) 相对峰强度％
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
峰位置2θ角(°) 相对峰强度％
24.149 11.9
25.171 19.1
25.816 58.1
27.263 28.5
通过HPLC计算自由碱含量、水分测定，再跟核磁共振中 1H-NMR中氢的比例(见下表)，可以推断得到该琥珀酸盐的碱/酸/H 2O为1:2:4。
Figure PCTCN2021073285-appb-000059
实施例14：芳胺基嘌呤衍生物的醋酸盐
Figure PCTCN2021073285-appb-000060
将制备例1所得芳胺基嘌呤衍生物(7g,15.8mmol)和28ml纯化水、28ml丙酮加入反应器中，搅拌升温至40±5℃后，向反应器中加入醋酸(1.13g,18.9mmol)，加毕，再加入147ml丙酮，保持温度40±5℃，继续反应1h，然后搅拌降温至10±5℃析晶2h，抽滤，滤饼用30ml丙酮洗涤，得类白色醋酸盐7.51g。 1H-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)。所得醋酸盐呈现良好的结晶性，其XRPD表征谱图如图15所示，主要衍射峰数据如下：
峰位置2θ角(°) 相对峰强度％
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
峰位置2θ角(°) 相对峰强度％
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
通过HPLC计算自由碱含量、水分测定，再跟核磁共振中 1H-NMR中氢的比例(见下表)，可以推断得到该醋酸盐的碱/酸/H 2O为1:1:1。
Figure PCTCN2021073285-appb-000061
实施例15：芳胺基嘌呤衍生物的醋酸盐
Figure PCTCN2021073285-appb-000062
将制备例1所得芳胺基嘌呤衍生物(10g,22.5mmol)和10ml纯化水、40ml丙酮加入反应器中，搅拌升温至40±5℃后，向反应器中加入醋酸(4.74g,78.9mmol)，加毕，再加入210ml丙酮，保持温度40±5℃，继续反应1h，然后搅拌降温至10±5℃析晶2h，抽滤，滤饼用40ml丙酮洗涤，得类白色醋酸盐9.04g。 1H-NMR(600MHz,D 2O)δ:1.542(d,6H),δ:1.951(s,6H),δ:2.902(s,1H),δ:2.934(m,4H),δ:3.126(m,2H),δ:3.553(m,4H),δ:4.541(m,1H),δ:6.885(m,2H),δ:7.284(m,2H),δ:7.417(m,1H),δ:7.899(m,1H),δ:7.997(s,1H),δ:8.181(s,1H),δ:8.552(s,1H)。所得醋酸盐呈现良好的结晶性，其XRPD表征谱图如图16所示，主要衍射峰数据如下：
峰位置2θ角(°) 相对峰强度％
6.174 100
8.109 29.6
9.097 33.4
12.231 92.9
15.024 16.9
峰位置2θ角(°) 相对峰强度％
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
通过HPLC计算自由碱含量、水分测定，再跟核磁共振中 1H-NMR中氢的比例(见下表)，可以推断得到该醋酸盐的碱/酸/H 2O为1:2:1。
Figure PCTCN2021073285-appb-000063
实施例16：芳胺基嘌呤衍生物的硫酸盐
Figure PCTCN2021073285-appb-000064
将制备例1所得芳胺基嘌呤衍生物(7g,15.8mmol)和7ml纯化水、28ml丙酮加入反应器中，搅拌升温至40±5℃后，向反应器中加入硫酸(1.86g,18.9mmol)，加毕，再加入147ml丙酮，保持温度40±5℃，继续反应1h，然后搅拌降温至10±5℃析晶2h，抽滤，滤饼用30ml丙酮洗涤，得淡黄色硫酸盐7.5g。 1H-NMR(600MHz,D 2O)δ:1.533(d,6H),δ:2.894(s,3H),δ:3.009(m,2H),δ:3.086(m,2H),δ:3.547(d,2H),δ:3.634(d,2H),δ:4.699(m,1H),δ:6.936(d,2H),δ:7.291(d,2H),δ:7.929(m,1H),δ:8.114(s,1H),δ:8.387(d,1H),δ:8.640(m,1H),δ:9.217(d,1H)。所得硫酸盐呈现良好的结晶性，其XRPD表征谱图如图17所示，主要衍射峰数据如下：
峰位置2θ角(°) 相对峰强度％
4.825 59.1
7.010 89.3
8.553 46.5
9.183 64.5
峰位置2θ角(°) 相对峰强度％
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
通过HPLC计算自由碱含量、水分测定，再跟核磁共振中 1H-NMR中氢的比例(见下表)，可以推断得到该硫酸盐的碱/酸/H 2O为1:1:1。
Figure PCTCN2021073285-appb-000065
实施例17：芳胺基嘌呤衍生物的硫酸盐
Figure PCTCN2021073285-appb-000066
参照实施例16制备方法，只是将硫酸投料量改为(3.71g,37.9mmol)，得淡黄色硫酸盐10.0g。 1H-NMR(600MHz,D 2O)δ:1.600(d,6H),δ:2.957(s,3H),δ:3.243(m,4H),δ:3.644(d,2H),δ:3.829(d,2H),δ:4.757(m,1H),δ:7.208(d,2H),δ:7.294(d,2H),δ:8.014(m,1H),δ:8.155(s,1H),δ:8.485(d,1H),δ:8.685(m,1H),δ:9.217(d,1H)。所得硫酸盐呈现良好的结晶性，其XRPD表征谱图如图18所示，主要衍射峰数据如下：
峰位置2θ角(°) 相对峰强度％
8.622 33.2
