CN116018141A

CN116018141A - Salt and crystal form containing indole derivatives, and preparation method and application thereof

Info

Publication number: CN116018141A
Application number: CN202180051559.5A
Authority: CN
Inventors: 李媛媛; 呙临松
Original assignee: Jiangsu Hansoh Pharmaceutical Group Co Ltd; Shanghai Hansoh Biomedical Co Ltd
Current assignee: Jiangsu Hansoh Pharmaceutical Group Co Ltd; Shanghai Hansoh Biomedical Co Ltd
Priority date: 2020-11-19
Filing date: 2021-11-19
Publication date: 2023-04-25
Also published as: WO2022105882A1; TW202222795A

Abstract

Salt and crystal form containing indole derivatives, and preparation method and application thereof. In particular to a compound salt shown in a general formula (I), a crystal form, a preparation method and a pharmaceutical composition containing the compound or the crystal form thereof in a therapeutically effective amount, and the application of the compound serving as a kinase inhibitor, especially a receptor Tyrosine Kinase Inhibitor (TKI), more specifically an EGFR or HER2 inhibitor in treating cancers, inflammations, chronic liver diseases, diabetes, cardiovascular diseases, AIDS and other related diseases, wherein the compound has good inhibitory activity in EGFR and HER2 20 exon mutation.

Description

Salt and crystal form containing indole derivatives, and preparation method and application thereof

Technical Field

The invention belongs to the field of biological medicine, and in particular relates to a salt and a crystal form containing indole derivatives, and a preparation method and application thereof.

Background

The presence of multiple signaling pathway interactions in cells controls proliferation, growth, migration, and apoptosis of the cells. Abnormal activation of the signal pathway can lead to the occurrence of tumors. Receptor tyrosine kinases play an important role in the regulation of cells. Epidermal Growth Factor Receptor (EGFR) is a member of the transmembrane protein tyrosine kinase ErbB receptor family (including ErbB1, erbB2, erbB3, erbB 4) that forms homodimers on the membrane or heterodimers with other receptors in the ErbB family (e.g., erbB2, erbB3, erbB 4) by binding to its ligand Epidermal Growth Factor (EGF), resulting in activation of EGFR tyrosine kinase activity. Activated EGFR can phosphorylate different substrates, thereby activating the downstream PI3K-AKT pathway, RAS-MAPK pathway and the like, and playing a role in a plurality of processes such as cell survival, proliferation, apoptosis and the like.

Deregulation of EGFR signaling pathways, including increased expression of ligands and receptors, amplification and mutation of the EGFR gene, etc., can promote transformation of cells into malignancy, leading to the development of a variety of tumors. About 35% of chinese non-small cell lung cancer (NSCLC) patients are EGFR mutations, with the most common types of mutations being the 19 exon deletion mutation (Del 19) and the 21 exon L858R activating mutation, both occupying about 80% of EGFR mutations. The EGFR 20 exon insertion mutation is another large mutation of EGFR mutation, accounting for 4% -10% of EGFR mutation in NSCLC, the mutation types are tens of, and the common mutation types are Ex20Ins D770_N771InsSVD, ex20Ins V769_D770InsASV and the like.

A number of targeting agents have been developed over the years for EGFR mutations in NSCLC, such as the first-generation reversible tyrosinase inhibitors (TKI) gefitinib and erlotinib, the second-generation irreversible covalent binding inhibitor afatinib, and the third-generation inhibitor of octatinib for the drug-resistant mutation EGFR T790M, all with very good clinical efficacy. However, the EGFR inhibitors on the market at present have poor effect on EGFR 20 exon insertion mutation, the survival time of patients is short, the target point needs a more specific inhibitor, and a great clinical demand exists.

HER2, another member of the ErbB family, has been amplified and mutated in a variety of cancers. Wherein HER2 mutations account for about 4% of NSCLC and HER2 mutations account for about 90% of 20 exon insertion mutations, the most common type of mutation being p.a775_g776insyvma, for which EGFR inhibitors currently on the market are generally effective.

At present, a plurality of domestic and foreign pharmaceutical enterprises develop active researches on EGFR & HER2 exon insertion mutation, wherein TAK-788 of Poziotinib, takeda of Spectrum company and Tarloxotinib of Rain Therapeutics enter clinical researches, and in addition, compound TAS-6417 of Cullinan & Taiho company also has better activity in preclinical experiments. Because many EGFR inhibitors have strong inhibition effect on EGFR wild type, side effects such as rash appear clinically, and the inhibition activity on EGFR 20 exon insertion mutation and HER2 exon insertion mutation targets is still to be improved, the compounds with obvious effect on EGFR and HER2 20 exon mutation and high selectivity on wild type EGFR still have great demands, and have good market prospect.

In the subsequent research and development of a series of indole derivative inhibitor-containing structures disclosed in PCT/CN2020/091558, the invention comprehensively researches the salt form of the compound and the crystal form of the salt in order to improve the solubility and solid stability of the product, reduce the storage cost, prolong the product period and improve the bioavailability of the product.

Disclosure of Invention

All that is referred to in patent PCT/CN2020/091558 is incorporated herein by reference.

The invention aims to provide an acid salt of a compound shown in a general formula (I),

wherein:

R ₁ selected from hydrogen, cyano, oxazolyl, pyrazolyl, and,

R ₂ Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;

R ₃ selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; .

In a preferred embodiment of the invention, wherein R ₂ Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C _1-6 Alkyl, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, C _3-8 Cycloalkyl or 3-8 membered heterocyclyl;

R ₂ preferably hydrogen, deuterium, halogen, cyano, C _1-3 Alkyl, C _1-3 Deuterated alkyl, C _1-3 Haloalkyl, C _1-3 Alkoxy, C _1-3 Haloalkoxy groups、C _3-6 Cycloalkyl or 3-6 membered heterocyclyl;

R ₂ more preferably hydrogen, deuterium, methyl, ethyl, propyl, cyclopropyl or oxetanyl;

R ₂ Most preferred is hydrogen, methyl, cyclopropyl or oxetanyl.

In a preferred embodiment of the invention, R ₃ Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C _1-6 Alkyl, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy or C _1-6 Haloalkoxy groups;

R ₃ preferably hydrogen, deuterium, halogen, cyano, C _1-3 Alkyl, C _1-3 Deuterated alkyl, C _1-3 Haloalkyl, C _1-3 Alkoxy or C _1-3 Haloalkoxy groups;

R ₃ more preferably hydrogen, deuterium, fluorine, chlorine, bromine, methoxy or ethoxy;

R ₃ most preferred are hydrogen, fluorine or methoxy.

In a preferred embodiment of the invention, the specific compound structure is as follows:

in a further preferred embodiment of the invention, the compound is N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide, N- (5- ((5-cyano-4- (6-methoxy-1- (oxetan-3-yl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide, N- (5- ((5-cyano-4- (1-cyclopropyl-5-fluoro-6-methoxy-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide, N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) -5- (oxazol-2-yl) pyrimidin-2-yl) amino) phenyl) acrylamide.

In a further preferred embodiment of the invention, the number of acids is 0.2-3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3; more preferably 0.5, 1, 2 or 3; further preferably 1.

In a further preferred embodiment of the invention, the acid salt is

In a further preferred embodiment of the invention, the acid salt is a hydrate or anhydrate; when the acid salt is hydrate, the number of water is 0.2-3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3; more preferably 0.5, 1, 2 or 3.

In a further preferred embodiment of the invention, the acid salt is in crystalline form or amorphous form.

In a further preferred embodiment of the invention, the acid salt of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide is in the form of a crystalline form, preferably the hydrochloride salt of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide is in the form of a crystalline form, a hydrobromide salt, a p-toluenesulfonate salt, a sulfate salt, a fumarate salt, an oxalate salt, a benzoylglycinate salt, a phosphate salt, a maleate salt, a malate salt, a methanesulfonate salt, a benzenesulfonate salt, a malonate salt, an adipate salt or a succinate salt; more preferably the hydrochloride, hydrobromide, p-toluenesulfonate, sulfate, fumarate, oxalate, benzoylglycinate, phosphate, maleate, methanesulfonate, benzenesulfonate or succinate salt forms of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide; further preferred is the hydrochloride, hydrobromide, p-toluenesulfonate or benzoylglycinate form of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide.

In a further preferred embodiment of the invention, the acid salt form of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide is hydrochloride form a, hydrobromide form a, p-toluenesulfonate form a, sulfate form a, fumarate form a, oxalate form a, benzoylglycinate form B, benzoylglycinate form C, benzoylglycinate form D, benzoylglycinate form E, benzoylglycinate form F, phosphate form a, maleate form B, maleate form C, maleate form D, methanesulfonate form a, benzenesulfonate form a, malonate form B, succinate form a or succinate form B, wherein:

the X-ray powder diffraction pattern of the hydrochloride crystal form A has diffraction peaks at 26.4+/-0.2 degrees; or a diffraction peak at 10.8±0.2°; or a diffraction peak at 20.9±0.2°; or a diffraction peak at 14.2±0.2°; or a diffraction peak at 12.5±0.2°; or a diffraction peak at 6.3±0.2°; or a diffraction peak at 25.0±0.2°; or a diffraction peak at 21.0±0.2°; or a diffraction peak at 22.1±0.2°; or a diffraction peak at 24.9±0.2°; preferably any of the above diffraction peaks is contained at 2 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8, more preferably any 6, 7 or 8 thereof;

The X-ray powder diffraction pattern of the hydrobromide crystal form A has diffraction peaks at 24.9+/-0.2 degrees of 2 theta; or a diffraction peak at 26.3±0.2°; or a diffraction peak at 6.2±0.2°; or a diffraction peak at 20.4±0.2°; or a diffraction peak at 15.6±0.2°; or a diffraction peak at 10.5±0.2°; or a diffraction peak at 22.6 + -0.2 deg.; or a diffraction peak at 14.0±0.2°; or a diffraction peak at 21.0±0.2°; or a diffraction peak at 25.8±0.2°; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof;

the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form A has diffraction peaks at 5.5+/-0.2 degrees of 2 theta; or a diffraction peak at 14.1±0.2°; or a diffraction peak at 21.7±0.2°; or a diffraction peak at 15.6±0.2°; or a diffraction peak at 22.2 + -0.2 deg.; or a diffraction peak at 24.3±0.2°; or a diffraction peak at 26.8±0.2°; or a diffraction peak at 21.1±0.2°; or a diffraction peak at 9.9±0.2°; or a diffraction peak at 23.9±0.2°; preferably comprises any of the diffraction peaks described above at 2 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8, more preferably comprises any of 6, 7 or 8;

The X-ray powder diffraction pattern of the sulfate crystal form A has diffraction peaks at the 2 theta of 12.0 plus or minus 0.2 degrees; or a diffraction peak at 11.9±0.2°; or a diffraction peak at 6.1±0.2°; or a diffraction peak at 14.1±0.2°; or a diffraction peak at 21.3±0.2°; or a diffraction peak at 22.1±0.2°; or a diffraction peak at 22.3 + -0.2 deg.; or a diffraction peak at 9.6±0.2°; or a diffraction peak at 10.4±0.2°; or a diffraction peak at 22.4 + -0.2 deg.; preferably comprises any of the diffraction peaks described above at 2 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8, more preferably comprises any of 6, 7 or 8;

the X-ray powder diffraction pattern of the fumarate salt crystal form A has diffraction peaks at 24.0+/-0.2 degrees of 2 theta; or a diffraction peak at 15.2±0.2°; or a diffraction peak at 9.4±0.2°; or a diffraction peak at 20.9±0.2°; or a diffraction peak at 25.7±0.2°; or a diffraction peak at 13.8±0.2°; or a diffraction peak at 22.1±0.2°; or a diffraction peak at 9.7±0.2°; or a diffraction peak at 17.6±0.2°; or a diffraction peak at 18.7±0.2°; preferably comprises any of the diffraction peaks described above at 2 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8, more preferably comprises any of 6, 7 or 8;

The X-ray powder diffraction pattern of the oxalate crystal form A has diffraction peaks at the 2 theta of 5.8 plus or minus 0.2 degrees; or a diffraction peak at 11.6±0.2°; or a diffraction peak at 21.4±0.2°; or a diffraction peak at 20.6±0.2°; or a diffraction peak at 14.3±0.2°; or a diffraction peak at 18.4±0.2°; or a diffraction peak at 19.6±0.2°; or a diffraction peak at 23.8±0.2°; or a diffraction peak at 9.7±0.2°; or a diffraction peak at 27.7±0.2°; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof;

the X-ray powder diffraction pattern of the benzoyl glycinate salt crystal form A has diffraction peaks at the 2 theta of 5.4 plus or minus 0.2 degrees; or a diffraction peak at 25.1±0.2°; or a diffraction peak at 10.6 + -0.2 deg.; or a diffraction peak at 21.3±0.2°; or a diffraction peak at 18.3±0.2°; or a diffraction peak at 14.6±0.2°; or a diffraction peak at 19.4±0.2°; or a diffraction peak at 19.0±0.2°; or a diffraction peak at 25.9±0.2°; or a diffraction peak at 16.6±0.2°; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof;

The X-ray powder diffraction pattern of the benzoyl glycinate salt crystal form B has diffraction peaks at the 2 theta of 5.4 plus or minus 0.2 degrees; or a diffraction peak at 24.7±0.2°; or a diffraction peak at 19.1±0.2°; or a diffraction peak at 18.9±0.2°; or a diffraction peak at 10.5±0.2°; or a diffraction peak at 23.1±0.2°; or a diffraction peak at 20.9±0.2°; or a diffraction peak at 14.4±0.2°; or a diffraction peak at 10.8±0.2°; or a diffraction peak at 22.8±0.2°; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof;

the X-ray powder diffraction pattern of the benzoyl glycinate salt crystal form C has diffraction peaks at the 2 theta of 5.7 plus or minus 0.2 degrees; or a diffraction peak at 20.4±0.2°; or a diffraction peak at 26.4±0.2°; or a diffraction peak at 14.5±0.2°; or a diffraction peak at 15.5±0.2°; or a diffraction peak at 11.1±0.2°; or a diffraction peak at 18.5±0.2°; or a diffraction peak at 16.8±0.2°; or a diffraction peak at 19.4±0.2°; or a diffraction peak at 17.5±0.2°; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof;

The X-ray powder diffraction pattern of the benzoyl glycinate salt crystal form D has diffraction peaks at 17.6+/-0.2 degrees of 2 theta; or a diffraction peak at 21.0±0.2°; or a diffraction peak at 5.8±0.2°; or a diffraction peak at 25.2±0.2°; or a diffraction peak at 16.6±0.2°; or a diffraction peak at 15.0 + -0.2 deg.; or a diffraction peak at 9.7±0.2°; or a diffraction peak at 10.2 + -0.2 deg.; or a diffraction peak at 14.8±0.2°; or a diffraction peak at 19.9±0.2°; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof;

the X-ray powder diffraction pattern of the benzoyl glycinate salt crystal form E has diffraction peaks at the 2 theta of 5.4 plus or minus 0.2 degrees; or a diffraction peak at 5.3 + -0.2 deg.; or a diffraction peak at 5.6±0.2°; or a diffraction peak at 10.7±0.2°; or a diffraction peak at 20.8±0.2°; or a diffraction peak at 24.7±0.2°; or a diffraction peak at 16.5±0.2°; or a diffraction peak at 21.5±0.2°; or a diffraction peak at 14.5±0.2°; or a diffraction peak at 18.4±0.2°; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof;

The X-ray powder diffraction pattern of the benzoyl glycinate salt crystal form F has diffraction peaks at 6.1+/-0.2 degrees of 2 theta; or a diffraction peak at 6.3±0.2°; or a diffraction peak at 10.3 + -0.2 deg.; or a diffraction peak at 12.3±0.2°; or a diffraction peak at 9.3±0.2°; or a diffraction peak at 9.8±0.2°; or a diffraction peak at 11.6±0.2°; or a diffraction peak at 5.5±0.2°; or a diffraction peak at 11.1±0.2°; or a diffraction peak at 13.8±0.2°; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof;

the X-ray powder diffraction pattern of the phosphate crystal form A has diffraction peaks at the 2 theta of 10.6 plus or minus 0.2 degrees; or a diffraction peak at 12.3±0.2°; or a diffraction peak at 9.2±0.2°; or a diffraction peak at 21.4±0.2°; or a diffraction peak at 13.5±0.2°; or a diffraction peak at 6.3±0.2°; or a diffraction peak at 10.9±0.2°; or a diffraction peak at 25.3±0.2°; or a diffraction peak at 11.7±0.2°; or a diffraction peak at 12.1±0.2°; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof;

The X-ray powder diffraction pattern of the maleate crystal form A has diffraction peaks at 6.0+/-0.2 degrees of 2 theta; or a diffraction peak at 22.3 + -0.2 deg.; or a diffraction peak at 8.2±0.2°; or a diffraction peak at 16.3±0.2°; or a diffraction peak at 23.5±0.2°; or a diffraction peak at 19.5±0.2°; or a diffraction peak at 19.2±0.2°; or a diffraction peak at 11.8±0.2°; or a diffraction peak at 7.1±0.2°; or a diffraction peak at 21.7±0.2°; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof;

the X-ray powder diffraction pattern of the maleate crystal form B has diffraction peaks at the 2 theta of 7.7 plus or minus 0.2 degrees; or a diffraction peak at 16.1±0.2°; or a diffraction peak at 23.6±0.2°; or a diffraction peak at 22.2 + -0.2 deg.; or a diffraction peak at 19.2±0.2°; or a diffraction peak at 21.7±0.2°; or a diffraction peak at 6.5±0.2°; or a diffraction peak at 19.8±0.2°; or a diffraction peak at 6.0±0.2°; or a diffraction peak at 8.2±0.2°; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof;

An X-ray powder diffraction pattern of the maleate crystal form C has diffraction peaks at 17.1+/-0.2 degrees of 2 theta; or a diffraction peak at 10.3 + -0.2 deg.; or a diffraction peak at 23.8±0.2°; or a diffraction peak at 14.3±0.2°; or a diffraction peak at 13.3±0.2°; or a diffraction peak at 24.5±0.2°; or a diffraction peak at 25.5±0.2°; or a diffraction peak at 23.5±0.2°; or a diffraction peak at 13.1±0.2°; or a diffraction peak at 22.9±0.2°; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof;

the X-ray powder diffraction pattern of the maleate crystal form D has diffraction peaks at 20.4+/-0.2 degrees of 2 theta; or a diffraction peak at 8.2±0.2°; or a diffraction peak at 14.6±0.2°; or a diffraction peak at 25.9±0.2°; or a diffraction peak at 18.4±0.2°; or a diffraction peak at 8.9±0.2°; or a diffraction peak at 24.1±0.2°; or a diffraction peak at 24.5±0.2°; or a diffraction peak at 16.1±0.2°; or a diffraction peak at 21.8±0.2°; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof;

The X-ray powder diffraction pattern of the mesylate salt crystal form A has diffraction peaks at the 2 theta of 5.9 plus or minus 0.2 degrees; or a diffraction peak at 21.7±0.2°; or a diffraction peak at 10.2 + -0.2 deg.; or a diffraction peak at 14.2±0.2°; or a diffraction peak at 20.8±0.2°; or a diffraction peak at 25.7±0.2°; or a diffraction peak at 22.2 + -0.2 deg.; or a diffraction peak at 17.4±0.2°; or a diffraction peak at 11.7±0.2°; or a diffraction peak at 18.0±0.2°; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof;

the X-ray powder diffraction pattern of the benzenesulfonate crystal form A has diffraction peaks at the 2 theta of 5.6 plus or minus 0.2 degrees; or a diffraction peak at 21.2±0.2°; or a diffraction peak at 13.4±0.2°; or a diffraction peak at 18.9±0.2°; or a diffraction peak at 26.6±0.2°; or a diffraction peak at 23.7±0.2°; or a diffraction peak at 19.5±0.2°; or a diffraction peak at 26.4±0.2°; or a diffraction peak at 10.0 + -0.2 deg.; or a diffraction peak at 10.6 + -0.2 deg.; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof;

The X-ray powder diffraction pattern of the malonate crystal form A has diffraction peaks at the 2 theta of 7.5 plus or minus 0.2 degrees; or a diffraction peak at 5.5±0.2°; or a diffraction peak at 23.6±0.2°; or a diffraction peak at 20.3±0.2°; or a diffraction peak at 9.7±0.2°; or a diffraction peak at 11.7±0.2°; or a diffraction peak at 23.0±0.2°; or a diffraction peak at 21.0±0.2°; or a diffraction peak at 14.3±0.2°; or a diffraction peak at 25.6±0.2°; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof;

the X-ray powder diffraction pattern of the malonate crystal form B has diffraction peaks at 21.4+/-0.2 degrees of 2 theta; or a diffraction peak at 5.9±0.2°; or a diffraction peak at 20.5±0.2°; or a diffraction peak at 11.4±0.2°; or a diffraction peak at 19.1±0.2°; or a diffraction peak at 20.8±0.2°; or a diffraction peak at 16.1±0.2°; or a diffraction peak at 27.4±0.2°; or a diffraction peak at 18.4±0.2°; or a diffraction peak at 13.9±0.2°; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof;

The X-ray powder diffraction pattern of the succinate salt crystal form A has diffraction peaks at the 2 theta of 21.4 plus or minus 0.2 degrees; or a diffraction peak at 10.7±0.2°; or a diffraction peak at 16.6±0.2°; or a diffraction peak at 19.6±0.2°; or a diffraction peak at 26.2±0.2°; or a diffraction peak at 19.3±0.2°; or a diffraction peak at 21.6±0.2°; or a diffraction peak at 21.0±0.2°; or a diffraction peak at 16.0±0.2°; or a diffraction peak at 14.4±0.2°; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof;

the X-ray powder diffraction pattern of the succinate salt crystal form B has diffraction peaks at the position that 2 theta is 19.2 plus or minus 0.2 degrees; or a diffraction peak at 21.3±0.2°; or a diffraction peak at 20.7±0.2°; or a diffraction peak at 14.1±0.2°; or a diffraction peak at 20.4±0.2°; or a diffraction peak at 18.5±0.2°; or a diffraction peak at 11.4±0.2°; or a diffraction peak at 23.7±0.2°; or a diffraction peak at 27.3±0.2°; or a diffraction peak at 20.8±0.2°; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof.

In a further preferred embodiment of the invention, there is provided hydrochloride form a of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (example 1), the number of acids being 1, the X-ray powder diffraction pattern of which comprises at least one or more diffraction peaks at 26.4±0.2°, 10.8±0.2°, 20.9±0.2°, preferably at 2, more preferably at 3; optionally, it may further comprise at least one of 2 theta of 14.2±0.2°, 12.5±0.2°, 6.3±0.2°, 25.0±0.2°, 21.0±0.2, preferably 2, 3, 4 or 5;

for example, the X-ray powder diffraction pattern of hydrochloride form a has diffraction peaks at 2θ:26.4±0.2°, 10.8±0.2°, 20.9±0.2°, 14.2±0.2°, 12.5±0.2° and 6.3±0.2°.

The X-ray powder diffraction pattern of hydrochloride form a optionally further comprises one or more diffraction peaks at 22.1±0.2°, 24.9±0.2°, 18.9±0.2°, 8.8±0.2°, 26.6±0.2°, 15.7±0.2°, 26.1±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

For example, the X-ray powder diffraction pattern of hydrochloride form a has diffraction peaks at 2θ:26.4±0.2°, 10.8±0.2°, 14.2±0.2°, 12.5±0.2°, 6.3±0.2°, 25.0±0.2°, 22.1±0.2°, 24.9±0.2° and 8.8±0.2°.

The X-ray powder diffraction pattern of the hydrochloride crystal form A comprises diffraction peaks at one or more positions of 26.4+/-0.2 degrees, 10.8+/-0.2 degrees, 20.9+/-0.2 degrees, 14.2+/-0.2 degrees, 12.5+/-0.2 degrees, 6.3+/-0.2 degrees, 25.0+/-0.2 degrees, 21.0+/-0.2 degrees, 22.1+/-0.2 degrees, 24.9+/-0.2 degrees, 18.9+/-0.2 degrees, 8.8+/-0.2 degrees, 26.6+/-0.2 degrees, 15.7+/-0.2 degrees and 26.1+/-0.2 degrees; preferably, the method comprises the steps of optionally having diffraction peaks at 4, 5, 6, 8 and 10;

for example, the X-ray powder diffraction pattern of hydrochloride form a has diffraction peaks at 2θ:26.4±0.2°, 10.8±0.2°, 20.9±0.2° and 14.2±0.2°;

alternatively, 26.4±0.2°, 10.8±0.2°, 20.9±0.2°, 14.2±0.2°, 6.3±0.2° and 22.1±0.2°;

alternatively, 26.4±0.2°, 10.8±0.2°, 20.9±0.2°, 14.2±0.2°, 12.5±0.2°, 6.3±0.2°, 22.1±0.2° and 18.9±0.2°;

alternatively, 26.4±0.2°, 10.8±0.2°, 20.9±0.2°, 14.2±0.2°, 12.5±0.2°, 6.3±0.2°, 25.0±0.2°, 21.0±0.2°, 22.1±0.2° and 18.9±0.2°.

The X-ray powder diffraction pattern of hydrochloride form a comprises diffraction peaks at one or more of 26.4±0.2°, 10.8±0.2°, 20.9±0.2°, 14.2±0.2°, 12.5±0.2°, 6.3±0.2°, 25.0±0.2°, 21.0±0.2, 22.1±0.2°, 24.9±0.2°, 18.9±0.2°, 8.8±0.2°, 26.6±0.2°, 15.7±0.2°, 26.1±0.2°, 20.6±0.2°, 22.9±0.2°, 23.1±0.2°, 10.4±0.2°, 22.6±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 7 to 8, or 10 to 12, or 15 to 18; further preferably, the diffraction peaks at any 2, 3, 4, 5, 6, 8, 10, 12, 16, 18 are included;

for example, the X-ray powder diffraction pattern of hydrochloride form a has diffraction peaks at 2θ:26.4±0.2°, 10.8±0.2°, 20.9±0.2°, 14.2±0.2°, 12.5±0.2°, 6.3±0.2°, 22.1±0.2°, 20.6±0.2°, 22.9±0.2° and 18.9±0.2°.

Most preferably, cu-K alpha radiation is used, and the X-ray characteristic diffraction peaks expressed in terms of 2 theta angles and interplanar spacing d values are shown in Table 1.

TABLE 1

Further preferably, the compound of example 1, N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide, in its hydrochloride form A, has an X-ray powder diffraction pattern substantially as shown in FIG. 1; the DSC spectrum is basically shown in figure 2; the TGA profile is substantially as shown in figure 3.

In a further preferred embodiment of the invention, there is provided the hydrobromide crystalline form a of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (example 1), the number of acids being 1, and the X-ray powder diffraction pattern thereof having one or more diffraction peaks in the 2θ of 24.9±0.2°, 26.3±0.2°, 6.2±0.2°, preferably comprising two of them, more preferably three of them; optionally, the composition further comprises at least one of 20.4+/-0.2 °, 15.6+/-0.2 °, 10.5+/-0.2 °, 22.6+/-0.2 °, and 14.0+/-0.2 °; preferably 2, 3, 4 or 5 of these;

for example, the X-ray powder diffraction pattern of hydrobromide form a has diffraction peaks at 2θ: 24.9.+ -. 0.2 °, 26.3.+ -. 0.2 °, 6.2.+ -. 0.2 °, 20.4.+ -. 0.2 °, 15.6.+ -. 0.2 ° and 10.5.+ -. 0.2 °.

The X-ray powder diffraction pattern of hydrobromide crystalline form a optionally further comprises one or more diffraction peaks at 21.0±0.2°, 25.8±0.2°, 18.9±0.2°, 26.5±0.2°, 20.8±0.2°, 12.4±0.2°, 28.1±0.2° in 2θ; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

For example, the X-ray powder diffraction pattern of hydrobromide form a has diffraction peaks at 2θ:24.9±0.2°, 26.3±0.2°, 6.2±0.2°, 20.4±0.2°, 15.6±0.2°, 10.5±0.2°, 21.0±0.2° and 25.8±0.2°;

or, at 24.9±0.2°, 26.3±0.2°, 20.4±0.2°, 15.6±0.2°, 10.5±0.2°, 22.6±0.2°, 21.0±0.2°, 25.8±0.2° and 18.9±0.2°;

alternatively, 24.9±0.2°, 6.2±0.2°, 20.4±0.2°, 15.6±0.2°, 10.5±0.2°, 22.6±0.2°, 21.0±0.2°, 25.8±0.2°, 18.9±0.2° and 26.5±0.2°.

The X-ray powder diffraction pattern of hydrobromide crystalline form a comprises one or more diffraction peaks at 24.9±0.2°, 26.3±0.2°, 6.2±0.2°, 20.4±0.2°, 15.6±0.2°, 10.5±0.2°, 22.6±0.2°, 14.0±0.2°, 21.0±0.2°, 25.8±0.2°, 18.9±0.2°, 26.5±0.2°, 20.8±0.2°, 12.4±0.2°, 28.1±0.2°; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

for example, the X-ray powder diffraction pattern of hydrobromide form a has diffraction peaks at 2θ:24.9±0.2°, 26.3±0.2°, 6.2±0.2° and 20.4±0.2°;

Alternatively, 24.9±0.2°, 26.3±0.2°, 6.2±0.2°, 20.4±0.2°, 15.6±0.2° and 21.0±0.2°;

alternatively, 24.9±0.2°, 26.3±0.2°, 6.2±0.2°, 20.4±0.2°, 15.6±0.2°, 10.5±0.2°, 22.6±0.2°, 14.0±0.2°, 21.0±0.2° and 25.8±0.2°.

The X-ray powder diffraction pattern of hydrobromide crystalline form a comprises one or more diffraction peaks at 24.9±0.2°, 26.3±0.2°, 6.2±0.2°, 20.4±0.2°, 15.6±0.2°, 10.5±0.2°, 22.6±0.2°, 14.0±0.2°, 21.0±0.2°, 25.8±0.2°, 18.9±0.2°, 26.5±0.2°, 20.8±0.2°, 12.4±0.2°, 28.1±0.2°, 19.5±0.2°, 22.1±0.2°, 18.5±0.2°, 32.5±0.2°, 8.7±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 7 to 8, or 10 to 12, or 15 to 18; further preferably, the diffraction peaks at any 2, 3, 4, 5, 6, 8, 10, 12, 16, 18 are included;

for example, the X-ray powder diffraction pattern of hydrobromide form a has diffraction peaks at 2θ: 24.9.+ -. 0.2 °, 26.3.+ -. 0.2 °, 6.2.+ -. 0.2 °, 20.4.+ -. 0.2 °, 15.6.+ -. 0.2 °, 10.5.+ -. 0.2 °, 21.0.+ -. 0.2 °, 19.5.+ -. 0.2 °, 22.1.+ -. 0.2 ° and 18.9.+ -. 0.2 °.

Most preferably, cu-K alpha radiation is used, and the X-ray characteristic diffraction peaks expressed in terms of 2 theta angles and interplanar spacing d values are shown in Table 2.

TABLE 2

Further preferably, the compound of example 1, N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide, has a hydrobromide salt form A, and an X-ray powder diffraction pattern substantially as shown in FIG. 4; the DSC spectrum is basically shown in figure 5; the TGA profile is substantially as shown in figure 6.

In a further preferred embodiment of the invention, there is provided p-toluenesulfonate salt form a of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (example 1), the number of acids being 1, and the X-ray powder diffraction pattern thereof having one or more diffraction peaks in the 2 theta range of 5.5±0.2°, 14.1±0.2°, 21.7±0.2°, preferably comprising two of them, more preferably three of them; optionally, the composition further comprises at least one of 15.6+/-0.2 °, 22.2+/-0.2 °, 24.3+/-0.2 °, 26.8+/-0.2 °, and 21.1+/-0.2 °; preferably 2, 3, 4 or 5 of these;

For example, the X-ray powder diffraction pattern of p-toluenesulfonate form a has diffraction peaks at 2θ: 5.5.+ -. 0.2 °, 14.1.+ -. 0.2 °, 21.7.+ -. 0.2 °, 15.6.+ -. 0.2 °, 22.2.+ -. 0.2 ° and 24.3.+ -. 0.2 °.

The X-ray powder diffraction pattern of p-toluenesulfonate form a optionally further comprises one or more diffraction peaks at 9.9±0.2°, 23.9±0.2°, 18.0±0.2°, 8.5±0.2°, 12.1±0.2°, 22.0±0.2°, 8.0±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

for example, the X-ray powder diffraction pattern of p-toluenesulfonate form a has diffraction peaks at 2θ:5.5±0.2°, 14.1±0.2°, 21.7±0.2°, 15.6±0.2°, 22.2±0.2°, 24.3±0.2°, 9.9±0.2° and 23.9±0.2°;

alternatively, 5.5±0.2°, 14.1±0.2°, 15.6±0.2°, 22.2±0.2°, 24.3±0.2°, 26.8±0.2°, 9.9±0.2°, 23.9±0.2° and 18.0±0.2°;

alternatively, 5.5±0.2°, 21.7±0.2°, 15.6±0.2°, 22.2±0.2°, 24.3±0.2°, 26.8±0.2°, 9.9±0.2°, 23.9±0.2°, 18.0±0.2° and 8.5±0.2°.

The X-ray powder diffraction pattern of p-toluenesulfonate form a comprises one or more diffraction peaks at 5.5±0.2°, 14.1±0.2°, 21.7±0.2°, 15.6±0.2°, 22.2±0.2°, 24.3±0.2°, 26.8±0.2°, 21.1±0.2°, 9.9±0.2°, 23.9±0.2°, 18.0±0.2°, 8.5±0.2°, 12.1±0.2°, 22.0±0.2°, 8.0±0.2°; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

for example, the X-ray powder diffraction pattern of p-toluenesulfonate form a has diffraction peaks at 2θ:5.5±0.2°, 14.1±0.2°, 21.7±0.2° and 15.6±0.2°;

alternatively, 5.5±0.2°, 14.1±0.2°, 21.7±0.2°, 15.6±0.2°, 24.3±0.2° and 9.9±0.2°;

alternatively, 5.5±0.2°, 14.1±0.2°, 21.7±0.2°, 15.6±0.2°, 22.2±0.2°, 24.3±0.2°, 9.9±0.2° and 18.0±0.2°;

alternatively, 5.5±0.2°, 14.1±0.2°, 21.7±0.2°, 15.6±0.2°, 22.2±0.2°, 24.3±0.2°, 26.8±0.2°, 21.1±0.2°, 9.9±0.2° and 23.9±0.2°.

The X-ray powder diffraction pattern of p-toluenesulfonate form a comprises one or more diffraction peaks at 5.5±0.2°, 14.1±0.2°, 21.7±0.2°, 15.6±0.2°, 22.2±0.2°, 24.3±0.2°, 26.8±0.2°, 21.1±0.2°, 9.9±0.2°, 23.9±0.2°, 18.0±0.2°, 8.5±0.2°, 12.1±0.2°, 22.0±0.2°, 8.0±0.2°, 19.7±0.2°, 20.3±0.2°, 18.5±0.2°, 10.8±0.2°, 21.5±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 7 to 8, or 10 to 12, or 15 to 18; further preferably, the diffraction peaks at any 2, 3, 4, 5, 6, 8, 10, 12, 16, 18 are included;

For example, the X-ray powder diffraction pattern of p-toluenesulfonate form a has diffraction peaks at 2θ: alternatively, 5.5±0.2°, 14.1±0.2°, 21.7±0.2°, 15.6±0.2°, 22.2±0.2°, 24.3±0.2°, 9.9±0.2°, 19.7±0.2°, 20.3±0.2° and 18.0±0.2.

Most preferably, cu-K alpha radiation is used, and the diffraction peaks of the X-ray characteristic expressed in terms of 2 theta angle and d value of interplanar spacing are shown in Table 3.

TABLE 3 Table 3

Further preferably, the compound of example 1, N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide, in the form a, has an X-ray powder diffraction pattern substantially as shown in figure 7; the DSC spectrum is basically shown in figure 8; the TGA profile is substantially as shown in figure 9.

In a further preferred embodiment of the invention, there is provided a crystalline form a of the sulfate salt of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (example 1), the number of acids being 1, and the X-ray powder diffraction pattern thereof having one or more diffraction peaks in 2θ of 12.0±0.2°, 11.9±0.2°, 6.1±0.2°, preferably comprising two of them, more preferably comprising three of them; optionally, the composition further comprises at least one of 14.1+/-0.2 °, 21.3+/-0.2 °, 22.1+/-0.2 °, 22.3+/-0.2 °, and 9.6+/-0.2 °; preferably 2, 3, 4 or 5 of these;

For example, the X-ray powder diffraction pattern of sulfate form a has diffraction peaks at 2θ: 12.0.+ -. 0.2 °, 11.9.+ -. 0.2 °, 6.1.+ -. 0.2 °, 14.1.+ -. 0.2 °, 21.3.+ -. 0.2 ° and 22.1.+ -. 0.2 °.

The X-ray powder diffraction pattern of sulfate form a optionally further comprises one or more diffraction peaks at 2θ of 10.4±0.2°, 22.4±0.2°, 17.9±0.2°, 18.1±0.2°, 18.2±0.2°, 21.0±0.2°, 22.0±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

for example, the X-ray powder diffraction pattern of sulfate form a has diffraction peaks at 2θ: 12.0.+ -. 0.2 °, 11.9.+ -. 0.2 °, 14.1.+ -. 0.2 °, 21.3.+ -. 0.2 °, 22.1.+ -. 0.2 °, 22.3.+ -. 0.2 °, 10.4.+ -. 0.2 °, 22.4.+ -. 0.2 ° and 17.9.+ -. 0.2 °.

