Salt form and crystal form of nitrogen-containing heterocyclic derivative inhibitor as well as preparation method and application of salt form and crystal form

Abstract

The invention relates to a salt form and a crystal form of a nitrogen-containing heterocyclic derivative inhibitor as well as a preparation method and application of the salt form and the crystal form. Particularly, the invention relates to a salt form and a crystal form of a compound shown in a general formula, a preparation method of the salt form and the crystal form, a pharmaceutical composition containing the compound, and application of the pharmaceutical composition serving as an inhibitor in cancer treatment.

Description

Salt form, crystal form, preparation method and application of nitrogen-containing heterocyclic derivative inhibitor Technical Field

[0001] The present invention belongs to the field of biomedicine, and specifically relates to a salt form, a crystal form, a preparation method and an application of a nitrogen-containing heterocyclic derivative inhibitor. Background Art

[0002] EGFR (Epidermal Growth Factor Receptor) is a member of the ErbB family of transmembrane receptor tyrosine kinases and is activated by binding to its ligands, epidermal growth factor (EGF) or transforming growth factor α (TGFα). Activated EGFR forms homodimers on the cell membrane, or forms heterodimers with other receptors in the family (such as ErbB-2, ErbB-3, or ErbB-4), causing phosphorylation of key tyrosine residues in the EGFR cell, thereby activating downstream signaling pathways in the cell and playing an important role in cell proliferation, survival, and anti-apoptosis. Activating mutations, overexpression, or gene amplification of EGFR can lead to excessive activation of EGFR, promoting the transformation of cells into tumor cells, and playing an important role in the proliferation, invasion, metastasis, and angiogenesis of tumor cells. It is an important target for the development of anticancer drugs, especially for the treatment of lung cancer.

[0003] First-generation EGFR small-molecule inhibitors, including gefitinib (Iressa) and erlotinib (Tarceva), have demonstrated promising efficacy in the treatment of lung cancer and are used as first-line treatment for non-small cell lung cancer (NSCLC) harboring activating EGFR mutations, including L858R and delE746_A750. However, after 10-12 months of treatment with first-generation small-molecule EGFR inhibitors, nearly all NSCLC patients develop resistance to these inhibitors, with more than half of these resistance mechanisms attributed to secondary mutations at residue T790M in the EGFR gatekeeper gene.

[0004] Osimertinib (AZD9291) is a third-generation EGFR TKI inhibitor with a high response rate and excellent therapeutic efficacy against drug resistance caused by the EGFR T790M mutation. It received accelerated approval from the US FDA in November 2015 and is clinically effective in treating patients with advanced non-small cell lung cancer (NSCLC) harboring the EGFR T790M resistance mutation. Despite the significant clinical success of osimertinib in treating NSCLC harboring the EGFR T790M mutation, resistance inevitably develops in patients after 9 to 14 months of treatment. Studies have shown that up to 20 to 40% of these patients are attributable to the EGFR C797S mutation. The EGFR C797S mutation converts cysteine ​​at position 797 to serine, preventing osimertinib from forming a covalent bond with the EGFR protein and thus causing drug resistance. Currently, no effective inhibitors are available for the EGFR C797S resistance mutation. Therefore, there is an urgent need to develop new and highly active EGFR inhibitors to address the drug resistance problem caused by the EGFR C797S mutation.

[0005] Novartis reported that EAI0450, an allosteric EGFR inhibitor targeting EGFR C797S resistance, demonstrated promising antitumor efficacy in a mouse model harboring the L858R / T790M / C797S mutation when combined with an EGFR monoclonal antibody, such as cetuximab. However, the compound was ineffective alone and failed to inhibit the C797S resistance mutation, including deIE746_A750, and thus failed to enter clinical trials. In 2017, Ken Uchibori et al. reported that the combination of brigatinib (AP26113) and an EGFR monoclonal antibody, such as cetuximab, could overcome resistance to third-generation EGFR inhibitors caused by the C797S mutation. The compound demonstrated promising antitumor efficacy in the PC9 (EGFR-C797S / T790M / de119) mouse model. However, brigatinib also faced low in vitro activity and no significant in vivo antitumor activity as a single agent, and thus has not been further studied in clinical trials.

[0006] Lung cancer is a major threat to human health, with the highest mortality rate among all malignant tumors. In my country, the incidence of lung cancer continues to rise, with approximately 700,000 new cases reported annually. Approximately 35% of all NSCLC cases in my country harbor activating EGFR mutations. While first- and third-generation EGFR inhibitors offer promising treatment outcomes, these treatments often lead to the development of new resistance mutations. Therefore, developing a new generation of EGFR inhibitors with resistance-fighting potential holds significant clinical and market value.