9.588 78.1
15.681 44.6
峰位置2θ角(°) 相对峰强度％
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
通过HPLC计算自由碱含量、水分测定，再跟核磁共振中 1H-NMR中氢的比例(见下表)，可以推断得到该硫酸盐的碱/酸/H 2O为1:2:1。
Figure PCTCN2021073285-appb-000067
测试例1：DSC及TGA测试
将实施例1,3-17所得盐与式1化合物在介质中进行DSC和TGA测试，测试结果如下表所示：
Figure PCTCN2021073285-appb-000068
Figure PCTCN2021073285-appb-000069
Figure PCTCN2021073285-appb-000070
测试例2：溶解度测试
将实施例1,3-17所得盐与式1化合物在介质中进行溶解度测试，测试结果如下表所示：
Figure PCTCN2021073285-appb-000071
测试例3：加速稳定性测试
取实施例1,3-17所得盐样品适量，分别在25±2℃，0％±5％RH，敞口放置10天及40±2℃；75％±5％RH，敞口放置10天，进行加速试验，结果如下：
Figure PCTCN2021073285-appb-000072
Figure PCTCN2021073285-appb-000073
测试例4：吸湿性测试
取实施例1,3-17所得盐样品适量，分别在25±1℃，相对湿度为80％士2％，进行吸湿性试验，结果如下：
Figure PCTCN2021073285-appb-000074
测试例5：长期稳定性测试
取实施例1所得盐样品适量，内包为药用低密度聚乙烯袋，外包为聚酯/铝/聚乙烯药品包装用复合袋，在温度25±2℃，相对湿度60％±5％，分别于第3、6、9、12和18个月末取样，比较外观后测试其它考察指标，结果与0个月比较，实 验结果见下表：
时间 性状 水分(％) 酸度 有关物质(％) 含量(％)
0月 黄色结晶性粉末 13.9 3.1 0.33 100.9
3月 黄色结晶性粉末 13.9 3.3 0.34 100.4
6月 黄色结晶性粉末 14.3 3.3 0.34 100.8
9月 黄色结晶性粉末 14.3 3.3 0.31 101.7
12月 黄色结晶性粉末 13.9 3.3 0.34 99.6
18月 黄色结晶性粉末 14.2 3.3 0.26 100.2
测试例6：生物活性测试
根据专利申请WO 2011/147066的生物学评价中记载的激酶抑制活性评价，对实施例1所得的盐样品进行测试。测试结果表明，所述样品能够抑制FLT3、EGFR、Abl、Fyn、Hck、Lck、Lyn、Ret、Yes、VEGFR2、ALK、BTK、c-KIT、c-SRC、FGFR1、KDR、MET和PDGFRα激酶的活性，部分激酶测试结果见下表。
激酶 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
根据专利申请WO 2011/147066的生物学评价中记载的体内抗肿瘤实验，对实施例1所得的盐样品进行测试(分别具体针对FLT3-ITD的急性髓性白血病、EGFR激活突变的非小细胞肺癌、或Ph阳性的慢性髓性白血病)。测试结果表明，在MV4-11(FLT3-ITD突变)皮下瘤模型实验中(参考WO 2011/147066的例4建立模型)，所述样品(每天口服一次，给药21天)在给药剂量为5mg/kg时可以完 全抑制肿瘤生长，而在给药剂量为10mg/kg和20mg/kg时，可以引起肿瘤的完全消退。在非小细胞肺癌模型中(参考WO 2011/147066的例3建立模型)，所述样品可剂量依赖性地抑制人非小细胞肺癌HCC827的生长，在7.5mg/kg、15mg/kg、30mg/kg三个剂量组(每天口服一次，给药30天)均引起肿瘤缩小(与起始肿瘤相比)，其中，30mg/kg组可引起肿瘤的近乎完全消退。在K562(BCR-Abl基因重排)皮下瘤模型实验中(以类似于MV4-11皮下瘤模型建立模型)，所述样品(每天口服一次，给药18天)在给药剂量为70mg/kg时可以有效抑制肿瘤生长，抑瘤率达到71.3％。
本发明提供了下述技术方案，但本发明不局限于此，本发明的保护范围根据权利要求所限定的范围来确定：
[技术方案1].式2所示的芳胺基嘌呤衍生物的盐：
Figure PCTCN2021073285-appb-000075
其中，
HA是酸；
H 2O为结晶水；
m为1-4的整数或半整数；
n为0-5的整数或半整数。
[技术方案2].根据技术方案1所述的芳胺基嘌呤衍生物的盐，其特征在于，所述酸选自：盐酸、甲磺酸、L-苹果酸、L-酒石酸、草酸、琥珀酸、醋酸或硫酸；优选为：盐酸、L-苹果酸、L-酒石酸、草酸、琥珀酸、醋酸或硫酸；更优选为：盐酸、L-苹果酸、L-酒石酸、草酸、琥珀酸或醋酸；进一步优选为：盐酸。
[技术方案3].根据技术方案1所述的芳胺基嘌呤衍生物的盐，其特征在于，所述盐为式3所示的盐酸盐：
Figure PCTCN2021073285-appb-000076
n选自0、0.5、1、1.5、2、2.5、3、3.5、4、4.5或5；
优选地，所述盐为式3'所示的盐酸盐：
Figure PCTCN2021073285-appb-000077
优选地，
所述式3和式3'所示的盐酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在8.5±0.2°、11.8±0.2°、19.6±0.2°、25.2±0.2°、27.2±0.2°处具有特征峰；
或者，所述式3和式3'所示的盐酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在8.5±0.2°、11.8±0.2°、12.6±0.2°、19.6±0.2°、20.0±0.2°、23.7±0.2°、25.2±0.2°、27.2±0.2°处具有特征峰；