The X-ray powder diffraction pattern of sulfate form a comprises one or more diffraction peaks at 2θ of 12.0±0.2°, 11.9±0.2°, 6.1±0.2°, 14.1±0.2°, 21.3±0.2°, 22.1±0.2°, 22.3±0.2°, 9.6±0.2°, 10.4±0.2°, 22.4±0.2°, 17.9±0.2°, 18.1±0.2°, 18.2±0.2°, 21.0±0.2°, 22.0±0.2°; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

For example, the X-ray powder diffraction pattern of sulfate form a has diffraction peaks at 2θ:12.0±0.2°, 11.9±0.2°, 6.1±0.2° and 14.1±0.2°;

alternatively, 12.0±0.2°, 11.9±0.2°, 6.1±0.2°, 14.1±0.2°, 21.3±0.2° and 10.4±0.2°;

alternatively, 12.0±0.2°, 11.9±0.2°, 6.1±0.2°, 14.1±0.2°, 21.3±0.2°, 22.1±0.2°, 10.4±0.2° and 17.9±0.2°;

alternatively, 12.0±0.2°, 11.9±0.2°, 6.1±0.2°, 14.1±0.2°, 21.3±0.2°, 22.1±0.2°, 22.3±0.2°, 9.6±0.2°, 10.4±0.2° and 17.9±0.2°.

The X-ray powder diffraction pattern of sulfate form a comprises one or more diffraction peaks at 2θ of 12.0±0.2°, 11.9±0.2°, 6.1±0.2°, 14.1±0.2°, 21.3±0.2°, 22.1±0.2°, 22.3±0.2°, 9.6±0.2°, 10.4±0.2°, 22.4±0.2°, 17.9±0.2°, 18.1±0.2°, 18.2±0.2°, 21.0±0.2°, 22.0±0.2°, 16.5±0.2°, 25.9±0.2°, 19.9±0.2°, 20.0±0.2°, 23.5±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 7 to 8, or 10 to 12, or 15 to 18; further preferably, the diffraction peaks at any 2, 3, 4, 5, 6, 8, 10, 12, 16, 18 are included;

For example, the X-ray powder diffraction pattern of sulfate form a has diffraction peaks at 2θ: 12.0.+ -. 0.2 °, 11.9.+ -. 0.2 °, 6.1.+ -. 0.2 °, 14.1.+ -. 0.2 °, 21.3.+ -. 0.2 °, 22.1.+ -. 0.2 °, 10.4.+ -. 0.2 °, 16.5.+ -. 0.2 °, 25.9.+ -. 0.2 ° and 17.9.+ -. 0.2 °.

Most preferably, cu-K alpha radiation is used, and the X-ray characteristic diffraction peaks expressed in terms of 2 theta angles and interplanar spacing d values are shown in Table 4.

TABLE 4 Table 4

Further preferred is crystalline form a of the sulfate salt of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide, having an X-ray powder diffraction pattern substantially as shown in figure 10.

In a further preferred embodiment of the invention, there is provided the fumarate salt form a of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (example 1), the number of acids being 1, and the X-ray powder diffraction pattern thereof having one or more diffraction peaks in the 2θ of 24.0±0.2°, 15.2±0.2°, 9.4±0.2°, preferably comprising two of them, more preferably three of them; optionally, the composition further comprises at least one of 20.9+/-0.2 °, 25.7+/-0.2 °, 13.8+/-0.2 °, 22.1+/-0.2 ° and 9.7+/-0.2 °; preferably 2, 3, 4 or 5 of these;

For example, the fumarate salt form a has an X-ray powder diffraction pattern with diffraction peaks at 2θ: 24.0.+ -. 0.2 °, 15.2.+ -. 0.2 °, 9.4.+ -. 0.2 °, 20.9.+ -. 0.2 °, 25.7.+ -. 0.2 ° and 13.8.+ -. 0.2 °.

The X-ray powder diffraction pattern of fumarate salt form a optionally further comprises one or more diffraction peaks at 17.6±0.2°, 18.7±0.2°, 18.9±0.2°, 8.9±0.2°, 7.4±0.2°, 23.1±0.2°, 12.2±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

for example, the fumarate salt form a has an X-ray powder diffraction pattern with diffraction peaks at 2θ:24.0±0.2°, 15.2±0.2°, 9.4±0.2°, 20.9±0.2°, 25.7±0.2°, 13.8±0.2°, 17.6±0.2° and 18.7±0.2°;

or, at 24.0±0.2°, 15.2±0.2°, 20.9±0.2°, 25.7±0.2°, 13.8±0.2°, 22.1±0.2°, 17.6±0.2°, 18.7±0.2° and 18.9±0.2°;

alternatively, 24.0±0.2°, 9.4±0.2°, 20.9±0.2°, 25.7±0.2°, 13.8±0.2°, 22.1±0.2°, 17.6±0.2°, 18.7±0.2°, 18.9±0.2° and 8.9±0.2°.

The X-ray powder diffraction pattern of fumarate salt form a comprises one or more diffraction peaks at 24.0±0.2°, 15.2±0.2°, 9.4±0.2°, 20.9±0.2°, 25.7±0.2°, 13.8±0.2°, 22.1±0.2°, 9.7±0.2°, 17.6±0.2°, 18.7±0.2°, 18.9±0.2°, 8.9±0.2°, 7.4±0.2°, 23.1±0.2°, 12.2±0.2°; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

for example, the fumarate salt form a has an X-ray powder diffraction pattern with diffraction peaks at 2θ:24.0±0.2°, 15.2±0.2°, 9.4±0.2° and 20.9±0.2°;

alternatively, 24.0±0.2°, 15.2±0.2°, 9.4±0.2°, 20.9±0.2°, 25.7±0.2° and 17.6±0.2°;

alternatively, 24.0±0.2°, 15.2±0.2°, 9.4±0.2°, 20.9±0.2°, 25.7±0.2°, 13.8±0.2°, 17.6±0.2° and 18.9±0.2°;

alternatively, 24.0±0.2°, 15.2±0.2°, 9.4±0.2°, 20.9±0.2°, 25.7±0.2°, 13.8±0.2°, 22.1±0.2°, 9.7±0.2°, 17.6±0.2° and 18.7±0.2°.

The X-ray powder diffraction pattern of fumarate salt form a comprises one or more diffraction peaks at 24.0±0.2°, 15.2±0.2°, 9.4±0.2°, 20.9±0.2°, 25.7±0.2°, 13.8±0.2°, 22.1±0.2°, 9.7±0.2°, 17.6±0.2°, 18.7±0.2°, 18.9±0.2°, 8.9±0.2°, 7.4±0.2°, 23.1±0.2°, 12.2±0.2°, 19.4±0.2°, 21.2±0.2°, 22.7±0.2°, 14.7±0.2°, 23.5±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 7 to 8, or 10 to 12, or 15 to 18; further preferably, the diffraction peaks at any 2, 3, 4, 5, 6, 8, 10, 12, 16, 18 are included;

For example, the fumarate salt form a has an X-ray powder diffraction pattern with diffraction peaks at 2θ: 24.0.+ -. 0.2 °, 15.2.+ -. 0.2 °, 9.4.+ -. 0.2 °, 20.9.+ -. 0.2 °, 25.7.+ -. 0.2 °, 13.8.+ -. 0.2 °, 17.6.+ -. 0.2 °, 19.4.+ -. 0.2 °, 21.2.+ -. 0.2 ° and 18.9.+ -. 0.2 °.

Most preferably, cu-K alpha radiation is used, and the X-ray characteristic diffraction peaks expressed in terms of 2 theta angles and interplanar spacing d values are shown in Table 5.

TABLE 5

Further preferred is the fumarate salt form a of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide, having an X-ray powder diffraction pattern substantially as shown in figure 11.

In a further preferred embodiment of the invention, there is provided the oxalate crystalline form a of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (example 1), the number of acids being 1, and the X-ray powder diffraction pattern thereof having one or more diffraction peaks in the 2θ of 5.8±0.2°, 11.6±0.2°, 21.4±0.2°, preferably comprising two of them, more preferably comprising three of them; optionally, the composition further comprises at least one of 20.6+/-0.2 °, 14.3+/-0.2 °, 18.4+/-0.2 °, 19.6+/-0.2 °, and 23.8+/-0.2 °; preferably 2, 3, 4 or 5 of these;

For example, the X-ray powder diffraction pattern of oxalate form a has diffraction peaks at 2θ: 5.8.+ -. 0.2 °, 11.6.+ -. 0.2 °, 21.4.+ -. 0.2 °, 20.6.+ -. 0.2 °, 14.3.+ -. 0.2 ° and 18.4.+ -. 0.2 °.

The X-ray powder diffraction pattern of oxalate crystalline form a optionally further comprises one or more diffraction peaks at 9.7±0.2°, 27.7±0.2°, 8.6±0.2°, 17.4±0.2°, 21.2±0.2°, 20.8±0.2°, 18.6±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

for example, the X-ray powder diffraction pattern of oxalate form a has diffraction peaks at 2θ:5.8±0.2°, 11.6±0.2°, 21.4±0.2°, 20.6±0.2°, 14.3±0.2°, 18.4±0.2°, 9.7±0.2° and 27.7±0.2°;

alternatively, 5.8±0.2°, 11.6±0.2°, 20.6±0.2°, 14.3±0.2°, 18.4±0.2°, 19.6±0.2°, 9.7±0.2°, 27.7±0.2° and 8.6±0.2°;

alternatively, 5.8±0.2°, 21.4±0.2°, 20.6±0.2°, 14.3±0.2°, 18.4±0.2°, 19.6±0.2°, 9.7±0.2°, 27.7±0.2°, 8.6±0.2° and 17.4±0.2°.

The X-ray powder diffraction pattern of oxalate crystalline form a comprises one or more diffraction peaks at 5.8±0.2°, 11.6±0.2°, 21.4±0.2°, 20.6±0.2°, 14.3±0.2°, 18.4±0.2°, 19.6±0.2°, 23.8±0.2°, 9.7±0.2°, 27.7±0.2°, 8.6±0.2°, 17.4±0.2°, 21.2±0.2°, 20.8±0.2°, 18.6±0.2°; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

for example, the X-ray powder diffraction pattern of oxalate form a has diffraction peaks at 2θ:5.8±0.2°, 11.6±0.2°, 21.4±0.2° and 20.6±0.2°;

alternatively, 5.8±0.2°, 11.6±0.2°, 21.4±0.2°, 20.6±0.2°, 14.3±0.2° and 9.7±0.2°;

alternatively, 5.8±0.2°, 11.6±0.2°, 21.4±0.2°, 20.6±0.2°, 14.3±0.2°, 18.4±0.2°, 27.7±0.2° and 8.6±0.2°;

alternatively, 5.8±0.2°, 11.6±0.2°, 21.4±0.2°, 20.6±0.2°, 14.3±0.2°, 18.4±0.2°, 19.6±0.2°, 23.8±0.2°, 9.7±0.2° and 27.7±0.2°.

The X-ray powder diffraction pattern of oxalate crystalline form a comprises one or more diffraction peaks at 5.8±0.2°, 11.6±0.2°, 21.4±0.2°, 20.6±0.2°, 14.3±0.2°, 18.4±0.2°, 19.6±0.2°, 23.8±0.2°, 9.7±0.2°, 27.7±0.2°, 8.6±0.2°, 17.4±0.2°, 21.2±0.2°, 20.8±0.2°, 18.6±0.2°, 20.5±0.2°, 16.4±0.2°, 15.7±0.2°, 23.4±0.2°, 22.3±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 7 to 8, or 10 to 12, or 15 to 18; further preferably, the diffraction peaks at any 2, 3, 4, 5, 6, 8, 10, 12, 16, 18 are included;

For example, the X-ray powder diffraction pattern of oxalate form a has diffraction peaks at 2θ: 5.8.+ -. 0.2 °, 11.6.+ -. 0.2 °, 21.4.+ -. 0.2 °, 20.6.+ -. 0.2 °, 14.3.+ -. 0.2 °, 18.4.+ -. 0.2 °, 9.7.+ -. 0.2 °, 20.5.+ -. 0.2 °, 16.4.+ -. 0.2 ° and 8.6.+ -. 0.2 °.

Most preferably, cu-K alpha radiation is used, and the X-ray characteristic diffraction peaks expressed in terms of 2 theta angles and interplanar spacing d values are shown in Table 6.

TABLE 6

Further preferred is the oxalate crystalline form a of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide, whose X-ray powder diffraction pattern is substantially as shown in figure 12.

In a further preferred embodiment of the invention, there is provided a benzoylglycinate salt form a of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (example 1), having a number of acids of 1, and an X-ray powder diffraction pattern with one or more diffraction peaks in the 2 theta range of 5.4±0.2°, 25.1±0.2°, 10.6±0.2°, preferably comprising two of these, more preferably three of these; optionally, the composition further comprises at least one of 21.3+/-0.2 °, 18.3+/-0.2 °, 14.6+/-0.2 °, 19.4+/-0.2 °, and 19.0+/-0.2 °; preferably 2, 3, 4 or 5 of these;

For example, the X-ray powder diffraction pattern of benzoylglycinate form a has diffraction peaks at 2θ: 5.4.+ -. 0.2 °, 25.1.+ -. 0.2 °, 10.6.+ -. 0.2 °, 21.3.+ -. 0.2 °, 18.3.+ -. 0.2 ° and 14.6.+ -. 0.2 °.

The X-ray powder diffraction pattern of benzoylglycinate form a optionally further comprises one or more diffraction peaks at 25.9±0.2°, 16.6±0.2°, 23.3±0.2°, 9.8±0.2°, 22.8±0.2°, 22.7±0.2°, 17.2±0.2° in 2θ; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

for example, the X-ray powder diffraction pattern of benzoylglycinate form a has diffraction peaks at 2θ:5.4±0.2°, 25.1±0.2°, 10.6±0.2°, 21.3±0.2°, 18.3±0.2°, 14.6±0.2°, 25.9±0.2° and 16.6±0.2°;

alternatively, 5.4±0.2°, 25.1±0.2°, 21.3±0.2°, 18.3±0.2°, 14.6±0.2°, 19.4±0.2°, 25.9±0.2°, 16.6±0.2° and 23.3±0.2°;

alternatively, 5.4±0.2°, 10.6±0.2°, 21.3±0.2°, 18.3±0.2°, 14.6±0.2°, 19.4±0.2°, 25.9±0.2°, 16.6±0.2°, 23.3±0.2° and 9.8±0.2°.

The X-ray powder diffraction pattern of benzoylglycinate salt form a comprises one or more diffraction peaks at 5.4±0.2°, 25.1±0.2°, 10.6±0.2°, 21.3±0.2°, 18.3±0.2°, 14.6±0.2°, 19.4±0.2°, 19.0±0.2°, 25.9±0.2°, 16.6±0.2°, 23.3±0.2°, 9.8±0.2°, 22.8±0.2°, 22.7±0.2°, 17.2±0.2°; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

for example, the X-ray powder diffraction pattern of benzoylglycinate form a has diffraction peaks at 2θ:5.4±0.2°, 25.1±0.2°, 10.6±0.2° and 21.3±0.2°;

alternatively, 5.4±0.2°, 25.1±0.2°, 10.6±0.2°, 21.3±0.2°, 18.3±0.2° and 25.9±0.2°;

alternatively, 5.4±0.2°, 25.1±0.2°, 10.6±0.2°, 21.3±0.2°, 18.3±0.2°, 14.6±0.2°, 25.9±0.2° and 23.3±0.2°;

alternatively, 5.4±0.2°, 25.1±0.2°, 10.6±0.2°, 21.3±0.2°, 18.3±0.2°, 14.6±0.2°, 19.4±0.2°, 19.0±0.2°, 25.9±0.2° and 16.6±0.2°.

The X-ray powder diffraction pattern of benzoylglycinate salt form a comprises one or more diffraction peaks at 5.4±0.2°, 25.1±0.2°, 10.6±0.2°, 21.3±0.2°, 18.3±0.2°, 14.6±0.2°, 19.4±0.2°, 19.0±0.2°, 25.9±0.2°, 16.6±0.2°, 23.3±0.2°, 9.8±0.2°, 22.8±0.2°, 22.7±0.2°, 17.2±0.2°, 24.5±0.2°, 19.2±0.2°, 14.4±0.2°, 23.6±0.2°, 20.5±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 7 to 8, or 10 to 12, or 15 to 18; further preferably, the diffraction peaks at any 2, 3, 4, 5, 6, 8, 10, 12, 16, 18 are included;

For example, the X-ray powder diffraction pattern of benzoylglycinate form a has diffraction peaks at 2θ: 5.4.+ -. 0.2 °, 25.1.+ -. 0.2 °, 10.6.+ -. 0.2 °, 21.3.+ -. 0.2 °, 18.3.+ -. 0.2 °, 14.6.+ -. 0.2 °, 25.9.+ -. 0.2 °, 24.5.+ -. 0.2 °, 19.2.+ -. 0.2 ° and 23.3.+ -. 0.2 °.

Most preferably, cu-K alpha radiation is used, and the X-ray characteristic diffraction peaks expressed in terms of 2 theta angles and interplanar spacing d values are shown in Table 7.

TABLE 7

Further preferred is the benzoylglycinate salt form a of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide, having an X-ray powder diffraction pattern substantially as shown in figure 13.

In a further preferred embodiment of the invention, there is provided a benzoylglycinate salt form B of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (example 1), having an acid number of 1, and an X-ray powder diffraction pattern with one or more diffraction peaks in the 2 theta range of 5.4±0.2°, 24.7±0.2°, 19.1±0.2°, preferably comprising two of these, more preferably three of these; optionally, the composition further comprises at least one of 18.9+/-0.2 °, 10.5+/-0.2 °, 23.1+/-0.2 °, 20.9+/-0.2 °, and 14.4+/-0.2 °; preferably 2, 3, 4 or 5 of these;

For example, the X-ray powder diffraction pattern of benzoylglycinate form B has diffraction peaks at 2θ: 5.4.+ -. 0.2 °, 24.7.+ -. 0.2 °, 19.1.+ -. 0.2 °, 18.9.+ -. 0.2 °, 10.5.+ -. 0.2 ° and 23.1.+ -. 0.2 °.

The X-ray powder diffraction pattern of benzoylglycinate form B optionally further comprises one or more diffraction peaks at 10.8±0.2°, 22.8±0.2°, 17.3±0.2°, 25.7±0.2°, 9.9±0.2°, 24.2±0.2°, 14.3±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

for example, the X-ray powder diffraction pattern of benzoylglycinate form B has diffraction peaks at 2θ:5.4±0.2°, 24.7±0.2°, 19.1±0.2°, 18.9±0.2°, 10.5±0.2°, 23.1±0.2°, 10.8±0.2° and 22.8±0.2°;

alternatively, 5.4±0.2°, 24.7±0.2°, 18.9±0.2°, 10.5±0.2°, 23.1±0.2°, 20.9±0.2°, 10.8±0.2°, 22.8±0.2° and 17.3±0.2°;

alternatively, 5.4±0.2°, 19.1±0.2°, 18.9±0.2°, 10.5±0.2°, 23.1±0.2°, 20.9±0.2°, 10.8±0.2°, 22.8±0.2°, 17.3±0.2° and 25.7±0.2°.

The X-ray powder diffraction pattern of benzoylglycinate form B comprises one or more diffraction peaks at 5.4±0.2°, 24.7±0.2°, 19.1±0.2°, 18.9±0.2°, 10.5±0.2°, 23.1±0.2°, 20.9±0.2°, 14.4±0.2°, 10.8±0.2°, 22.8±0.2°, 17.3±0.2°, 25.7±0.2°, 9.9±0.2°, 24.2±0.2°, 14.3±0.2°; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

for example, the X-ray powder diffraction pattern of benzoylglycinate form B has diffraction peaks at 2θ:5.4±0.2°, 24.7±0.2°, 19.1±0.2° and 18.9±0.2°;

alternatively, 5.4±0.2°, 24.7±0.2°, 19.1±0.2°, 18.9±0.2°, 10.5±0.2° and 10.8±0.2°;

alternatively, 5.4±0.2°, 24.7±0.2°, 19.1±0.2°, 18.9±0.2°, 10.5±0.2°, 23.1±0.2°, 10.8±0.2° and 17.3±0.2°;

alternatively, 5.4±0.2°, 24.7±0.2°, 19.1±0.2°, 18.9±0.2°, 10.5±0.2°, 23.1±0.2°, 20.9±0.2°, 14.4±0.2°, 10.8±0.2° and 22.8±0.2°.

The X-ray powder diffraction pattern of benzoylglycine salt form B comprises one or more diffraction peaks at 2θ of 5.4±0.2°, 24.7±0.2°, 19.1±0.2°, 18.9±0.2°, 10.5±0.2°, 23.1±0.2°, 20.9±0.2°, 14.4±0.2°, 10.8±0.2°, 22.8±0.2°, 17.3±0.2°, 25.7±0.2°, 9.9±0.2°, 24.2±0.2°, 14.3±0.2°, 29.0±0.2°, 14.8±0.2°, 16.6±0.2°, 18.0±0.2°, 13.4±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 7 to 8, or 10 to 12, or 15 to 18; further preferably, the diffraction peaks at any 2, 3, 4, 5, 6, 8, 10, 12, 16, 18 are included;

For example, the X-ray powder diffraction pattern of benzoylglycinate form B has diffraction peaks at 2θ: 5.4.+ -. 0.2 °, 24.7.+ -. 0.2 °, 19.1.+ -. 0.2 °, 18.9.+ -. 0.2 °, 10.5.+ -. 0.2 °, 23.1.+ -. 0.2 °, 10.8.+ -. 0.2 °, 29.0.+ -. 0.2 °, 14.8.+ -. 0.2 ° and 17.3.+ -. 0.2 °.

Most preferably, cu-K alpha radiation is used, and the X-ray characteristic diffraction peaks expressed in terms of 2 theta angles and interplanar spacing d values are shown in Table 8.

TABLE 8

Further preferred is the benzoylglycinate salt form B of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide, having an X-ray powder diffraction pattern substantially as shown in figure 14.

In a further preferred embodiment of the invention, there is provided a benzoylglycinate salt form C of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (example 1), having a number of acids of 1, and an X-ray powder diffraction pattern with one or more diffraction peaks in the 2 theta range of 5.7±0.2°, 20.4±0.2°, 26.4±0.2°, preferably comprising two of these, more preferably three of these; optionally, the composition further comprises at least one of 14.5+/-0.2 °, 15.5+/-0.2 °, 11.1+/-0.2 °, 18.5+/-0.2 °, and 16.8+/-0.2 °; preferably 2, 3, 4 or 5 of these;

For example, the X-ray powder diffraction pattern of benzoylglycinate form C has diffraction peaks at 2θ: 5.7.+ -. 0.2 °, 20.4.+ -. 0.2 °, 26.4.+ -. 0.2 °, 14.5.+ -. 0.2 °, 15.5.+ -. 0.2 ° and 11.1.+ -. 0.2 °.

The X-ray powder diffraction pattern of benzoylglycinate form C optionally further comprises one or more diffraction peaks at 19.4±0.2°, 17.5±0.2°, 18.9±0.2°, 10.5±0.2°, 13.8±0.2°, 9.9±0.2°, 21.6±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

for example, the X-ray powder diffraction pattern of benzoylglycinate form C has diffraction peaks at 2θ:5.7±0.2°, 20.4±0.2°, 26.4±0.2°, 14.5±0.2°, 15.5±0.2°, 11.1±0.2°, 19.4±0.2° and 17.5±0.2°;

alternatively, 5.7±0.2°, 20.4±0.2°, 14.5±0.2°, 15.5±0.2°, 11.1±0.2°, 18.5±0.2°, 19.4±0.2°, 17.5±0.2° and 18.9±0.2°;

alternatively, 5.7±0.2°, 26.4±0.2°, 14.5±0.2°, 15.5±0.2°, 11.1±0.2°, 18.5±0.2°, 19.4±0.2°, 17.5±0.2°, 18.9±0.2° and 10.5±0.2°.

The X-ray powder diffraction pattern of benzoylglycinate form C comprises one or more diffraction peaks at 5.7±0.2°, 20.4±0.2°, 26.4±0.2°, 14.5±0.2°, 15.5±0.2°, 11.1±0.2°, 18.5±0.2°, 16.8±0.2°, 19.4±0.2°, 17.5±0.2°, 18.9±0.2°, 10.5±0.2°, 13.8±0.2°, 9.9±0.2°, 21.6±0.2°; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

for example, the X-ray powder diffraction pattern of benzoylglycinate form C has diffraction peaks at 2θ:5.7±0.2°, 20.4±0.2°, 26.4±0.2° and 14.5±0.2°;

alternatively, 5.7±0.2°, 20.4±0.2°, 26.4±0.2°, 14.5±0.2°, 15.5±0.2° and 19.4±0.2°;

alternatively, 5.7±0.2°, 20.4±0.2°, 26.4±0.2°, 14.5±0.2°, 15.5±0.2°, 11.1±0.2°, 19.4±0.2° and 18.9±0.2°;

alternatively, 5.7±0.2°, 20.4±0.2°, 26.4±0.2°, 14.5±0.2°, 15.5±0.2°, 11.1±0.2°, 18.5±0.2°, 16.8±0.2°, 19.4±0.2° and 17.5±0.2°.

The X-ray powder diffraction pattern of benzoylglycinate form C comprises one or more diffraction peaks at 5.7±0.2°, 20.4±0.2°, 26.4±0.2°, 14.5±0.2°, 15.5±0.2°, 11.1±0.2°, 18.5±0.2°, 16.8±0.2°, 19.4±0.2°, 17.5±0.2°, 18.9±0.2°, 10.5±0.2°, 13.8±0.2°, 9.9±0.2°, 21.6±0.2°, 23.4±0.2°, 25.0±0.2°, 20.8±0.2°, 25.7±0.2°, 24.7±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 7 to 8, or 10 to 12, or 15 to 18; further preferably, the diffraction peaks at any 2, 3, 4, 5, 6, 8, 10, 12, 16, 18 are included;

For example, the X-ray powder diffraction pattern of benzoylglycinate form C has diffraction peaks at 2θ: 5.7.+ -. 0.2 °, 20.4.+ -. 0.2 °, 26.4.+ -. 0.2 °, 14.5.+ -. 0.2 °, 15.5.+ -. 0.2 °, 11.1.+ -. 0.2 °, 19.4.+ -. 0.2 °, 23.4.+ -. 0.2 °, 25.0.+ -. 0.2 ° and 18.9.+ -. 0.2 °.

Most preferably, cu-K alpha radiation is used, and the X-ray characteristic diffraction peaks expressed in terms of 2 theta angles and interplanar spacing d values are shown in Table 9.

TABLE 9

Further preferred is the benzoylglycinate salt form C of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide, having an X-ray powder diffraction pattern substantially as shown in figure 15.

In a further preferred embodiment of the invention, there is provided a benzoylglycinate salt form D of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (example 1), having an acid number of 1, and an X-ray powder diffraction pattern with one or more diffraction peaks in the 2θ of 17.6±0.2°, 21.0±0.2°, 5.8±0.2°, preferably comprising two of them, more preferably three of them; optionally, the composition further comprises at least one of 25.2+ -0.2 °, 16.6+ -0.2 °, 15.0+ -0.2 °, 9.7+ -0.2 °, 10.2+ -0.2 °; preferably 2, 3, 4 or 5 of these;

For example, the X-ray powder diffraction pattern of benzoylglycinate form D has diffraction peaks at 2θ:17.6±0.2° and 21.0±0.2°; alternatively, 21.0±0.2° and 5.8±0.2°;

alternatively, 17.6±0.2°,21.0±0.2° and 5.8±0.2°;

alternatively, 17.6±0.2°, 5.8±0.2°, 16.6±0.2° and 25.2±0.2°;

alternatively, 17.6±0.2°, 5.8±0.2°, 16.6±0.2° and 15.0±0.2°;

alternatively, 17.6±0.2°,21.0±0.2°, 5.8±0.2°, 25.2±0.2° and 16.6±0.2°;

alternatively, 17.6±0.2°,21.0±0.2°, 5.8±0.2°, 25.2±0.2°, 16.6±0.2°, 15.0±0.2°, 9.7±0.2° and 10.2±0.2°;

alternatively, 17.6±0.2°, 25.2±0.2°, 16.6±0.2°, 15.0±0.2°, 9.7±0.2° and 10.2±0.2°;

alternatively, 17.6±0.2°,21.0±0.2°, 5.8±0.2°, 25.2±0.2°, 15.0±0.2° and 9.7±0.2°.

The X-ray powder diffraction pattern of benzoylglycinate form D optionally further comprises one or more diffraction peaks at 14.8±0.2°, 19.9±0.2°, 14.1±0.2°, 22.8±0.2°, 18.2±0.2°, 10.5±0.2°, 18.8±0.2° in 2θ; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

For example, the X-ray powder diffraction pattern of benzoylglycinate form D has diffraction peaks at 2θ:17.6±0.2°, 21.0±0.2°, 5.8±0.2°, 25.2±0.2°, 15.0±0.2°, 10.2±0.2°, 19.9±0.2° and 14.8±0.2°;

alternatively, 17.6±0.2°, 21.0±0.2°, 5.8±0.2°, 25.2±0.2°, 16.6±0.2°, 15.0±0.2°, 9.7±0.2°, 10.2±0.2°, 14.8±0.2° and 19.9±0.2°.

The X-ray powder diffraction pattern of benzoylglycinate form D comprises one or more diffraction peaks at 17.6±0.2°, 21.0±0.2°, 5.8±0.2°, 25.2±0.2°, 16.6±0.2°, 15.0±0.2°, 9.7±0.2°, 10.2±0.2°, 14.8±0.2°, 19.9±0.2°, 14.1±0.2°, 22.8±0.2°, 18.2±0.2°, 10.5±0.2°, 18.8±0.2°; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

for example, the X-ray powder diffraction pattern of benzoylglycinate form D has diffraction peaks at 2θ: 5.8+ -0.2 °, 9.7+ -0.2 °, 14.8+ -0.2 °, 25.2+ -0.2 °;

alternatively, 17.6±0.2°, 21.0±0.2°, 5.8±0.2° and 25.2±0.2°;

alternatively, 17.6±0.2°, 21.0±0.2°, 5.8±0.2°, 25.2±0.2°, 16.6±0.2° and 15.0±0.2°;

Alternatively, 17.6±0.2°, 21.0±0.2°,5.8±0.2°, 25.2±0.2°, 16.6±0.2° and 9.7±0.2°;

alternatively, 5.8±0.2°, 9.7±0.2°, 14.1±0.2°, 15.0±0.2°, 16.6±0.2°,17.6±0.2°, 21.0±0.2°, 25.2±0.2°;

alternatively, 17.6±0.2°, 21.0±0.2°,5.8±0.2°, 25.2±0.2°, 16.6±0.2°, 15.0±0.2°, 9.7±0.2° and 19.9±0.2°;

or 5.8±0.2°, 9.7±0.2°, 10.2±0.2°, 15.0±0.2°, 16.6±0.2°,17.6±0.2°, 18.8±0.2°, 19.9±0.2°, 21.0±0.2°, 25.2±0.2°;

alternatively, 17.6±0.2°, 21.0±0.2°,5.8±0.2°, 25.2±0.2°, 16.6±0.2°, 15.0±0.2°, 9.7±0.2°, 10.2±0.2°, 14.8±0.2° and 19.9±0.2°.

The X-ray powder diffraction pattern of benzoylglycinate form D comprises one or more diffraction peaks at 17.6±0.2°, 21.0±0.2°,5.8±0.2°, 25.2±0.2°, 16.6±0.2°, 15.0±0.2°, 9.7±0.2°, 10.2±0.2°, 14.8±0.2°, 19.9±0.2°, 14.1±0.2°, 22.8±0.2°, 18.2±0.2°, 10.5±0.2°, 18.8±0.2°, 22.4±0.2°, 17.9±0.2°, 18.9±0.2°, 25.8±0.2°, 19.8±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 7 to 8, or 10 to 12, or 15 to 18; further preferably, the diffraction peaks at any 2, 3, 4, 5, 6, 8, 10, 12, 16, 18 are included;

For example, the X-ray powder diffraction pattern of benzoylglycinate form D has diffraction peaks at 2θ:17.6±0.2°, 21.0±0.2°, 5.8±0.2°, 22.4±0.2°, 17.9±0.2° and 25.2±0.2°;

or 17.6±0.2°, 21.0±0.2°, 5.8±0.2°, 25.2±0.2°, 16.6±0.2°, 15.0±0.2°, 9.7±0.2°, 22.4±0.2°, 17.9±0.2° and 14.8±0.2°;

or, 17.6±0.2°, 21.0±0.2°, 5.8±0.2°, 25.2±0.2°, 16.6±0.2°, 15.0±0.2°, 9.7±0.2°, 10.2±0.2°, 19.9±0.2°, 22.8±0.2°, 18.8±0.2° and 14.1±0.2°;

or, 17.6±0.2°, 21.0±0.2°, 5.8±0.2°, 25.2±0.2°, 16.6±0.2°, 15.0±0.2°, 9.7±0.2°, 10.2±0.2°, 14.8±0.2°, 22.4±0.2°, 17.9±0.2° and 19.9±0.2°;

alternatively, 17.6±0.2°, 21.0±0.2°, 5.8±0.2°, 25.2±0.2°, 16.6±0.2°, 15.0±0.2°, 9.7±0.2°, 10.2±0.2°, 19.9±0.2°, 22.4±0.2°, 17.9±0.2° and 14.1±0.2°.

Most preferably, cu-K alpha radiation is used, and the X-ray characteristic diffraction peaks expressed in terms of 2 theta angles and interplanar spacing d values are shown in Table 10.

Table 10

Further preferred, the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide is in the form D as benzoylglycinate salt having an X-ray powder diffraction pattern substantially as shown in figure 16; the DSC spectrum is basically shown in figure 17; the TGA profile is substantially as shown in figure 18.

In a further preferred embodiment of the invention, there is provided a benzoylglycinate salt form E of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (example 1), the number of acids being 1, and the X-ray powder diffraction pattern thereof having one or more diffraction peaks in the 2 theta range of 5.4±0.2°, 5.3±0.2°, 5.6±0.2°, preferably comprising two of them, more preferably three of them; optionally, the composition further comprises at least one of 10.7+/-0.2 °, 20.8+/-0.2 °, 24.7+/-0.2 °, 16.5+/-0.2 °, and 21.5+/-0.2 °; preferably 2, 3, 4 or 5 of these;

for example, the X-ray powder diffraction pattern of benzoylglycinate form E has diffraction peaks at 2θ: 5.4.+ -. 0.2 °, 5.3.+ -. 0.2 °, 5.6.+ -. 0.2 °, 10.7.+ -. 0.2 °, 20.8.+ -. 0.2 ° and 24.7.+ -. 0.2 °.

The X-ray powder diffraction pattern of benzoylglycinate form E optionally further comprises one or more diffraction peaks at 14.5±0.2°, 18.4±0.2°, 12.3±0.2°, 21.1±0.2°, 20.4±0.2°, 16.9±0.2°, 26.3±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

For example, the X-ray powder diffraction pattern of benzoylglycinate form E has diffraction peaks at 2θ:5.4±0.2°, 5.3±0.2°, 5.6±0.2°, 10.7±0.2°, 20.8±0.2°, 24.7±0.2°, 14.5±0.2° and 18.4±0.2°;

alternatively, 5.4±0.2°, 5.3±0.2°, 10.7±0.2°, 20.8±0.2°, 24.7±0.2°, 16.5±0.2°, 14.5±0.2°, 18.4±0.2° and 12.3±0.2°;

alternatively, 5.4±0.2°, 5.6±0.2°, 10.7±0.2°, 20.8±0.2°, 24.7±0.2°, 16.5±0.2°, 14.5±0.2°, 18.4±0.2°, 12.3±0.2° and 21.1±0.2°.

The X-ray powder diffraction pattern of benzoylglycinate form E comprises one or more diffraction peaks at 5.4±0.2°, 5.3±0.2°, 5.6±0.2°, 10.7±0.2°, 20.8±0.2°, 24.7±0.2°, 16.5±0.2°, 21.5±0.2°, 14.5±0.2°, 18.4±0.2°, 12.3±0.2°, 21.1±0.2°, 20.4±0.2°, 16.9±0.2°, 26.3±0.2°; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

for example, the X-ray powder diffraction pattern of benzoylglycinate form E has diffraction peaks at 2θ:5.4±0.2°, 5.3±0.2°, 5.6±0.2° and 10.7±0.2°; alternatively, 5.4±0.2°, 5.3±0.2°, 5.6±0.2°, 10.7±0.2°, 20.8±0.2° and 14.5±0.2°; alternatively, 5.4±0.2°, 5.3±0.2°, 5.6±0.2°, 10.7±0.2°, 20.8±0.2°, 24.7±0.2° and 14.5±0.2°;

Alternatively, 5.4±0.2°, 5.3±0.2°, 5.6±0.2°, 10.7±0.2°, 20.8±0.2°, 24.7±0.2°, 16.5±0.2°, 21.5±0.2°, 14.5±0.2° and 18.4±0.2°.