[0007] Patent PCT / CN2023 / 082178 discloses a series of nitrogen-containing heterocyclic derivative inhibitors. In subsequent research and development, in order to facilitate product handling, filtration, and drying, and to seek suitable crystals that are easy to store, have long-term product stability, and high bioavailability, the present invention conducted a comprehensive study of the crystalline forms of the above-mentioned compounds.

[0008] Summary of the Invention

[0009] All contents involved in patent PCT / CN2023 / 082178 are added to the present invention by reference.

[0010] The object of the present invention is to provide a compound represented by general formula (I) or a crystalline form of its stereoisomer or an acid addition salt thereof.

[0011] Wherein: M1 is independently selected from a bond, NR4 or CR5R6;

[0012] R1 is selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl or deuterated C 1-6 alkyl;

[0013] R 2-1 、R 2-2 、R 2-3 and R 2-4 are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl or deuterated C 1-6 alkyl;

[0014] R 2-5 Selected from amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl or deuterated C 1-6 Alkyl, the amino, C 1- 6 alkyl, halogenated C 1-6 Alkyl or deuterated C 1-6 The alkyl group may be further optionally substituted with deuterium, halogen, cyano, hydroxyl, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl and deuterated C 1-6 one or more substitutions in the alkyl group;

[0015] R 3-1 、R 3-2 and R 3-3 are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl or deuterated C 1-6 alkyl;

[0016] R4 is selected from hydrogen, deuterium, C 1-6 Alkyl, halogenated C 1-6 Alkyl or deuterated C 1-6 alkyl;

[0017] R5 and R6 are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl or deuterated C 1- 6-alkyl;

[0018] The acid in the acid addition salt is selected from an inorganic acid or an organic acid; wherein the inorganic acid is selected from 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, hexanoic 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 , dodecyl sulfuric acid, dibenzoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactosonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalene disulfonic 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, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, n-butyric acid, p-hydroxybenzoic acid, or L-malic acid;

[0019] Preferably, the acid in the acid addition salt is selected from phosphoric acid, hydrochloric acid, sulfuric acid, hydrobromic acid, citric acid, oxalic acid, maleic acid, salicylic acid or p-hydroxybenzoic acid.

[0020] In certain embodiments of the present invention,

[0021] R1 is selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, halogenated C 1-3 Alkyl or deuterated C 1-3 alkyl;

[0022] R 2-1 、R 2-2 、R 2-3 and R 2-4 are each independently selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, halogenated C 1-3 Alkyl or deuterated C 1-3 alkyl;

[0023] R 2-5 Selected from amino, C 1-3 Alkyl, halogenated C 1-3 Alkyl or deuterated C 1-3 Alkyl, the amino, C 1- 3 alkyl, halogenated C 1-3 Alkyl or deuterated C 1-3 The alkyl group may be further optionally substituted with deuterium, halogen, cyano, hydroxyl, nitro, C 1-3 Alkyl, halogenated C 1-3 Alkyl and deuterated C 1-3 one or more substitutions in the alkyl group;

[0024] R 3-1 、R 3-2 and R 3-3 are each independently selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, halogenated C 1-3 Alkyl or deuterated C 1-3 alkyl;

[0025] R4 is selected from hydrogen, deuterium, C 1-3 Alkyl, halogenated C 1-3 Alkyl or deuterated C 1-3 alkyl;

[0026] R5 and R6 are each independently selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, halogenated C 1-3 Alkyl or deuterated C 1- 3 alkyl.

[0027] In certain embodiments of the present invention, the number of acids in the acid addition salt is 1, 2 or 3.

[0028] In certain embodiments of the present invention, the acid addition salt is a hydrate or an anhydrate, preferably an anhydrate.

[0029] In certain embodiments of the present invention, the acid addition salt is amorphous or crystalline.

[0030] In certain embodiments of the present invention, the crystalline form is a hydrate or anhydrate, preferably anhydrate.

[0031] In certain embodiments of the present invention, the crystalline form is N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide phosphate crystalline form A.

[0032] The X-ray powder diffraction pattern of Form A has a diffraction peak at 2θ of 4.5±0.2°; or a diffraction peak at 8.8±0.2°; or a diffraction peak at 10.8±0.2°; or a diffraction peak at 12.9±0.2°; or a diffraction peak at 14.4±0.2°; or a diffraction peak at 15.3±0.2°; or a diffraction peak at 16.3±0.2°. ; or has a diffraction peak at 17.1±0.2°; or has a diffraction peak at 17.9±0.2°; or has a diffraction peak at 25.2±0.2°; preferably includes any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9 or 10 thereof;

[0033] Preferably, the X-ray powder diffraction pattern of Form A comprises at least one or more diffraction peaks located at 2θ of 4.5±0.2°, 8.8±0.2°, and 10.8±0.2°, preferably 2 of them, and more preferably 3 of them; optionally, it may further comprise at least one of 2θ of 12.9±0.2°, 14.4±0.2°, 16.3±0.2°, and 17.1±0.2°; preferably 2, 3, 4, or 5 of them;