或者，所述式3和式3'所示的盐酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在7.3±0.2°、8.5±0.2°、9.0±0.2°、11.8±0.2°、12.6±0.2°、14.3±0.2°、18.1±0.2°、19.6±0.2°、20.0±0.2°、21.1±0.2°、21.9±0.2°、23.7±0.2°、25.2±0.2°、26.1±0.2°、27.2±0.2°处具有特征峰；
或者，所述式3和式3'所示的盐酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在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°处具有特征峰；
或者，所述式3和式3'所示的盐酸盐使用CuKα辐射，具有基本上如图1或图3所示的X射线粉末衍射谱图；
或者，所述式3和式3'所示的盐酸盐的单晶使用CuKα辐射，属三斜晶系，
Figure PCTCN2021073285-appb-000078
空间群，其单胞参数为：{
Figure PCTCN2021073285-appb-000079
α＝93.2215(5)°,β＝95.3039(6)°,γ＝91.9554(6)°,
Figure PCTCN2021073285-appb-000080
}。
[技术方案4].根据技术方案1所述的芳胺基嘌呤衍生物的盐，其特征在于，所述盐为式4、或式5、或式6所示的甲磺酸盐：
Figure PCTCN2021073285-appb-000081
n选自0、0.5、1、1.5、2、2.5、3、3.5、4、4.5或5；
优选地，所述盐为式4'、或式5'、或式6'所示的甲磺酸盐：
Figure PCTCN2021073285-appb-000082
优选地，
所述式4和式4'所示的甲磺酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在6.8±0.2°、15.1±0.2°、16.3±0.2°、21.0±0.2°、25.0±0.2°处具有特征峰；
或者，所述式4和式4'所示的甲磺酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在6.8±0.2°、8.6±0.2°、10.7±0.2°、12.6±0.2°、13.1±0.2°、13.4±0.2°、15.1±0.2°、16.3±0.2°、17.7±0.2°、19.0±0.2°、19.9±0.2°、21.0±0.2°、25.0±0.2°处具有特征峰；
或者，所述式4和式4'所示的甲磺酸盐使用CuKα辐射，具有基本上如图4所示的X射线粉末衍射谱图；
或者优选地，
所述式5和式5'所示的甲磺酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在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°处具有特征峰；
或者，所述式5和式5'所示的甲磺酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在6.1±0.2°、6.4±0.2°、17.5±0.2°、18.9±0.2°、19.3±0.2°、24.4±0.2°、26.4±0.2°处具有特征峰；
或者，所述式5和式5'所示的甲磺酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在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°处具有特征峰；
或者，所述式5和式5'所示的甲磺酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在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°处具有特征峰；
或者，所述式5和式5'所示的甲磺酸盐使用CuKα辐射，具有基本上如图5所示的X射线粉末衍射谱图；
或者优选地，
所述式6和式6'所示的甲磺酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在4.9±0.2°、11.5±0.2°、14.5±0.2°、18.5±0.2°、18.9±0.2°处具有特征峰；
或者，所述式6和式6'所示的甲磺酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在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°处具有特征峰；
或者，所述式6和式6'所示的甲磺酸盐使用CuKα辐射，具有基本上如图6所示的X射线粉末衍射谱图。
[技术方案5].根据技术方案1所述的芳胺基嘌呤衍生物的盐，其特征在于，所述盐为式7所示的L-苹果酸盐：
Figure PCTCN2021073285-appb-000083
n选自0、0.5、1、1.5、2、2.5、3、3.5、4、4.5或5；
优选地，所述盐为式7'所示的L-苹果酸盐：
Figure PCTCN2021073285-appb-000084
优选地，
所述式7和式7'所示的L-苹果酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在7.0±0.2°、9.3±0.2°、17.6±0.2°、19.7±0.2°、25.9±0.2°处具有特征峰；
或者，所述式7和式7'所示的L-苹果酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在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°处具有特征峰；
或者，所述式7和式7'所示的L-苹果酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在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°处具有特征峰；