The X-ray powder diffraction pattern of benzoylglycinate form E comprises one or more diffraction peaks at 2θ of 5.4±0.2°, 5.3±0.2°, 5.6±0.2°, 10.7±0.2°, 20.8±0.2°, 24.7±0.2°, 16.5±0.2°, 21.5±0.2°, 14.5±0.2°, 18.4±0.2°, 12.3±0.2°, 21.1±0.2°, 20.4±0.2°, 16.9±0.2°, 26.3±0.2°, 18.5±0.2°, 15.5±0.2°, 8.3±0.2°, 26.1±0.2°, 11.0±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 7 to 8, or 10 to 12, or 15 to 18; further preferably, the diffraction peaks at any 2, 3, 4, 5, 6, 8, 10, 12, 16, 18 are included;

for example, the X-ray powder diffraction pattern of benzoylglycinate form E has diffraction peaks at 2θ:5.4±0.2°, 5.3±0.2°, 5.6±0.2°, 18.5±0.2°, 15.5±0.2° and 10.7±0.2°;

alternatively, 5.4±0.2°, 5.3±0.2°, 5.6±0.2°, 10.7±0.2°, 20.8±0.2°, 18.5±0.2°, 15.5±0.2° and 14.5±0.2°;

Alternatively, 5.4±0.2°, 5.3±0.2°, 5.6±0.2°, 10.7±0.2°, 20.8±0.2°, 24.7±0.2°, 18.5±0.2°, 15.5±0.2° and 14.5±0.2°.

Most preferably, cu-K alpha radiation is used, and the X-ray characteristic diffraction peaks expressed in terms of 2 theta angles and interplanar spacing d values are shown in Table 11.

TABLE 11

Further preferred is the benzoylglycinate salt form E of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide, having an X-ray powder diffraction pattern substantially as shown in figure 19.

In a further preferred embodiment of the invention, there is provided a benzoylglycinate salt form F of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (example 1), the number of acids being 1, and the X-ray powder diffraction pattern of which comprises one or more diffraction peaks in the 2θ of 6.1±0.2°, 6.3±0.2°, 10.3±0.2°, preferably two of which comprise three of them; optionally, it may further comprise at least one of 12.3±0.2°, 9.3±0.2°, 9.8±0.2°, 11.6±0.2°, and 5.5±0.2°; preferably 2, 3, 4 or 5 of these;

For example, the X-ray powder diffraction pattern of benzoylglycinate form F has diffraction peaks at 2θ: 6.1.+ -. 0.2 °, 6.3.+ -. 0.2 °, 10.3.+ -. 0.2 °, 12.3.+ -. 0.2 °, 9.3.+ -. 0.2 ° and 9.8.+ -. 0.2 °.

The X-ray powder diffraction pattern of benzoylglycinate form F optionally further comprises one or more diffraction peaks at 11.1±0.2°, 13.8±0.2°, 26.1±0.2°, 18.9±0.2°, 18.2±0.2°, 20.2±0.2°, 22.1±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

for example, the X-ray powder diffraction pattern of benzoylglycinate form F has diffraction peaks at 2θ:6.1±0.2°, 6.3±0.2°, 10.3±0.2°, 12.3±0.2°, 9.3±0.2°, 9.8±0.2°, 11.1±0.2° and 13.8±0.2°; alternatively, 6.1±0.2°, 10.3±0.2°, 12.3±0.2°, 9.3±0.2°, 9.8±0.2°, 11.6±0.2°, 11.1±0.2°, 13.8±0.2°, 26.1±0.2° and 18.9±0.2°.

The X-ray powder diffraction pattern of benzoylglycinate form F comprises one or more diffraction peaks at 6.1±0.2°, 6.3±0.2°, 10.3±0.2°, 12.3±0.2°, 9.3±0.2°, 9.8±0.2°, 11.6±0.2°, 5.5±0.2°, 11.1±0.2°, 13.8±0.2°, 26.1±0.2°, 18.9±0.2°, 18.2±0.2°, 20.2±0.2°, 22.1±0.2°; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

For example, the X-ray powder diffraction pattern of benzoylglycinate form F has diffraction peaks at 2θ:6.1±0.2°, 6.3±0.2°, 10.3±0.2° and 12.3±0.2°;

alternatively, 6.1±0.2°, 6.3±0.2°, 10.3±0.2°, 12.3±0.2°, 9.3±0.2° and 11.1±0.2°;

alternatively, 6.1±0.2°, 6.3±0.2°, 10.3±0.2°, 12.3±0.2°, 9.3±0.2°, 9.8±0.2°, 11.1±0.2° and 26.1±0.2°;

alternatively, 6.1±0.2°, 6.3±0.2°, 10.3±0.2°, 12.3±0.2°, 9.3±0.2°, 9.8±0.2°, 11.6±0.2°, 5.5±0.2°, 11.1±0.2° and 13.8±0.2°.

The X-ray powder diffraction pattern of benzoylglycinate form F comprises one or more diffraction peaks at 6.1±0.2°, 6.3±0.2°, 10.3±0.2°, 12.3±0.2°, 9.3±0.2°, 9.8±0.2°, 11.6±0.2°, 5.5±0.2°, 11.1±0.2°, 13.8±0.2°, 26.1±0.2°, 18.9±0.2°, 18.2±0.2°, 20.2±0.2°, 22.1±0.2°, 19.6±0.2°, 19.2±0.2°, 25.8±0.2°, 23.9±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 7 to 8, or 10 to 12, or 15 to 18; further preferably, the diffraction peaks at any 2, 3, 4, 5, 6, 8, 10, 12, 16, 18 are included;

For example, the X-ray powder diffraction pattern of benzoylglycinate form F has diffraction peaks at 2θ:6.1±0.2°, 6.3±0.2°, 10.3±0.2°, 19.6±0.2°, 19.2±0.2° and 12.3±0.2°;

alternatively, 6.1±0.2°, 6.3±0.2°, 10.3±0.2°, 12.3±0.2°, 9.3±0.2°, 19.6±0.2°, 19.2±0.2° and 11.1±0.2°;

alternatively, 6.1±0.2°, 6.3±0.2°, 10.3±0.2°, 12.3±0.2°, 9.3±0.2°, 9.8±0.2°, 11.1±0.2°, 19.6±0.2°, 19.2±0.2° and 26.1±0.2°.

Most preferably, cu-K alpha radiation is used, and the X-ray characteristic diffraction peaks expressed in terms of 2 theta angles and interplanar spacing d values are shown in Table 12.

Table 12

Further preferred is the benzoylglycinate salt form F of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide, having an X-ray powder diffraction pattern substantially as shown in figure 20.

In a further preferred embodiment of the invention, there is provided a phosphate form a of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (example 1), the number of acids being 1, and the X-ray powder diffraction pattern thereof having one or more diffraction peaks in the range of 10.6±0.2°, 12.3±0.2°, 9.2±0.2°, preferably comprising two of them, more preferably comprising three of them; optionally, the composition further comprises at least one of 21.4+/-0.2 °, 13.5+/-0.2 °, 6.3+/-0.2 °, 10.9+/-0.2 ° and 25.3+/-0.2 °; preferably 2, 3, 4 or 5 of these;

For example, the X-ray powder diffraction pattern of phosphate form a has diffraction peaks at 2θ: 10.6.+ -. 0.2 °, 12.3.+ -. 0.2 °, 9.2.+ -. 0.2 °, 21.4.+ -. 0.2 °, 13.5.+ -. 0.2 ° and 6.3.+ -. 0.2 °.

The X-ray powder diffraction pattern of phosphate form a optionally further comprises one or more diffraction peaks at 11.7±0.2°, 12.1±0.2°, 12.6±0.2°; preferably at least any 2-3 thereof; further preferably, any of

positions

2 and 3 is included;

for example, the X-ray powder diffraction pattern of phosphate form a has diffraction peaks at 2θ:10.6±0.2°, 12.3±0.2°, 9.2±0.2°, 21.4±0.2°, 13.5±0.2°, 6.3±0.2°, 11.7±0.2° and 12.1±0.2°;

alternatively, 10.6±0.2°, 12.3±0.2°, 21.4±0.2°, 13.5±0.2°, 6.3±0.2°, 10.9±0.2°, 11.7±0.2° and 12.1±0.2°;

alternatively, 10.6±0.2°, 9.2±0.2°, 21.4±0.2°, 13.5±0.2°, 6.3±0.2°, 10.9±0.2°, 11.7±0.2°, 12.1±0.2° and 12.6±0.2°.

The X-ray powder diffraction pattern of phosphate form a comprises one or more diffraction peaks at 2θ of 10.6±0.2°, 12.3±0.2°, 9.2±0.2°, 21.4±0.2°, 13.5±0.2°, 6.3±0.2°, 10.9±0.2°, 25.3±0.2°, 11.7±0.2°, 12.1±0.2°, 12.6±0.2°; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

For example, the X-ray powder diffraction pattern of phosphate form a has diffraction peaks at 2θ:10.6±0.2°, 12.3±0.2°, 9.2±0.2° and 21.4±0.2°;

alternatively, 10.6±0.2°, 12.3±0.2°, 9.2±0.2°, 21.4±0.2°, 13.5±0.2° and 11.7±0.2°;

alternatively, 10.6±0.2°, 12.3±0.2°, 9.2±0.2°, 21.4±0.2°, 13.5±0.2°, 6.3±0.2°, 11.7±0.2° and 12.6±0.2°;

alternatively, 10.6±0.2°, 12.3±0.2°, 9.2±0.2°, 21.4±0.2°, 13.5±0.2°, 6.3±0.2°, 10.9±0.2°, 25.3±0.2°, 11.7±0.2° and 12.6±0.2°.

Most preferably, cu-K alpha radiation is used, and the X-ray characteristic diffraction peaks expressed in terms of 2 theta angles and interplanar spacing d values are shown in Table 13.

TABLE 13

Further preferred is phosphate form a of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide, which has an X-ray powder diffraction pattern substantially as shown in figure 21.

In a further preferred embodiment of the invention, there is provided the maleate form a of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (example 1), the number of acids being 1, and the X-ray powder diffraction pattern thereof having one or more diffraction peaks in the 2θ of 6.0±0.2°, 22.3±0.2°, 8.2±0.2°, preferably comprising two of them, more preferably three of them; optionally, the composition further comprises at least one of 16.3+ -0.2 °, 23.5+ -0.2 °, 19.5+ -0.2 °, 19.2+ -0.2 °, 11.8+ -0.2 °; preferably 2, 3, 4 or 5 of these;

For example, the X-ray powder diffraction pattern of maleate form a has diffraction peaks at 2θ: 6.0.+ -. 0.2 °, 22.3.+ -. 0.2 °, 8.2.+ -. 0.2 °, 16.3.+ -. 0.2 °, 23.5.+ -. 0.2 ° and 19.5.+ -. 0.2 °.

The X-ray powder diffraction pattern of maleate form a optionally further comprises one or more diffraction peaks at 7.1±0.2°, 21.7±0.2°, 19.8±0.2°, 16.6±0.2°, 15.3±0.2°, 21.1±0.2°, 7.7±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

for example, the X-ray powder diffraction pattern of maleate form a has diffraction peaks at 2θ:6.0±0.2°, 22.3±0.2°, 8.2±0.2°, 16.3±0.2°, 23.5±0.2°, 19.5±0.2°, 7.1±0.2° and 21.7±0.2°;

or, at 6.0±0.2°, 22.3±0.2°, 16.3±0.2°, 23.5±0.2°, 19.5±0.2°, 19.2±0.2°, 7.1±0.2°, 21.7±0.2° and 19.8±0.2°;

alternatively, 6.0±0.2°, 8.2±0.2°, 16.3±0.2°, 23.5±0.2°, 19.5±0.2°, 19.2±0.2°, 7.1±0.2°, 21.7±0.2°, 19.8±0.2° and 16.6±0.2°.

The X-ray powder diffraction pattern of maleate form a comprises one or more diffraction peaks at 6.0±0.2°, 22.3±0.2°, 8.2±0.2°, 16.3±0.2°, 23.5±0.2°, 19.5±0.2°, 19.2±0.2°, 11.8±0.2°, 7.1±0.2°, 21.7±0.2°, 19.8±0.2°, 16.6±0.2°, 15.3±0.2°, 21.1±0.2°, 7.7±0.2°; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

for example, the X-ray powder diffraction pattern of maleate form a has diffraction peaks at 2θ:6.0±0.2°, 22.3±0.2°, 8.2±0.2° and 16.3±0.2°;

alternatively, 6.0±0.2°, 22.3±0.2°, 8.2±0.2°, 16.3±0.2°, 23.5±0.2° and 7.1±0.2°;

alternatively, 6.0±0.2°, 22.3±0.2°, 8.2±0.2°, 16.3±0.2°, 23.5±0.2°, 19.5±0.2°, 7.1±0.2° and 19.8±0.2°;

alternatively, 6.0±0.2°, 22.3±0.2°, 8.2±0.2°, 16.3±0.2°, 23.5±0.2°, 19.5±0.2°, 19.2±0.2°, 11.8±0.2°, 7.1±0.2° and 21.7±0.2°.

The X-ray powder diffraction pattern of maleate form a comprises one or more diffraction peaks at 6.0±0.2°, 22.3±0.2°, 8.2±0.2°, 16.3±0.2°, 23.5±0.2°, 19.5±0.2°, 19.2±0.2°, 11.8±0.2°, 7.1±0.2°, 21.7±0.2°, 19.8±0.2°, 16.6±0.2°, 15.3±0.2°, 21.1±0.2°, 7.7±0.2°, 24.2±0.2°, 25.9±0.2°, 13.8±0.2°, 25.3±0.2°, 11.2±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 7 to 8, or 10 to 12, or 15 to 18; further preferably, the diffraction peaks at any 2, 3, 4, 5, 6, 8, 10, 12, 16, 18 are included;

For example, the X-ray powder diffraction pattern of maleate form a has diffraction peaks at 2θ: 6.0.+ -. 0.2 °, 22.3.+ -. 0.2 °, 8.2.+ -. 0.2 °, 24.2.+ -. 0.2 °, 25.9.+ -. 0.2 ° and 16.3.+ -. 0.2 °;

alternatively, 6.0±0.2°, 22.3±0.2°, 8.2±0.2°, 16.3±0.2°, 23.5±0.2°, 24.2±0.2°, 25.9±0.2° and 7.1±0.2°;

alternatively, 6.0±0.2°, 22.3±0.2°, 8.2±0.2°, 16.3±0.2°, 23.5±0.2°, 19.5±0.2°, 7.1±0.2°, 24.2±0.2°, 25.9±0.2° and 19.8±0.2°.

Most preferably, cu-K alpha radiation is used, and the X-ray characteristic diffraction peaks expressed in terms of 2 theta angles and interplanar spacing d values are shown in Table 14.

TABLE 14

Further preferred is maleate form a of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide having an X-ray powder diffraction pattern substantially as shown in figure 22.

In a further preferred embodiment of the invention, there is provided maleate form B of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (example 1), the number of acids being 1, and the X-ray powder diffraction pattern thereof having one or more diffraction peaks in the 2θ of 7.7±0.2°, 16.1±0.2°, 23.6±0.2°, preferably comprising two of them, more preferably comprising three of them; optionally, it may further comprise at least one of 22.2±0.2°, 19.2±0.2°, 21.7±0.2°, 6.5±0.2°, and 19.8±0.2°; preferably 2, 3, 4 or 5 of these;

For example, the X-ray powder diffraction pattern of maleate form B has diffraction peaks at 2θ:7.7±0.2°, 16.1±0.2°, 23.6±0.2°, 22.2±0.2°, 19.2±0.2° and 21.7±0.2°.

The X-ray powder diffraction pattern of maleate form B optionally further comprises one or more diffraction peaks at 6.0±0.2°, 8.2±0.2°, 20.9±0.2°, 15.3±0.2°, 11.7±0.2°, 11.0±0.2°, 24.5±0.2° in 2θ; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

for example, the X-ray powder diffraction pattern of maleate form B has diffraction peaks at 2θ:7.7±0.2°, 16.1±0.2°, 23.6±0.2°, 22.2±0.2°, 19.2±0.2°, 21.7±0.2°, 6.0±0.2° and 8.2±0.2°;

or, at 7.7±0.2°, 16.1±0.2°, 22.2±0.2°, 19.2±0.2°, 21.7±0.2°, 6.5±0.2°, 6.0±0.2°, 8.2±0.2° and 20.9±0.2°;

alternatively, 7.7±0.2°, 23.6±0.2°, 22.2±0.2°, 19.2±0.2°, 21.7±0.2°, 6.5±0.2°, 6.0±0.2°, 8.2±0.2°, 20.9±0.2° and 15.3±0.2°.

The X-ray powder diffraction pattern of the maleate crystal form B comprises a powder diffraction pattern of the maleate crystal form B, which is positioned at the angles of 7.7+/-0.2 degrees, 16.1+/-0.2 degrees, 23.6+/-0.2 degrees, 22.2+/-0.2 degrees, 19.2+/-0.2 degrees, 21.7+/-0.2 degrees, 6.5+/-0.2 degrees, 19.8+/-0.2 degrees, 6.0+/-0.2 degrees, 8.2+/-0.2 degrees, 20.9+/-0.2 degrees, 15.3+/-0.2 degrees, 11.7+/-0.2 degrees, 11.0+/-0.2 degrees and 24.5+/-0.2 degrees

Diffraction peaks of (a) and (b); preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

for example, the X-ray powder diffraction pattern of maleate form B has diffraction peaks at 2θ:7.7±0.2°, 16.1±0.2°, 23.6±0.2° and 22.2±0.2°;

alternatively, 7.7±0.2°, 16.1±0.2°, 23.6±0.2°, 22.2±0.2°, 19.2±0.2° and 6.0±0.2°;

or, at 7.7±0.2°, 16.1±0.2°, 23.6±0.2°, 22.2±0.2°, 19.2±0.2°, 21.7±0.2°, 6.0±0.2° and 20.9±0.2°;

alternatively, 7.7±0.2°, 16.1±0.2°, 23.6±0.2°, 22.2±0.2°, 19.2±0.2°, 21.7±0.2°, 6.5±0.2°, 19.8±0.2°, 6.0±0.2° and 8.2±0.2°.

The X-ray powder diffraction pattern of maleate form B comprises one or more diffraction peaks at 7.7±0.2°, 16.1±0.2°, 23.6±0.2°, 22.2±0.2°, 19.2±0.2°, 21.7±0.2°, 6.5±0.2°, 19.8±0.2°, 6.0±0.2°, 8.2±0.2°, 20.9±0.2°, 15.3±0.2°, 11.7±0.2°, 11.0±0.2°, 24.5±0.2°, 13.8±0.2°, 13.3±0.2°, 17.9±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 7 to 8, or 10 to 12, or 15 to 18; further preferably, the diffraction peaks at any 2, 3, 4, 5, 6, 8, 10, 12, 16, 18 are included; for example, the X-ray powder diffraction pattern of maleate form B has diffraction peaks at 2θ:7.7±0.2°, 16.1±0.2°, 23.6±0.2°, 13.8±0.2°, 13.3±0.2° and 22.2±0.2°;

Or, at 7.7±0.2°, 16.1±0.2°, 23.6±0.2°, 22.2±0.2°, 19.2±0.2°, 13.8±0.2°, 13.3±0.2° and 6.0±0.2°;

alternatively, 7.7±0.2°, 16.1±0.2°, 23.6±0.2°, 22.2±0.2°, 19.2±0.2°, 21.7±0.2°, 6.0±0.2°, 13.8±0.2°, 13.3±0.2° and 20.9±0.2°.

Most preferably, cu-K alpha radiation is used, and the X-ray characteristic diffraction peaks expressed in terms of 2 theta angles and interplanar spacing d values are shown in Table 15.

TABLE 15

Further preferred is maleate form B of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide, having an X-ray powder diffraction pattern substantially as shown in figure 23.

In a further preferred embodiment of the invention, there is provided maleate form C of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (example 1), the number of acids being 1, and the X-ray powder diffraction pattern thereof having one or more diffraction peaks in the range of 17.1±0.2°, 10.3±0.2°, 23.8±0.2°, preferably comprising two of them, more preferably comprising three of them; optionally, the composition further comprises at least one of 14.3+/-0.2 degrees, 13.3+/-0.2 degrees, 24.5+/-0.2 degrees, 25.5+/-0.2 degrees and 23.5+/-0.2 degrees; preferably 2, 3, 4 or 5 of these;

For example, the X-ray powder diffraction pattern of maleate form C has diffraction peaks at 2θ: 17.1.+ -. 0.2 °, 10.3.+ -. 0.2 °, 23.8.+ -. 0.2 °, 14.3.+ -. 0.2 °, 13.3.+ -. 0.2 ° and 24.5.+ -. 0.2 °.

The X-ray powder diffraction pattern of maleate form C optionally further comprises one or more diffraction peaks at 13.1±0.2°, 22.9±0.2°, 21.3±0.2°, 13.5±0.2°, 20.8±0.2°, 14.9±0.2°, 16.0±0.2° in 2θ; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

for example, the X-ray powder diffraction pattern of maleate form C has diffraction peaks at 2θ:

17.1±0.2°, 10.3±0.2°, 23.8±0.2°, 14.3±0.2°, 13.3±0.2°, 24.5±0.2°, 13.1±0.2° and 22.9±0.2°;

or 17.1±0.2°, 10.3±0.2°, 14.3±0.2°, 13.3±0.2°, 24.5±0.2°, 25.5±0.2°, 13.1±0.2°, 22.9±0.2° and 21.3±0.2°;

alternatively, 17.1±0.2°, 23.8±0.2°, 14.3±0.2°, 13.3±0.2°, 24.5±0.2°, 25.5±0.2°, 13.1±0.2°, 22.9±0.2°, 21.3±0.2° and 13.5±0.2°.

The X-ray powder diffraction pattern of maleate form C comprises one or more diffraction peaks at 17.1±0.2°, 10.3±0.2°, 23.8±0.2°, 14.3±0.2°, 13.3±0.2°, 24.5±0.2°, 25.5±0.2°, 23.5±0.2°, 13.1±0.2°, 22.9±0.2°, 21.3±0.2°, 13.5±0.2°, 20.8±0.2°, 14.9±0.2°, 16.0±0.2°; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

for example, the X-ray powder diffraction pattern of maleate form C has diffraction peaks at 2θ:17.1±0.2°, 10.3±0.2°, 23.8±0.2° and 14.3±0.2°;

alternatively, 17.1±0.2°, 10.3±0.2°, 23.8±0.2°, 14.3±0.2°, 13.3±0.2° and 13.1±0.2°;

alternatively, 17.1±0.2°, 10.3±0.2°, 23.8±0.2°, 14.3±0.2°, 13.3±0.2°, 24.5±0.2°, 13.1±0.2° and 21.3±0.2°;

alternatively, 17.1±0.2°, 10.3±0.2°, 23.8±0.2°, 14.3±0.2°, 13.3±0.2°, 24.5±0.2°, 25.5±0.2°, 23.5±0.2°, 13.1±0.2° and 22.9±0.2°.

The X-ray powder diffraction pattern of maleate form C comprises one or more diffraction peaks at 17.1±0.2°, 10.3±0.2°, 23.8±0.2°, 14.3±0.2°, 13.3±0.2°, 24.5±0.2°, 25.5±0.2°, 23.5±0.2°, 13.1±0.2°, 22.9±0.2°, 21.3±0.2°, 13.5±0.2°, 20.8±0.2°, 14.9±0.2°, 16.0±0.2°, 5.4±0.2°, 25.3±0.2°, 17.7±0.2°, 14.1±0.2°, 30.0.2°; preferably at least any of 2 to 3, or 4 to 5, or 7 to 8, or 10 to 12, or 15 to 18; further preferably, the diffraction peaks at any 2, 3, 4, 5, 6, 8, 10, 12, 16, 18 are included;

For example, the X-ray powder diffraction pattern of maleate form C has diffraction peaks at 2θ:17.1±0.2°, 10.3±0.2°, 23.8±0.2°, 5.4±0.2°, 25.3±0.2° and 14.3±0.2°;

alternatively, 17.1±0.2°, 10.3±0.2°, 23.8±0.2°, 14.3±0.2°, 13.3±0.2°, 5.4±0.2°, 25.3±0.2° and 13.1±0.2°;

alternatively, 17.1±0.2°, 10.3±0.2°, 23.8±0.2°, 14.3±0.2°, 13.3±0.2°, 24.5±0.2°, 13.1±0.2°, 5.4±0.2°, 25.3±0.2° and 21.3±0.2°.

Most preferably, cu-K alpha radiation is used, and the X-ray characteristic diffraction peaks expressed in terms of 2 theta angles and interplanar spacing d values are shown in Table 16.

Table 16

Further preferred is maleate form C of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide, having an X-ray powder diffraction pattern substantially as shown in figure 24.

In a further preferred embodiment of the invention, there is provided maleate form D of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (example 1), having an acid number of 1, and an X-ray powder diffraction pattern with one or more diffraction peaks in 2 theta of 20.4±0.2°, 8.2±0.2°, 14.6±0.2°, preferably comprising two of them, more preferably comprising three of them; optionally, the composition further comprises at least one of 25.9+/-0.2 °, 18.4+/-0.2 °, 8.9+/-0.2 °, 24.1+/-0.2 °, and 24.5+/-0.2 °; preferably 2, 3, 4 or 5 of these;

For example, the X-ray powder diffraction pattern of maleate form D has diffraction peaks at 2θ: 20.4.+ -. 0.2 °, 8.2.+ -. 0.2 °, 14.6.+ -. 0.2 °, 25.9.+ -. 0.2 °, 18.4.+ -. 0.2 ° and 8.9.+ -. 0.2 °.

The X-ray powder diffraction pattern of maleate form D optionally further comprises one or more diffraction peaks at 16.1±0.2°, 21.8±0.2°, 17.0±0.2°, 28.4±0.2°, 22.3±0.2°, 12.6±0.2°, 28.8±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

for example, the X-ray powder diffraction pattern of maleate form D has diffraction peaks at 2θ:20.4±0.2°, 8.2±0.2°, 14.6±0.2°, 25.9±0.2°, 18.4±0.2°, 8.9±0.2°, 16.1±0.2° and 21.8±0.2°;

alternatively, 20.4±0.2°, 8.2±0.2°, 25.9±0.2°, 18.4±0.2°, 8.9±0.2°, 24.1±0.2°, 16.1±0.2°, 21.8±0.2° and 17.0±0.2°;

alternatively, 20.4±0.2°, 14.6±0.2°, 25.9±0.2°, 18.4±0.2°, 8.9±0.2°, 24.1±0.2°, 16.1±0.2°, 21.8±0.2°, 17.0±0.2° and 28.4±0.2°.

The X-ray powder diffraction pattern of maleate form D comprises one or more diffraction peaks at 20.4±0.2°, 8.2±0.2°, 14.6±0.2°, 25.9±0.2°, 18.4±0.2°, 8.9±0.2°, 24.1±0.2°, 24.5±0.2°, 16.1±0.2°, 21.8±0.2°, 17.0±0.2°, 28.4±0.2°, 22.3±0.2°, 12.6±0.2°, 28.8±0.2°; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

for example, the X-ray powder diffraction pattern of maleate form D has diffraction peaks at 2θ:20.4±0.2°, 8.2±0.2°, 14.6±0.2° and 25.9±0.2°;

alternatively, 20.4±0.2°, 8.2±0.2°, 14.6±0.2°, 25.9±0.2°, 18.4±0.2° and 16.1±0.2°;

alternatively, 20.4±0.2°, 8.2±0.2°, 14.6±0.2°, 25.9±0.2°, 18.4±0.2°, 8.9±0.2°, 16.1±0.2° and 17.0±0.2°;

alternatively, 20.4±0.2°, 8.2±0.2°, 14.6±0.2°, 25.9±0.2°, 18.4±0.2°, 8.9±0.2°, 24.1±0.2°, 24.5±0.2°, 16.1±0.2° and 21.8±0.2°.

The X-ray powder diffraction pattern of maleate form D comprises one or more diffraction peaks at 20.4±0.2°, 8.2±0.2°, 14.6±0.2°, 25.9±0.2°, 18.4±0.2°, 8.9±0.2°, 24.1±0.2°, 24.5±0.2°, 16.1±0.2°, 21.8±0.2°, 17.0±0.2°, 28.4±0.2°, 22.3±0.2°, 12.6±0.2°, 28.8±0.2°, 21.5±0.2°, 10.8±0.2°, 23.2±0.2°, 10.4±0.2°, 17.5±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 7 to 8, or 10 to 12, or 15 to 18; further preferably, the diffraction peaks at any 2, 3, 4, 5, 6, 8, 10, 12, 16, 18 are included;

For example, the X-ray powder diffraction pattern of maleate form D has diffraction peaks at 2θ:20.4±0.2°, 8.2±0.2°, 14.6±0.2°, 21.5±0.2°, 10.8±0.2° and 25.9±0.2°;

alternatively, 20.4±0.2°, 8.2±0.2°, 14.6±0.2°, 25.9±0.2°, 18.4±0.2°, 21.5±0.2°, 10.8±0.2° and 16.1±0.2°;

alternatively, 20.4±0.2°, 8.2±0.2°, 14.6±0.2°, 25.9±0.2°, 18.4±0.2°, 8.9±0.2°, 16.1±0.2°, 21.5±0.2°, 10.8±0.2° and 17.0±0.2°.

Most preferably, cu-K alpha radiation is used, and the X-ray characteristic diffraction peaks expressed in terms of 2 theta angles and interplanar spacing d values are shown in Table 17.

TABLE 17

Further preferred is maleate form D of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide, having an X-ray powder diffraction pattern substantially as shown in figure 25.

In a further preferred embodiment of the invention, the mesylate salt form a of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (example 1) is provided with a number of acids of 1, an X-ray powder diffraction pattern of which diffracts peaks at one or more of 5.9±0.2°, 21.7±0.2°, 10.2±0.2°, preferably comprising two of them, more preferably comprising three of them; optionally, the composition further comprises at least one of 14.2+ -0.2 °, 20.8+ -0.2 °, 25.7+ -0.2 °, 22.2+ -0.2 °, 17.4+ -0.2 °; preferably 2, 3, 4 or 5 of these;

For example, the X-ray powder diffraction pattern of mesylate form a has diffraction peaks at 2θ: 5.9.+ -. 0.2 °, 21.7.+ -. 0.2 °, 10.2.+ -. 0.2 °, 14.2.+ -. 0.2 °, 20.8.+ -. 0.2 ° and 25.7.+ -. 0.2 °.

The X-ray powder diffraction pattern of mesylate form a optionally further comprises one or more diffraction peaks at 11.7±0.2°, 18.0±0.2°, 23.6±0.2°, 7.1±0.2°, 19.6±0.2°, 20.3±0.2°, 9.5±0.2° in 2θ; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

for example, the X-ray powder diffraction pattern of mesylate form a has diffraction peaks at 2θ:5.9±0.2°, 21.7±0.2°, 10.2±0.2°, 14.2±0.2°, 20.8±0.2°, 25.7±0.2°, 11.7±0.2° and 18.0±0.2°;

alternatively, 5.9±0.2°, 21.7±0.2°, 14.2±0.2°, 20.8±0.2°, 25.7±0.2°, 22.2±0.2°, 11.7±0.2°, 18.0±0.2° and 23.6±0.2°;

alternatively, 5.9±0.2°, 10.2±0.2°, 14.2±0.2°, 20.8±0.2°, 25.7±0.2°, 22.2±0.2°, 11.7±0.2°, 18.0±0.2°, 23.6±0.2° and 7.1±0.2°.

The X-ray powder diffraction pattern of mesylate form a comprises one or more diffraction peaks at 5.9±0.2°, 21.7±0.2°, 10.2±0.2°, 14.2±0.2°, 20.8±0.2°, 25.7±0.2°, 22.2±0.2°, 17.4±0.2°, 11.7±0.2°, 18.0±0.2°, 23.6±0.2°, 7.1±0.2°, 19.6±0.2°, 20.3±0.2°, 9.5±0.2°; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

for example, the X-ray powder diffraction pattern of mesylate form a has diffraction peaks at 2θ:5.9±0.2°, 21.7±0.2°, 10.2±0.2° and 14.2±0.2°;

alternatively, 5.9±0.2°, 21.7±0.2°, 10.2±0.2°, 14.2±0.2°, 20.8±0.2° and 11.7±0.2°;

alternatively, 5.9±0.2°, 21.7±0.2°, 10.2±0.2°, 14.2±0.2°, 20.8±0.2°, 25.7±0.2°, 11.7±0.2° and 23.6±0.2°;

alternatively, 5.9±0.2°, 21.7±0.2°, 10.2±0.2°, 14.2±0.2°, 20.8±0.2°, 25.7±0.2°, 22.2±0.2°, 17.4±0.2°, 11.7±0.2° and 18.0±0.2°.

The X-ray powder diffraction pattern of mesylate form a comprises one or more diffraction peaks at 5.9±0.2°, 21.7±0.2°, 10.2±0.2°, 14.2±0.2°, 20.8±0.2°, 25.7±0.2°, 22.2±0.2°, 17.4±0.2°, 11.7±0.2°, 18.0±0.2°, 23.6±0.2°, 7.1±0.2°, 19.6±0.2°, 20.3±0.2°, 9.5±0.2°, 16.6±0.2°, 16.2±0.2°, 18.9±0.2°, 23.0±0.2°, 17.8±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 7 to 8, or 10 to 12, or 15 to 18; further preferably, the diffraction peaks at any 2, 3, 4, 5, 6, 8, 10, 12, 16, 18 are included;

For example, the X-ray powder diffraction pattern of mesylate form a has diffraction peaks at 2θ:5.9±0.2°, 21.7±0.2°, 10.2±0.2°, 16.6±0.2°, 16.2±0.2° and 14.2±0.2°;

alternatively, 5.9±0.2°, 21.7±0.2°, 10.2±0.2°, 14.2±0.2°, 20.8±0.2°, 16.6±0.2°, 16.2±0.2° and 11.7±0.2°;

alternatively, 5.9±0.2°, 21.7±0.2°, 10.2±0.2°, 14.2±0.2°, 20.8±0.2°, 25.7±0.2°, 11.7±0.2°, 16.6±0.2°, 16.2±0.2° and 23.6±0.2°.

Most preferably, cu-K alpha radiation is used, and the X-ray characteristic diffraction peaks expressed in terms of 2 theta angles and interplanar spacing d values are shown in Table 18.

TABLE 18

Further preferred is mesylate form a of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide, which has an X-ray powder diffraction pattern substantially as shown in figure 26.

In a further preferred embodiment of the present invention, provided is the benzenesulfonate salt form a of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (example 1), the number of acids being 1, and the X-ray powder diffraction pattern of which comprises one or more diffraction peaks in the 2θ of 5.6±0.2°, 21.2±0.2°, 13.4±0.2°, preferably two of which, more preferably three of which; optionally, the composition further comprises at least one of 18.9+/-0.2 °, 26.6+/-0.2 °, 23.7+/-0.2 °, 19.5+/-0.2 °, and 26.4+/-0.2 °; preferably 2, 3, 4 or 5 of these;

For example, the X-ray powder diffraction pattern of besylate form a has diffraction peaks at the following positions of 2θ: 5.6.+ -. 0.2 °, 21.2.+ -. 0.2 °, 13.4.+ -. 0.2 °, 18.9.+ -. 0.2 °, 26.6.+ -. 0.2 ° and 23.7.+ -. 0.2 °.

The X-ray powder diffraction pattern of besylate form a optionally further comprises one or more diffraction peaks at 10.0±0.2°, 10.6±0.2°, 24.5±0.2°, 14.9±0.2°, 24.9±0.2°, 14.6±0.2°, 22.4±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

for example, the X-ray powder diffraction pattern of besylate form a has diffraction peaks at the following positions of 2θ:5.6±0.2°, 21.2±0.2°, 13.4±0.2°, 18.9±0.2°, 26.6±0.2°, 23.7±0.2°, 10.0±0.2° and 10.6±0.2°;

alternatively, 5.6±0.2°, 21.2±0.2°, 18.9±0.2°, 26.6±0.2°, 23.7±0.2°, 19.5±0.2°, 10.0±0.2°, 10.6±0.2° and 24.5±0.2°;

alternatively, 5.6±0.2°, 13.4±0.2°, 18.9±0.2°, 26.6±0.2°, 23.7±0.2°, 19.5±0.2°, 10.0±0.2°, 10.6±0.2°, 24.5±0.2° and 14.9±0.2°.

The X-ray powder diffraction pattern of the benzenesulfonate crystal form a comprises one or more diffraction peaks located in 5.6±0.2°, 21.2±0.2°, 13.4±0.2°, 18.9±0.2°, 26.6±0.2°, 23.7±0.2°, 19.5±0.2°, 26.4±0.2°, 10.0±0.2°, 10.6±0.2°, 24.5±0.2°, 14.9±0.2°, 24.9±0.2°, 14.6±0.2°, 22.4±0.2°; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

for example, the X-ray powder diffraction pattern of besylate form a has diffraction peaks at the following positions of 2θ:5.6±0.2°, 21.2±0.2°, 13.4±0.2° and 18.9±0.2°;

alternatively, 5.6±0.2°, 21.2±0.2°, 13.4±0.2°, 18.9±0.2°, 26.6±0.2° and 10.0±0.2°;

alternatively, 5.6±0.2°, 21.2±0.2°, 13.4±0.2°, 18.9±0.2°, 26.6±0.2°, 23.7±0.2°, 10.0±0.2° and 24.5±0.2°;

alternatively, 5.6±0.2°, 21.2±0.2°, 13.4±0.2°, 18.9±0.2°, 26.6±0.2°, 23.7±0.2°, 19.5±0.2°, 26.4±0.2°, 10.0±0.2° and 10.6±0.2°.