或者，所述式7和式7'所示的L-苹果酸盐使用CuKα辐射，具有基本上如图7所示的X射线粉末衍射谱图。
[技术方案6].根据技术方案1所述的芳胺基嘌呤衍生物的盐，其特征在于，所述盐为式8、或式9、或式10所示的L-酒石酸盐：
Figure PCTCN2021073285-appb-000085
n选自0、0.5、1、1.5、2、2.5、3、3.5、4、4.5或5；
优选地，所述盐为式8'、或式9'、或式10'所示的L-酒石酸盐：
Figure PCTCN2021073285-appb-000086
优选地，
所述式8和式8'所示的L-酒石酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在6.9±0.2°、9.1±0.2°、17.8±0.2°、19.4±0.2°、25.5±0.2°处具有特征峰；
或者，所述式8和式8'所示的L-酒石酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在6.9±0.2°、9.1±0.2°、12.9±0.2°、13.8±0.2°、16.5±0.2°、17.8±0.2°、19.4±0.2°、20.1±0.2°、25.5±0.2°、26.9±0.2°处具有特征峰；
或者，所述式8和式8'所示的L-酒石酸盐使用CuKα辐射，具有基本上如图8所示的X射线粉末衍射谱图；
或者优选地，
所述式9和式9'所示的L-酒石酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在8.5±0.2°、14.8±0.2°、17.1±0.2°、18.8±0.2°、24.6±0.2°、26.1±0.2°处具有特征峰；
或者，所述式9和式9'所示的L-酒石酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在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°处具有特征峰；
或者，所述式9和式9'所示的L-酒石酸盐使用CuKα辐射，具有基本上如图9所示的X射线粉末衍射谱图；
或者优选地，
所述式10和式10'所示的L-酒石酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在8.3±0.2°、8.9±0.2°、9.5±0.2°、14.8±0.2°、17.7±0.2°、21.0±0.2°、24.0±0.2°处具有特征峰；
或者，所述式10和式10'所示的L-酒石酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在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°处具有特征峰；
或者，所述式10和式10'所示的L-酒石酸盐使用CuKα辐射，具有基本上如图 10所示的X射线粉末衍射谱图。
[技术方案7].根据技术方案1所述的芳胺基嘌呤衍生物的盐，其特征在于，所述盐为式11、或式12所示的草酸盐：
Figure PCTCN2021073285-appb-000087
n选自0、0.5、1、1.5、2、2.5、3、3.5、4、4.5或5；
优选地，所述盐为式11'、或式12'所示的草酸盐：
Figure PCTCN2021073285-appb-000088
优选地，
所述式11和式11'所示的草酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在8.1±0.2°、8.4±0.2°、9.0±0.2°、14.1±0.2°、16.7±0.2°、25.6±0.2°处具有特征峰；
或者，所述式11和式11'所示的草酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在8.1±0.2°、8.4±0.2°、9.0±0.2°、14.1±0.2°、14.8±0.2°、16.7±0.2°、17.9±0.2°、18.5±0.2°、19.6±0.2°、23.6±0.2°、25.6±0.2°处具有特征峰；
或者，所述式11和式11'所示的草酸盐使用CuKα辐射，具有基本上如图11所示的X射线粉末衍射谱图；
或者优选地，
所述式12和式12'所示的草酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在7.1±0.2°、12.2±0.2°、14.2±0.2°、16.4±0.2°、17.7±0.2°、19.0±0.2°、24.4±0.2°处具有特征峰；
或者，所述式12和式12'所示的草酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在7.1±0.2°、8.3±0.2°、12.2±0.2°、14.2±0.2°、16.4±0.2°、17.7±0.2°、 18.6±0.2°、19.0±0.2°、24.4±0.2°处具有特征峰；
或者，所述式12和式12'所示的草酸盐使用CuKα辐射，具有基本上如图12所示的X射线粉末衍射谱图。
[技术方案8].根据技术方案1所述的芳胺基嘌呤衍生物的盐，其特征在于，所述盐为式13、或式14所示的琥珀酸盐：
Figure PCTCN2021073285-appb-000089
n选自0、0.5、1、1.5、2、2.5、3、3.5、4、4.5或5；
优选地，所述盐为式13'、或式14'所示的琥珀酸盐：
Figure PCTCN2021073285-appb-000090
优选地，
所述式13和式13'所示的琥珀酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在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°处具有特征峰；
或者，所述式13和式13'所示的琥珀酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在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°处具有特征峰；
或者，所述式13和式13'所示的琥珀酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在7.0±0.2°、9.1±0.2°、11.3±0.2°、13.1±0.2°、13.8±0.2°、14.4±0.2°、16.0±0.2°、16.8±0.2°、17.7±0.2°、18.5±0.2°、20.4±0.2°、21.0±0.2°、22.4±0.2°、24.2±0.2°、25.9±0.2°、27.1±0.2°处具有特征峰；
或者，所述式13和式13'所示的琥珀酸盐使用CuKα辐射，具有基本上如图13所示的X射线粉末衍射谱图；
或者优选地，
所述式14和式14'所示的琥珀酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在7.0±0.2°、9.2±0.2°、17.6±0.2°、18.4±0.2°、19.7±0.2°、25.8±0.2°、27.3±0.2°处具有特征峰；
或者，所述式14和式14'所示的琥珀酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在7.0±0.2°、9.2±0.2°、11.9±0.2°、16.7±0.2°、17.6±0.2°、18.4±0.2°、19.7±0.2°、23.0±0.2°、24.1±0.2°、25.2±0.2°、25.8±0.2°、27.3±0.2°处具有特征峰；
或者，所述式14和式14'所示的琥珀酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在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°处具有特征峰；
或者，所述式14和式14'所示的琥珀酸盐使用CuKα辐射，具有基本上如图14所示的X射线粉末衍射谱图。
[技术方案9].根据技术方案1所述的芳胺基嘌呤衍生物的盐，其特征在于，所述盐为式15、或式16所示的醋酸盐：
Figure PCTCN2021073285-appb-000091
n选自0、0.5、1、1.5、2、2.5、3、3.5、4、4.5或5；
优选地，所述盐为式15'、或式16'所示的醋酸盐：
Figure PCTCN2021073285-appb-000092
优选地，
所述式15和式15'所示的醋酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在10.9±0.2°、12.6±0.2°、15.1±0.2°、17.8±0.2°、19.2±0.2°、19.6±0.2°、21.0±0.2°、21.8±0.2°、22.3±0.2°、24.6±0.2°、25.4±0.2°处具有特征峰；
或者，所述式15和式15'所示的醋酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在6.3±0.2°、8.9±0.2°、10.9±0.2°、11.5±0.2°、12.2±0.2°、12.6±0.2°、15.1±0.2°、17.8±0.2°、19.2±0.2°、19.6±0.2°、21.0±0.2°、21.8±0.2°、22.3±0.2°、24.6±0.2°、25.4±0.2°处具有特征峰；
或者，所述式15和式15'所示的醋酸盐使用CuKα辐射，具有基本上如图15所示的X射线粉末衍射谱图；
或者优选地，
所述式16和式16'所示的醋酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在6.2±0.2°、12.2±0.2°、16.1±0.2°、17.5±0.2°、23.4±0.2°、24.8±0.2°或者6.2±0.2°、12.2±0.2°、17.5±0.2°、21.5±0.2°、23.4±0.2°、24.8±0.2°处具有特征峰；
或者，所述式16和式16'所示的醋酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在6.2±0.2°、8.1±0.2°、9.1±0.2°、12.2±0.2°、15.0±0.2°、16.1±0.2°、17.5±0.2°、18.2±0.2°、20.7±0.2°、21.5±0.2°、23.4±0.2°、24.8±0.2°、28.8±0.2°处具有特征峰；
或者，所述式16和式16'所示的醋酸盐使用CuKα辐射，具有基本上如图16所示的X射线粉末衍射谱图。
[技术方案10].根据技术方案1所述的芳胺基嘌呤衍生物的盐，其特征在于，所述盐为式17、或式18所示的硫酸盐：
Figure PCTCN2021073285-appb-000093
n选自0、0.5、1、1.5、2、2.5、3、3.5、4、4.5或5；
优选地，所述盐为式17'、或式18'所示的硫酸盐：
Figure PCTCN2021073285-appb-000094
优选地，所述式17和式17'所示的硫酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在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°处具有特征峰；
或者，所述式17和式17'所示的硫酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在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°处具有特征峰；
或者，所述式17和式17'所示的硫酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在4.8±0.2°、7.0±0.2°、8.6±0.2°、9.2±0.2°、9.5±0.2°、11.6±0.2°、12.8±0.2°、13.6±0.2°、15.7±0.2°、17.6±0.2°、18.6±0.2°、20.5±0.2°、21.6±0.2°、23.8±0.2°、25.7±0.2°处具有特征峰；