The X-ray powder diffraction pattern of the besylate salt form a comprises one or more diffraction peaks at 5.6±0.2°, 21.2±0.2°, 13.4±0.2°, 18.9±0.2°, 26.6±0.2°, 23.7±0.2°, 19.5±0.2°, 26.4±0.2°, 10.0±0.2°, 10.6±0.2°, 24.5±0.2°, 14.9±0.2°, 24.9±0.2°, 14.6±0.2°, 22.4±0.2°, 28.7±0.2°, 22.7±0.2°, 15.7±0.2°, 17.4±0.2°, 26.9±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 7 to 8, or 10 to 12, or 15 to 18; further preferably, the diffraction peaks at any 2, 3, 4, 5, 6, 8, 10, 12, 16, 18 are included;

For example, the X-ray powder diffraction pattern of besylate form a has diffraction peaks at the following positions of 2θ: 5.6.+ -. 0.2 °, 21.2.+ -. 0.2 °, 13.4.+ -. 0.2 °, 28.7.+ -. 0.2 °, 22.7.+ -. 0.2 ° and 18.9.+ -. 0.2 °

Alternatively, 5.6±0.2°, 21.2±0.2°, 13.4±0.2°, 18.9±0.2°, 26.6±0.2°, 28.7±0.2°, 22.7±0.2° and 10.0±0.2°;

alternatively, 5.6±0.2°, 21.2±0.2°, 13.4±0.2°, 18.9±0.2°, 26.6±0.2°, 23.7±0.2°, 10.0±0.2°, 28.7±0.2°, 22.7±0.2° and 24.5±0.2°.

Most preferably, using Cu-K alpha radiation, the X-ray characteristic diffraction peaks expressed in terms of 2 theta angles and interplanar spacing d values are shown in Table 19.

TABLE 19

Further preferred is the benzenesulfonate salt form a of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide, which has an X-ray powder diffraction pattern substantially as shown in figure 27.

In a further preferred embodiment of the present invention, there is provided a malonic acid salt form a of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (example 1), the number of acids being 1, and the X-ray powder diffraction pattern thereof having one or more diffraction peaks in the range of 7.5±0.2°, 5.5±0.2°, 23.6±0.2°, preferably comprising two of them, more preferably comprising three of them; optionally, the composition further comprises at least one of 20.3+ -0.2 °, 9.7+ -0.2 °, 11.7+ -0.2 °, 23.0+ -0.2 °, 21.0+ -0.2 °; preferably 2, 3, 4 or 5 of these;

For example, the malonate form a has an X-ray powder diffraction pattern with diffraction peaks at 2θ: 7.5.+ -. 0.2 °, 5.5.+ -. 0.2 °, 23.6.+ -. 0.2 °, 20.3.+ -. 0.2 °, 9.7.+ -. 0.2 ° and 11.7.+ -. 0.2 °.

The X-ray powder diffraction pattern of malonate form a optionally further comprises one or more diffraction peaks at 14.3±0.2°, 25.6±0.2°, 19.4±0.2°, 19.7±0.2°, 20.7±0.2°, 18.2±0.2°, 22.0±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

for example, the malonate form a has an X-ray powder diffraction pattern with diffraction peaks at 2θ:7.5±0.2°, 5.5±0.2°, 23.6±0.2°, 20.3±0.2°, 9.7±0.2°, 11.7±0.2°, 14.3±0.2° and 25.6±0.2°;

or, at 7.5±0.2°, 5.5±0.2°, 20.3±0.2°, 9.7±0.2°, 11.7±0.2°, 23.0±0.2°, 14.3±0.2°, 25.6±0.2° and 19.4±0.2°;

alternatively, 7.5±0.2°, 23.6±0.2°, 20.3±0.2°, 9.7±0.2°, 11.7±0.2°, 23.0±0.2°, 14.3±0.2°, 25.6±0.2°, 19.4±0.2° and 19.7±0.2°.

The X-ray powder diffraction pattern of malonate form a comprises one or more diffraction peaks at 7.5±0.2°, 5.5±0.2°, 23.6±0.2°, 20.3±0.2°, 9.7±0.2°, 11.7±0.2°, 23.0±0.2°, 21.0±0.2°, 14.3±0.2°, 25.6±0.2°, 19.4±0.2°, 19.7±0.2°, 20.7±0.2°, 18.2±0.2°, 22.0±0.2°; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

for example, the malonate form a has an X-ray powder diffraction pattern with diffraction peaks at 2θ:7.5±0.2°, 5.5±0.2°, 23.6±0.2° and 20.3±0.2°;

alternatively, 7.5±0.2°, 5.5±0.2°, 23.6±0.2°, 20.3±0.2°, 9.7±0.2° and 14.3±0.2°;

alternatively, 7.5±0.2°, 5.5±0.2°, 23.6±0.2°, 20.3±0.2°, 9.7±0.2°, 11.7±0.2°, 14.3±0.2° and 19.4±0.2°;

alternatively, 7.5±0.2°, 5.5±0.2°, 23.6±0.2°, 20.3±0.2°, 9.7±0.2°, 11.7±0.2°, 23.0±0.2°, 21.0±0.2°, 14.3±0.2° and 25.6±0.2°.

The X-ray powder diffraction pattern of malonate form a comprises one or more diffraction peaks at 7.5±0.2°, 5.5±0.2°, 23.6±0.2°, 20.3±0.2°, 9.7±0.2°, 11.7±0.2°, 23.0±0.2°, 21.0±0.2°, 14.3±0.2°, 25.6±0.2°, 19.4±0.2°, 19.7±0.2°, 20.7±0.2°, 18.2±0.2°, 22.0±0.2°, 15.2±0.2°, 22.8±0.2°, 27.2±0.2°, 18.7±0.2°, 16.6±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 7 to 8, or 10 to 12, or 15 to 18; further preferably, the diffraction peaks at any 2, 3, 4, 5, 6, 8, 10, 12, 16, 18 are included;

For example, the malonate form a has an X-ray powder diffraction pattern with diffraction peaks at 2θ:7.5±0.2°, 5.5±0.2°, 23.6±0.2°, 15.2±0.2°, 22.8±0.2° and 20.3±0.2°;

or, at 7.5±0.2°, 5.5±0.2°, 23.6±0.2°, 20.3±0.2°, 9.7±0.2°, 15.2±0.2°, 22.8±0.2° and 14.3±0.2°;

alternatively, 7.5±0.2°, 5.5±0.2°, 23.6±0.2°, 20.3±0.2°, 9.7±0.2°, 11.7±0.2°, 14.3±0.2°, 15.2±0.2°, 22.8±0.2° and 19.4±0.2°.

Most preferably, cu-K alpha radiation is used, and the X-ray characteristic diffraction peaks expressed in terms of 2 theta angles and interplanar spacing d values are shown in Table 20.

Table 20

Further preferred is malonic acid salt form a of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide, whose X-ray powder diffraction pattern is substantially as shown in fig. 28.

In a further preferred embodiment of the present invention, there is provided a malonic acid salt form B of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (example 1), the number of acids being 1, and the X-ray powder diffraction pattern thereof having one or more diffraction peaks in the 2θ of 21.4±0.2°, 5.9±0.2°, 20.5±0.2°, preferably comprising two of them, more preferably comprising three of them; optionally, the composition further comprises at least one of 11.4+/-0.2 °, 19.1+/-0.2 °, 20.8+/-0.2 °, 16.1+/-0.2 °, and 27.4+/-0.2 °; preferably 2, 3, 4 or 5 of these;

For example, the malonate form B has an X-ray powder diffraction pattern with diffraction peaks at 2θ: 21.4.+ -. 0.2 °, 5.9.+ -. 0.2 °, 20.5.+ -. 0.2 °, 11.4.+ -. 0.2 °, 19.1.+ -. 0.2 ° and 20.8.+ -. 0.2 °.

The X-ray powder diffraction pattern of malonic acid salt form B optionally further comprises one or more diffraction peaks at 18.4±0.2°, 13.9±0.2°, 15.2±0.2°, 18.8±0.2°, 23.6±0.2°, 21.8±0.2°, 27.0±0.2° in 2θ; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

for example, the malonate form B has an X-ray powder diffraction pattern with diffraction peaks at 2θ:21.4±0.2°, 5.9±0.2°, 20.5±0.2°, 11.4±0.2°, 19.1±0.2°, 20.8±0.2°, 18.4±0.2° and 13.9±0.2°;

alternatively, 21.4±0.2°, 5.9±0.2°, 11.4±0.2°, 19.1±0.2°, 20.8±0.2°, 16.1±0.2°, 18.4±0.2°, 13.9±0.2° and 15.2±0.2°;

alternatively, 21.4±0.2°, 20.5±0.2°, 11.4±0.2°, 19.1±0.2°, 20.8±0.2°, 16.1±0.2°, 18.4±0.2°, 13.9±0.2°, 15.2±0.2° and 18.8±0.2°.

The X-ray powder diffraction pattern of malonate form B comprises one or more diffraction peaks at 21.4±0.2°, 5.9±0.2°, 20.5±0.2°, 11.4±0.2°, 19.1±0.2°, 20.8±0.2°, 16.1±0.2°, 27.4±0.2°, 18.4±0.2°, 13.9±0.2°, 15.2±0.2°, 18.8±0.2°, 23.6±0.2°, 21.8±0.2°, 27.0±0.2°; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

for example, the malonate form B has an X-ray powder diffraction pattern with diffraction peaks at 2θ:21.4±0.2°, 5.9±0.2°, 20.5±0.2° and 11.4±0.2°;

alternatively, 21.4±0.2°, 5.9±0.2°, 20.5±0.2°, 11.4±0.2°, 19.1±0.2° and 18.4±0.2°;

alternatively, 21.4±0.2°, 5.9±0.2°, 20.5±0.2°, 11.4±0.2°, 19.1±0.2°, 20.8±0.2°, 18.4±0.2° and 15.2±0.2°;

alternatively, 21.4±0.2°, 5.9±0.2°, 20.5±0.2°, 11.4±0.2°, 19.1±0.2°, 20.8±0.2°, 16.1±0.2°, 27.4±0.2°, 18.4±0.2° and 13.9±0.2°.

The X-ray powder diffraction pattern of malonic acid salt form B comprises one or more diffraction peaks located at 21.4±0.2°, 5.9±0.2°, 20.5±0.2°, 11.4±0.2°, 19.1±0.2°, 20.8±0.2°, 16.1±0.2°, 27.4±0.2°, 18.4±0.2°, 13.9±0.2°, 15.2±0.2°, 18.8±0.2°, 23.6±0.2°, 21.8±0.2°, 27.0±0.2°, 24.7±0.2°, 17.7±0.2°, 14.1±0.2°, 28.4±0.2°, 11.0.2°. Preferably at least any of 2 to 3, or 4 to 5, or 7 to 8, or 10 to 12, or 15 to 18; further preferably, the diffraction peaks at any 2, 3, 4, 5, 6, 8, 10, 12, 16, 18 are included;

For example, the malonate form B has an X-ray powder diffraction pattern with diffraction peaks at 2θ:21.4±0.2°, 5.9±0.2°, 20.5±0.2°, 24.7±0.2°, 17.7±0.2° and 11.4±0.2°;

alternatively, 21.4±0.2°, 5.9±0.2°, 20.5±0.2°, 11.4±0.2°, 19.1±0.2°, 24.7±0.2°, 17.7±0.2° and 18.4±0.2°;

alternatively, 21.4±0.2°, 5.9±0.2°, 20.5±0.2°, 11.4±0.2°, 19.1±0.2°, 20.8±0.2°, 18.4±0.2°, 24.7±0.2°, 17.7±0.2° and 15.2±0.2°.

Most preferably, cu-K alpha radiation is used, and the X-ray characteristic diffraction peaks expressed in terms of 2 theta angles and interplanar spacing d values are shown in Table 21.

Table 21

Further preferred is malonic acid salt form B of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide, having an X-ray powder diffraction pattern substantially as shown in fig. 29.

In a further preferred embodiment of the invention, there is provided the succinate crystalline form a of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (example 1), the number of acids being 1, and the X-ray powder diffraction pattern thereof having one or more diffraction peaks in 21.4±0.2°, 10.7±0.2°, 16.6±0.2°, preferably comprising two of them, more preferably comprising three of them; optionally, it may further comprise at least one of 19.6±0.2°, 26.2±0.2°, 19.3±0.2°, 21.6±0.2°, and 21.0±0.2°; preferably 2, 3, 4 or 5 of these;

For example, the X-ray powder diffraction pattern of succinate salt form a has diffraction peaks at 2θ:21.4±0.2°, 10.7±0.2°, 16.6±0.2°, 19.6±0.2°, 26.2±0.2° and 19.3±0.2°; .

The X-ray powder diffraction pattern of succinate crystalline form a optionally further comprises one or more diffraction peaks at 16.0±0.2°, 14.4±0.2°, 10.2±0.2°, 23.7±0.2°, 6.5±0.2°, 22.3±0.2°, 15.7±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

for example, the X-ray powder diffraction pattern of succinate salt form a has diffraction peaks at 2θ:21.4±0.2°, 10.7±0.2°, 16.6±0.2°, 19.6±0.2°, 26.2±0.2°, 19.3±0.2°, 16.0±0.2° and 14.4±0.2°;

alternatively, 21.4±0.2°, 10.7±0.2°, 19.6±0.2°, 26.2±0.2°, 19.3±0.2°, 21.6±0.2°, 16.0±0.2°, 14.4±0.2° and 10.2±0.2°;

alternatively, 21.4±0.2°, 16.6±0.2°, 19.6±0.2°, 26.2±0.2°, 19.3±0.2°, 21.6±0.2°, 16.0±0.2°, 14.4±0.2°, 10.2±0.2° and 23.7±0.2°.

The X-ray powder diffraction pattern of succinate crystalline form a comprises one or more diffraction peaks at 21.4±0.2°, 10.7±0.2°, 16.6±0.2°, 19.6±0.2°, 26.2±0.2°, 19.3±0.2°, 21.6±0.2°, 21.0±0.2°, 16.0±0.2°, 14.4±0.2°, 10.2±0.2°, 23.7±0.2°, 6.5±0.2°, 22.3±0.2°, 15.7±0.2°; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

for example, the X-ray powder diffraction pattern of succinate salt form a has diffraction peaks at 2θ at the following positions: 21.4±0.2°, 10.7±0.2°, 16.6±0.2° and 19.6±0.2°;

alternatively, 21.4±0.2°, 10.7±0.2°, 16.6±0.2°, 19.6±0.2°, 26.2±0.2° and 16.0±0.2°;

alternatively, 21.4±0.2°, 10.7±0.2°, 16.6±0.2°, 19.6±0.2°, 26.2±0.2°, 19.3±0.2°, 16.0±0.2° and 10.2±0.2°;

alternatively, 21.4±0.2°, 10.7±0.2°, 16.6±0.2°, 19.6±0.2°, 26.2±0.2°, 19.3±0.2°, 21.6±0.2°, 21.0±0.2°, 16.0±0.2° and 14.4±0.2°.

The X-ray powder diffraction pattern of succinate crystalline form a comprises one or more diffraction peaks at 21.4±0.2°, 10.7±0.2°, 16.6±0.2°, 19.6±0.2°, 26.2±0.2°, 19.3±0.2°, 21.6±0.2°, 21.0±0.2°, 16.0±0.2°, 14.4±0.2°, 10.2±0.2°, 23.7±0.2°, 6.5±0.2°, 22.3±0.2°, 15.7±0.2°, 25.5±0.2°, 12.9±0.2°, 8.0±0.2°, 29.9±0.2°, 25.1±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 7 to 8, or 10 to 12, or 15 to 18; further preferably, the diffraction peaks at any 2, 3, 4, 5, 6, 8, 10, 12, 16, 18 are included;

For example, the X-ray powder diffraction pattern of succinate salt form a has diffraction peaks at 2θ:21.4±0.2°, 10.7±0.2°, 16.6±0.2°, 25.5±0.2°, 12.9±0.2° and 19.6±0.2°;

alternatively, 21.4±0.2°, 10.7±0.2°, 16.6±0.2°, 19.6±0.2°, 26.2±0.2°, 25.5±0.2°, 12.9±0.2° and 16.0±0.2°;

alternatively, 21.4±0.2°, 10.7±0.2°, 16.6±0.2°, 19.6±0.2°, 26.2±0.2°, 19.3±0.2°, 16.0±0.2°, 25.5±0.2°, 12.9±0.2° and 10.2±0.2°.

Most preferably, cu-K alpha radiation is used, and the X-ray characteristic diffraction peaks expressed in terms of 2 theta angles and interplanar spacing d values are shown in Table 22.

Table 22

Further preferred is crystalline form a of the succinate salt of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide, having an X-ray powder diffraction pattern substantially as shown in figure 30.

In a further preferred embodiment of the invention, there is provided the succinate crystalline form B of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (example 1), the number of acids being 1, and the X-ray powder diffraction pattern thereof having one or more diffraction peaks in the 2θ of 19.2±0.2°, 21.3±0.2°, 20.7±0.2°, preferably comprising two of them, more preferably three of them; optionally, the composition further comprises at least one of 14.1+ -0.2 °, 20.4+ -0.2 °, 18.5+ -0.2 °, 11.4+ -0.2 °, 23.7+ -0.2 °; preferably 2, 3, 4 or 5 of these;

For example, the X-ray powder diffraction pattern of succinate salt form B has diffraction peaks at the following positions of 2θ: 19.2.+ -. 0.2 °, 21.3.+ -. 0.2 °, 20.7.+ -. 0.2 °, 14.1.+ -. 0.2 °, 20.4.+ -. 0.2 ° and 18.5.+ -. 0.2 °.

The X-ray powder diffraction pattern of succinate crystalline form B optionally further comprises one or more diffraction peaks at 27.3±0.2°, 20.8±0.2°, 22.0±0.2°, 16.2±0.2°, 5.8±0.2°, 25.5±0.2°, 18.7±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

for example, the X-ray powder diffraction pattern of succinate salt form B has diffraction peaks at the following positions of 2θ:19.2±0.2°, 21.3±0.2°, 20.7±0.2°, 14.1±0.2°, 20.4±0.2°, 18.5±0.2°, 27.3±0.2° and 20.8±0.2°;

or, at 19.2±0.2°, 21.3±0.2°, 14.1±0.2°, 20.4±0.2°, 18.5±0.2°, 11.4±0.2°, 27.3±0.2°, 20.8±0.2° and 22.0±0.2°;

alternatively, 19.2±0.2°, 20.7±0.2°, 14.1±0.2°, 20.4±0.2°, 18.5±0.2°, 11.4±0.2°, 27.3±0.2°, 20.8±0.2°, 22.0±0.2° and 16.2±0.2°.

The X-ray powder diffraction pattern of succinate crystalline form B comprises one or more diffraction peaks at 19.2±0.2°, 21.3±0.2°, 20.7±0.2°, 14.1±0.2°, 20.4±0.2°, 18.5±0.2°, 11.4±0.2°, 23.7±0.2°, 27.3±0.2°, 20.8±0.2°, 22.0±0.2°, 16.2±0.2°, 5.8±0.2°, 25.5±0.2°, 18.7±0.2°; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

for example, the X-ray powder diffraction pattern of succinate salt form B has diffraction peaks at 2θ at the following positions: 19.2±0.2°, 21.3±0.2°, 20.7±0.2° and 14.1±0.2°;

alternatively, 19.2±0.2°, 21.3±0.2°, 20.7±0.2°, 14.1±0.2°, 20.4±0.2° and 27.3±0.2°;

alternatively, 19.2±0.2°, 21.3±0.2°, 20.7±0.2°, 14.1±0.2°, 20.4±0.2°, 18.5±0.2°, 27.3±0.2° and 22.0±0.2°;

alternatively, 19.2±0.2°, 21.3±0.2°, 20.7±0.2°, 14.1±0.2°, 20.4±0.2°, 18.5±0.2°, 11.4±0.2°, 23.7±0.2°, 27.3±0.2° and 20.8±0.2°.

The X-ray powder diffraction pattern of succinate crystalline form B comprises one or more diffraction peaks at 19.2±0.2°, 21.3±0.2°, 20.7±0.2°, 14.1±0.2°, 20.4±0.2°, 18.5±0.2°, 11.4±0.2°, 23.7±0.2°, 27.3±0.2°, 20.8±0.2°, 22.0±0.2°, 16.2±0.2°, 5.8±0.2°, 25.5±0.2°, 18.7±0.2°, 17.8±0.2°, 7.1±0.2°, 15.3±0.2°, 9.3±0.2°, 24.8±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 7 to 8, or 10 to 12, or 15 to 18; further preferably, the diffraction peaks at any 2, 3, 4, 5, 6, 8, 10, 12, 16, 18 are included;

For example, the X-ray powder diffraction pattern of succinate salt form B has diffraction peaks at the following positions of 2θ:19.2±0.2°, 21.3±0.2°, 20.7±0.2°, 17.8±0.2°, 7.1±0.2° and 14.1±0.2°;

alternatively, 19.2±0.2°, 21.3±0.2°, 20.7±0.2°, 14.1±0.2°, 20.4±0.2°, 17.8±0.2°, 7.1±0.2° and 27.3±0.2°;

alternatively, 19.2±0.2°, 21.3±0.2°, 20.7±0.2°, 14.1±0.2°, 20.4±0.2°, 18.5±0.2°, 27.3±0.2°, 17.8±0.2°, 7.1±0.2° and 22.0±0.2°.

Most preferably, cu-K alpha radiation is used, and the X-ray characteristic diffraction peaks expressed in terms of 2 theta angles and interplanar spacing d values are shown in Table 23.

Table 23

Further preferred is crystalline form B of the succinate salt of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide, having an X-ray powder diffraction pattern substantially as shown in figure 31.

In a further preferred embodiment of the present invention, hydrochloride form a, hydrobromide form a, p-toluenesulfonate form a, sulfate form a, fumarate form a, oxalate form a, benzoylglycinate form B, benzoylglycinate form C, benzoylglycinate form D, benzoylglycinate form E, benzoylglycinate form F, phosphate form a, maleate form a, the positions of diffraction peaks with relative peak intensities of the front ten intensities in the X-ray powder diffraction patterns of the maleate crystal form B, the maleate crystal form C, the maleate crystal form D, the methanesulfonate crystal form A, the benzenesulfonate crystal form A, the malonate crystal form B, the succinate crystal form A and the succinate crystal form B are respectively 0.2 DEG to 0.5 DEG corresponding to the 2 theta errors of the diffraction peaks at the positions corresponding to the positions of the diffraction peaks in the diffraction patterns of the positions of 1 DEG, the diffraction peak positions of the diffraction patterns of the corresponding to the diffraction patterns of the diffraction pattern of the maleate, the maleate crystal form D, the methanesulfonate crystal form A, the benzenesulfonate crystal form A, the malonate crystal form A, the malonic acid, the malonate crystal form 30 and the respective 30, preferably + -0.2 deg. to + -0.3 deg., most preferably + -0.2 deg..

In a preferred embodiment of the invention, the acid salt form of any one of the compounds of formula (I) is a hydrate or anhydrate; when the acid salt form is a hydrate, the number of water is 0.2 to 3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3; further, the water in the hydrate is pipeline water or crystal water or a combination of the pipeline water and the crystal water.

It is well known to those of ordinary skill in the art that XRPD may experience certain displacements and intensity deviations due to detection methods, conditions, and instrumentation. As a specific example of a crystalline form of the present invention, XRPD is shown in pattern X, but it will be appreciated by one of ordinary skill that the same crystalline form can be identified when the peak shift 2θ deviation of the key feature is about ±0.5, and especially about ±0.2.

The invention also provides a method for preparing the acid salt of the compound shown in the general formula (I), which comprises the following steps:

1) Weighing a proper amount of free alkali, and dissolving with benign solvent;

2) Weighing a proper amount of acid, and dissolving the acid in an organic solvent; the amount of acid is preferably 1.0 to 1.5 equivalents;

3) Mixing the above two solutions, stirring to separate out or dripping poor solvent, and stirring to separate out;

4) Rapidly centrifuging or standing and drying to obtain a target product;

Wherein:

the benign solvent is selected from acetone, toluene, acetonitrile, methanol, methylene dichloride, tetrahydrofuran, ethyl formate, ethyl acetate, 2-methyl-tetrahydrofuran, 2-butanone, N-butanol, 1, 4-dioxane, isobutanol, N-dimethylformamide, N-dimethylacetamide, N-propanol or tert-butanol; toluene, ethyl acetate, acetone, methanol or acetonitrile are preferred;

the organic solvent is selected from methanol, ethanol, ethyl acetate, methylene dichloride, acetone, normal hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-methyl-tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tertiary butyl ether, isopropyl ether, 1, 4-dioxane, tertiary butanol or N, N-dimethylformamide; preferably methanol, ethanol or acetonitrile; the benign solvent and the organic solution need to be mutually soluble when in use;

the poor solvent is selected from heptane, water, methyl tertiary butyl ether, cyclohexane, toluene, isopropyl ether, ethyl acetate, acetone or acetonitrile; preferably water, methyl tert-butyl ether or isopropyl ether;

the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2, 5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecylsulfuric acid, dibenzoyltartaric acid ethane-1, 2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, benzoylglycine, hydroxyethanesulfonic acid, lactonic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1, 5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, pamoic acid, formic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid or L-malic acid; preferably hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, sulfuric acid, fumaric acid, oxalic acid, benzoylglycine, phosphoric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, malonic acid, succinic acid, hydroxyethanesulfonic acid, 1, 5-naphthalenedisulfonic acid, tartaric acid, adipic acid, formic acid, lauric acid or stearic acid; more preferably hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, sulfuric acid, fumaric acid, oxalic acid, benzoylglycine, phosphoric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, malonic acid or succinic acid; most preferred is benzoylglycine.

1) Weighing a proper amount of free alkali, and suspending with an unfavorable solvent;

3) Adding the solution to the suspension, stirring, preferably for 2 hours;

4) Rapidly centrifuging or standing and drying to obtain a target product;

wherein:

the poor solvent is selected from ethanol, acetone, ethyl acetate, ethyl formate, isopropanol, isopropyl acetate, methyl tertiary butyl ether, methanol, 1, 4-dioxane, 2-butanone, 2-methyl-tetrahydrofuran, anisole, acetonitrile, chlorobenzene, benzene, toluene, n-butanol, isobutanol or 3-pentanone; preferably ethanol, 2-methyl-tetrahydrofuran, anisole or ethyl acetate;

The acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2, 5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecylsulfuric acid, dibenzoyltartaric acid ethane-1, 2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, benzoylglycine, hydroxyethanesulfonic acid, lactonic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1, 5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, pamoic acid, formic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid or L-malic acid; preferably hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, sulfuric acid, fumaric acid, oxalic acid, benzoylglycine, phosphoric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, malonic acid or succinic acid; more preferably benzoylglycine.

The invention also provides a crystal form method for preparing the acid salt of the compound shown in the general formula (I), which comprises the following steps:

1) Weighing a proper amount of compound salt, and suspending with a poor solvent, wherein the suspension density is preferably 50-200 mg/mL;

2) The suspension obtained above is shaken for a certain time at a certain temperature, the temperature is preferably 25-50 ℃, and the time is preferably 1-15 days;

3) Centrifuging the suspension rapidly, removing supernatant, drying the rest solid to constant weight to obtain target product, and preferably drying in a vacuum drying oven at 50deg.C to constant weight to obtain target product;

wherein:

the poor solvent is selected from methanol, ethanol, methylene dichloride, 1, 4-dioxane, acetonitrile, methylene dichloride, chlorobenzene, benzene, toluene, acetone, ethyl acetate, water, 88% acetone, isopropyl acetate, 3-pentanone, ethyl formate, tetrahydrofuran, 2-methyl-tetrahydrofuran, isopropanol, n-butanol, isobutanol, n-propanol, methyl tertiary butyl ether, n-heptane, tertiary butanol or 2-butanone.

The invention also aims to provide a pharmaceutical composition which contains a therapeutically effective amount of the acid salt of the compound shown in the general formula (I) and a crystal form thereof, and one or more pharmaceutically acceptable carriers or excipients.

The invention also aims to provide the application of the acid salt of the general formula compound shown in the formula (I) and the crystal form thereof and the pharmaceutical composition in preparing kinase inhibitor medicines.

The invention also aims to provide an acid salt of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide and a crystal form thereof, and application of the pharmaceutical composition in preparation of kinase inhibitor drugs.

The kinase inhibitor is a receptor tyrosine kinase inhibitor, preferably a HER2 inhibitor, an EGFR inhibitor and EGFR monoclonal antibody and related drugs for combination thereof, and more preferably a HER2 exon mutant inhibitor, an EGFR20 exon mutant inhibitor and EGFR20 exon mutant monoclonal antibody and related drugs for combination thereof.

The invention aims to provide the acid salt of the compound shown in the general formula (I) and the crystal forms thereof and the application of the pharmaceutical composition in medicaments for treating cancers, inflammations, chronic liver diseases, diabetes, cardiovascular diseases and AIDS related diseases, preferably, diseases mediated by HER2 exon mutation and/or EGFR20 exon mutation.

It is also an object of the present invention to provide the acid salt of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide and its crystalline form and the use of said pharmaceutical composition in a medicament for the treatment of cancer, inflammation, chronic liver disease, diabetes, cardiovascular disease and AIDS related diseases, preferably, the cancer, inflammation, chronic liver disease, diabetes, cardiovascular disease and AIDS related diseases are diseases mediated by HER2 exon mutations and/or EGFR20 exon mutations.

The cancer is selected from breast cancer, cervical cancer, colon cancer, lung cancer, gastric cancer, rectal cancer, pancreatic cancer, brain cancer, liver cancer, solid tumor, glioma, neuroglioblastoma, leukemia, lymphoma, myeloma and non-small cell lung cancer.

The third-generation EGFR inhibitor is mainly aimed at EGFR activating mutant and T790M drug resistant mutant, and the compound of the invention has the following remarkable advantages in EGFR and/or HER2 20 exon insertion mutation targets compared with the third-generation EGFR inhibitor:

1. the inhibition activity of the Ba/F3EGFR mutant cell strain is obviously improved, and the activity of the preferable compound is more than 10 times and even 20 times higher;

2. The selectivity of proliferation inhibition activity of the Ba/F3EGFR mutant cell strain and the A431 cell strain is improved, and the compound is preferably 3 times or more and even 10 times higher;

3. the method also has obvious advantages in the in-vivo efficacy tumor inhibition rate of the mouse primary B cell Ba/F3EGFR-D770-N771 ins-SVD transplanted tumor model.

Detailed description of the invention

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group containing from 1 to 8 carbon atoms, more preferably an alkyl group containing from 1 to 6 carbon atoms, and most preferably an alkyl group containing from 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl 4, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate, with methyl, ethyl, isopropyl, t-butyl, haloalkyl, deuteroalkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl being preferred.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 8 carbon atoms, and most preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms in which one or more ring atoms are selected from nitrogen, oxygen or S (O) _m (wherein m is an integer from 0 to 2), but does not include a ring moiety of-O-O-, -O-S-, or-S-S-, and the remaining ring atoms are carbon. Preferably containing 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 8 ring atoms; most preferably containing 3 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, thietanyl, pyrrolidinyl, Pyrrolidinonyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl and the like, preferably oxetanyl, pyrrolidinonyl, tetrahydrofuranyl, pyrazolidinyl, morpholinyl, piperazinyl and pyranyl. Polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups; the heterocyclic groups of the spiro ring, the condensed ring and the bridged ring are optionally connected with other groups through single bonds, or are further connected with other cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups through any two or more atoms on the ring in a parallel ring mode.

The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate groups.

The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, including a benzo 3-8 membered cycloalkyl, a benzo 3-8 membered heteroalkyl, preferably a benzo 3-6 membered cycloalkyl, a benzo 3-6 membered heteroalkyl, wherein heterocyclyl is a heterocyclyl containing 1-3 nitrogen, oxygen, sulfur atoms; or further comprises a ternary nitrogen-containing fused ring comprising a benzene ring, wherein the ring attached to the parent structure is an aryl ring.

Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.

The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered, more preferably 5 or 6 membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, and the like, preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl, or thiazolyl; more preferably pyrazolyl and oxazolyl. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring.

The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy. The alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.

"haloalkyl" refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.

"haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.

"alkenyl" refers to alkenyl groups, also known as alkenyl groups, wherein the alkenyl groups may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.

"alkynyl" refers to (CH≡C-), wherein the alkynyl group may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.

"hydroxy" refers to an-OH group.

"halogen" means fluorine, chlorine, bromine or iodine.

"amino" means-NH ₂ 。

"cyano" refers to-CN.

"nitro" means-NO ₂ 。

"carboxy" means-C (O) OH.

"THF" refers to tetrahydrofuran.

"EtOAc" refers to ethyl acetate.

"MeOH" refers to methanol.

"DMF" refers to N, N-dimethylformamide.

"DIPEA" refers to diisopropylethylamine.

"TFA" refers to trifluoroacetic acid.

"MeCN" refers to acetonitrile.

"DMA" refers to N, N-dimethylacetamide.

“Et ₂ O "refers to diethyl ether.

"DCE" refers to 1,2 dichloroethane.

"DIPEA" refers to N, N-diisopropylethylamine.

"NBS" refers to N-bromosuccinimide.

"NIS" refers to N-iodosuccinimide.

"Cbz-Cl" refers to benzyl chloroformate.

“Pd ₂ (dba) ₃ "means tris (dibenzylideneacetone) dipalladium.

"Dppf" refers to 1,1' -bis-diphenylphosphino ferrocene.

"HATU" refers to 2- (7-oxo-benzotriazol) -N, N' -tetramethylurea hexafluorophosphate.

"KHMDS" refers to potassium hexamethyldisilazide.

"LiHMDS" refers to lithium bis (trimethylsilylamide).

"MeLi" refers to lithium-based.

"n-BuLi" refers to n-butyllithium.

“NaBH(OAc) ₃ "means sodium triacetoxyborohydride.

"DMAP" refers to 4-dimethylaminopyridine.

"SEM-Cl" refers to chloromethyl trimethylsilanylethyl ether.

"Xantphos" refers to 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene.

"DCM" refers to dichloromethane.

The terms "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C", etc. all express the same meaning, that is, X may be any one or several of A, B, C.

The hydrogen atoms of the invention can be replaced by the isotope deuterium thereof, and any hydrogen atom in the compound of the embodiment of the invention can be replaced by deuterium atoms.

"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

"substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds. Optional substituent packageIncluding deuterium, halogen, amino, hydroxy, cyano, oxo, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, haloalkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, preferably deuterium, halogen, amino, hydroxy, cyano, oxo, thio, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Haloalkoxy, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl.

"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.

By "pharmaceutically acceptable salts" is meant salts of the compounds of the present invention which are safe and effective when used in a mammal, and which possess the desired biological activity.

The same sample of the same crystal form will typically have the same main XRPD characteristic peaks, but there may be some operational error, when the same crystal form sample obtained by the corresponding method is detected by the same instrument and detection method by a person of ordinary skill in the art, the characteristic peak error will typically be within + -0.2 deg. (although a small number of characteristic peaks may occur accidentally by different technicians using different instruments, if the error is within + -0.5 deg. or + -0.3 deg. as an XRPD characteristic peak belonging to the same crystal form), and thus peaks within + -0.5 deg., + -0.3 deg. or + -0.2 deg. may be interpreted as being within the scope of the invention.

Drawings

FIG. 1 is an XRPD representation of crystalline form A of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide hydrochloride.

FIG. 2 is a DSC plot of crystalline form A of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide hydrochloride.

FIG. 3 is a TGA graphic representation of crystalline form A of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide hydrochloride.

FIG. 4 is an XRPD representation of crystalline form A of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide hydrobromide.

FIG. 5 is a DSC plot of crystalline form A of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide hydrobromide.

FIG. 6 is a TGA graphic representation of crystalline form A of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide hydrobromide.

FIG. 7 is an XRPD pattern for crystalline form A of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide p-toluenesulfonate.

FIG. 8 is a DSC plot of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide p-toluenesulfonate form A.

FIG. 9 is a TGA graphic representation of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide p-toluenesulfonate form A.

FIG. 10 is an XRPD pattern for crystalline form A of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide sulfate.

FIG. 11 is an XRPD representation of crystalline form A of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide fumarate.

FIG. 12 is an XRPD pattern for crystalline form A of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide oxalate.

FIG. 13 is an XRPD representation of crystal form A of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide benzoylglycinate.

FIG. 14 is an XRPD representation of crystalline form B of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide benzoylglycinate.

FIG. 15 is an XRPD representation of crystal form C of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide benzoylglycinate.

FIG. 16 is an XRPD representation of crystal form D of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide benzoylglycinate.

FIG. 17 is a DSC plot of crystal form D of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide benzoylglycinate.

FIG. 18 is a TGA graphic representation of crystal form D of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide benzoylglycinate.

FIG. 19 is an XRPD representation of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide benzoylglycinate form E.

FIG. 20 is an XRPD representation of crystalline form F of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide benzoylglycinate.

FIG. 21 is an XRPD pattern for crystalline form A of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide phosphate.

FIG. 22 is an XRPD pattern for crystalline form A of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide maleate.

FIG. 23 is an XRPD pattern for crystalline form B of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide maleate.

FIG. 24 is an XRPD pattern for crystalline form C of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide maleate.

FIG. 25 is an XRPD pattern for crystalline form D of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide maleate.

FIG. 26 is an XRPD representation of crystalline form A of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide mesylate.

FIG. 27 is an XRPD representation of crystalline form A of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide benzenesulfonate.

FIG. 28 is an XRPD pattern for crystalline form A of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide malonate.

FIG. 29 is an XRPD pattern for crystalline form B of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide malonate.

FIG. 30 is an XRPD pattern for crystalline form A of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide succinic acid.

FIG. 31 is an XRPD pattern for crystalline form B of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide succinic acid.