或者，所述式17和式17'所示的硫酸盐使用CuKα辐射，具有基本上如图17所示的X射线粉末衍射谱图；
或者优选地，
所述式18和式18'所示的硫酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在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°处具有特征峰；
或者，所述式18和式18'所示的硫酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在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°处具有特征峰；
或者，所述式18和式18'所示的硫酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在8.6±0.2°、9.6±0.2°、15.7±0.2°、16.5±0.2°、17.1±0.2°、19.3±0.2°、20.0±0.2°、21.9±0.2°、23.5±0.2°、24.4±0.2°、26.6±0.2°处具有特征峰；
或者，所述式18和式18'所示的硫酸盐使用CuKα辐射，具有基本上如图18所示的X射线粉末衍射谱图。
[技术方案11].一种药物组合物，其包含技术方案1-10任一项所述式2所示的芳胺基嘌呤衍生物的盐。
[技术方案12].技术方案1-10任一项所述式2所示的芳胺基嘌呤衍生物的盐或技术方案11所述的药物组合物用于制备作为蛋白激酶抑制剂药物的用途，所述激酶选自：FLT3、EGFR、Abl、Fyn、Hck、Lck、Lyn、Ret、Yes，VEGFR2、ALK、BTK、c-KIT、c-SRC、FGFR1、KDR、MET或PDGFRα；
优选地，所述蛋白激酶抑制剂药物为抗肿瘤药物，所述肿瘤选自非小细胞肺癌、急性髓性白血病、慢性粒细胞白血病、慢性髓性白血病、表皮鳞癌、乳腺癌、结直肠癌、肝癌、胃癌、和恶性黑色素瘤，更优选为白血病或肺癌，进一步更优选为急性髓性白血病或非小细胞肺癌，进一步优选为FLT3突变阳性的 急性髓性白血病(如FLT3-ITD的急性髓性白血病)、Ph阳性的慢性髓性白血病或EGFR激活突变的非小细胞肺癌。
[技术方案13].一种技术方案1所述的式2所示的芳胺基嘌呤衍生物的盐的制备方法，包括将式1所示的芳胺基嘌呤衍生物与酸在水和有机溶剂的存在下进行反应，得到式2所示的芳胺基嘌呤衍生物的盐：
Figure PCTCN2021073285-appb-000095
其中，
HA是酸；
H 2O为结晶水；
m为1-4的整数或半整数；
n为0-5的整数或半整数。
[技术方案14].如技术方案13所述的芳胺基嘌呤衍生物的盐的制备方法，其特征在于，所述式1所示的芳胺基嘌呤衍生物与酸的摩尔比为1:1～1:4，优选为1:1.2～1:3.5；
反应温度为0-70℃，优选35-45℃；
反应在水和选自醇类、醚类、酯类、酮类、腈类、和烷烃类的有机溶剂中的一种或者多种的组合的存在下进行，优选地在C 1-C 3的低级醇和水的存在下、在酮类和水的存在下，在腈类和水的存在下，或者在醚类和水的存在下进行，更优选地在甲醇-水、乙醇-水、异丙醇-水、四氢呋喃-水、二氧六环-水、丙酮-水或乙腈-水的存在下进行；有机溶剂与水用量体积比为1:10～10:1，例如1:1～10:1或1:10～1:1。

Claims (14)

  1. 式2所示的芳胺基嘌呤衍生物的盐：
    Figure PCTCN2021073285-appb-100001
    其中，
    HA是酸；
    H 2O为结晶水；
    m为1-4的整数或半整数；
    n为0-5的整数或半整数。
  2. 根据权利要求1所述的芳胺基嘌呤衍生物的盐，其特征在于，所述酸选自：盐酸、甲磺酸、L-苹果酸、L-酒石酸、草酸、琥珀酸、醋酸或硫酸；优选为：盐酸、L-苹果酸、L-酒石酸、草酸、琥珀酸、醋酸或硫酸；更优选为：盐酸、L-苹果酸、L-酒石酸、草酸、琥珀酸或醋酸；进一步优选为：盐酸。
  3. 根据权利要求1所述的芳胺基嘌呤衍生物的盐，其特征在于，所述盐为式3所示的盐酸盐：
    Figure PCTCN2021073285-appb-100002
    n选自0、0.5、1、1.5、2、2.5、3、3.5、4、4.5或5；
    优选地，所述盐为式3'所示的盐酸盐：
    Figure PCTCN2021073285-appb-100003
    更优选地，所述式3和式3'所示的盐酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在8.5±0.2°、11.8±0.2°、19.6±0.2°、25.2±0.2°、27.2±0.2°处具有特征峰；进一步更优选地，所述式3和式3'所示的盐酸盐使用CuKα辐射，具有基本上如图1或图3所示的X射线粉末衍射谱图；
    或者更优选地，所述式3和式3'所示的盐酸盐的单晶使用CuKα辐射，属三斜晶系，
    Figure PCTCN2021073285-appb-100004
    空间群，其单胞参数为：
    Figure PCTCN2021073285-appb-100005
    Figure PCTCN2021073285-appb-100006
  4. 根据权利要求1所述的芳胺基嘌呤衍生物的盐，其特征在于，所述盐为式4、或式5、或式6所示的甲磺酸盐：
    Figure PCTCN2021073285-appb-100007
    n选自0、0.5、1、1.5、2、2.5、3、3.5、4、4.5或5；
    优选地，所述盐为式4'、或式5'、或式6'所示的甲磺酸盐：
    Figure PCTCN2021073285-appb-100008