FIG. 32 is an XRPD pattern for crystalline form A of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide free base.

Detailed Description

The invention is further described below in connection with examples, which are not intended to limit the scope of the invention.

1. Preparation of the Compounds

Examples

The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was performed using Bruker AVANCE-400 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated methanol (CD) ₃ OD) and deuterated chloroform (CDCl) ₃ ) The internal standard is Tetramethylsilane (TMS).

An Agilent 1200 affinity Series mass spectrometer was used for LC-MS measurement. HPLC was performed using Agilent 1200DAD high pressure liquid chromatography (Sunfire C18X 4.6mm column) and Waters 2695-2996 high pressure liquid chromatography (Gimini C18X 4.6mm column).

The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. Column chromatography generally uses yellow sea silica gel with 200-300 meshes as a carrier.

The starting materials in the examples of the present invention are known and commercially available or may be synthesized according to methods known in the art.

All reactions of the invention were carried out under continuous magnetic stirring under dry nitrogen or argon atmosphere, with the solvent being a dry solvent and the reaction temperature being in degrees celsius, without specific explanation.

Example 1

N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide

The first step: preparation of 2-chloro-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidine-5-carbonitrile

2, 4-dichloropyrimidine-5-carbonitrile (2 g,12 mmol) was dissolved in dichloroethane (30 mL), cooled to 0deg.C, ferric chloride (3.9 g,24 mmol) was added, the reaction stirred at room temperature for half an hour, 1-cyclopropyl-1H-indole (2.17 g,14 mmol) was added and the reaction stirred at 60deg.C for 2 hours. Water (30 mL) was added, the filtrate was filtered, the filtrate was extracted with dichloromethane (30 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, spin-dried, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate: 100/1-3/1) to give 2-chloro-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidine-5-carbonitrile (1.6 g, yield: 47%) as a brown solid.

And a second step of: preparation of 4- (1-cyclopropyl-1H-indol-3-yl) -2- ((4-fluoro-2-methoxy-5-nitrophenyl) amino) pyrimidine-5-carbonitrile

2-chloro-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidine-5-carbonitrile (1 g,3.4 mmol), 4-fluoro-2-methoxy-5-nitroaniline (0.7 g,3.7 mmol) and p-toluenesulfonic acid (0.7 g,3.7 mmol) were dissolved in 2-pentanol (40 mL) and the reaction stirred at 100℃overnight. Cooled to room temperature, water (50 mL) was added, extracted with dichloromethane (50 mL x 2), the organic phase dried over anhydrous sodium sulfate, filtered, dried, and the crude product purified by column chromatography (petroleum ether/ethyl acetate: 100/1-1/1-dichloromethane/ethyl acetate: 100/1-10/1) to give 4- (1-cyclopropyl-1H-indol-3-yl) -2- ((4-fluoro-2-methoxy-5-nitrophenyl) amino) pyrimidine-5-carbonitrile (1 g, 67%) as a brown solid.

And a third step of: preparation of 4- (1-cyclopropyl-1H-indol-3-yl) -2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) amino) pyrimidine-5-carbonitrile

4- (1-cyclopropyl-1H-indol-3-yl) -2- ((4-fluoro-2-methoxy-5-nitrophenyl) amino) pyrimidine-5-carbonitrile (0.4 g,0.9 mmol) was dissolved in acetonitrile (20 mL), potassium carbonate (0.37 g,2.7 mmol) and N1, N1, N2-trimethylethane-1, 2-diamine (0.11 g,1.1 mmol) were added and the reaction stirred at 80℃for 1 hour. Cooled to room temperature, the reaction solution was filtered and the filtrate was dried by spin to give crude 4- (1-cyclopropyl-1H-indol-3-yl) -2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) amino) pyrimidine-5-carbonitrile (0.48 g, yield: 100% trude) as a yellow solid.

Fourth step: preparation of 2- ((5-amino-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) -4- (1-cyclopropyl-1H-indol-3-yl) pyrimidine-5-carbonitrile

4- (1-cyclopropyl-1H-indol-3-yl) -2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) amino) pyrimidine-5-carbonitrile (0.48 g,0.97 mmol) was dissolved in ethanol (20 mL), saturated sodium bicarbonate solution (10 mL) and iron powder (0.54 g,9.7 mmol) were added and the reaction stirred at 80℃for 2 hours. Cooled to room temperature, the reaction solution was filtered, the filtrate was extracted with dichloromethane (20 mL. Times.2), the organic phase was dried over anhydrous sodium sulfate, filtered and dried by spin-drying to give 2- ((5-amino-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) -4- (1-cyclopropyl-1H-indol-3-yl) pyrimidine-5-carbonitrile (0.4 g, yield: 88%) as a yellow solid.

Fifth step: preparation of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide

2- ((5-amino-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) -4- (1-cyclopropyl-1H-indol-3-yl) pyrimidine-5-carbonitrile (0.4 g,0.8 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to 0deg.C, triethylamine (0.12 g,1.2 mmol) was added, 3-chloropropionyl chloride (0.12 g,0.97 mmol) was added and the reaction stirred at 0deg.C for 1 hour. 3M sodium hydroxide solution (3 mL) was added and the reaction stirred at room temperature for 1 hour. Water (30 mL) was added and extracted with dichloromethane (30 mL x 2), the organic phase dried over anhydrous sodium sulfate, filtered, and dried by spin-on, and the crude product was purified by prep-TLC (dichloromethane/MeOH: 20/1) to give N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (0.15 g, yield: 34%) as a yellow solid.

MS m/z(ESI):551.4[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ10.08(s,1H),9.42(s,1H),8.68(s,1H),8.49-8.47(m,2H),7.76(s,1H),7.61(d,J＝8.0Hz,1H),7.30-7.26(m,2H),6.81(s,1H),6.39(s,2H),5.69-5.67(m,1H),3.89(s,3H),3.48-3.44(m,1H),2.93-2.91(m,2H),2.73(s,3H),2.35-2.30(m,8H),1.17-1.11(m,4H).

Example 2

N- (5- ((5-cyano-4- (1- (oxetan-3-yl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide

The first step: preparation of 3- (5-bromo-2-chloropyrimidin-4-yl) -1H-indole

Indole (5.0 g,54.86 mmol) was dissolved in 2-methyltetrahydrofuran (50 mL) in an ice bath, then methylmagnesium bromide (3.0M 2-methyltetrahydrofuran solution, 18.3mL,54.86 mmol) was added dropwise, the internal temperature was maintained at 30℃or less, and after the completion of the dropwise addition, the mixture was stirred at room temperature for 30 minutes. Then, a solution of 2, 4-dichloro-5-bromopyrimidine in 2-methyltetrahydrofuran (5.0 g,21.94mmol,10mL of solvent) was added dropwise, and after the completion of the addition, the reaction was stirred at room temperature for half an hour, then heated to 70℃and reacted for 14 hours. Cooling to room temperature, pouring the reaction solution into saturated ammonium chloride aqueous solution, separating out solid, and filtering to obtain solid. The resulting solid was resuspended in water, sonicated, filtered to give a solid, which was dried to give the product 3- (5-bromo-2-chloropyrimidin-4-yl) -1H-indole (4.0 g, yield: 59%, yellow solid).

MS m/z(ESI):308.0[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ12.21(s,1H),8.86(s,1H),8.80(s,1H),8.46(d,J＝7.2Hz,1H),7.55(d,J＝7.2Hz,1H),7.30-7.23(m,2H).

And a second step of: preparation of 5-bromo-N- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (1H-indol-3-yl) pyrimidin-2-amine

3- (5-bromo-2-chloropyrimidin-4-yl) -1H-indole (0.50 g,1.62 mmol), 4-fluoro-2-methoxy-5-nitroaniline (0.33 g,1.78 mmol) and p-toluenesulfonic acid (0.34 g,1.78 mmol) were dissolved in 2-pentanol (25 mL) and reacted at 100℃for 14H. Cooling to room temperature, neutralizing the reaction solution with saturated sodium bicarbonate solution, stirring at room temperature for 20 min, filtering, washing the filter cake with 2-pentanol, finally washing with petroleum ether, and drying the filter cake to obtain 5-bromo-N- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (1H-indol-3-yl) pyrimidin-2-amine (0.40 g,54%, earthy yellow solid).

MS m/z(ESI):458.0，460.0[M+H] ⁺ .

And a third step of: preparation of N1- (5-bromo-4- (1H-indol-3-yl) pyrimidin-2-yl) -N4- (2- (dimethylamino) ethyl) -2-methoxy-N4-methyl-5-nitrobenzene-1, 4-diamine

5-bromo-N- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (1H-indol-3-yl) pyrimidin-2-amine (0.40 g,0.87 mmol) was dissolved in acetonitrile (20 mL), potassium carbonate (0.36 g,2.61 mmol) and N1, N1, N2-trimethylethane-1, 2-diamine (0.10 g,0.96 mmol) were added and the reaction stirred at 80℃for two hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered and spin-dried to give N1- (5-bromo-4- (1H-indol-3-yl) pyrimidin-2-yl) -N4- (2- (dimethylamino) ethyl) -2-methoxy-N4-methyl-5-nitrobenzene-1, 4-diamine (0.40 g, yield: 87%, red solid).

MS m/z(ESI):540.2，542.2[M+H] ⁺ .

Fourth step: preparation of N1- (5-bromo-4- (1- (oxetan-3-yl) -1H-indol-3-yl) pyrimidin-2-yl) -N4- (2- (dimethylamino) ethyl) -2-methoxy-N4-methyl-5-nitrobenzene-1, 4-diamine

N1- (5-bromo-4- (1H-indol-3-yl) pyrimidin-2-yl) -N4- (2- (dimethylamino) ethyl) -2-methoxy-N4-methyl-5-nitrobenzene-1, 4-diamine (0.30 g,0.56 mmol), cesium carbonate (0.13 g,0.72 mmol) and 3-iodo-oxetan ring (0.36 g,1.11 mmol) were dissolved in N, N-dimethylformamide (8 mL), reacted at 110℃for 1.5 hours with microwaves, and cooled to room temperature. The reaction solution was diluted with ethyl acetate, filtered, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin-drying, and the crude product was isolated by plate separation with silica gel (dichloromethane: methanol: 20:1) to give N1- (5-bromo-4- (1- (oxetan-3-yl) -1H-indol-3-yl) pyrimidin-2-yl) -N4- (2- (dimethylamino) ethyl) -2-methoxy-N4-methyl-5-nitrobenzene-1, 4-diamine (0.12 g, yield: 36% as a red solid).

MS m/z(ESI):596.0[M+H] ⁺ .

Fifth step: preparation of 2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) amino) -4- (1- (oxetan-3-yl) -1H-indol-3-yl) pyrimidine-5-carbonitrile

N1- (5-bromo-4- (1- (oxetan-3-yl) -1H-indol-3-yl) pyrimidin-2-yl) -N4- (2- (dimethylamino) ethyl) -2-methoxy-N4-methyl-5-nitrobenzene-1, 4-diamine (0.12)g,0.20mmol)，Pd ₂ (dba) ₃ (18.4 mg,0.02 mmol), X-Phos (19 mg,0.04 mmol), zinc cyanide (23.5 mg,0.20 mmol) and zinc powder (13 mg,0.20 mmol) were dissolved in N, N-dimethylacetamide (3 mL), replaced with nitrogen and reacted at 110℃for 1.5 hours under microwaves. Cooled to room temperature, filtered, the solid washed with ethyl acetate and the organic phase concentrated under reduced pressure and the crude product was isolated (dichloromethane: methanol: 20:1) using a preparative plate to give 2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) amino) -4- (1- (oxetan-3-yl) -1H-indol-3-yl) pyrimidine-5-carbonitrile (0.096 g, yield: 88%, yellow solid).

MS m/z(ESI):543.1[M+H] ⁺ .

Sixth step: preparation of 2- ((5-amino-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) -4- (1- (oxetan-3-yl) -1H-indol-3-yl) pyrimidine-5-carbonitrile

2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) amino) -4- (1- (oxetan-3-yl) -1H-indol-3-yl) pyrimidine-5-carbonitrile (0.12 g,0.22 mmol) was dissolved in ethanol (10 mL), then aqueous ammonium chloride (0.06 g,1.1mmol, water, 2 mL) and iron powder (0.12 g,2.2 mmol) were added and the reaction stirred at 80℃for 2 hours. The reaction solution was cooled to room temperature, filtered, the filter cake was washed with dichloromethane, the organic solvent was removed under reduced pressure, the residue was dissolved with dichloromethane and water, the aqueous phase was extracted with dichloromethane (20 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried by spin-on to give 2- ((5-amino-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) -4- (1- (oxetan-3-yl) -1H-indol-3-yl) pyrimidine-5-carbonitrile (0.095 g, yield: 83.8%, yellow oil).

MS m/z(ESI):513.2[M+H] ⁺ .

Seventh step: preparation of N- (5- ((5-cyano-4- (1- (oxetan-3-yl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide

2- ((5-amino-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) -4- (1- (oxetan-3-yl) -1H-indol-3-yl) pyrimidine-5-carbonitrile (0.075 g,0.146 mmol) was dissolved in dichloromethane (5 mL), cooled to 0 ℃, triethylamine (0.03 g,0.292 mmol) was added, and 3-chloropropionyl chloride (0.024 g,0.19 mmol) was added and the reaction stirred at 0℃for 1 hour. At the end of the reaction, the crude product was dried by spinning, dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered and dried by spinning. The crude product was dissolved in acetonitrile (5 mL) and then aqueous sodium hydroxide (0.058 g,1.46mmol, water, 0.5 mL) was added and reacted at 40℃for two hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin-drying to give N- (5- ((5-cyano-4- (1- (oxetan-3-yl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (0.04 g, yield: 48% as a yellow solid) as a crude product by preparative chromatography.

MS m/z(ESI):567.2[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ10.15-9.82(br,1H),9.45(s,1H),8.69(s,2H),8.55-8.38(br,1H)7.80(s,1H),7.61(d,J＝8.0Hz,1H),7.33-7.29(m,2H),6.78(s,1H),6.42-6.38(m,1H),5.72-5.66(m,2H),5.28-5.13(m,5H),3.90(s,3H),3.13-2.95(br,2H),2.74(s,3H),2.61-2.24(br,6H),1.85-1.53(m,2H).

Example 3

N- (5- ((5-cyano-4- (1-cyclopropyl-6-methoxy-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide

The preparation method of example 3 is described with reference to example 1.

MS m/z(ESI):581.4[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ10.04(s,1H),9.38(s,1H),8.66(s,1H),8.40-8.38(m,2H),7.71(s,1H),7.06(s,1H),6.92(s,1H),6.77(s,1H),6.42-6.38(m,1H),5.71-5.68(m,1H),3.91-3.89(m,6H),3.41-3.40(m,1H),3.10-2.90(m,3H),2.74(s,3H),2.70-2.30(m,8H),1.16-1.10(m,4H).

Example 4

N- (5- ((5-cyano-4- (1-cyclopropyl-6-fluoro-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide

The preparation method of example 4 is described with reference to example 1.

MS m/z(ESI):569.4[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ10.03–9.64(m,1H),9.48–9.26(m,1H),8.66(s,1H),8.54–8.33(m,2H),7.73(s,1H),7.12–6.92(m,1H),6.76(s,1H),6.38(d,J＝17.0Hz,1H),5.70(d,J＝11.4Hz,1H),3.90(s,3H),3.48–3.35(m,1H),3.18–2.98(m,2H),2.74(s,3H),2.71–2.31(m,6H),2.12–1.47(m,4H),1.22–1.02(m,4H).

Example 5

N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxypyridin-3-yl) acrylamide

The first step: preparation of 6-chloro-2-methoxypyridin-3-amine

6-chloro-2-methoxy-3-nitropyridine (5 g,26.6 mmol) was dissolved in ethanol (100 mL) and water (30 mL), ammonium chloride (7.0 g,133 mmol) was added, iron powder (7.5 g,133 mmol) was added in portions, and the reaction was stirred at 85℃for 2 hours. The reaction solution was cooled to room temperature, filtered through celite, and ethyl acetate (150 mL) and saturated brine (120 mL) were added to the filtrate, and the organic layer was separated, dried over anhydrous sodium sulfate, filtered and dried by spin-drying to give 6-chloro-2-methoxypyridin-3-amine (4 g, yield: 95%) as a brown solid.

MS m/z(ESI):159.1[M+H] ⁺ .

And a second step of: preparation of N- (6-chloro-2-methoxypyridin-3-yl) acetamide

6-chloro-2-methoxypyridin-3-amine (4.0 g,25.0 mmol) was dissolved in dichloromethane (100 mL), diisopropylethylamine (4.8 g,37.5 mmol) was added, cooled to 0deg.C, acetyl chloride (2.4 g,30.0 mmol) was added, and stirring was continued for 2 hours. The reaction solution was washed with 80mL of water, 80mL of 1N hydrochloric acid and 80mL of saturated brine, dried over anhydrous sodium sulfate, filtered and dried by spin to give N- (6-chloro-2-methoxypyridin-3-yl) acetamide (4.0 g, yield: 79%) as a brown solid.

MS m/z(ESI):201.1[M+H] ⁺ .

And a third step of: preparation of N- (6-chloro-2-methoxy-5-nitropyridin-3-yl) acetamide

6-chloro-2-methoxypyridin-3-amine (2.0 g,10.0 mmol) was dissolved in trifluoroacetic anhydride (20 mL), cooled to-10℃and fuming nitric acid (0.5 mL,10 mmol) was added dropwise and stirring was continued for 2 hours. Crushed ice was added to the reaction mixture, which was extracted with methylene chloride (50 mL), dried over anhydrous sodium sulfate, filtered and dried by spin to give N- (6-chloro-2-methoxy-5-nitropyridin-3-yl) acetamide (1.6 g, yield: 65%) as a brown solid.

MS m/z(ESI):244.1[M-H] ⁺ .

Fourth step: preparation of N- (6- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitropyridin-3-yl) acetamide

N- (6-chloro-2-methoxy-5-nitropyridin-3-yl) acetamide (1.6 g,6.5 mmol) was dissolved in acetonitrile (30 mL), N1, N2-trimethylethane-1, 2-diamine (1 g,9.8 mmol) was added and the reaction stirred at 80℃for 3 hours. The solvent was dried by spin-drying, and the crude product was purified by column chromatography (dichloromethane/methanol: 100/1-10/1) to give N- (6- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitropyridin-3-yl) acetamide (0.9 g, yield: 45%) as a brown solid.

MS m/z(ESI):312.1[M+H] ⁺ .

Fifth step: preparation of N2- (2- (dimethylamino) ethyl) -6-methoxy-N2-methyl-3-nitropyridine-2, 5-diamine

N- (6- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitropyridin-3-yl) acetamide (0.9 g,2.9 mmol) was dissolved in methanol (30 mL), concentrated hydrochloric acid (5 mL) and the reaction stirred at 60℃for 3 hours. The solvent was dried by spinning, methylene chloride (50 mL) and saturated sodium bicarbonate (50 mL) were added, stirring was carried out until no bubbles were separated, the organic layer was separated, dried over anhydrous sodium sulfate, filtered, and the crude product was purified by column chromatography (methylene chloride/methanol: 100/1 to 10/1) to give N2- (2- (dimethylamino) ethyl) -6-methoxy-N2-methyl-3-nitropyridine-2, 5-diamine (0.15 g, yield: 19%) as a brown solid.

MS m/z(ESI):270.1[M+H] ⁺ .

Sixth step: preparation of 4- (1-cyclopropyl-1H-indol-3-yl) -2- ((6- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitropyridin-3-yl) amino) pyrimidine-5-carbonitrile

N2- (2- (dimethylamino) ethyl) -6-methoxy-N2-methyl-3-nitropyridine-2, 5-diamine (0.11 g,0.41 mmol), 2-chloro-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidine-5-carbonitrile (0.12 g,0.41 mmol), tris (dibenzylideneacetone) dipalladium (0.18 g,0.2 mmol), x-phos (0.2 g,0.41 mmol), sodium t-butoxide (0.12 g,1.2 mmol) were dissolved in dioxane (5 mL), replaced with nitrogen and the reaction stirred at 140℃under microwaves for 1 hour. Cooled to room temperature, the reaction solution was filtered, and the filtrate was dried by spin-drying, and the crude product was isolated by prep-TLC (dichloromethane/methanol: 20/1) to give 4- (1-cyclopropyl-1H-indol-3-yl) -2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) amino) pyrimidine-5-carbonitrile (0.1 g, yield: 47%) as a yellow solid.

MS m/z(ESI):528.1[M+H] ⁺ .

Seventh step: preparation of 2- ((5-amino-6- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxypyridin-3-yl) amino) -4- (1-cyclopropyl-1H-indol-3-yl) pyrimidine-5-carbonitrile

4- (1-cyclopropyl-1H-indol-3-yl) -2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) amino) pyrimidine-5-carbonitrile (80 mg,0.15 mmol) was dissolved in methanol (10 mL), raney nickel (80 mg) and 85% hydrazine hydrate (90 mg,1.5 mmol) were added at 0deg.C and the reaction stirred at room temperature for 2 hours. The reaction solution was filtered, the filtrate was dried by spin-drying, water (15 mL) was added, extracted with dichloromethane (15 mL. Times.2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin-drying to give 2- ((5-amino-6- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxypyridin-3-yl) amino) -4- (1-cyclopropyl-1H-indol-3-yl) pyrimidine-5-carbonitrile (80 mg, yield: 100% crude) as a brown solid.

MS m/z(ESI):498.1[M+H] ⁺ .

Eighth step: preparation of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxypyridin-3-yl) acrylamide

2- ((5-amino-6- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxypyridin-3-yl) amino) -4- (1-cyclopropyl-1H-indol-3-yl) pyrimidine-5-carbonitrile (80 mg,0.16 mmol) was dissolved in dichloromethane (10 mL), cooled to 0 ℃, triethylamine (24 mg,0.24 mmol) was added, and 3-chloropropionyl chloride (25 mg,0.19 mmol) was added and the reaction stirred at 0℃for 1 hour. Water (10 mL) was added, extracted with dichloromethane (10 mL x 2), the organic phase dried over anhydrous sodium sulfate, filtered, dried by spin-drying, tetrahydrofuran (5 mL) was added, a solution of sodium hydroxide (64 mg,1.6 mmol) in water (0.5 mL) was added and the reaction stirred at 40℃overnight. Water (10 mL) was added and extracted with ethyl acetate (10 mL x 2), the organic phase dried over anhydrous sodium sulfate, filtered, and the dried, and the crude product was separated by prep-HPLC to give N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxypyridin-3-yl) acrylamide (0.9 mg, yield: 0.7%) as a yellow solid.

MS m/z(ESI):552.1[M+H] ⁺ .

Example 6

N- (5- ((5-cyano-4- (1-cyclopropyl-5-methoxy-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide

The preparation method of example 6 is described in example 1.

MS m/z(ESI):581.4[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ10.08–9.55(m,1H),9.42(s,1H),8.68(s,1H),8.44(s,1H),8.03(s,1H),7.76(s,1H),7.51(d,J＝8.6Hz,1H),6.97(d,J＝8.6Hz,1H),6.77(s,1H),6.39(d,J＝15.7Hz,1H),5.69(d,J＝10.5Hz,1H),3.89(s,6H),3.51–3.38(m,1H),3.03(s,2H),2.73(s,3H),2.65–2.18(m,6H),1.89–1.54(m,3H),1.23–1.04(m,4H).

Example 7

N- (5- ((5-cyano-4- (1-cyclopropyl-7-methoxy-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide

The preparation of example 7 is described in example 1.

MS m/z(ESI):581.3[M+H] ⁺ .

¹ H NMR(400MHz,Chloroform-d)δ10.32–9.79(m,1H),9.56–9.18(m,1H),8.80–8.55(m,1H),8.47–8.27(m,1H),8.24–7.97(m,1H),7.88–7.61(m,1H),7.22–7.04(m,1H),6.89–6.68(m,2H),6.56–6.21(m,2H),5.83–5.55(m,1H),4.20–3.77(m,7H),3.16–2.81(m,2H),2.73(s,3H),2.59–2.15(m,8H),1.19–1.02(m,4H).

Example 8

N- (5- ((5-cyano-4- (1-cyclopropyl-4-fluoro-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide

The preparation of example 8 is described in example 1.

MS m/z(ESI):569.2[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ10.22(s,1H),8.90(s,1H),8.75(s,1H),8.69(s,1H),8.27(s,1H),7.48(d,J＝7.6Hz,1H),7.28-7.23(m,1H),7.09(s,1H),6.92-6.87(m,1H),6.46-6.39(m,1H),6.30-6.26(m,1H),5.78(d,J＝9.6Hz,1H),3.84(s,3H),3.61-3.52(m,1H),2.96-2.92(m,2H),2.75(s,3H),2.37-2.29(m,2H),2.22(s,6H),1.16-1.04(m,4H).

Example 9

N- (5- ((5-cyano-4- (1-cyclopropyl-5-fluoro-6-methoxy-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide

The preparation method of example 9 is described in example 1.

MS m/z(ESI):599.2[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ10.06(s,1H),9.54(s,1H),8.66(s,1H),8.38(s,1H),8.32(s,1H),7.75–7.55(m,1H),7.27–7.25(m,1H),7.05(s,1H),6.41–6.34(m,1H),6.17(d,J＝16.9Hz,1H),5.72(d,J＝10.3Hz,1H),3.91(s,3H),3.72(s,3H),3.63–3.54(m,1H),2.90–2.88(m,2H),2.75(s,3H),2.63–2.56(m,1H),2.37–2.35(m,2H),2.21(s,5H),1.18–1.16(m,2H),1.04–0.93(m,2H).

Example 10

N- (5- ((5-cyano-4- (6-methoxy-1- (oxetan-3-yl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide

The preparation method of example 10 is described with reference to example 2.

MS m/z(ESI):597.2[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ10.29-10.22(br,1H),9.42(s,1H),8.67(s,1H),8.59(m,1H),8.34(s,1H),7.77(s,1H),7.08(s,1H),6.97-6.88(br,1H),6.79(s,1H),6.39(d,J＝14.4Hz,1H),5.72-5.69(m,1H),5.61-5.58(m,1H),5.20(d,J＝6.4Hz,4H),3.90(s,6H),3.06-2.84(br,3H),2.74(s,3H),2.50-2.16(br,6H),1.69-1.50(br,2H).

2.Biological test evaluation

The invention is further illustrated below in conjunction with test examples, which are not meant to limit the scope of the invention.

1. Testing of enzymology experiments

Test example 1 determination of the inhibition of EGFR 20 exon insertion mutant kinase Activity by Compounds of the invention

The purpose of the experiment is as follows: the purpose of this test example was to measure the ability of a compound to inhibit EGFR 20 exon insertion mutant kinase activity.

Experimental instrument: centrifuge (Eppendorf 5810R), microplate reader (BioTek Synergy H1), pipettor (Eppendorf & Rainin)

The experimental method comprises the following steps: the inhibition activity of the compounds on EGFR 20 exon insertion mutant kinase was studied by the TR-FRET (time resolved fluorescence resonance energy transfer) method. The experiment was developed in 384 well plates and assay buffers were prepared (50mM HEPES,1mM EGTA,10mM MgCl) ₂ 2mM DTT,0.01%Tween-20) using experimental protocolsThe compound is diluted to different concentrations by gradient, 2.5 mu L of each well is added into 384 well plates, 2.5 mu L of diluted EGFR kinase solution (0.001-0.5 nM) is added, incubation is carried out for 10 minutes at room temperature, 5 mu L of ULIGHT-poly GT/ATP mixed solution is added, incubation is carried out for 30 minutes to 60 minutes at room temperature, 5 mu L of EDTA termination reaction and 5 mu L of Eu marked antibody detection solution are added, incubation is carried out for 1 hour at room temperature, and the fluorescence signal value of 665nM of each well is measured by an enzyme-labelling instrument.

The experimental data processing method comprises the following steps:

the inhibition ratio ((positive control Kong Zhi-sample Kong Zhi)/(positive control Kong Zhi-negative control Kong Zhi))) was calculated 100% using fluorescence signal values at 665nm, and the concentration and inhibition ratio were fitted to a non-linear regression curve using Graphpad Prism software to give IC ₅₀ Values, specific data are shown in table 2.1 below:

table 2.1 Compounds IC for EGFR 20 exon insertion mutant kinase inhibitory Activity ₅₀

Conclusion of experiment:

the compound of the embodiment of the invention has better inhibition effect in EGFR 20 exon insertion mutation kinase activity inhibition experiments.

Test example 2 determination of the inhibition of EGFR wild type kinase Activity by Compounds of the present invention

The purpose of the experiment is as follows: the purpose of this test example was to measure the ability of a compound to inhibit EGFR wild-type kinase activity.

The experimental method comprises the following steps: the inhibition activity of the compounds on EGFR wild type kinase was studied in this experiment using the TR-FRET (time resolved fluorescence resonance energy transfer) method. The experiment was developed in 384 well plates and assay buffers were prepared (50mM HEPES,1mM EGTA,10mM MgCl) ₂ ，2mM DTT，0.01％Tween-20), the compounds were diluted in gradient to different concentrations using assay buffer, 2. Mu.L per well was added to 384 well plates, 4. Mu.L of diluted EGFR kinase solution (0.001-0.5 nM) was added, incubated at room temperature for 10 min, 4. Mu.L of ULIght-poly GT/ATP mixed solution was added, incubated at room temperature for 30 min to 60 min, 5. Mu.L of EDTA termination reaction and 5. Mu.L of Eu-labeled antibody detection solution were added, and incubated at room temperature for 1 hour, and the enzyme-labeled instrument determined 665nM fluorescent signal values for each well.

The experimental data processing method comprises the following steps:

the inhibition ratio ((positive control Kong Zhi-sample Kong Zhi)/(positive control Kong Zhi-negative control Kong Zhi))) was calculated 100% using fluorescence signal values at 665nm, and the concentration and inhibition ratio were fitted to a non-linear regression curve using Graphpad Prism software to give IC ₅₀ Values, specific data are shown in table 2.2 below:

compounds of table 2.2 IC for EGFR wild type kinase inhibitory activity ₅₀

Conclusion of experiment:

from the above scheme, the compounds of the embodiment of the invention have smaller inhibition effect in EGFR wild type kinase inhibition test.

Test example 3 determination of proliferation inhibition by Compounds of the invention on Ba/F3EGFR mutant cell lines and A431 cell lines

The purpose of the experiment is as follows: the purpose of this test example was to measure the inhibition of the proliferation activity of compounds on the Ba/F3EGFR mutant cell line and the A431 cell line.

Experimental instrument: enzyme label instrument (BioTek Synergy H1), pipettor (Eppendorf & Rainin)

The experimental method comprises the following steps:

culturing Ba/F3EGFR mutant cells to proper density, collecting cells, adjusting the cells to proper cell concentration with complete culture medium, spreading cell suspension in 96-well plate with 90 μl of each well, placing into 37 deg.C, 5% CO ₂ Incubator labelPreparing compound solutions with different concentrations using DMSO and culture medium, setting solvent control, adding compound solution into 96-well plate, adding 10 μl of each well, adding 37deg.C, 5% CO ₂ After the culture is continued for 72 to 144 hours in the incubator, cellTiter-Glo solution is added, the mixture is uniformly mixed by shaking, and then incubated for 10 minutes in a dark place, and the reading is carried out by using a BioTek Synergy H1 enzyme label instrument.

The experimental method comprises the following steps:

culturing A431 cells to proper density, collecting cells, adjusting cell concentration to proper cell concentration with complete culture medium, spreading cell suspension in 96-well plate with 90 μl of each well, placing into 37deg.C, 5% CO ₂ Adhering an incubator overnight, preparing compound solutions with different concentrations by using DMSO and a culture medium, setting a solvent control, adding the compound solutions into a 96-well plate, adding 10 mu L of each well, and placing into 37 ℃ and 5% CO ₂ After continuous incubation in an incubator for 72H, cellTiter-Glo solution was added, mixed well with shaking, incubated for 10 min in the dark, and read with a BioTek Synergy H1 microplate reader.

The experimental data processing method comprises the following steps:

calculating inhibition rate by using the luminous signal value, and performing nonlinear regression curve fitting on the concentration and inhibition rate by using Graphpad Prism software to obtain the IC ₅₀ Values, specific data are shown in table 2.3 below:

table 2.3 Compounds IC for proliferation inhibition Activity of Ba/F3EGFR mutant cell lines and A431 cell lines ₅₀

Conclusion of experiment:

according to the scheme, the compound has good inhibition effect in the inhibition test of the proliferation activity of the Ba/F3EGFR mutant cells, has poor inhibition effect on A431 cells, and the comparison data show that the series of examples have high selectivity on the inhibition of the proliferation activity of the Ba/F3EGFR mutant cells.

Test example 4 in vivo pharmacodynamics study of the Compounds of the invention on the model of murine primordial B cell Ba/F3EGFR-D770-N771 ins-SVD transplantation tumor

4.1 The purpose of the experiment is as follows:

the in vivo efficacy of the compounds on the mouse primordial B cell Ba/F3EGFR-D770-N771 ins-SVD transplantation tumor model was evaluated.

4.2 Experimental instrument and reagents:

4.2.1 Instrument:

1. biological safety cabinet (BSC-1300 II A2, shanghai Bo Xie medical equipment factory)

2. Ultra clean bench (CJ-2F, von Willebrand laboratory animal Co., ltd.)

3、CO ₂ Incubator (Thermo-311, thermo)

4. Centrifuge (Centrifuge 5720R, eppendorf)

5. Full-automatic cell counter (Countess II, life Technologies)

6. Vernier caliper (CD-6' AX, sanfeng Japan)

7. Cell culture bottle (T75/T225, corning)

8. Electronic balance (CPA 2202S, sidoris)

9. Electronic balance (BSA 2202S-CW, sidoris)

4.2.2 Reagent:

1. RPMI-1640 medium (22400-089, gibco)

2. Fetal Bovine Serum (FBS) (10099-141C, gibco)

3. Phosphate Buffered Saline (PBS) (10010-023, gibco)

4. Tween 80 (30189828, national medicine)

5. Sodium carboxymethyl cellulose (30036365, national medicine reagent)

4.3 Experimental operation and data processing:

4.3.1 Animals

BALB/c nude mice, 6-8 weeks, male, purchased from Shanghai Sipule-BiKai laboratory animal Co.

4.3.2 Cell culture and cell suspension preparation

a, taking out a strain of Ba/F3EGFR-D770-N771 ins-SVD cells from a cell bank, resuscitating the cells by using RPMI-1640 culture medium (RPMI-1640+10% FBS), placing the resuscitated cells in a cell culture flask (marked with cell types, dates, names of cultured people and the like on the flask wall), and placing the resuscitated cells in CO ₂ Culturing in incubator (temperature of incubator is 37deg.C, CO) ₂ Concentration 5%).

b, passaging once every three days, and placing the cells in CO after passaging ₂ Culturing in an incubator. This process is repeated until the number of cells meets the in vivo pharmacodynamic requirements.

c, collecting cultured cells, counting with a fully automatic cell counter, and re-suspending the cells with PBS according to the counting result to obtain a cell suspension (density 2×10) ⁷ /mL), placed in an ice bin for use.

4.3.3 Cell seeding

a, marking nude mice with disposable universal ear tags for large and small mice before inoculation

b, mixing the cell suspension during inoculation, extracting 0.1-1mL of the cell suspension by using a 1mL syringe, removing bubbles, and then placing the syringe on an ice bag for standby.

c, the left hand is kept to be a nude mouse, the right shoulder position (inoculation position) of the right back of the nude mouse is sterilized by 75% alcohol, and the inoculation is started after 30 seconds.

d, the test nude mice were inoculated sequentially (0.1 mL cell suspension was inoculated per mouse).

4.3.4 Tumor-bearing mice are metered, grouped and dosed

a, tumor is measured on the 8 th to 14 th days after inoculation according to the growth condition of the tumor, and the tumor size is calculated.

Tumor volume calculation: tumor volume (mm) ³ ) =length (mm) ×width (mm)/2

b, grouping according to the weight of the tumor-bearing mice and the tumor size by adopting a random grouping method, wherein 5 mice are grouped in each group.

c, according to the grouping result, starting to administer the test drug (administration mode: oral administration; administration frequency: 1 time/day; administration period: 14 days; vehicle: 0.5% CMC/1% Tween 80).

d, tumor twice weekly after starting to administer test drug, and weighing.

e, euthanized animals after the end of the experiment.

f, processing the data by Excel and other software.

Calculation of compound tumor inhibition rate TGI (%):

TGI (%) = [ (1-average tumor volume at the end of treatment group administration)/average tumor volume at the end of treatment of solvent control group ] ×100%.

TGI is more than or equal to 60%, and the compound is effective in the model;

TGI <60%, compounds were ineffective in this model.

4.4 The test results are shown in Table 2.4 below:

drug efficacy parameters of the compounds of Table 2.4 in mice with transplantations

Remarks: the data in brackets indicate that this example corresponds to tumor volume at the time corresponding to Vehicle QD x 2w group (i.e., control group).

4.5, experimental results

The above data show: after 14 days of continuous oral dosing, AZD9291 40mpk was not effective in the Ba/F3EGFR-D770-N771 ins-SVD efficacy model, whereas example 1 was effective at an equivalent dose of 40 mpk.

Test example 5, plasma stability test protocol

5.1 Purpose of experiment

The purpose of this experiment was to examine the stability of the compounds of the examples in mouse, rat and human plasma.

5.2 Experimental procedure

5.2.1 Solution preparation

1. Plasma preparation: after whole blood collection of animals or humans, the whole blood is put into a test tube containing an anticoagulant, centrifuged at 3500rpm for 10min, and the upper pale yellow plasma is collected.

2.1mM test compound (M/M/V=C), compound was weighed and stock solution was prepared with DMSO.

5.2.2 The experimental procedure is as follows:

1. 398. Mu.L of plasma, 2. Mu.L of 1mM compound (test compound) were added in sequence to a 96-well plate and incubated at 37 ℃.

2. At 0, 15, 30, 60, 120min, 50. Mu.L each was removed and 400. Mu.L of methanol stop solution containing an internal standard was added.

3. After centrifugation (3220 g,30 min), 50. Mu.L of supernatant was taken and 50. Mu.L of DDH was added ₂ LC-MS/MS sample injection after O dilution.

5.3 Chromatographic conditions

Instrument: shimadzu Shimadzu LC-30AD (Nexera X2)

Chromatographic column: XSelectron HSS T3C ₁₈ (50 x 2.1mm,2.5 μm particle size);

mobile phase:

a: a 0.1% formic acid solution in water,

b: acetonitrile containing 0.1% of formic acid,

0～0.3min：95％A→95％A；

0.3～0.8min：95％A→5％A；

flow rate: 0.5mL/min;

run time: 2.0min;

sample injection volume: 3. Mu.L.

5.4 Mass spectrometry conditions

Instrument:

API4000 type liquid chromatography-mass spectrometer (AB company of America);

the ion source is an electrospray ionization source (ESI);

drying gas (N) ₂ ) The temperature is 500 ℃;

the electrospray voltage is 5500V;

the detection mode is positive ion detection;

the scanning mode is a selective reaction monitoring (MRM) mode;

table 2.5 example compound 1 plasma stability results

5.5 Conclusion of experiment:

the above data show that compound 1 of the present invention has high plasma stability and small species differences.

3. Salt of compound and study of crystal forms thereof

As is well known to those of ordinary skill in the art, the compounds of the above examples demonstrate significant pharmacological activity in inhibiting EGFR and/or HER2 20 exon insertion mutants, and the pharmaceutically acceptable salts thereof tend to have the same pharmacological activity. Based on this, the inventors further studied the physicochemical properties of the salt forms and crystal forms of the corresponding compounds, but the preparation and characterization of the specific salt forms or crystal forms described below do not represent limitations on the scope of the present invention, and those skilled in the art can obtain more salt forms and crystals of the compounds of the present invention based on the present invention through conventional salt formation or crystallization means, which are all schemes protected by the present invention. The method comprises the following steps:

1. experimental instrument

1.1 Some parameters of the physicochemical detecting instrument

2. Study of Compound salt form

2.1 The purpose of the experiment is as follows:

screening the salt form of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide.

2.2 The experimental steps are as follows:

(1) Apparatus and device

Name of the name	Model number	Source
Analytical balance	XA105	METTLER TOLEDO
Ultrasonic cleaning instrument	SK5200LHC	Shanghai department ultrasonic guide instrument
Pipetting gun	Eppendorf(5mL,100μL)	Eppendorf

(2) Salt formation step

1) Dissolving or suspending the mixture into salt crystals by using ethyl acetate as a solvent

N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide free base form A10 mg was weighed, 200 μl of ethyl acetate was added, and different counter ion acid solutions (base: acid=1:1.2 molar reaction ratio) were added respectively to react at 50deg.C, with the following results:

remarks: with respect to N/A representation undetected

2) Dissolving or suspending toluene as solvent to form salt

N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide free base form A10 mg was weighed, 200 μl of toluene was added, and different counter ion acid solutions (base: acid=1:1.2 molar reaction ratio) were added respectively to react at 50deg.C, with the following results:

remarks: with respect to N/A representation undetected

As mentioned above, one skilled in the art can obtain more pharmaceutically acceptable salts using conventional methods based on the present invention.

In addition, those skilled in the art can refer to the above-described methods for preparing N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide salts, and prepare other compositions comprising N- (5- ((5-cyano-4- (6-methoxy-1- (oxetan-3-yl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide, N- (5- ((5-cyano-4- (1-cyclopropyl-5-fluoro-6-methoxy-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide, pharmaceutically acceptable salts of other compounds of the invention, including N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) -5- (oxazol-2-yl) pyrimidin-2-yl) amino) phenyl) acrylamide.

3. Crystal form study of Compound salt

3.1 Crystal form study of salt of compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide

3.1.1 The purpose of the experiment is as follows:

screening the salt of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide in crystalline form.

3.1.2 The experimental steps are as follows:

1) Apparatus and device

Name of the name	Model number	Source
Analytical balance	BSA224S-CW	Sartorius
Ultrasonic cleaning instrument	SK5200LHC	Shanghai department ultrasonic guide instrument
Pipetting gun	Eppendorf(50mL,1000μL)	Eppendorf

2) Investigation of the salt Crystal form

(1) Dissolving out or suspending into salt crystallization by using acetone and acetonitrile as solvents

N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide free base form A10 mg is weighed, 200 μl of acetone or acetonitrile is added, and different counter ion acid solutions (molar reaction ratio of alkali: acid=1:1.2) are respectively added for reaction at 50 ℃, and the result is as follows:

remarks: the product was shown to be an oil with respect to N/A and was not further characterized

(2) Dissolving or suspending into salt crystallization by using methanol as solvent

N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide free base form A10 mg is weighed, 200 μl of methanol is added, and different counter ion acid solutions (molar reaction ratio of alkali: acid=1:1.2) are respectively added for reaction at 50 ℃, and the following results are obtained:

(3) Dissolving or suspending into other solvents such as 2-methyl-tetrahydrofuran to form salt crystal

N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidine-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide free base form A10 mg is weighed, 200 mu L of 2-methyl-tetrahydrofuran, ethanol and anisole are respectively added as reaction solvents, and different counter ionic acid liquids or solids (molar reaction ratio of alkali: acid=1:1.2) are added according to the molar ratio to react at 50 ℃ to obtain the following results:

3.1.3 Experimental results

Through a salt crystal form screening experiment, the hydrochloride, hydrobromide, p-toluenesulfonate and benzoyl glycinate are most advantageous according to the salt form crystallinity and the difficulty of crystallization process.

3.2 Crystalline form screening of salts of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide

3.2.1 The purpose of the experiment is as follows:

screening a crystalline form of a salt of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide.

3.2.2 The experimental steps are as follows:

(1) Apparatus and device

(2) Operating program

I. Preparation of the free base form A of the Compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide

66.0g of 4- (1-cyclopropyl-1H-indol-3-yl) -2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) amino) pyrimidine-5-carbonitrile, and 660mL of tetrahydrofuran were added to a 2L three-necked flask; palladium on carbon (6.6 g), N ₂ Bubbling under the liquid surface for half an hour; hydrogen is replaced for 3 times, heated to 35-40 ℃ for reaction for 20-24 hours, filtered, filter cake is washed by tetrahydrofuran (100 mL), and the filtration is completed ₂ Protecting filtrate, cooling to 0-5deg.C, and adding triethylamine (12.6 g); 3-Chloropropionyl chloride (23.7 g) in tetrahydrofuran (120 mL) was added dropwise at 0-5deg.C for about 45 min; the reaction was maintained at 0-5℃for 2-3 hours, filtered, and the filter cake was washed with tetrahydrofuran (100 mL) followed by rinsing with 100mL of N-heptane to give N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) 3-chloropropionamide hydrochloride (98.9 g, yield 100%).

N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) 3-chloropropionamide hydrochloride 50.0g, THF 420mL was added to a 2L three-necked flask and stirred; 42.0g of potassium hydroxide solution 42mL is added dropwise, after the dropwise addition is completed for about 10min, the mixture is stirred for 30min at room temperature; heating to 35-40 ℃ for reaction for 1h, and completely reacting the raw materials; cooling to room temperature, adding 500mL of water, stirring for 10 minutes, standing for layering, reserving an organic phase, and extracting a water phase with 300mL of 2-methyltetrahydrofuran; the organic phases were combined and washed with 200mL of water and 200mL of saturated brine in this order; 2.5g of active carbon and 25g of anhydrous sodium sulfate are added into the organic phase, and the mixture is stirred for 1h at room temperature (20+/-5 ℃); filtering, concentrating the filtrate to obtain yellow solid of about 70g, adding 150mL of 2-methyltetrahydrofuran, heating to 80 ℃ for refluxing, heating and stirring for 1 hour, and naturally cooling to room temperature; ice bath (0-5 ℃) cooling, stirring continued for 1 hour, filtering, washing the filter cake with 2-methyltetrahydrofuran (50 ml) to give the target product N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide crystalline form a (24.0 g, 69.7% yield), which was detected and analyzed with an XRPD pattern as shown in figure 32.

1) Preparation of hydrochloride form A

10mg of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidine-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide free base crystal form A is weighed, 200 mu L of acetonitrile is added, heating and stirring are carried out at 50 ℃, 22 mu L1.0M hydrochloric acid in methanol solution is slowly added into the system, a large amount of solid is precipitated after dissolution, and vacuum drying is carried out after centrifugation, so as to obtain hydrochloride crystal form A. A detected analysis, having an XRPD pattern as shown in figure 1, a DSC pattern as shown in figure 2, and a TGA pattern as shown in figure 3.

2) Preparation of hydrobromide form A

10mg of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidine-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide free base form A is weighed, 200 mu L of acetone is added, heating and stirring are carried out at 50 ℃, 22 mu L1.0M hydrobromic acid in methanol is slowly added into the system, a large amount of solid is precipitated after dissolution, and the mixture is centrifuged and dried in vacuum to obtain hydrobromide form A. A detected analysis, having an XRPD pattern as shown in figure 4, a DSC pattern as shown in figure 5, and a TGA pattern as shown in figure 6.

3) Preparation of p-toluenesulfonate form A

10mg of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidine-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide free base form A is weighed, 200 mu L of ethyl acetate is added, heating and stirring are carried out at 50 ℃, 22 mu L1.0M of methanol solution of p-toluenesulfonic acid is slowly added into the system, a large amount of solid is precipitated after dissolving, and the solution is centrifuged and dried in vacuum to obtain p-toluenesulfonate form A. A detected analysis, having an XRPD pattern as shown in figure 7, a DSC pattern as shown in figure 8, and a TGA pattern as shown in figure 9.

4) Preparation of sulfate form A

10mg of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidine-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide free base crystal form A is weighed, 200 mu L of ethyl acetate is added, heating and stirring are carried out at 50 ℃, 22 mu L1.0M sulfuric acid in methanol is slowly added into the system, a large amount of solid is precipitated after oil formation, and the sulfate crystal form A is obtained after centrifugation and vacuum drying. It has an XRPD pattern as shown in figure 10, analyzed by detection.

5) Preparation of fumarate salt form A

10mg of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidine-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide free base form A is weighed, 200 mu L of methanol is added, heating and stirring are carried out at 50 ℃, 88 mu L0.25M fumaric acid in ethanol solution is slowly added into the system, a large amount of solids are precipitated after dissolution, and the mixture is centrifuged and dried in vacuum to obtain fumarate salt form A. It has an XRPD pattern as shown in figure 11, as analyzed by detection.

6) Preparation of oxalate Crystal form A

10mg of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidine-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide free base crystal form A is weighed, 200 mu L of toluene is added, heating and stirring are carried out at 50 ℃, 22 mu L1.0M oxalic acid in methanol is slowly added into the system, a large amount of solid is precipitated after dissolving, and the oxalate crystal form A is obtained after centrifugation and vacuum drying. A detected analysis, having an XRPD pattern as shown in figure 12.

7) Preparation of benzoylglycinate form A

10mg of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidine-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide free base form A is weighed, 200 mu L of toluene is added, heating and stirring are carried out at 50 ℃, 110 mu L0.2M benzoyl glycine ethanol solution is slowly added into the system, a large amount of solids are precipitated after dissolution, and after centrifugation, vacuum drying is carried out, thus obtaining benzoyl glycine salt form A. It has an XRPD pattern as shown in figure 13, as analyzed by detection.

8) Preparation of benzoylglycinate form B

10mg of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidine-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide free base crystal form A is weighed, 200 mu L of 2-methyl-tetrahydrofuran is added, heating and stirring are carried out at 50 ℃, 110 mu L0.2M benzoyl glycine ethanol solution is slowly added into the system, a large amount of solids are separated out after solution, and the mixture is centrifuged and dried in vacuum to obtain benzoyl glycine salt crystal form B. It has an XRPD pattern as shown in figure 14, analyzed by detection.

9) Preparation of benzoylglycinate form C

10mg of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide as free base form A was weighed, 200. Mu.L of 0.11M benzoyl glycine in 2-methyl-tetrahydrofuran was slowly added to the system and heated and stirred at 50℃until the suspension turned from yellow to white, and after centrifugation, the suspension was dried in vacuo to give benzoyl glycine salt form C. It has an XRPD pattern as shown in figure 15, as analyzed by detection.

10 Preparation of benzoylglycinate form D

10mg of benzoyl glycinate crystal form C is weighed, 100 mu L of methanol is added into the system, pulping is carried out for 1 week at 50 ℃, and vacuum drying is carried out after centrifugation, thus obtaining benzoyl glycinate crystal form D. A detected analysis having an XRPD pattern as shown in figure 16, a DSC pattern as shown in figure 2917, and a TGA pattern as shown in figure 3018.

11 Preparation of benzoylglycinate form E

10mg of benzoyl glycinate crystal form C is weighed, 100 mu L of acetone is added into the system, pulping is carried out for 1 week at 25 ℃, and vacuum drying is carried out after centrifugation, thus obtaining benzoyl glycinate crystal form E. It has an XRPD pattern as shown in figure 19, analyzed by detection.

12 Preparation of benzoylglycinate form F

10mg of benzoyl glycinate crystal form C is weighed, 100 mu L of dichloromethane is added into the system, pulping is carried out for 1 week at 25 ℃, and vacuum drying is carried out after centrifugation, thus obtaining benzoyl glycinate crystal form F. It has an XRPD pattern as shown in figure 20, as analyzed by detection.

13 Preparation of phosphate form A

10mg of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidine-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide free base crystal form A is weighed, 200 mu L of ethyl acetate is added, heating and stirring are carried out at 50 ℃, 22 mu L1.0M of phosphoric acid in methanol is slowly added into the system, a small amount of solid is precipitated after oil formation, and vacuum drying is carried out after centrifugation, thus obtaining the phosphate crystal form A. It has an XRPD pattern as shown in figure 21, as analyzed by detection.

14 Preparation of maleate form A

10mg of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide free base form A is weighed, 200 mu L of ethyl acetate is added, the mixture is heated and stirred at 50 ℃, 22 mu L1.0M maleic acid in methanol is slowly added into the system, the mixture is suspended, stirred overnight, centrifuged and dried in vacuum to obtain maleate form A. It has an XRPD pattern as shown in figure 22, as analyzed by detection.

15 Preparation of maleate form B

10mg of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidine-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide free base crystal form A is weighed, 200 mu L of toluene is added, heating and stirring are carried out at 50 ℃, 22 mu L1.0M maleic acid in methanol is slowly added into the system, a large amount of solid is precipitated after dissolution, and the mixture is centrifuged and dried in vacuum to obtain maleate crystal form B. It has an XRPD pattern as shown in figure 23, analyzed by detection.

16 Preparation of maleate form C

20mg of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide free base form A is weighed, 200 mu L of toluene is added, heating and stirring are carried out at 50 ℃, 44 mu L1.0M of maleic acid in methanol is slowly added into the system, a large amount of solid is precipitated after dissolution, and the mixture is centrifuged and dried in vacuum to obtain maleate form C. It has an XRPD pattern as shown in figure 24, as analyzed by detection.

17 Preparation of maleate form D

10mg of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide free base form A was weighed, 200 μl of 0.11M maleic acid in toluene was slowly added to the system, suspended, stirred overnight, centrifuged and dried under vacuum to give maleate form D. It has an XRPD pattern as shown in figure 25, analyzed by detection.

18 Preparation of mesylate form A

10mg of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidine-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide free base crystal form A is weighed, 200 mu L of 0.11M methanesulfonic acid 2-methyl-tetrahydrofuran solution is slowly added into the system, the mixture is heated and stirred at 50 ℃, solid is precipitated after oil formation, and the mixture is centrifuged and dried in vacuum to obtain methanesulfonate crystal form A. It has an XRPD pattern as shown in figure 26, analyzed by detection.

19 Preparation of benzenesulfonate form a

10mg of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidine-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide free base crystal form A is weighed, 200 mu L of 0.11M benzenesulfonic acid 2-methyl-tetrahydrofuran solution is slowly added into the system, the mixture is heated and stirred at 50 ℃, solid is precipitated after oil formation, and the mixture is centrifuged and dried in vacuum to obtain benzenesulfonate crystal form A. It has an XRPD pattern as shown in figure 27, as analyzed by detection.

20 Preparation of malonic acid salt form A

10mg of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidine-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide free base crystal form A is weighed, 200 mu L of 0.11M malonic acid 2-methyl-tetrahydrofuran solution is slowly added into the system, the mixture is heated and stirred at 50 ℃, solid is precipitated after oil formation, and the mixture is centrifuged and dried in vacuum to obtain malonic acid salt crystal form A. It has an XRPD pattern as shown in figure 28, as analyzed by detection.

21 Preparation of malonic acid salt form B

10mg of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidine-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide free base crystal form A is weighed, 200 mu L of toluene is added, heating and stirring are carried out at 50 ℃, 22 mu L1.0M malonic acid in methanol solution is slowly added into the system, a small amount of solid is separated out after solution, and the mixture is centrifuged and dried in vacuum to obtain malonic acid salt crystal form B. It has an XRPD pattern as shown in figure 29, analyzed by detection.

22 Preparation of succinate crystalline form a

10mg of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide free base form A is weighed, 200 mu L of 0.11M succinic acid 2-methyl-tetrahydrofuran solution is slowly added into the system, heated and stirred at 50 ℃, suspended, stirred overnight, centrifuged and dried in vacuum to obtain succinate form A. It has an XRPD pattern as shown in figure 30, as analyzed by detection.

23 Preparation of succinate crystalline form B

10mg of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidine-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide free base crystal form A is weighed, 200 mu L of toluene is added, heating and stirring are carried out at 50 ℃, 22 mu L1.0M succinic acid in methanol is slowly added into the system, a small amount of solid is separated out after solution cleaning, and vacuum drying is carried out after centrifugation, so as to obtain succinate crystal form B. It has an XRPD pattern as shown in figure 31, as analyzed by detection.

4. Quantitative investigation of Compound salts

4.1 Quantitative investigation of hydrochloride salt of the Compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide

4.1.1 The purpose of the experiment is as follows:

the number of bound acids in the hydrochloride salt of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide was quantified by HPLC-ELSD assay.

4.1.2 The experimental steps are as follows:

weighing a proper amount of NaCl, and preparing serial linear solutions with different concentrations by using a diluent acetonitrile-water (50:50) respectively; the appropriate amount of hydrochloride in different batches is weighed, and 2mg/mL solution containing hydrochloride is prepared by using acetonitrile-water (50:50) serving as a diluent.

The above solution was taken and filtered to give a linear solution and a hydrochloride sample, which was filtered and subjected to HPLC-ELSD. Specific HPLC-ELSD analysis method:

chromatographic column	HILIC ZIC(4.6*150mm，3.5um)
Mobile phase	A:75mM ammonium acetate; b: acetonitrile
Proportion of	70％B
ELSD temperature	80℃
Run time	8min

4.1.3 Experimental results:

TABLE 3.1 quantitative study results of hydrochloride

4.1.4 Conclusion of experiment:

according to the calculation of Cl in hydrochloride of different batches ^- The percentage confirms that the hydrochloride salt form a of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide has a combined hydrochloride number of 1.

4.2 Benzoyl glycinate quantification of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide

4.2.1 The purpose of the experiment is as follows:

the number of bound acids in the benzoylglycinate salt of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide was quantified by HPLC-ELSD assay.

4.2.2 The experimental steps are as follows:

weighing a proper amount of benzoyl glycine, and preparing serial linear solutions with different concentrations by using a diluent acetonitrile-water (50:50) respectively; the appropriate amount of hydrochloride in different batches is weighed, and 2mg/mL solution containing benzoyl glycinate is prepared by using acetonitrile-water (50:50) as diluent.

Taking the solution, filtering the linear solution and benzoyl glycinate samples, and carrying out HPLC-ELSD after filtering. Specific HPLC-ELSD analysis method:

chromatographic column	HILIC ZIC(4.6*150mm，3.5um)
Mobile phase	A:75mM ammonium acetate; b: acetonitrile
Proportion of	80％B
ELSD temperature	80℃
Run time	3.5min

4.2.3 Experimental results:

TABLE 3.2 quantitative investigation results of benzoylglycinates

4.2.4 Conclusion of experiment:

according to the calculated percentage of benzoylglycine in the benzoylglycinate salt of the different batches, the number of benzoylglycinate salt forms C and D of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide combined with benzoylglycine was confirmed to be 1.

5. Solid stability test

5.1 The purpose of the experiment is as follows:

the physical and chemical stability of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidine-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide salt under the conditions of 5000lx illumination, high temperature 60 ℃, high humidity 92.5% RH and high temperature high humidity 50 ℃ 75% RH are examined, and the basis is provided for compound storage.

5.2 Instrument and conditions for liquid phase analysis

5.2.1 Instrument and apparatus:

instrument name	Model number
Analytical balance	Sartorius BSA224S-CW
Water purifier	Milli-Q Plus，Millipore
High performance liquid chromatograph	Agilent1260
Pump with a pump body	Agilent G1311B

Sample injector	G1329B
Column temperature box	G1316A
Detector for detecting a target object	G1315D

5.2.2 Chromatographic conditions:

5.3 Experimental protocol:

taking about 1mg of each of different salt crystal forms of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidine-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acryloyl, and under the conditions of 5000lx illumination, 60 ℃ high temperature, 92.5% RH with high humidity and 75% RH with high temperature and high humidity at 50 ℃, examining for 5 days and 10 days, measuring the content by using HPLC and an external standard method, and calculating the change of related substances by using a chromatographic peak area normalization method.

5.4 Experimental results:

TABLE 3.3 stability results

5.5 Conclusion of experiment:

the above data indicate that the benzoylglycinate form D and hydrochloride form a of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide are stable under light, high temperature, and high humidity conditions.

6. Dynamic hygroscopicity test

6.1 The purpose of the experiment is as follows:

the wettability of the crystal form of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidine-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide salt under different relative humidity conditions is examined, and a basis is provided for the crystal form screening and storage of the compound salt.

6.2 Experimental protocol:

the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamido hydrochloride form a, benzoylglycinate form D, p-toluenesulfonate form a and hydrobromide form a were placed in saturated water vapor of different relative humidity, the compound and water vapor were brought into dynamic equilibrium, and the percentage of moisture absorption gain of the compound after equilibrium was calculated.

6.3 Experimental results:

the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide hydrochloride form a has a moisture absorption gain of 0.3608% under RH 80%; the XRPD pattern of hydrochloride form a was unchanged by 2 cycles of moisture absorption and desorption at 0-95% relative humidity, i.e. form no conversion.

The compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide glycinate form D has a moisture absorption gain of 0.2218% under RH 80%; the XRPD pattern of benzoylglycinate form D was unchanged by 2 cycles of hygroscopic and desorbed humidity at 0-95% relative humidity, i.e. form was not converted.

The compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide p-toluenesulfonate crystal form A has a moisture absorption gain of 1.443% under RH 80%; the XRPD pattern of hydrochloride form a was unchanged by 2 cycles of moisture absorption and desorption at 0-95% relative humidity, i.e. form no conversion.

The compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide hydrobromide form a had a moisture absorption gain of 0.577% at RH 80%; the XRPD pattern of hydrochloride form a was unchanged by 2 cycles of moisture absorption and desorption at 0-95% relative humidity, i.e. form no conversion.

6.4 Conclusion of experiment:

the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide hydrochloride form a, benzoylglycinate form D, p-toluenesulfonate form a and hydrobromide form a are stable in the wet environment.

7. Solubility experiments in different Medium

7.1 The purpose of the experiment is as follows:

the solubility of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidine-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide hydrochloride crystal form A, benzoyl glycinate crystal form C and benzoyl glycinate crystal form D in simulated artificial gastrointestinal fluids is compared, and a basis is provided for salt patentability evaluation.

7.2 Experimental protocol:

about 2mg of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamido hydrochloride form a, benzoylglycinate form C, benzoylglycinate form D were separately suspended in 1mL of non-fasted artificial simulated intestinal fluid (FeSSCoF) and pure water for 4 hours, and the thermodynamic solubility of the compound was determined by HPLC detection, external standard method at 37 ℃.

7.3 Experimental results:

table 3.4 solubility results

7.4 Conclusion of experiment:

comparing the above data, it can be seen that the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide has significantly improved solubility in water and FeSSCoF due to the change in environmental pH after salifying.

8. Thermodynamic stability experiment

8.1 The purpose of the experiment is as follows:

and obtaining a crystal form with thermodynamic stability through polycrystalline screening and crystal form competition experiments.

8.2 Experimental protocol:

(1) Poly crystalline screening assay:

the organic solvent with certain solubility is selected, the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidine-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide benzoyl glycinate crystal form D is suspended in a solvent system, stirred and beaten for 1 week at 50 ℃, centrifuged, the supernatant is discarded, and after the solid is dried in vacuum (-0.1 Mpa) at 50 ℃ for 16 hours, the XRPD of the solid is determined and compared with the XRPD of the starting compound salt.

(2) Crystal form competition test

Weighing a proper amount of compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidine-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide benzoyl glycinate crystal form A, benzoyl glycinate crystal form B, benzoyl glycinate crystal form C, benzoyl glycinate crystal form E and benzoyl glycinate crystal form F, respectively mixing with benzoyl glycinate crystal form D, performing a crystal form competition test, adding 100 mu L of methyl tertiary butyl ether, pulping at 50 ℃ for 1 week, and measuring XRPD to determine the most stable crystal form.

8.3 Experimental results:

(1) The results of the polycrystalline screening test are as follows:

TABLE 3.5 polycrystalline screening test results

Solvent(s)	Results
Methanol	Benzoyl glycinate crystalline form D
Ethanol	Benzoyl glycinate crystalline form D
Acetone (acetone)	Benzoyl glycinate crystalline form E
Acetonitrile	Benzoyl glycinate crystalline form D
Isopropyl alcohol	Benzoyl glycinate crystalline form D
Toluene (toluene)	Benzoyl glycinate crystalline form A
Dichloromethane (dichloromethane)	Benzoyl glycinate crystalline form F
Tetrahydrofuran (THF)	Benzoyl glycinate crystalline form B
2-methyltetrahydrofuran	Benzoyl glycinate crystalline form B
2-butanone	Benzoyl glycinate crystalline form D
3-pentanone	Benzoyl glycinate crystalline form D
Acetic acid isopropyl ester	Benzoyl glycinate crystalline form D
Acetic acid ethyl ester	Benzoyl glycinate crystalline form D

(2) The results of the crystal form competition test are as follows:

table 3.6 results of competitive assay for crystalline forms

Crystal form combination	Results
Benzoyl glycinate crystalline form a+benzoyl glycinate crystalline form D	Benzoyl glycinate crystalline form D
Benzoyl glycinate crystalline form b+benzoyl glycinate crystalline form D	Benzoyl glycinate crystalline form D
Benzoyl glycinate crystalline form c+benzoyl glycinate crystalline form D	Benzoyl glycinate crystalline form D
Benzoyl glycinate crystalline form E+benzoyl glycinate crystalline form D	Benzoyl glycinate crystalline form D
Benzoyl glycinate crystalline form F+benzoyl glycinate crystalline form D	Benzoyl glycinate crystalline form D

8.4 Conclusion of experiment:

and (3) pulping to change a crystallization solvent and a crystallization mode to obtain 6 crystal forms of the benzoyl glycinate, namely a crystal form A, a crystal form B, a crystal form C, a crystal form D, a crystal form E and a crystal form F of the benzoyl glycinate respectively. And comparing DSC patterns of different crystal forms and crystal form competitive test results, the benzoyl glycinate crystal form D is judged to be the most stable thermodynamic crystal form of the crystal forms and is an anhydrous substance.

9. Rat pharmacokinetic study

9.1 The purpose of the experiment is as follows:

the rat pharmacokinetic parameters of compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide hydrochloride form a and benzoylglycinate form D were compared by animal PK studies.

9.2 Laboratory instruments and reagents:

9.2.1 Instrument:

9.2.2 Reagent:

reagent(s)	Suppliers (suppliers)	Lot number	Remarks
DMSO	Vetech	WXBD0293V
Acetonitrile	Sigma-Aldrich	WXBD0232V
Methyl Alcohol	Sigma-Aldrich	WXBC6573V
Formic Acid	Fisher Scientific	193497
Dexamethasone	Soy pal	822A0523	Internal Standard
HP-β-CD	SHANDONG BINZHOU ZHIYUAN BIOTECHNOLOGY Co.,Ltd.	20190517
HPMC K4M	Damas-beta	P1575251

9.3 Experimental animals:

animal species	Strain of strain	Age of	Sex (sex)	Suppliers (suppliers)
Rat (rat)	SD	7 weeks, weight 200g	Male male	JOINN LABORATORIES (SUZHOU) Co.,Ltd.

9.4 Test compounds:

the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide hydrochloride form a and benzoylglycinate form D.

9.5 Experimental protocol:

compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide hydrochloride form a and benzoylglycinate form D were uniformly suspended in an aqueous solution containing 0.5% HPMC (hydroxypropyl methylcellulose) K4M (1% tween 80) and then administered to rats in a dose of 30mg/kg in parallel with all the amounts of the compounds converted to the same amount of free base.

9.6 Experimental results:

TABLE 3.7 rat drug substitution test results

9.7 Conclusion of experiment:

from the results of the rat drug generation experiments in the table, it can be seen that the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide hydrochloride crystal form A and benzoyl glycine salt crystal form D of the invention show good metabolic properties at a dose of 30 mg/kg.

Claims

An acid salt of a compound of formula (I),

wherein:

R ₁ selected from hydrogen, cyano, oxazolyl, pyrazolyl, and,

R ₂ Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;

R ₃ Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuteratedAlkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl.
An acid salt of a compound according to claim 1, wherein R ₂ Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C _1-6 Alkyl, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, C _3-8 Cycloalkyl or 3-8 membered heterocyclyl;

preferably hydrogen, deuterium, halogen, cyano, C _1-3 Alkyl, C _1-3 Deuterated alkyl, C _1-3 Haloalkyl, C _1-3 Alkoxy, C _1-3 Haloalkoxy, C _3-6 Cycloalkyl or 3-6 membered heterocyclyl;

more preferably hydrogen, deuterium, methyl, ethyl, propyl, cyclopropyl or oxetanyl;

most preferred is hydrogen, methyl, cyclopropyl or oxetanyl.
An acid salt of a compound according to claim 1, wherein R ₃ Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C _1-6 Alkyl, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy or C _1-6 Haloalkoxy groups;

preferably hydrogen, deuterium, halogen, cyano, C _1-3 Alkyl, C _1-3 Deuterated alkyl, C _1-3 Haloalkyl, C _1-3 Alkoxy or C _1-3 Haloalkoxy groups;

More preferably hydrogen, deuterium, fluorine, chlorine, bromine, methoxy or ethoxy;

most preferred are hydrogen, fluorine or methoxy.
An acid salt of a compound according to claim 1, wherein the specific compound structure is as follows:
an acid salt of a compound according to any one of claims 1 to 4 wherein the acid in the acid salt is selected from the group consisting of an inorganic acid selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, or phosphoric acid; the organic acid is selected from 2, 5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexane sulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecylsulfuric acid, dibenzoyltartaric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, benzoylglycine, hydroxyethanesulfonic acid, lactonic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1, 5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, pamoic acid, formic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid or L-malic acid;

Preferably, the acid is selected from hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, sulfuric acid, fumaric acid, oxalic acid, benzoylglycine, phosphoric acid, maleic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, malonic acid, adipic acid or succinic acid;

more preferably, the acid is selected from hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, sulfuric acid, fumaric acid, oxalic acid, benzoylglycine, phosphoric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, malonic acid or succinic acid;

further preferably, the acid is selected from hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid or benzoylglycine.
An acid salt of a compound according to any one of claims 1 to 5 wherein the number of acids is from 0.2 to 3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3; more preferably 0.5, 1, 2 or 3; further preferably 1.
An acid salt of a compound according to claim 1, wherein the acid salt is
An acid salt of a compound according to any one of claims 1 to 7, wherein the acid salt is a hydrate or anhydrate; when the acid salt is hydrate, the number of water is 0.2-3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3; more preferably 0.5, 1, 2 or 3.
An acid salt of a compound according to any one of claims 1 to 8, wherein the acid salt is in crystalline or amorphous form; preferably, the crystalline form is the acid salt of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide;

More preferably, the hydrochloride salt form, the hydrobromide salt form, the p-toluenesulfonate salt form, the sulfate salt form, the fumarate salt form, the oxalate salt form, the benzoylglycinate salt form, the phosphate salt form, the maleate salt form, the malate salt form, the methanesulfonate salt form, the benzenesulfonate salt form, the malonate salt form, the adipate salt form, or the succinate salt form of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide;

further preferred is the hydrochloride, hydrobromide, p-toluenesulfonate, sulfate, fumarate, oxalate, benzoylglycinate, phosphate, maleate, methanesulfonate, benzenesulfonate, malonate or succinate form of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide;

still more preferably, the hydrochloride salt form, the hydrobromide salt form, the p-toluenesulfonate salt form or the benzoylglycinate salt form of N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide.
The acid salt form of the compound of claim 9, wherein the acid salt form of the compound N- (5- ((5-cyano-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide is hydrochloride form a, hydrobromide form a, p-toluenesulfonate form a, sulfate form a, fumarate form a, oxalate form a, benzoylglycinate form B, benzoylglycinate form C, benzoylglycinate form D, benzoylglycinate form E, benzoylglycinate form F, phosphate form a, maleate form B, maleate form C, maleate form D, methanesulfonate form a, benzenesulfonate form a, malonate form B, succinate form a or salt form B, wherein:

the X-ray powder diffraction pattern of the hydrochloride crystal form A has diffraction peaks at 26.4+/-0.2 degrees; or a diffraction peak at 10.8±0.2°; or a diffraction peak at 20.9±0.2°; or a diffraction peak at 14.2±0.2°; or a diffraction peak at 12.5±0.2°; or a diffraction peak at 6.3±0.2°; or a diffraction peak at 25.0±0.2°; or a diffraction peak at 21.0±0.2°; or a diffraction peak at 22.1±0.2°; or a diffraction peak at 24.9±0.2°; preferably any of the above diffraction peaks is contained at 2 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8, more preferably any 6, 7 or 8 thereof;

The X-ray powder diffraction pattern of the hydrobromide crystal form A has diffraction peaks at 24.9+/-0.2 degrees of 2 theta; or a diffraction peak at 26.3±0.2°; or a diffraction peak at 6.2±0.2°; or a diffraction peak at 20.4±0.2°; or a diffraction peak at 15.6±0.2°; or a diffraction peak at 10.5±0.2°; or a diffraction peak at 22.6 + -0.2 deg.; or a diffraction peak at 14.0±0.2°; or a diffraction peak at 21.0±0.2°; or a diffraction peak at 25.8±0.2°; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof;

the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form A has diffraction peaks at 5.5+/-0.2 degrees of 2 theta; or a diffraction peak at 14.1±0.2°; or a diffraction peak at 21.7±0.2°; or a diffraction peak at 15.6±0.2°; or a diffraction peak at 22.2 + -0.2 deg.; or a diffraction peak at 24.3±0.2°; or a diffraction peak at 26.8±0.2°; or a diffraction peak at 21.1±0.2°; or a diffraction peak at 9.9±0.2°; or a diffraction peak at 23.9±0.2°; preferably comprises any of the diffraction peaks described above at 2 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8, more preferably comprises any of 6, 7 or 8;

The X-ray powder diffraction pattern of the sulfate crystal form A has diffraction peaks at the 2 theta of 12.0 plus or minus 0.2 degrees; or a diffraction peak at 11.9±0.2°; or a diffraction peak at 6.1±0.2°; or a diffraction peak at 14.1±0.2°; or a diffraction peak at 21.3±0.2°; or a diffraction peak at 22.1±0.2°; or a diffraction peak at 22.3 + -0.2 deg.; or a diffraction peak at 9.6±0.2°; or a diffraction peak at 10.4±0.2°; or a diffraction peak at 22.4 + -0.2 deg.; preferably comprises any of the diffraction peaks described above at 2 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8, more preferably comprises any of 6, 7 or 8;

the X-ray powder diffraction pattern of the fumarate salt crystal form A has diffraction peaks at 24.0+/-0.2 degrees of 2 theta; or a diffraction peak at 15.2±0.2°; or a diffraction peak at 9.4±0.2°; or a diffraction peak at 20.9±0.2°; or a diffraction peak at 25.7±0.2°; or a diffraction peak at 13.8±0.2°; or a diffraction peak at 22.1±0.2°; or a diffraction peak at 9.7±0.2°; or a diffraction peak at 17.6±0.2°; or a diffraction peak at 18.7±0.2°; preferably comprises any of the diffraction peaks described above at 2 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8, more preferably comprises any of 6, 7 or 8;