    更优选地，所述式4和式4'所示的甲磺酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在6.8±0.2°、15.1±0.2°、16.3±0.2°、21.0±0.2°、25.0±0.2°处具有特征峰；进一步更优选地，所述式4和式4'所示的甲磺酸盐使用CuKα辐射，具有基 本上如图4所示的X射线粉末衍射谱图；
    或者更优选地，所述式5和式5'所示的甲磺酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在6.1±0.2°、6.4±0.2°、17.5±0.2°、18.9±0.2°、19.3±0.2°、24.4±0.2°、26.4±0.2°处具有特征峰；进一步更优选地，所述式5和式5'所示的甲磺酸盐使用CuKα辐射，具有基本上如图5所示的X射线粉末衍射谱图；
    或者更优选地，所述式6和式6'所示的甲磺酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在4.9±0.2°、11.5±0.2°、14.5±0.2°、18.5±0.2°、18.9±0.2°处具有特征峰；进一步更优选地，所述式6和式6'所示的甲磺酸盐使用CuKα辐射，具有基本上如图6所示的X射线粉末衍射谱图。
  5. 根据权利要求1所述的芳胺基嘌呤衍生物的盐，其特征在于，所述盐为式7所示的L-苹果酸盐：
    Figure PCTCN2021073285-appb-100009
    n选自0、0.5、1、1.5、2、2.5、3、3.5、4、4.5或5；
    优选地，所述盐为式7'所示的L-苹果酸盐：
    Figure PCTCN2021073285-appb-100010
    更优选地，所述式7和式7'所示的L-苹果酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在7.0±0.2°、9.3±0.2°、17.6±0.2°、19.7±0.2°、25.9±0.2°处具有特征峰；进一步更优选地，所述式7和式7'所示的L-苹果酸盐使用CuKα辐射，具有基本上如图7所示的X射线粉末衍射谱图。
  6. 根据权利要求1所述的芳胺基嘌呤衍生物的盐，其特征在于，所述盐为式8、或式9、或式10所示的L-酒石酸盐：
    Figure PCTCN2021073285-appb-100011
    n选自0、0.5、1、1.5、2、2.5、3、3.5、4、4.5或5；
    优选地，所述盐为式8'、或式9'、或式10'所示的L-酒石酸盐：
    Figure PCTCN2021073285-appb-100012
    更优选地，所述式8和式8'所示的L-酒石酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在6.9±0.2°、9.1±0.2°、17.8±0.2°、19.4±0.2°、25.5±0.2°处具有特征峰；进一步更优选地，所述式8和式8'所示的L-酒石酸盐使用CuKα辐射，具有基本上如图8所示的X射线粉末衍射谱图；
    或者更优选地，所述式9和式9'所示的L-酒石酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在8.5±0.2°、14.8±0.2°、17.1±0.2°、18.8±0.2°、24.6±0.2°、26.1±0.2°处具有特征峰；进一步更优选地，所述式9和式9'所示的L-酒石酸盐使用CuKα辐射，具有基本上如图9所示的X射线粉末衍射谱图；
    或者更优选地，所述式10和式10'所示的L-酒石酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在8.3±0.2°、8.9±0.2°、9.5±0.2°、14.8±0.2°、17.7±0.2°、21.0±0.2°、24.0±0.2°处具有特征峰；进一步更优选地，所述式10和式10'所示的L-酒石酸盐使用CuKα辐射，具有基本上如图10所示的X射线粉末衍射谱图。
  7. 根据权利要求1所述的芳胺基嘌呤衍生物的盐，其特征在于，所述盐为式11、或式12所示的草酸盐：
    Figure PCTCN2021073285-appb-100013
    n选自0、0.5、1、1.5、2、2.5、3、3.5、4、4.5或5；
    优选地，所述盐为式11'、或式12'所示的草酸盐：
    Figure PCTCN2021073285-appb-100014
    更优选地，所述式11和式11'所示的草酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在8.1±0.2°、8.4±0.2°、9.0±0.2°、14.1±0.2°、16.7±0.2°、25.6±0.2°处具有特征峰；进一步更优选地，所述式11和式11'所示的草酸盐使用CuKα辐射，具有基本上如图11所示的X射线粉末衍射谱图；
    或者更优选地，所述式12和式12'所示的草酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在7.1±0.2°、12.2±0.2°、14.2±0.2°、16.4±0.2°、17.7±0.2°、19.0±0.2°、24.4±0.2°处具有特征峰；进一步更优选地，所述式12和式12'所示的草酸盐使用CuKα辐射，具有基本上如图12所示的X射线粉末衍射谱图。
  8. 根据权利要求1所述的芳胺基嘌呤衍生物的盐，其特征在于，所述盐为式13、或式14所示的琥珀酸盐：
    Figure PCTCN2021073285-appb-100015
    n选自0、0.5、1、1.5、2、2.5、3、3.5、4、4.5或5；
    优选地，所述盐为式13'、或式14'所示的琥珀酸盐：
    Figure PCTCN2021073285-appb-100016