The X-ray powder diffraction pattern of the oxalate crystal form A has diffraction peaks at the 2 theta of 5.8 plus or minus 0.2 degrees; or a diffraction peak at 11.6±0.2°; or a diffraction peak at 21.4±0.2°; or a diffraction peak at 20.6±0.2°; or a diffraction peak at 14.3±0.2°; or a diffraction peak at 18.4±0.2°; or a diffraction peak at 19.6±0.2°; or a diffraction peak at 23.8±0.2°; or a diffraction peak at 9.7±0.2°; or a diffraction peak at 27.7±0.2°; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof;

the X-ray powder diffraction pattern of the benzoyl glycinate salt crystal form A has diffraction peaks at the 2 theta of 5.4 plus or minus 0.2 degrees; or a diffraction peak at 25.1±0.2°; or a diffraction peak at 10.6 + -0.2 deg.; or a diffraction peak at 21.3±0.2°; or a diffraction peak at 18.3±0.2°; or a diffraction peak at 14.6±0.2°; or a diffraction peak at 19.4±0.2°; or a diffraction peak at 19.0±0.2°; or a diffraction peak at 25.9±0.2°; or a diffraction peak at 16.6±0.2°; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof;

The X-ray powder diffraction pattern of the benzoyl glycinate salt crystal form B has diffraction peaks at the 2 theta of 5.4 plus or minus 0.2 degrees; or a diffraction peak at 24.7±0.2°; or a diffraction peak at 19.1±0.2°; or a diffraction peak at 18.9±0.2°; or a diffraction peak at 10.5±0.2°; or a diffraction peak at 23.1±0.2°; or a diffraction peak at 20.9±0.2°; or a diffraction peak at 14.4±0.2°; or a diffraction peak at 10.8±0.2°; or a diffraction peak at 22.8±0.2°; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof;

the X-ray powder diffraction pattern of the benzoyl glycinate salt crystal form C has diffraction peaks at the 2 theta of 5.7 plus or minus 0.2 degrees; or a diffraction peak at 20.4±0.2°; or a diffraction peak at 26.4±0.2°; or a diffraction peak at 14.5±0.2°; or a diffraction peak at 15.5±0.2°; or a diffraction peak at 11.1±0.2°; or a diffraction peak at 18.5±0.2°; or a diffraction peak at 16.8±0.2°; or a diffraction peak at 19.4±0.2°; or a diffraction peak at 17.5±0.2°; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof;

The X-ray powder diffraction pattern of the benzoyl glycinate salt crystal form D has diffraction peaks at 17.6+/-0.2 degrees of 2 theta; or a diffraction peak at 21.0±0.2°; or a diffraction peak at 5.8±0.2°; or a diffraction peak at 25.2±0.2°; or a diffraction peak at 16.6±0.2°; or a diffraction peak at 15.0 + -0.2 deg.; or a diffraction peak at 9.7±0.2°; or a diffraction peak at 10.2 + -0.2 deg.; or a diffraction peak at 14.8±0.2°; or a diffraction peak at 19.9±0.2°; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof;

the X-ray powder diffraction pattern of the benzoyl glycinate crystal form E has diffraction peaks at the 2 theta of 5.4 plus or minus 0.2 degrees; or a diffraction peak at 5.3 + -0.2 deg.; or a diffraction peak at 5.6±0.2°; or a diffraction peak at 10.7±0.2°; or a diffraction peak at 20.8±0.2°; or a diffraction peak at 24.7±0.2°; or a diffraction peak at 16.5±0.2°; or a diffraction peak at 21.5±0.2°; or a diffraction peak at 14.5±0.2°; or a diffraction peak at 18.4±0.2°; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof;

The X-ray powder diffraction pattern of the benzoyl glycinate salt crystal form F has diffraction peaks at 6.1+/-0.2 degrees of 2 theta; or a diffraction peak at 6.3±0.2°; or a diffraction peak at 10.3 + -0.2 deg.; or a diffraction peak at 12.3±0.2°; or a diffraction peak at 9.3±0.2°; or a diffraction peak at 9.8±0.2°; or a diffraction peak at 11.6±0.2°; or a diffraction peak at 5.5±0.2°; or a diffraction peak at 11.1±0.2°; or a diffraction peak at 13.8±0.2°; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof;

the X-ray powder diffraction pattern of the phosphate crystal form A has diffraction peaks at the 2 theta of 10.6 plus or minus 0.2 degrees; or a diffraction peak at 12.3±0.2°; or a diffraction peak at 9.2±0.2°; or a diffraction peak at 21.4±0.2°; or a diffraction peak at 13.5±0.2°; or a diffraction peak at 6.3±0.2°; or a diffraction peak at 10.9±0.2°; or a diffraction peak at 25.3±0.2°; or a diffraction peak at 11.7±0.2°; or a diffraction peak at 12.1±0.2°; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof;

The X-ray powder diffraction pattern of the maleate crystal form A has diffraction peaks at 6.0+/-0.2 degrees of 2 theta; or a diffraction peak at 22.3 + -0.2 deg.; or a diffraction peak at 8.2±0.2°; or a diffraction peak at 16.3±0.2°; or a diffraction peak at 23.5±0.2°; or a diffraction peak at 19.5±0.2°; or a diffraction peak at 19.2±0.2°; or a diffraction peak at 11.8±0.2°; or a diffraction peak at 7.1±0.2°; or a diffraction peak at 21.7±0.2°; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof;

the X-ray powder diffraction pattern of the maleate crystal form B has diffraction peaks at the 2 theta of 7.7 plus or minus 0.2 degrees; or a diffraction peak at 16.1±0.2°; or a diffraction peak at 23.6±0.2°; or a diffraction peak at 22.2 + -0.2 deg.; or a diffraction peak at 19.2±0.2°; or a diffraction peak at 21.7±0.2°; or a diffraction peak at 6.5±0.2°; or a diffraction peak at 19.8±0.2°; or a diffraction peak at 6.0±0.2°; or a diffraction peak at 8.2±0.2°; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof;

An X-ray powder diffraction pattern of the maleate crystal form C has diffraction peaks at 17.1+/-0.2 degrees of 2 theta; or a diffraction peak at 10.3 + -0.2 deg.; or a diffraction peak at 23.8±0.2°; or a diffraction peak at 14.3±0.2°; or a diffraction peak at 13.3±0.2°; or a diffraction peak at 24.5±0.2°; or a diffraction peak at 25.5±0.2°; or a diffraction peak at 23.5±0.2°; or a diffraction peak at 13.1±0.2°; or a diffraction peak at 22.9±0.2°; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof;

the X-ray powder diffraction pattern of the maleate crystal form D has diffraction peaks at 20.4+/-0.2 degrees of 2 theta; or a diffraction peak at 8.2±0.2°; or a diffraction peak at 14.6±0.2°; or a diffraction peak at 25.9±0.2°; or a diffraction peak at 18.4±0.2°; or a diffraction peak at 8.9±0.2°; or a diffraction peak at 24.1±0.2°; or a diffraction peak at 24.5±0.2°; or a diffraction peak at 16.1±0.2°; or a diffraction peak at 21.8±0.2°; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof;

The X-ray powder diffraction pattern of the mesylate salt crystal form A has diffraction peaks at the 2 theta of 5.9 plus or minus 0.2 degrees; or a diffraction peak at 21.7±0.2°; or a diffraction peak at 10.2 + -0.2 deg.; or a diffraction peak at 14.2±0.2°; or a diffraction peak at 20.8±0.2°; or a diffraction peak at 25.7±0.2°; or a diffraction peak at 22.2 + -0.2 deg.; or a diffraction peak at 17.4±0.2°; or a diffraction peak at 11.7±0.2°; or a diffraction peak at 18.0±0.2°; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof;

the X-ray powder diffraction pattern of the benzenesulfonate crystal form A has diffraction peaks at the 2 theta of 5.6 plus or minus 0.2 degrees; or a diffraction peak at 21.2±0.2°; or a diffraction peak at 13.4±0.2°; or a diffraction peak at 18.9±0.2°; or a diffraction peak at 26.6±0.2°; or a diffraction peak at 23.7±0.2°; or a diffraction peak at 19.5±0.2°; or a diffraction peak at 26.4±0.2°; or a diffraction peak at 10.0 + -0.2 deg.; or a diffraction peak at 10.6 + -0.2 deg.; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof;

The X-ray powder diffraction pattern of the malonate crystal form A has diffraction peaks at the 2 theta of 7.5 plus or minus 0.2 degrees; or a diffraction peak at 5.5±0.2°; or a diffraction peak at 23.6±0.2°; or a diffraction peak at 20.3±0.2°; or a diffraction peak at 9.7±0.2°; or a diffraction peak at 11.7±0.2°; or a diffraction peak at 23.0±0.2°; or a diffraction peak at 21.0±0.2°; or a diffraction peak at 14.3±0.2°; or a diffraction peak at 25.6±0.2°; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof;

the X-ray powder diffraction pattern of the malonate crystal form B has diffraction peaks at 21.4+/-0.2 degrees of 2 theta; or a diffraction peak at 5.9±0.2°; or a diffraction peak at 20.5±0.2°; or a diffraction peak at 11.4±0.2°; or a diffraction peak at 19.1±0.2°; or a diffraction peak at 20.8±0.2°; or a diffraction peak at 16.1±0.2°; or a diffraction peak at 27.4±0.2°; or a diffraction peak at 18.4±0.2°; or a diffraction peak at 13.9±0.2°; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof;

The X-ray powder diffraction pattern of the succinate salt crystal form A has diffraction peaks at the 2 theta of 21.4 plus or minus 0.2 degrees; or a diffraction peak at 10.7±0.2°; or a diffraction peak at 16.6±0.2°; or a diffraction peak at 19.6±0.2°; or a diffraction peak at 26.2±0.2°; or a diffraction peak at 19.3±0.2°; or a diffraction peak at 21.6±0.2°; or a diffraction peak at 21.0±0.2°; or a diffraction peak at 16.0±0.2°; or a diffraction peak at 14.4±0.2°; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof;

the X-ray powder diffraction pattern of the succinate salt crystal form B has diffraction peaks at the position that 2 theta is 19.2 plus or minus 0.2 degrees; or a diffraction peak at 21.3±0.2°; or a diffraction peak at 20.7±0.2°; or a diffraction peak at 14.1±0.2°; or a diffraction peak at 20.4±0.2°; or a diffraction peak at 18.5±0.2°; or a diffraction peak at 11.4±0.2°; or a diffraction peak at 23.7±0.2°; or a diffraction peak at 27.3±0.2°; or a diffraction peak at 20.8±0.2°; preferably comprises any of the diffraction peaks described above at 2-5, alternatively 3-6, alternatively 3-8, alternatively 5-8, alternatively 6-8; more preferably any 6, 7 or 8 thereof.
The acid salt form of the compound according to claim 10, wherein the X-ray powder diffraction pattern of hydrochloride form a comprises at least one or more diffraction peaks at 26.4±0.2°, 10.8±0.2°, 20.9±0.2° in 2Θ, preferably at 2 thereof, more preferably at 3 thereof; optionally, it may further comprise at least one of 2 theta of 14.2±0.2°, 12.5±0.2°, 6.3±0.2°, 25.0±0.2°, 21.0±0.2, preferably 2, 3, 4 or 5;

for example, the X-ray powder diffraction pattern of hydrochloride form a has diffraction peaks at 2θ at the following positions: 26.4±0.2°, 10.8±0.2°, 20.9±0.2°, 14.2±0.2°, 12.5±0.2° and 6.3±0.2°;

the X-ray powder diffraction pattern of the hydrobromide salt crystal form A at least comprises one or more diffraction peaks positioned in 24.9+/-0.2 DEG, 26.3+/-0.2 DEG and 6.2+/-0.2 DEG of 2 theta, preferably comprises two of the diffraction peaks, more preferably comprises three of the diffraction peaks; optionally, the composition further comprises at least one of 20.4+/-0.2 °, 15.6+/-0.2 °, 10.5+/-0.2 °, 22.6+/-0.2 °, and 14.0+/-0.2 °; preferably 2, 3, 4 or 5 of these;

for example, the X-ray powder diffraction pattern of hydrobromide form a has diffraction peaks at 2θ at the following positions: 24.9.+ -. 0.2 °, 26.3.+ -. 0.2 °, 6.2.+ -. 0.2 °, 20.4.+ -. 0.2 °, 15.6.+ -. 0.2 ° and 10.5.+ -. 0.2 °

The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form a comprises at least one or more diffraction peaks in the 2θ of 5.5±0.2°, 14.1±0.2°, 21.7±0.2°, preferably two of them, more preferably three of them; optionally, the composition further comprises at least one of 15.6+/-0.2 °, 22.2+/-0.2 °, 24.3+/-0.2 °, 26.8+/-0.2 °, and 21.1+/-0.2 °; preferably 2, 3, 4 or 5 of these;

for example, the X-ray powder diffraction pattern of p-toluenesulfonate form a has diffraction peaks at 2θ:5.5±0.2°, 14.1±0.2°, 21.7±0.2°, 15.6±0.2°, 22.2±0.2° and 24.3±0.2°;

the X-ray powder diffraction pattern of the sulfate crystal form A at least comprises one or more diffraction peaks positioned in the angles of 12.0+/-0.2 DEG, 11.9+/-0.2 DEG and 6.1+/-0.2 DEG, preferably comprises two of the diffraction peaks, more preferably comprises three of the diffraction peaks; optionally, the composition further comprises at least one of 14.1+/-0.2 °, 21.3+/-0.2 °, 22.1+/-0.2 °, 22.3+/-0.2 °, and 9.6+/-0.2 °; preferably 2, 3, 4 or 5 of these;

for example, the X-ray powder diffraction pattern of sulfate form a has diffraction peaks at 2θ:12.0±0.2°, 11.9±0.2°, 6.1±0.2°, 14.1±0.2°, 21.3±0.2° and 22.1±0.2°;

The X-ray powder diffraction pattern of fumarate salt form a comprises at least one or more diffraction peaks at 24.0±0.2°, 15.2±0.2°, 9.4±0.2°, preferably two of them, more preferably three of them; optionally, the composition further comprises at least one of 20.9+/-0.2 °, 25.7+/-0.2 °, 13.8+/-0.2 °, 22.1+/-0.2 ° and 9.7+/-0.2 °; preferably 2, 3, 4 or 5 of these;

for example, the X-ray powder diffraction pattern of fumarate salt form a has diffraction peaks at the following positions of 2θ:24.0±0.2°, 15.2±0.2°, 9.4±0.2°, 20.9±0.2°, 25.7±0.2° and 13.8±0.2°;

the X-ray powder diffraction pattern of oxalate crystalline form a comprises at least one or more diffraction peaks located in 5.8±0.2°, 11.6±0.2°, 21.4±0.2°, preferably two of them, more preferably three of them; optionally, the composition further comprises at least one of 20.6+/-0.2 °, 14.3+/-0.2 °, 18.4+/-0.2 °, 19.6+/-0.2 °, and 23.8+/-0.2 °; preferably 2, 3, 4 or 5 of these;

for example, the X-ray powder diffraction pattern of oxalate form a has diffraction peaks at the following positions of 2θ:5.8±0.2°, 11.6±0.2°, 21.4±0.2°, 20.6±0.2°, 14.3±0.2° and 18.4±0.2°;

The X-ray powder diffraction pattern of the benzoyl glycinate salt crystal form A at least comprises one or more diffraction peaks positioned in the 2 theta of 5.4 plus or minus 0.2 degrees, 25.1 plus or minus 0.2 degrees and 10.6 plus or minus 0.2 degrees, preferably comprises two of the diffraction peaks, more preferably comprises three of the diffraction peaks; optionally, the composition further comprises at least one of 21.3+/-0.2 °, 18.3+/-0.2 °, 14.6+/-0.2 °, 19.4+/-0.2 °, and 19.0+/-0.2 °; preferably 2, 3, 4 or 5 of these;

for example, the X-ray powder diffraction pattern of benzoylglycinate form a has diffraction peaks at the following positions in 2θ:5.4±0.2°, 25.1±0.2°, 10.6±0.2°, 21.3±0.2°, 18.3±0.2° and 14.6±0.2°;

the X-ray powder diffraction pattern of the benzoyl glycinate salt crystal form B at least comprises one or more diffraction peaks positioned in the angles of 5.4+/-0.2 DEG, 24.7+/-0.2 DEG and 19.1+/-0.2 DEG, preferably comprises two of the diffraction peaks, more preferably comprises three of the diffraction peaks; optionally, the composition further comprises at least one of 18.9+/-0.2 °, 10.5+/-0.2 °, 23.1+/-0.2 °, 20.9+/-0.2 °, and 14.4+/-0.2 °; preferably 2, 3, 4 or 5 of these;

for example, the X-ray powder diffraction pattern of benzoylglycinate form B has diffraction peaks at the following positions of 2θ:5.4±0.2°, 24.7±0.2°, 19.1±0.2°, 18.9±0.2°, 10.5±0.2° and 23.1±0.2°;

The X-ray powder diffraction pattern of the benzoyl glycinate salt crystal form C at least comprises one or more diffraction peaks positioned in the 2 theta of 5.7 plus or minus 0.2 degrees, 20.4 plus or minus 0.2 degrees and 26.4 plus or minus 0.2 degrees, preferably comprises two of the diffraction peaks, more preferably comprises three of the diffraction peaks; optionally, the composition further comprises at least one of 14.5+/-0.2 °, 15.5+/-0.2 °, 11.1+/-0.2 °, 18.5+/-0.2 °, and 16.8+/-0.2 °; preferably 2, 3, 4 or 5 of these;

for example, the X-ray powder diffraction pattern of benzoylglycinate form C has diffraction peaks at the following positions of 2θ:5.7±0.2°, 20.4±0.2°, 26.4±0.2°, 14.5±0.2°, 15.5±0.2° and 11.1±0.2°;

the X-ray powder diffraction pattern of the benzoylglycinate salt crystal form D at least comprises one or more diffraction peaks located in 17.6+ -0.2 DEG, 21.0+ -0.2 DEG, 5.8+ -0.2 DEG, preferably two of them, more preferably three of them; optionally, the composition further comprises at least one of 25.2+ -0.2 °, 16.6+ -0.2 °, 15.0+ -0.2 °, 9.7+ -0.2 °, 10.2+ -0.2 °; preferably 2, 3, 4 or 5 of these;

for example, the X-ray powder diffraction pattern of benzoylglycinate form D has diffraction peaks at the following positions of 2θ:17.6±0.2°, 21.0±0.2°, 5.8±0.2°, 25.2±0.2°, 15.0±0.2° and 9.7±0.2°; or 17.6±0.2°, 25.2±0.2°, 16.6±0.2°, 15.0±0.2°, 9.7±0.2° and 10.2±0.2°; alternatively, 17.6±0.2°, 21.0±0.2°, 5.8±0.2°, 25.2±0.2°, 15.0±0.2° and 9.7±0.2°;

The X-ray powder diffraction pattern of the benzoyl glycinate salt crystal form E at least comprises one or more diffraction peaks positioned in the degrees 2 theta of 5.4+/-0.2 degrees, 5.3+/-0.2 degrees and 5.6+/-0.2 degrees, preferably comprises two of the diffraction peaks, more preferably comprises three of the diffraction peaks; optionally, the composition further comprises at least one of 10.7+/-0.2 °, 20.8+/-0.2 °, 24.7+/-0.2 °, 16.5+/-0.2 °, and 21.5+/-0.2 °; preferably 2, 3, 4 or 5 of these;

for example, the X-ray powder diffraction pattern of benzoylglycinate form E has diffraction peaks at the following positions in 2θ:5.4±0.2°, 5.3±0.2°, 5.6±0.2°, 10.7±0.2°, 20.8±0.2° and 24.7±0.2°;

the X-ray powder diffraction pattern of the benzoylglycinate salt crystal form F at least comprises one or more diffraction peaks located in 6.1+/-0.2 DEG, 6.3+/-0.2 DEG and 10.3+/-0.2 DEG, preferably two, more preferably three of the diffraction peaks; optionally, it may further comprise at least one of 12.3±0.2°, 9.3±0.2°, 9.8±0.2°, 11.6±0.2°, and 5.5±0.2°; preferably 2, 3, 4 or 5 of these;

for example, the X-ray powder diffraction pattern of benzoylglycinate form F has diffraction peaks at the following positions of 2θ: 6.1+ -0.2 °, 6.3+ -0.2 °, 10.3+ -0.2 °, 12.3+ -0.2 °, 9.3+ -0.2 ° and 9.8+ -0.2 °;

The X-ray powder diffraction pattern of phosphate form a comprises at least one or more diffraction peaks in the 2θ of 10.6±0.2°, 12.3±0.2°, 9.2±0.2°, preferably two of them, more preferably three of them; optionally, the composition further comprises at least one of 21.4+/-0.2 °, 13.5+/-0.2 °, 6.3+/-0.2 °, 10.9+/-0.2 ° and 25.3+/-0.2 °; preferably 2, 3, 4 or 5 of these;

for example, the X-ray powder diffraction pattern of phosphate form a has diffraction peaks at the following positions of 2θ:10.6±0.2°, 12.3±0.2°, 9.2±0.2°, 21.4±0.2°, 13.5±0.2° and 6.3±0.2°;

the X-ray powder diffraction pattern of the maleate salt form A at least comprises one or more diffraction peaks positioned in the angles of 6.0+/-0.2 DEG, 22.3+/-0.2 DEG and 8.2+/-0.2 DEG of 2 theta, preferably comprises two of the diffraction peaks, more preferably comprises three of the diffraction peaks; optionally, the composition further comprises at least one of 16.3+ -0.2 °, 23.5+ -0.2 °, 19.5+ -0.2 °, 19.2+ -0.2 °, 11.8+ -0.2 °; preferably 2, 3, 4 or 5 of these;

for example, the X-ray powder diffraction pattern of maleate form a has diffraction peaks at 2θ at the following positions: 6.0.+ -. 0.2 °, 22.3.+ -. 0.2 °, 8.2.+ -. 0.2 °, 16.3.+ -. 0.2 °, 23.5.+ -. 0.2 ° and 19.5.+ -. 0.2 °;

The X-ray powder diffraction pattern of the maleate salt form B at least comprises one or more diffraction peaks positioned in the angles of 7.7+/-0.2 DEG, 16.1+/-0.2 DEG and 23.6+/-0.2 DEG, preferably comprises two of the diffraction peaks, more preferably comprises three of the diffraction peaks; optionally, it may further comprise at least one of 22.2±0.2°, 19.2±0.2°, 21.7±0.2°, 6.5±0.2°, and 19.8±0.2°; preferably 2, 3, 4 or 5 of these;

for example, the X-ray powder diffraction pattern of maleate form B has diffraction peaks at 2θ:7.7±0.2°, 16.1±0.2°, 23.6±0.2°, 22.2±0.2°, 19.2±0.2° and 21.7±0.2°;

the X-ray powder diffraction pattern of the maleate salt form C at least comprises one or more diffraction peaks positioned in 17.1+/-0.2 DEG, 10.3+/-0.2 DEG and 23.8+/-0.2 DEG, preferably comprises two of the diffraction peaks, more preferably comprises three of the diffraction peaks; optionally, the composition further comprises at least one of 14.3+/-0.2 degrees, 13.3+/-0.2 degrees, 24.5+/-0.2 degrees, 25.5+/-0.2 degrees and 23.5+/-0.2 degrees; preferably 2, 3, 4 or 5 of these;

for example, the X-ray powder diffraction pattern of maleate form C has diffraction peaks at 2θ:17.1±0.2°, 10.3±0.2°, 23.8±0.2°, 14.3±0.2°, 13.3±0.2° and 24.5±0.2°;

The X-ray powder diffraction pattern of the maleate salt form D at least comprises one or more diffraction peaks positioned in 20.4+/-0.2 DEG, 8.2+/-0.2 DEG and 14.6+/-0.2 DEG of 2 theta, preferably comprises two of the diffraction peaks, more preferably comprises three of the diffraction peaks; optionally, the composition further comprises at least one of 25.9+/-0.2 °, 18.4+/-0.2 °, 8.9+/-0.2 °, 24.1+/-0.2 °, and 24.5+/-0.2 °; preferably 2, 3, 4 or 5 of these;

for example, the X-ray powder diffraction pattern of maleate form D has diffraction peaks at 2θ:20.4±0.2°, 8.2±0.2°, 14.6±0.2°, 25.9±0.2°, 18.4±0.2° and 8.9±0.2°;

the X-ray powder diffraction pattern of mesylate form a comprises at least one or more diffraction peaks at 5.9±0.2°, 21.7±0.2°, 10.2±0.2° in 2θ, preferably two of them, more preferably three of them; optionally, the composition further comprises at least one of 14.2+ -0.2 °, 20.8+ -0.2 °, 25.7+ -0.2 °, 22.2+ -0.2 °, 17.4+ -0.2 °; preferably 2, 3, 4 or 5 of these;

for example, the X-ray powder diffraction pattern of mesylate form a has diffraction peaks at the following positions in 2θ:5.9±0.2°, 21.7±0.2°, 10.2±0.2°, 14.2±0.2°, 20.8±0.2° and 25.7±0.2°;

The X-ray powder diffraction pattern of the benzenesulfonate crystal form A at least comprises one or more diffraction peaks in 5.6+/-0.2 DEG, 21.2+/-0.2 DEG and 13.4+/-0.2 DEG, preferably two, more preferably three of the diffraction peaks; optionally, the composition further comprises at least one of 18.9+/-0.2 °, 26.6+/-0.2 °, 23.7+/-0.2 °, 19.5+/-0.2 °, and 26.4+/-0.2 °; preferably 2, 3, 4 or 5 of these;

for example, the X-ray powder diffraction pattern of besylate form a has diffraction peaks at the following positions of 2θ:5.6±0.2°, 21.2±0.2°, 13.4±0.2°, 18.9±0.2°, 26.6±0.2° and 23.7±0.2°;

the X-ray powder diffraction pattern of malonic acid salt form a comprises at least one or more diffraction peaks located in the degrees 2θ of 7.5±0.2°, 5.5±0.2°, 23.6±0.2°, preferably two of them, more preferably three of them; optionally, the composition further comprises at least one of 20.3+ -0.2 °, 9.7+ -0.2 °, 11.7+ -0.2 °, 23.0+ -0.2 °, 21.0+ -0.2 °; preferably 2, 3, 4 or 5 of these;

for example, the X-ray powder diffraction pattern of malonic acid salt form a has diffraction peaks at the following positions of 2θ:7.5±0.2°, 5.5±0.2°, 23.6±0.2°, 20.3±0.2°, 9.7±0.2° and 11.7±0.2°;

The X-ray powder diffraction pattern of malonic acid salt form B comprises at least one or more diffraction peaks located in 21.4±0.2°, 5.9±0.2°, 20.5±0.2°, preferably two of them, more preferably three of them; optionally, the composition further comprises at least one of 11.4+/-0.2 °, 19.1+/-0.2 °, 20.8+/-0.2 °, 16.1+/-0.2 °, and 27.4+/-0.2 °; preferably 2, 3, 4 or 5 of these;

for example, the X-ray powder diffraction pattern of malonic acid salt form B has diffraction peaks at the following positions of 2θ:21.4±0.2°, 5.9±0.2°, 20.5±0.2°, 11.4±0.2°, 19.1±0.2° and 20.8±0.2°;

the X-ray powder diffraction pattern of succinate crystalline form a comprises at least one or more diffraction peaks in 21.4±0.2°, 10.7±0.2°, 16.6±0.2°, preferably two of them, more preferably three of them; optionally, it may further comprise at least one of 19.6±0.2°, 26.2±0.2°, 19.3±0.2°, 21.6±0.2°, and 21.0±0.2°; preferably 2, 3, 4 or 5 of these;

for example, the X-ray powder diffraction pattern of succinate salt form a has diffraction peaks at the following positions in 2θ:21.4±0.2°, 10.7±0.2°, 16.6±0.2°, 19.6±0.2°, 26.2±0.2° and 19.3±0.2°;

The X-ray powder diffraction pattern of succinate crystalline form B comprises at least one or more diffraction peaks at 19.2±0.2°, 21.3±0.2°, 20.7±0.2°, preferably two of them, more preferably three of them; optionally, the composition further comprises at least one of 14.1+ -0.2 °, 20.4+ -0.2 °, 18.5+ -0.2 °, 11.4+ -0.2 °, 23.7+ -0.2 °; preferably 2, 3, 4 or 5 of these;

for example, the X-ray powder diffraction pattern of succinate salt form B has diffraction peaks at the following positions in 2θ: 19.2.+ -. 0.2 °, 21.3.+ -. 0.2 °, 20.7.+ -. 0.2 °, 14.1.+ -. 0.2 °, 20.4.+ -. 0.2 ° and 18.5.+ -. 0.2 °.
The acid salt form of the compound of claim 10 or 11, wherein the X-ray powder diffraction pattern of hydrochloride form a optionally further comprises one or more diffraction peaks at 22.1±0.2°, 24.9±0.2°, 18.9±0.2°, 8.8±0.2°, 26.6±0.2°, 15.7±0.2°, 26.1±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

for example, the X-ray powder diffraction pattern of hydrochloride form a has diffraction peaks at 2θ at the following positions: 26.4±0.2°, 10.8±0.2°, 20.9±0.2°, 14.2±0.2°, 12.5±0.2°, 6.3±0.2°, 22.1±0.2° and 24.9±0.2°;

The X-ray powder diffraction pattern of hydrobromide crystalline form a optionally further comprises one or more diffraction peaks at 21.0±0.2°, 25.8±0.2°, 18.9±0.2°, 26.5±0.2°, 20.8±0.2°, 12.4±0.2°, 28.1±0.2° in 2θ; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

for example, the X-ray powder diffraction pattern of hydrobromide form a has diffraction peaks at 2θ at the following positions: 24.9±0.2°, 26.3±0.2°, 6.2±0.2°, 20.4±0.2°, 15.6±0.2°, 10.5±0.2°, 21.0±0.2° and 25.8±0.2°;

the X-ray powder diffraction pattern of p-toluenesulfonate form a optionally further comprises one or more diffraction peaks at 9.9±0.2°, 23.9±0.2°, 18.0±0.2°, 8.5±0.2°, 12.1±0.2°, 22.0±0.2°, 8.0±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

for example, the X-ray powder diffraction pattern of p-toluenesulfonate form a has diffraction peaks at 2θ:5.5±0.2°, 14.1±0.2°, 21.7±0.2°, 15.6±0.2°, 22.2±0.2°, 24.3±0.2°, 9.9±0.2° and 23.9±0.2°;

The X-ray powder diffraction pattern of sulfate form a optionally further comprises one or more diffraction peaks at 2θ of 10.4±0.2°, 22.4±0.2°, 17.9±0.2°, 18.1±0.2°, 18.2±0.2°, 21.0±0.2°, 22.0±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

for example, the X-ray powder diffraction pattern of sulfate form a has diffraction peaks at 2θ:12.0±0.2°, 11.9±0.2°, 14.1±0.2°, 21.3±0.2°, 22.1±0.2°, 22.3±0.2°, 10.4±0.2°, 22.4±0.2° and 17.9±0.2°;

the X-ray powder diffraction pattern of fumarate salt form a optionally further comprises one or more diffraction peaks at 17.6±0.2°, 18.7±0.2°, 18.9±0.2°, 8.9±0.2°, 7.4±0.2°, 23.1±0.2°, 12.2±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

for example, the X-ray powder diffraction pattern of fumarate salt form a has diffraction peaks at the following positions of 2θ:24.0±0.2°, 15.2±0.2°, 20.9±0.2°, 25.7±0.2°, 13.8±0.2°, 22.1±0.2°, 17.6±0.2°, 18.7±0.2° and 18.9±0.2°;

The X-ray powder diffraction pattern of oxalate crystalline form a optionally further comprises one or more diffraction peaks at 9.7±0.2°, 27.7±0.2°, 8.6±0.2°, 17.4±0.2°, 21.2±0.2°, 20.8±0.2°, 18.6±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

for example, the X-ray powder diffraction pattern of oxalate form a has diffraction peaks at the following positions of 2θ: 5.8.+ -. 0.2 °, 11.6.+ -. 0.2 °, 20.6.+ -. 0.2 °, 14.3.+ -. 0.2 °, 18.4.+ -. 0.2 °, 19.6.+ -. 0.2 °, 9.7.+ -. 0.2 °, 27.7.+ -. 0.2 ° and 8.6.+ -. 0.2 °;

the X-ray powder diffraction pattern of benzoylglycinate form a optionally further comprises one or more diffraction peaks at 25.9±0.2°, 16.6±0.2°, 23.3±0.2°, 9.8±0.2°, 22.8±0.2°, 22.7±0.2°, 17.2±0.2° in 2θ; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

for example, the X-ray powder diffraction pattern of benzoylglycinate form a has diffraction peaks at the following positions in 2θ:5.4±0.2°, 25.1±0.2°, 21.3±0.2°, 18.3±0.2°, 14.6±0.2°, 19.4±0.2°, 25.9±0.2°, 16.6±0.2° and 23.3±0.2°;

The X-ray powder diffraction pattern of benzoylglycinate form B optionally further comprises one or more diffraction peaks at 10.8±0.2°, 22.8±0.2°, 17.3±0.2°, 25.7±0.2°, 9.9±0.2°, 24.2±0.2°, 14.3±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

for example, the X-ray powder diffraction pattern of benzoylglycinate form B has diffraction peaks at the following positions of 2θ:5.4±0.2°, 24.7±0.2°, 18.9±0.2°, 10.5±0.2°, 23.1±0.2°, 20.9±0.2°, 10.8±0.2°, 22.8±0.2° and 17.3±0.2°;

the X-ray powder diffraction pattern of benzoylglycinate form C optionally further comprises one or more diffraction peaks at 19.4±0.2°, 17.5±0.2°, 18.9±0.2°, 10.5±0.2°, 13.8±0.2°, 9.9±0.2°, 21.6±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

for example, the X-ray powder diffraction pattern of benzoylglycinate form C has diffraction peaks at the following positions of 2θ: 5.7.+ -. 0.2 °, 20.4.+ -. 0.2 °, 14.5.+ -. 0.2 °, 15.5.+ -. 0.2 °, 11.1.+ -. 0.2 °, 18.5.+ -. 0.2 °, 19.4.+ -. 0.2 °, 17.5.+ -. 0.2 ° and 18.9.+ -. 0.2 °;

The X-ray powder diffraction pattern of benzoylglycinate form D optionally further comprises one or more diffraction peaks at 14.8±0.2°, 19.9±0.2°, 14.1±0.2°, 22.8±0.2°, 18.2±0.2°, 10.5±0.2°, 18.8±0.2° in 2θ; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

for example, the X-ray powder diffraction pattern of benzoylglycinate form D has diffraction peaks at the following positions of 2θ:17.6±0.2°, 21.0±0.2°, 5.8±0.2°, 25.2±0.2°, 16.6±0.2°, 15.0±0.2°, 9.7±0.2°, 10.2±0.2° and 14.8±0.2°; the X-ray powder diffraction pattern of benzoylglycinate form E optionally further comprises one or more diffraction peaks at 14.5±0.2°, 18.4±0.2°, 12.3±0.2°, 21.1±0.2°, 20.4±0.2°, 16.9±0.2°, 26.3±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

for example, the X-ray powder diffraction pattern of benzoylglycinate form E has diffraction peaks at the following positions in 2θ:5.4±0.2°, 5.3±0.2°, 10.7±0.2°, 20.8±0.2°, 24.7±0.2°, 16.5±0.2°, 14.5±0.2°, 18.4±0.2° and 12.3±0.2°;

The X-ray powder diffraction pattern of benzoylglycinate form F optionally further comprises one or more diffraction peaks at 11.1±0.2°, 13.8±0.2°, 26.1±0.2°, 18.9±0.2°, 18.2±0.2°, 20.2±0.2°, 22.1±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

for example, the X-ray powder diffraction pattern of benzoylglycinate form F has diffraction peaks at the following positions of 2θ: 6.3.+ -. 0.2 °, 12.3.+ -. 0.2 °, 9.3.+ -. 0.2 °, 9.8.+ -. 0.2 °, 11.6.+ -. 0.2 °, 11.1.+ -. 0.2 °, 13.8.+ -. 0.2 ° and 26.1.+ -. 0.2 °;

the X-ray powder diffraction pattern of phosphate form a optionally further comprises one or more diffraction peaks at 11.7±0.2°, 12.1±0.2°, 12.6±0.2°; preferably at least any 2-3 thereof; further preferably, any of positions 2 and 3 is included;

for example, the X-ray powder diffraction pattern of phosphate form a has diffraction peaks at the following positions of 2θ:10.6±0.2°, 12.3±0.2°, 21.4±0.2°, 13.5±0.2°, 6.3±0.2°, 10.9±0.2°, 11.7±0.2° and 12.1±0.2°;

the X-ray powder diffraction pattern of maleate form a optionally further comprises one or more diffraction peaks at 7.1±0.2°, 21.7±0.2°, 19.8±0.2°, 16.6±0.2°, 15.3±0.2°, 21.1±0.2°, 7.7±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

For example, the X-ray powder diffraction pattern of maleate form a has diffraction peaks at 2θ at the following positions: 6.0.+ -. 0.2 °, 22.3.+ -. 0.2 °, 16.3.+ -. 0.2 °, 23.5.+ -. 0.2 °, 19.5.+ -. 0.2 °, 19.2.+ -. 0.2 °, 7.1.+ -. 0.2 °, 21.7.+ -. 0.2 ° and 19.8.+ -. 0.2 °;

the X-ray powder diffraction pattern of maleate form B optionally further comprises one or more diffraction peaks at 6.0±0.2°, 8.2±0.2°, 20.9±0.2°, 15.3±0.2°, 11.7±0.2°, 11.0±0.2°, 24.5±0.2° in 2θ; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

for example, the X-ray powder diffraction pattern of maleate form B has diffraction peaks at 2θ:7.7±0.2°, 16.1±0.2°, 22.2±0.2°, 19.2±0.2°, 21.7±0.2°, 6.5±0.2°, 6.0±0.2°, 8.2±0.2° and 20.9±0.2°;

the X-ray powder diffraction pattern of maleate form C optionally further comprises one or more diffraction peaks at 13.1±0.2°, 22.9±0.2°, 21.3±0.2°, 13.5±0.2°, 20.8±0.2°, 14.9±0.2°, 16.0±0.2° in 2θ; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

For example, the X-ray powder diffraction pattern of maleate form C has diffraction peaks at 2θ:17.1±0.2°, 10.3±0.2°, 14.3±0.2°, 13.3±0.2°, 24.5±0.2°, 25.5±0.2°, 13.1±0.2°, 22.9±0.2° and 21.3±0.2°;

the X-ray powder diffraction pattern of maleate form D optionally further comprises one or more diffraction peaks at 16.1±0.2°, 21.8±0.2°, 17.0±0.2°, 28.4±0.2°, 22.3±0.2°, 12.6±0.2°, 28.8±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

for example, the X-ray powder diffraction pattern of maleate form D has diffraction peaks at 2θ:20.4±0.2°, 8.2±0.2°, 25.9±0.2°, 18.4±0.2°, 8.9±0.2°, 24.1±0.2°, 16.1±0.2°, 21.8±0.2° and 17.0±0.2°;

the X-ray powder diffraction pattern of mesylate form a optionally further comprises one or more diffraction peaks at 11.7±0.2°, 18.0±0.2°, 23.6±0.2°, 7.1±0.2°, 19.6±0.2°, 20.3±0.2°, 9.5±0.2° in 2θ; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

For example, the X-ray powder diffraction pattern of mesylate form a has diffraction peaks at the following positions in 2θ:5.9±0.2°, 21.7±0.2°, 14.2±0.2°, 20.8±0.2°, 25.7±0.2°, 22.2±0.2°, 11.7±0.2°, 18.0±0.2° and 23.6±0.2°;

the X-ray powder diffraction pattern of besylate form a optionally further comprises one or more diffraction peaks at 10.0±0.2°, 10.6±0.2°, 24.5±0.2°, 14.9±0.2°, 24.9±0.2°, 14.6±0.2°, 22.4±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

for example, the X-ray powder diffraction pattern of besylate form a has diffraction peaks at the following positions of 2θ: 5.6.+ -. 0.2 °, 21.2.+ -. 0.2 °, 18.9.+ -. 0.2 °, 26.6.+ -. 0.2 °, 23.7.+ -. 0.2 °, 19.5.+ -. 0.2 °, 10.0.+ -. 0.2 °, 10.6.+ -. 0.2 ° and 24.5.+ -. 0.2 °;

the X-ray powder diffraction pattern of malonate form a optionally further comprises one or more diffraction peaks at 14.3±0.2°, 25.6±0.2°, 19.4±0.2°, 19.7±0.2°, 20.7±0.2°, 18.2±0.2°, 22.0±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

For example, the X-ray powder diffraction pattern of malonic acid salt form a has diffraction peaks at the following positions of 2θ:7.5±0.2°, 5.5±0.2°, 20.3±0.2°, 9.7±0.2°, 11.7±0.2°, 23.0±0.2°, 14.3±0.2°, 25.6±0.2° and 19.4±0.2°;

the X-ray powder diffraction pattern of malonic acid salt form B optionally further comprises one or more diffraction peaks at 18.4±0.2°, 13.9±0.2°, 15.2±0.2°, 18.8±0.2°, 23.6±0.2°, 21.8±0.2°, 27.0±0.2° in 2θ; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

for example, the X-ray powder diffraction pattern of malonic acid salt form B has diffraction peaks at the following positions of 2θ:21.4±0.2°, 5.9±0.2°, 11.4±0.2°, 19.1±0.2°, 20.8±0.2°, 16.1±0.2°, 18.4±0.2°, 13.9±0.2° and 15.2±0.2°;

the X-ray powder diffraction pattern of succinate crystalline form a optionally further comprises one or more diffraction peaks at 16.0±0.2°, 14.4±0.2°, 10.2±0.2°, 23.7±0.2°, 6.5±0.2°, 22.3±0.2°, 15.7±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

For example, the X-ray powder diffraction pattern of succinate salt form a has diffraction peaks at the following positions in 2θ:21.4±0.2°, 10.7±0.2°, 19.6±0.2°, 26.2±0.2°, 19.3±0.2°, 21.6±0.2°, 16.0±0.2°, 14.4±0.2° and 10.2±0.2°;

the X-ray powder diffraction pattern of succinate crystalline form B optionally further comprises one or more diffraction peaks at 27.3±0.2°, 20.8±0.2°, 22.0±0.2°, 16.2±0.2°, 5.8±0.2°, 25.5±0.2°, 18.7±0.2°; preferably at least any of 2 to 3, or 4 to 5, or 6 to 7; further preferably, any of 2, 3, 4, 5, 6, 7 is included;

for example, the X-ray powder diffraction pattern of succinate salt form B has diffraction peaks at the following positions in 2θ: 19.2.+ -. 0.2 °, 21.3.+ -. 0.2 °, 14.1.+ -. 0.2 °, 20.4.+ -. 0.2 °, 18.5.+ -. 0.2 °, 11.4.+ -. 0.2 °, 27.3.+ -. 0.2 °, 20.8.+ -. 0.2 ° and 22.0.+ -. 0.2 °.
The acid salt form of the compound of claim 10, wherein the X-ray powder diffraction pattern of hydrochloride form a comprises diffraction peaks at one or more of 26.4±0.2°, 10.8±0.2°, 20.9±0.2°, 14.2±0.2°, 12.5±0.2°, 6.3±0.2°, 25.0±0.2°, 21.0±0.2, 22.1±0.2°, 24.9±0.2°, 18.9±0.2°, 8.8±0.2°, 26.6±0.2°, 15.7±0.2°, 26.1±0.2°; preferably, the method comprises the steps of optionally having diffraction peaks at 4, 5, 6, 8 and 10;

For example, the X-ray powder diffraction pattern of hydrochloride form a has diffraction peaks at 2θ at the following positions: 26.4±0.2°, 10.8±0.2°, 20.9±0.2°, 14.2±0.2°, 12.5±0.2°, 6.3±0.2°, 25.0±0.2°, 21.0±0.2°, 22.1±0.2° and 18.9±0.2°;

the X-ray powder diffraction pattern of hydrobromide crystalline form a comprises one or more diffraction peaks at 24.9±0.2°, 26.3±0.2°, 6.2±0.2°, 20.4±0.2°, 15.6±0.2°, 10.5±0.2°, 22.6±0.2°, 14.0±0.2°, 21.0±0.2°, 25.8±0.2°, 18.9±0.2°, 26.5±0.2°, 20.8±0.2°, 12.4±0.2°, 28.1±0.2°; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

for example, the X-ray powder diffraction pattern of hydrobromide form a has diffraction peaks at 2θ at the following positions: 24.9±0.2°, 26.3±0.2°, 6.2±0.2°, 20.4±0.2°, 15.6±0.2°, 10.5±0.2°, 22.6±0.2°, 14.0±0.2°, 21.0±0.2° and 25.8±0.2°;

the X-ray powder diffraction pattern of p-toluenesulfonate form a comprises one or more diffraction peaks at 5.5±0.2°, 14.1±0.2°, 21.7±0.2°, 15.6±0.2°, 22.2±0.2°, 24.3±0.2°, 26.8±0.2°, 21.1±0.2°, 9.9±0.2°, 23.9±0.2°, 18.0±0.2°, 8.5±0.2°, 12.1±0.2°, 22.0±0.2°, 8.0±0.2°; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

For example, the X-ray powder diffraction pattern of p-toluenesulfonate form a has diffraction peaks at 2θ: 5.5.+ -. 0.2 °, 14.1.+ -. 0.2 °, 21.7.+ -. 0.2 °, 15.6.+ -. 0.2 °, 22.2.+ -. 0.2 °, 24.3.+ -. 0.2 °, 26.8.+ -. 0.2 °, 21.1.+ -. 0.2 °, 9.9.+ -. 0.2 ° and 23.9.+ -. 0.2 °;

the X-ray powder diffraction pattern of sulfate form a comprises one or more diffraction peaks at 2θ of 12.0±0.2°, 11.9±0.2°, 6.1±0.2°, 14.1±0.2°, 21.3±0.2°, 22.1±0.2°, 22.3±0.2°, 9.6±0.2°, 10.4±0.2°, 22.4±0.2°, 17.9±0.2°, 18.1±0.2°, 18.2±0.2°, 21.0±0.2°, 22.0±0.2°; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

for example, the X-ray powder diffraction pattern of sulfate form a has diffraction peaks at 2θ:12.0±0.2°, 11.9±0.2°, 6.1±0.2°, 14.1±0.2°, 21.3±0.2°, 22.1±0.2°, 22.3±0.2°, 9.6±0.2°, 10.4±0.2° and 17.9±0.2°;

the X-ray powder diffraction pattern of fumarate salt form a comprises one or more diffraction peaks at 24.0±0.2°, 15.2±0.2°, 9.4±0.2°, 20.9±0.2°, 25.7±0.2°, 13.8±0.2°, 22.1±0.2°, 9.7±0.2°, 17.6±0.2°, 18.7±0.2°, 18.9±0.2°, 8.9±0.2°, 7.4±0.2°, 23.1±0.2°, 12.2±0.2°; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

For example, the X-ray powder diffraction pattern of fumarate salt form a has diffraction peaks at the following positions of 2θ:24.0±0.2°, 15.2±0.2°, 9.4±0.2°, 20.9±0.2°, 25.7±0.2°, 13.8±0.2°, 18.7±0.2° and 18.9±0.2°;

the X-ray powder diffraction pattern of oxalate crystalline form a comprises one or more diffraction peaks at 5.8±0.2°, 11.6±0.2°, 21.4±0.2°, 20.6±0.2°, 14.3±0.2°, 18.4±0.2°, 19.6±0.2°, 23.8±0.2°, 9.7±0.2°, 27.7±0.2°, 8.6±0.2°, 17.4±0.2°, 21.2±0.2°, 20.8±0.2°, 18.6±0.2°; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

for example, the X-ray powder diffraction pattern of oxalate form a has diffraction peaks at the following positions of 2θ: 5.8.+ -. 0.2 °, 11.6.+ -. 0.2 °, 21.4.+ -. 0.2 °, 20.6.+ -. 0.2 °, 14.3.+ -. 0.2 °, 18.4.+ -. 0.2 °, 19.6.+ -. 0.2 °, 23.8.+ -. 0.2 °, 9.7.+ -. 0.2 ° and 8.6.+ -. 0.2 °;

the X-ray powder diffraction pattern of benzoylglycinate salt form a comprises one or more diffraction peaks at 5.4±0.2°, 25.1±0.2°, 10.6±0.2°, 21.3±0.2°, 18.3±0.2°, 14.6±0.2°, 19.4±0.2°, 19.0±0.2°, 25.9±0.2°, 16.6±0.2°, 23.3±0.2°, 9.8±0.2°, 22.8±0.2°, 22.7±0.2°, 17.2±0.2°; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

For example, the X-ray powder diffraction pattern of benzoylglycinate form a has diffraction peaks at the following positions in 2θ: 5.4.+ -. 0.2 °, 25.1.+ -. 0.2 °, 10.6.+ -. 0.2 °, 21.3.+ -. 0.2 °, 18.3.+ -. 0.2 °, 14.6.+ -. 0.2 °, 19.4.+ -. 0.2 °, 19.0.+ -. 0.2 °, 25.9.+ -. 0.2 ° and 16.6.+ -. 0.2 °;

the X-ray powder diffraction pattern of benzoylglycinate form B comprises one or more diffraction peaks at 5.4±0.2°, 24.7±0.2°, 19.1±0.2°, 18.9±0.2°, 10.5±0.2°, 23.1±0.2°, 20.9±0.2°, 14.4±0.2°, 10.8±0.2°, 22.8±0.2°, 17.3±0.2°, 25.7±0.2°, 9.9±0.2°, 24.2±0.2°, 14.3±0.2°; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

for example, the X-ray powder diffraction pattern of benzoylglycinate form B has diffraction peaks at the following positions of 2θ:5.4±0.2°, 24.7±0.2°, 19.1±0.2°, 18.9±0.2°, 10.5±0.2°, 23.1±0.2°, 20.9±0.2°, 14.4±0.2°, 10.8±0.2° and 22.8±0.2°;

the X-ray powder diffraction pattern of benzoylglycinate form C comprises one or more diffraction peaks at 5.7±0.2°, 20.4±0.2°, 26.4±0.2°, 14.5±0.2°, 15.5±0.2°, 11.1±0.2°, 18.5±0.2°, 16.8±0.2°, 19.4±0.2°, 17.5±0.2°, 18.9±0.2°, 10.5±0.2°, 13.8±0.2°, 9.9±0.2°, 21.6±0.2°; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

For example, the X-ray powder diffraction pattern of benzoylglycinate form C has diffraction peaks at the following positions of 2θ: 5.7.+ -. 0.2 °, 20.4.+ -. 0.2 °, 26.4.+ -. 0.2 °, 14.5.+ -. 0.2 °, 15.5.+ -. 0.2 °, 11.1.+ -. 0.2 °, 18.5.+ -. 0.2 °, 16.8.+ -. 0.2 °, 19.4.+ -. 0.2 ° and 17.5.+ -. 0.2 °;

the X-ray powder diffraction pattern of the benzoyl glycinate salt crystal form D comprises one or more diffraction peaks positioned in the angles of 17.6+/-0.2 degrees, 21.0+/-0.2 degrees, 5.8+/-0.2 degrees, 25.2+/-0.2 degrees, 16.6+/-0.2 degrees, 15.0+/-0.2 degrees, 9.7+/-0.2 degrees, 10.2+/-0.2 degrees, 14.8+/-0.2 degrees, 19.9+/-0.2 degrees, 14.1+/-0.2 degrees, 22.8+/-0.2 degrees, 18.2+/-0.2 degrees, 10.5+/-0.2 degrees and 18.8+/-0.2 degrees; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

for example, the X-ray powder diffraction pattern of benzoylglycinate form D has diffraction peaks at 2θ:17.6±0.2°, 21.0±0.2°, 5.8±0.2° and 25.2±0.2°;

alternatively, 17.6±0.2°, 21.0±0.2°, 5.8±0.2°, 25.2±0.2°, 16.6±0.2° and 15.0±0.2°;

or 17.6±0.2°, 21.0±0.2°, 5.8±0.2°, 25.2±0.2°, 16.6±0.2°, 15.0±0.2°, 9.7±0.2°, 10.2±0.2°, 19.9±0.2° and 14.1±0.2°;

The X-ray powder diffraction pattern of the benzoyl glycinate salt crystal form E comprises one or more diffraction peaks positioned in the angles of 5.4+/-0.2 degrees, 5.3+/-0.2 degrees, 5.6+/-0.2 degrees, 10.7+/-0.2 degrees, 20.8+/-0.2 degrees, 24.7+/-0.2 degrees, 16.5+/-0.2 degrees, 21.5+/-0.2 degrees, 14.5+/-0.2 degrees, 18.4+/-0.2 degrees, 12.3+/-0.2 degrees, 21.1+/-0.2 degrees, 20.4+/-0.2 degrees, 16.9+/-0.2 degrees and 26.3+/-0.2 degrees; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

for example, the X-ray powder diffraction pattern of benzoylglycinate form E has diffraction peaks at 2θ:5.4±0.2°, 5.3±0.2°, 5.6±0.2°, 10.7±0.2°, 20.8±0.2°, 24.7±0.2°, 16.5±0.2°, 21.5±0.2°, 14.5±0.2° and 18.4±0.2°;

the X-ray powder diffraction pattern of the benzoyl glycinate salt crystal form F comprises one or more diffraction peaks positioned in the angles of 6.1+/-0.2 degrees, 6.3+/-0.2 degrees, 10.3+/-0.2 degrees, 12.3+/-0.2 degrees, 9.3+/-0.2 degrees, 9.8+/-0.2 degrees, 11.6+/-0.2 degrees, 5.5+/-0.2 degrees, 11.1+/-0.2 degrees, 13.8+/-0.2 degrees, 26.1+/-0.2 degrees, 18.9+/-0.2 degrees, 18.2+/-0.2 degrees, 20.2+/-0.2 degrees and 22.1+/-0.2 degrees; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

For example, the X-ray powder diffraction pattern of benzoylglycinate form F has diffraction peaks at 2θ: 6.1.+ -. 0.2 °, 6.3.+ -. 0.2 °, 10.3.+ -. 0.2 °, 12.3.+ -. 0.2 °, 9.3.+ -. 0.2 °, 9.8.+ -. 0.2 °, 11.6.+ -. 0.2 °, 5.5.+ -. 0.2 °, 11.1.+ -. 0.2 ° and 13.8.+ -. 0.2 °;

the X-ray powder diffraction pattern of the phosphate crystal form A comprises one or more diffraction peaks positioned in the angles of 10.6+/-0.2 DEG, 12.3+/-0.2 DEG, 9.2+/-0.2 DEG, 21.4+/-0.2 DEG, 13.5+/-0.2 DEG, 6.3+/-0.2 DEG, 10.9+/-0.2 DEG, 25.3+/-0.2 DEG, 11.7+/-0.2 DEG, 12.1+/-0.2 DEG and 12.6+/-0.2 DEG of 2 theta; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

for example, the X-ray powder diffraction pattern of phosphate form a has diffraction peaks at 2θ:10.6±0.2°, 12.3±0.2°, 9.2±0.2°, 21.4±0.2°, 13.5±0.2°, 6.3±0.2°, 10.9±0.2°, 25.3±0.2°, 11.7±0.2° and 12.6±0.2°;

the X-ray powder diffraction pattern of the maleate crystal form A comprises one or more diffraction peaks positioned in the angles of 6.0+/-0.2 degrees, 22.3+/-0.2 degrees, 8.2+/-0.2 degrees, 16.3+/-0.2 degrees, 23.5+/-0.2 degrees, 19.5+/-0.2 degrees, 19.2+/-0.2 degrees, 11.8+/-0.2 degrees, 7.1+/-0.2 degrees, 21.7+/-0.2 degrees, 19.8+/-0.2 degrees, 16.6+/-0.2 degrees, 15.3+/-0.2 degrees, 21.1+/-0.2 degrees and 7.7+/-0.2 degrees; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

For example, the X-ray powder diffraction pattern of maleate form a has diffraction peaks at 2θ: 6.0.+ -. 0.2 °, 22.3.+ -. 0.2 °, 8.2.+ -. 0.2 °, 16.3.+ -. 0.2 °, 23.5.+ -. 0.2 °, 19.5.+ -. 0.2 °, 19.2.+ -. 0.2 °, 11.8.+ -. 0.2 °, 7.1.+ -. 0.2 ° and 21.7.+ -. 0.2 °;

the X-ray powder diffraction pattern of the maleate crystal form B comprises one or more diffraction peaks positioned in the angles of 7.7+/-0.2 degrees, 16.1+/-0.2 degrees, 23.6+/-0.2 degrees, 22.2+/-0.2 degrees, 19.2+/-0.2 degrees, 21.7+/-0.2 degrees, 6.5+/-0.2 degrees, 19.8+/-0.2 degrees, 6.0+/-0.2 degrees, 8.2+/-0.2 degrees, 20.9+/-0.2 degrees, 15.3+/-0.2 degrees, 11.7+/-0.2 degrees, 11.0+/-0.2 degrees and 24.5+/-0.2 degrees; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

for example, the X-ray powder diffraction pattern of maleate form B has diffraction peaks at 2θ:7.7±0.2°, 16.1±0.2°, 23.6±0.2°, 22.2±0.2°, 19.2±0.2°, 21.7±0.2°, 6.5±0.2°, 19.8±0.2°, 6.0±0.2° and 8.2±0.2°;

the X-ray powder diffraction pattern of the maleate crystal form C comprises one or more diffraction peaks positioned in the angles of 17.1+/-0.2 degrees, 10.3+/-0.2 degrees, 23.8+/-0.2 degrees, 14.3+/-0.2 degrees, 13.3+/-0.2 degrees, 24.5+/-0.2 degrees, 25.5+/-0.2 degrees, 23.5+/-0.2 degrees, 13.1+/-0.2 degrees, 22.9+/-0.2 degrees, 21.3+/-0.2 degrees, 13.5+/-0.2 degrees, 20.8+/-0.2 degrees, 14.9+/-0.2 degrees and 16.0+/-0.2 degrees; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

For example, the X-ray powder diffraction pattern of maleate form C has diffraction peaks at 2θ:17.1±0.2°, 10.3±0.2°, 23.8±0.2°, 14.3±0.2°, 13.3±0.2°, 24.5±0.2°, 25.5±0.2°, 23.5±0.2°, 13.1±0.2° and 22.9±0.2°;

the X-ray powder diffraction pattern of the maleate crystal form D comprises one or more diffraction peaks positioned in 20.4+/-0.2 degrees, 8.2+/-0.2 degrees, 14.6+/-0.2 degrees, 25.9+/-0.2 degrees, 18.4+/-0.2 degrees, 8.9+/-0.2 degrees, 24.1+/-0.2 degrees, 24.5+/-0.2 degrees, 16.1+/-0.2 degrees, 21.8+/-0.2 degrees, 17.0+/-0.2 degrees, 28.4+/-0.2 degrees, 22.3+/-0.2 degrees, 12.6+/-0.2 degrees and 28.8+/-0.2 degrees; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

for example, the X-ray powder diffraction pattern of maleate form D has diffraction peaks at 2θ:20.4±0.2°, 8.2±0.2°, 14.6±0.2°, 25.9±0.2°, 18.4±0.2°, 8.9±0.2°, 24.1±0.2°, 24.5±0.2°, 16.1±0.2° and 21.8±0.2°;

the X-ray powder diffraction pattern of the mesylate salt crystal form A comprises one or more diffraction peaks positioned in the angles of 5.9+/-0.2 degrees, 21.7+/-0.2 degrees, 10.2+/-0.2 degrees, 14.2+/-0.2 degrees, 20.8+/-0.2 degrees, 25.7+/-0.2 degrees, 22.2+/-0.2 degrees, 17.4+/-0.2 degrees, 11.7+/-0.2 degrees, 18.0+/-0.2 degrees, 23.6+/-0.2 degrees, 7.1+/-0.2 degrees, 19.6+/-0.2 degrees, 20.3+/-0.2 degrees and 9.5+/-0.2 degrees; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

For example, the X-ray powder diffraction pattern of mesylate form a has diffraction peaks at 2θ:5.9±0.2°, 21.7±0.2°, 10.2±0.2°, 14.2±0.2°, 20.8±0.2°, 25.7±0.2°, 22.2±0.2°, 17.4±0.2°, 11.7±0.2° and 18.0±0.2°;

the X-ray powder diffraction pattern of the benzenesulfonate crystal form A comprises one or more diffraction peaks positioned in the angles of 5.6+/-0.2 degrees, 21.2+/-0.2 degrees, 13.4+/-0.2 degrees, 18.9+/-0.2 degrees, 26.6+/-0.2 degrees, 23.7+/-0.2 degrees, 19.5+/-0.2 degrees, 26.4+/-0.2 degrees, 10.0+/-0.2 degrees, 10.6+/-0.2 degrees, 24.5+/-0.2 degrees, 14.9+/-0.2 degrees, 24.9+/-0.2 degrees, 14.6+/-0.2 degrees and 22.4+/-0.2 degrees; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

for example, the X-ray powder diffraction pattern of besylate form a has diffraction peaks at the following positions of 2θ: 5.6.+ -. 0.2 °, 21.2.+ -. 0.2 °, 13.4.+ -. 0.2 °, 18.9.+ -. 0.2 °, 26.6.+ -. 0.2 °, 23.7.+ -. 0.2 °, 19.5.+ -. 0.2 °, 26.4.+ -. 0.2 °, 10.0.+ -. 0.2 ° and 10.6.+ -. 0.2 °;

the X-ray powder diffraction pattern of the malonate crystal form A comprises one or more diffraction peaks positioned in the angles of 7.5+/-0.2 degrees, 5.5+/-0.2 degrees, 23.6+/-0.2 degrees, 20.3+/-0.2 degrees, 9.7+/-0.2 degrees, 11.7+/-0.2 degrees, 23.0+/-0.2 degrees, 21.0+/-0.2 degrees, 14.3+/-0.2 degrees, 25.6+/-0.2 degrees, 19.4+/-0.2 degrees, 19.7+/-0.2 degrees, 20.7+/-0.2 degrees, 18.2+/-0.2 degrees and 22.0+/-0.2 degrees; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

For example, the malonate form a has an X-ray powder diffraction pattern with diffraction peaks at 2θ:7.5±0.2°, 5.5±0.2°, 23.6±0.2°, 20.3±0.2°, 9.7±0.2°, 11.7±0.2°, 23.0±0.2°, 21.0±0.2°, 14.3±0.2° and 25.6±0.2°;

the X-ray powder diffraction pattern of the malonate crystal form B comprises one or more diffraction peaks positioned in 21.4+/-0.2 degrees, 5.9+/-0.2 degrees, 20.5+/-0.2 degrees, 11.4+/-0.2 degrees, 19.1+/-0.2 degrees, 20.8+/-0.2 degrees, 16.1+/-0.2 degrees, 27.4+/-0.2 degrees, 18.4+/-0.2 degrees, 13.9+/-0.2 degrees, 15.2+/-0.2 degrees, 18.8+/-0.2 degrees, 23.6+/-0.2 degrees, 21.8+/-0.2 degrees and 27.0+/-0.2 degrees; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

for example, the malonate form B has an X-ray powder diffraction pattern with diffraction peaks at 2θ:21.4±0.2°, 5.9±0.2°, 20.5±0.2°, 11.4±0.2°, 19.1±0.2°, 20.8±0.2°, 16.1±0.2°, 27.4±0.2°, 18.4±0.2° and 13.9±0.2°;

the X-ray powder diffraction pattern of the succinate salt crystal form A comprises one or more diffraction peaks positioned in 21.4+/-0.2 degrees, 10.7+/-0.2 degrees, 16.6+/-0.2 degrees, 19.6+/-0.2 degrees, 26.2+/-0.2 degrees, 19.3+/-0.2 degrees, 21.6+/-0.2 degrees, 21.0+/-0.2 degrees, 16.0+/-0.2 degrees, 14.4+/-0.2 degrees, 10.2+/-0.2 degrees, 23.7+/-0.2 degrees, 6.5+/-0.2 degrees, 22.3+/-0.2 degrees and 15.7+/-0.2 degrees; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

For example, the X-ray powder diffraction pattern of succinate salt form a has diffraction peaks at 2θ:21.4±0.2°, 10.7±0.2°, 16.6±0.2°, 19.6±0.2°, 26.2±0.2°, 19.3±0.2°, 21.6±0.2°, 21.0±0.2°, 16.0±0.2° and 14.4±0.2°;

the X-ray powder diffraction pattern of the succinate salt crystal form B comprises one or more diffraction peaks positioned at the angles of 19.2+/-0.2 DEG, 21.3+/-0.2 DEG, 20.7+/-0.2 DEG, 14.1+/-0.2 DEG, 20.4+/-0.2 DEG, 18.5+/-0.2 DEG, 11.4+/-0.2 DEG, 23.7+/-0.2 DEG, 27.3+/-0.2 DEG, 20.8+/-0.2 DEG, 22.0+/-0.2 DEG, 16.2+/-0.2 DEG, 5.8+/-0.2 DEG, 25.5+/-0.2 DEG and 18.7+/-0.2 DEG; preferably, it comprises a diffraction peak at 4, 5, 6, 8 or 10, optionally;

for example, the X-ray powder diffraction pattern of succinate salt form B has diffraction peaks at the following positions of 2θ: 19.2.+ -. 0.2 °, 21.3.+ -. 0.2 °, 20.7.+ -. 0.2 °, 14.1.+ -. 0.2 °, 20.4.+ -. 0.2 °, 18.5.+ -. 0.2 °, 11.4.+ -. 0.2 °, 23.7.+ -. 0.2 °, 27.3.+ -. 0.2 ° and 20.8.+ -. 0.2 °.
The acid salt form of the compound of claim 10, wherein the X-ray powder diffraction pattern of hydrochloride form a is shown in figure 1; the X-ray powder diffraction pattern of the hydrobromide crystal form A is shown in figure 4; the X-ray powder diffraction pattern of the p-toluenesulfonate salt form a is shown in fig. 7; the X-ray powder diffraction pattern of the sulfate crystal form A is shown in figure 10; the X-ray powder diffraction pattern of the fumarate salt form a is shown in fig. 11; the X-ray powder diffraction pattern of the oxalate crystal form A is shown in figure 12; the X-ray powder diffraction pattern of the benzoyl glycinate salt crystal form A is shown in figure 13; the X-ray powder diffraction pattern of the benzoyl glycinate salt crystal form B is shown in figure 14; the X-ray powder diffraction pattern of the benzoyl glycinate salt crystal form C is shown in figure 15; the X-ray powder diffraction pattern of the benzoyl glycinate salt crystal form D is shown in figure 16; the X-ray powder diffraction pattern of the benzoylglycinate salt form E is shown in figure 19; the X-ray powder diffraction pattern of the benzoyl glycinate salt crystal form F is shown in figure 20; the X-ray powder diffraction pattern of the phosphate crystal form A is shown in figure 21; the X-ray powder diffraction pattern of the maleate salt form A is shown in figure 22; the X-ray powder diffraction pattern of the maleate salt form B is shown in figure 23; the X-ray powder diffraction pattern of maleate form C is shown in figure 24; the X-ray powder diffraction pattern of the maleate salt form D is shown in figure 25; the X-ray powder diffraction pattern of the mesylate salt form a is shown in fig. 26; the X-ray powder diffraction pattern of the benzenesulfonate crystal form A is shown in FIG. 27; the X-ray powder diffraction pattern of malonate form A is shown in FIG. 28; the X-ray powder diffraction pattern of malonate form B is shown in fig. 29; the X-ray powder diffraction pattern of the succinate salt crystal form A is shown in a figure 30; the X-ray powder diffraction pattern of the succinate salt crystal form B is shown in figure 31;

Or, the diffraction peak positions of the relative peak intensities of the X-ray powder diffraction patterns of the hydrochloride crystal form a, the hydrobromide crystal form a, the p-toluenesulfonate crystal form a, the sulfate crystal form a, the fumarate crystal form a, the oxalate crystal form a, the benzoyl glycinate crystal form B, the benzoyl glycinate crystal form C, the benzoyl glycinate crystal form D, the benzoyl glycinate crystal form E, the benzoyl glycinate crystal form F, the phosphate crystal form a, the maleate crystal form B, the maleate crystal form C, the maleate crystal form D, the methanesulfonate crystal form a, the benzenesulfonate crystal form a, the malonate crystal form B, the succinate crystal form a and the succinate crystal form B are respectively in the most preferable diffraction angle of 0.2 ° to the diffraction peak positions of 3 to 2 ° in the X-ray powder diffraction patterns of fig. 1, fig. 4, fig. 7, fig. 10, fig. 11, fig. 12, fig. 13, fig. 14, fig. 15, fig. 16, fig. 19, fig. 20, fig. 21, fig. 22, fig. 23, fig. 24, fig. 25, fig. 26, fig. 27, fig. 29 to 2.30, ±2° 2 to 2.0.0 °;

alternatively, the hydrochloride form a has a DSC profile as shown in figure 2; or have a TGA profile as shown in fig. 3; the hydrobromide form a has a DSC profile as shown in figure 5; or have a TGA profile as shown in fig. 6; the p-toluenesulfonate crystal form A has a DSC chart shown in figure 8; or have a TGA profile as shown in fig. 9; the benzoyl glycinate salt crystal form D has a DSC profile as shown in figure 17; or have a TGA profile as shown in fig. 18.
A process for the preparation of an acid salt according to any one of claims 1 to 9, characterized in that it comprises in particular the following steps:

1) Weighing a proper amount of free alkali, and dissolving with benign solvent;

2) Weighing a proper amount of acid, optionally dissolving with an organic solvent; the amount of acid is preferably 1.0 to 1.5 equivalents;

3) Mixing the above two solutions, stirring to separate out or dripping poor solvent, and stirring to separate out;

4) Rapidly centrifuging or standing and drying to obtain a target product;

wherein:

the benign solvent is selected from acetone, toluene, acetonitrile, methanol, methylene dichloride, tetrahydrofuran, ethyl formate, ethyl acetate, 2-methyl-tetrahydrofuran, 2-butanone, N-butanol, 1, 4-dioxane, isobutanol, N-dimethylformamide, N-dimethylacetamide, N-propanol or tert-butanol; toluene, ethyl acetate, acetone, methanol or acetonitrile are preferred;

the organic solvent is selected from methanol, ethanol, ethyl acetate, methylene dichloride, acetone, normal hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-methyl-tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tertiary butyl ether, isopropyl ether, 1, 4-dioxane, tertiary butanol or N, N-dimethylformamide; preferably methanol, ethanol or acetonitrile; the benign solvent and the organic solution need to be mutually soluble when in use;

The poor solvent is selected from heptane, water, methyl tertiary butyl ether, cyclohexane, toluene, isopropyl ether, ethyl acetate, acetone or acetonitrile; preferably water, methyl tert-butyl ether or isopropyl ether;

or, specifically, the method comprises the following steps:

1) Weighing a proper amount of free alkali, and suspending with an unfavorable solvent;

2) Weighing a proper amount of acid, and dissolving the acid in an organic solvent; the amount of acid is preferably 1.0 to 1.5 equivalents;

3) Adding the solution obtained in the step 2) into the suspension obtained in the step 1), and stirring;

4) Rapidly centrifuging or standing and drying to obtain a target product;

wherein:

the poor solvent is selected from ethanol, acetone, ethyl acetate, ethyl formate, isopropanol, isopropyl acetate, methyl tertiary butyl ether, methanol, 1, 4-dioxane, 2-butanone, 2-methyl-tetrahydrofuran, anisole, acetonitrile, chlorobenzene, benzene, toluene, n-butanol, isobutanol or 3-pentanone; preferably ethanol, 2-methyl-tetrahydrofuran, anisole or ethyl acetate;

the organic solvent is selected from methanol, ethanol, ethyl acetate, methylene dichloride, acetone, normal hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-methyl-tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tertiary butyl ether, isopropyl ether, 1, 4-dioxane, tertiary butanol or N, N-dimethylformamide; preferably methanol, ethanol or acetonitrile; the benign solvent and the organic solution need to be mutually soluble when in use;

The acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2, 5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexane sulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecylsulfuric acid, dibenzoyltartaric acid ethane-1, 2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, benzoylglycine, hydroxyethanesulfonic acid, lactonic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1, 5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, pamoic acid, formic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid or L-malic acid; preferably hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, sulfuric acid, fumaric acid, oxalic acid, benzoylglycine, phosphoric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, malonic acid, succinic acid, hydroxyethanesulfonic acid, 1, 5-naphthalenedisulfonic acid, tartaric acid, adipic acid, formic acid, lauric acid or stearic acid; more preferably hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, sulfuric acid, fumaric acid, oxalic acid, benzoylglycine, phosphoric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, malonic acid or succinic acid; most preferred is benzoylglycine.
A process for the preparation of the acid salt form of a compound according to any one of claims 10 to 14, characterized in that it comprises in particular the following steps:

1) Weighing a proper amount of compound salt, and suspending with a poor solvent;

2) Shaking the suspension in the step 1) for a certain time at a certain temperature;

3) Centrifuging the suspension in the step 2) rapidly, removing supernatant, and drying the residual solid to constant weight to obtain a target product;

wherein:

the poor solvent is selected from methanol, ethanol, methylene dichloride, 1, 4-dioxane, acetonitrile, methylene dichloride, chlorobenzene, benzene, toluene, acetone, ethyl acetate, water, 88% acetone, isopropyl acetate, 3-pentanone, ethyl formate, tetrahydrofuran, 2-methyl-tetrahydrofuran, isopropanol, n-butanol, isobutanol, n-propanol, methyl tertiary butyl ether, n-heptane, tertiary butanol or 2-butanone.
A pharmaceutical composition comprising a therapeutically effective amount of an acid salt of a compound of any one of claims 1-9 or an acid salt form of any one of claims 10-14, and one or more pharmaceutically acceptable carriers or excipients.
The use of an acid salt of a compound according to any one of claims 1 to 9 or of an acid salt crystalline form according to any one of claims 10 to 14, and a pharmaceutical composition according to claim 17 in the manufacture of a kinase inhibitor medicament; preferably, the kinase inhibitor is a receptor tyrosine kinase inhibitor, more preferably a HER2 inhibitor, an EGFR inhibitor and an EGFR mab and combinations thereof, and further preferably a HER2 exon mutant inhibitor, an EGFR20 exon mutant inhibitor and an EGFR20 exon mutant mab and combinations thereof.
The use of an acid salt of a compound according to any one of claims 1-9 or an acid salt crystalline form according to any one of claims 10-14, and a pharmaceutical composition according to claim 17 in the manufacture of a medicament for the treatment of cancer, inflammation, chronic liver disease, diabetes, cardiovascular disease and AIDS related diseases, preferably, the cancer, inflammation, chronic liver disease, diabetes, cardiovascular disease and AIDS related diseases are diseases mediated by HER2 20 exon mutations and/or EGFR20 exon mutations; more preferably, the cancer is selected from the group consisting of breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, liver cancer, solid tumors, glioma, neuroglioblastoma, leukemia, lymphoma, myeloma, and non-small cell lung cancer.