    更优选地，所述式13和式13'所示的琥珀酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在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°处具有特征峰；进一步更优选地，所述式13和式13'所示的琥珀酸盐使用CuKα辐射，具有基本上如图13所示的X射线粉末衍射谱图；
    或者更优选地，所述式14和式14'所示的琥珀酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在7.0±0.2°、9.2±0.2°、17.6±0.2°、18.4±0.2°、19.7±0.2°、25.8±0.2°、27.3±0.2°处具有特征峰；进一步更优选地，所述式14和式14'所示的琥珀酸盐使用CuKα辐射，具有基本上如图14所示的X射线粉末衍射谱图。
  9. 根据权利要求1所述的芳胺基嘌呤衍生物的盐，其特征在于，所述盐为式15、或式16所示的醋酸盐：
    Figure PCTCN2021073285-appb-100017
    n选自0、0.5、1、1.5、2、2.5、3、3.5、4、4.5或5；
    优选地，所述盐为式15'、或式16'所示的醋酸盐：
    Figure PCTCN2021073285-appb-100018
    更优选地，所述式15和式15'所示的醋酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在10.9±0.2°、12.6±0.2°、15.1±0.2°、17.8±0.2°、19.2±0.2°、19.6±0.2°、 21.0±0.2°、21.8±0.2°、22.3±0.2°、24.6±0.2°、25.4±0.2°处具有特征峰；进一步更优选地，，所述式15和式15'所示的醋酸盐使用CuKα辐射，具有基本上如图15所示的X射线粉末衍射谱图；
    或者更优选地，所述式16和式16'所示的醋酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在6.2±0.2°、12.2±0.2°、17.5±0.2°、21.5±0.2°、23.4±0.2°、24.8±0.2°处具有特征峰；进一步更优选地，所述式16和式16'所示的醋酸盐使用CuKα辐射，具有基本上如图16所示的X射线粉末衍射谱图。
  10. 根据权利要求1所述的芳胺基嘌呤衍生物的盐，其特征在于，所述盐为式17、或式18所示的硫酸盐：
    Figure PCTCN2021073285-appb-100019
    n选自0、0.5、1、1.5、2、2.5、3、3.5、4、4.5或5；
    优选地，所述盐为式17'、或式18'所示的硫酸盐：
    Figure PCTCN2021073285-appb-100020
    更优选地，所述式17和式17'所示的硫酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在4.8±0.2°、7.0±0.2°、8.6±0.2°、9.2±0.2°、9.5±0.2°、11.6±0.2°、12.8±0.2°、13.6±0.2°、15.7±0.2°、17.6±0.2°、18.6±0.2°、20.5±0.2°、21.6±0.2°、23.8±0.2°、25.7±0.2°处具有特征峰；进一步更优选地，所述式17和式17'所示的硫酸盐使用CuKα辐射，具有基本上如图17所示的X射线粉末衍射谱图；
    或者更优选地，所述式18和式18'所示的硫酸盐使用CuKα辐射，以2θ角度表示的X射线粉末衍射在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°处具有特征峰；进一步更优选地，所述式18和式18'所示的硫酸盐使用CuKα辐射，具有基本上如图18所示的X射线粉末衍射谱图。
  11. 一种药物组合物，其包含权利要求1-10任一项所述式2所示的芳胺基嘌呤衍生物的盐。
  12. 权利要求1-10任一项所述式2所示的芳胺基嘌呤衍生物的盐或权利要求11所述的药物组合物用于制备作为蛋白激酶抑制剂药物的用途，所述激酶选自：FLT3、EGFR、Abl、Fyn、Hck、Lck、Lyn、Ret、Yes，VEGFR2、ALK、BTK、c-KIT、c-SRC、FGFR1、KDR、MET和PDGFRα；
    优选地，所述蛋白激酶抑制剂药物为抗肿瘤药物，所述肿瘤选自非小细胞肺癌、急性髓性白血病、慢性粒细胞白血病、慢性髓性白血病、表皮鳞癌、乳腺癌、结直肠癌、肝癌、胃癌、和恶性黑色素瘤，更优选为白血病或肺癌，进一步更优选为急性髓性白血病或非小细胞肺癌，进一步优选为FLT3突变阳性的急性髓性白血病(如FLT3-ITD的急性髓性白血病)、Ph阳性的慢性髓性白血病、或EGFR激活突变的非小细胞肺癌。
  13. 一种权利要求1所述的式2所示的芳胺基嘌呤衍生物的盐的制备方法，包括将式1所示的芳胺基嘌呤衍生物与酸在水和有机溶剂的存在下进行反应，得到式2所示的芳胺基嘌呤衍生物的盐：
    Figure PCTCN2021073285-appb-100021
    其中，
    HA是酸；
    H 2O为结晶水；
    m为1-4的整数或半整数；
    n为0-5的整数或半整数。
  14. 如权利要求13所述的芳胺基嘌呤衍生物的盐的制备方法，其特征在于，所述式1所示的芳胺基嘌呤衍生物与酸的摩尔比为1:1～1:4，优选为1:1.2～1:3.5；
    反应温度为0-70℃，优选35-45℃；
    反应在水和选自醇类、醚类、酯类、酮类、腈类、和烷烃类的有机溶剂中的一种或者多种的组合的存在下进行，优选地在C 1-C 3的低级醇和水的存在下、在酮类和水的存在下，在腈类和水的存在下，或者在醚类和水的存在下进行，更优选地在甲醇-水、乙醇-水、异丙醇-水、四氢呋喃-水、二氧六环-水、丙酮- 水或乙腈-水的存在下进行；有机溶剂与水用量体积比为1:10～10:1，例如1:1～10:1或1:10～1:1。
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