[0034] Preferably, the X-ray powder diffraction pattern of Form A optionally further comprises one or more diffraction peaks located at 2θ of 9.0±0.2°, 15.3±0.2°, 18.0±0.2°, 19.3±0.2°, 21.8±0.2°, 25.2±0.2°, and 27.9±0.2°; preferably, at least any 2-3, or 4-5 of them; further preferably, any 2, 3, 4, or 5 of them are included;

[0035] Further preferably, the X-ray powder diffraction pattern of Form A comprises diffraction peaks at 2θ of 4.5±0.2° and 8.8±0.2°; preferably, further comprises diffraction peaks at 10.8±0.2° and 17.1±0.2°; more preferably, further comprises diffraction peaks at 12.9±0.2° and 14.4±0.2°; further preferably, further comprises diffraction peaks at 15.3±0.2° and 16.3±0.2°; even more preferably, further comprises diffraction peaks at 18.0±0.2° and 25.2±0.2°;

[0036] For example, the X-ray powder diffraction pattern of the crystalline form A has diffraction peaks at the following positions at 2θ:

[0037] 8.8±0.2°, 10.8±0.2°;

[0038] 4.5±0.2°、10.8±0.2°；

[0039] 4.5±0.2°、8.8±0.2°；

[0040] 4.5±0.2°、8.8±0.2°、10.8±0.2°；

[0041] 8.8±0.2°、10.8±0.2°、12.9±0.2°；

[0042] 4.5±0.2°、10.8±0.2°、16.3±0.2°；

[0043] 4.5±0.2°、8.8±0.2°、17.1±0.2°；

[0044] 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°；

[0045] 4.5±0.2°、8.8±0.2°、10.8±0.2°、14.4±0.2°；

[0046] 8.8±0.2°、10.8±0.2°、12.9±0.2°、16.3±0.2°；

[0047] 4.5±0.2°、10.8±0.2°、14.4±0.2°、16.3±0.2°；

[0048] 4.5±0.2°、8.8±0.2°、12.9±0.2°、17.1±0.2°；

[0049] 8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、17.1±0.2°；

[0050] 4.5±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、17.1±0.2°；

[0051] 4.5±0.2°、8.8±0.2°、12.9±0.2°、14.4±0.2°、17.1±0.2°；

[0052] 4.5±0.2°、8.8±0.2°、10.8±0.2°、14.4±0.2°、17.1±0.2°；

[0053] 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、17.1±0.2°；

[0054] 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°；

[0055] 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、17.1±0.2°；

[0056] 8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、17.1±0.2°；

[0057] 4.5±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、16.3±0.2°、17.1±0.2°；

[0058] 4.5±0.2°、8.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、17.1±0.2°；

[0059] 4.5±0.2°、8.8±0.2°、10.8±0.2°、14.4±0.2°、16.3±0.2°、17.1±0.2°；

[0060] 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、15.3±0.2°、17.1±0.2°；

[0061] 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、16.3±0.2°；

[0062] 8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°；

[0063] 4.5±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°；

[0064] 4.5±0.2°、8.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°；

[0065] 4.5±0.2°、8.8±0.2°、10.8±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°；

[0066] 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°；

[0067] 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、16.3±0.2°、17.1±0.2°；

[0068] 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、17.1±0.2°；

[0069] 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°；

[0070] 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°；

[0071] 8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、18.0±0.2°；

[0072] 4.5±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、25.2±0.2°；

[0073] 4.5±0.2°、8.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、18.0±0.2°；

[0074] 4.5±0.2°、8.8±0.2°、10.8±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、 17.1±0.2°、25.2±0.2°；

[0075] 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、18.0±0.2°；

[0076] 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、16.3±0.2°、17.1±0.2°、25.2±0.2°；

[0077] 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、17.1±0.2°、18.0±0.2°；

[0078] 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、25.2±0.2°；

[0079] 8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、18.0±0.2°、25.2±0.2°；

[0080] 4.5±0.2°、9.0±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、18.0±0.2°、25.2±0.2°；

[0081] 4.5±0.2°、8.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、18.0±0.2°、19.3±0.2°、25.2±0.2°；

[0082] 4.5±0.2°、8.8±0.2°、10.8±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、18.0±0.2°、21.8±0.2°、25.2±0.2°；

[0083] 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、18.0±0.2°、25.2±0.2°、27.9±0.2°；

[0084] 4.5±0.2°、8.8±0.2°、9.0±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、16.3±0.2°、17.1±0.2°、18.0±0.2°、25.2±0.2°；

[0085] 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、17.1±0.2°、18.0±0.2°、19.3±0.2°、25.2±0.2°；

[0086] 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、18.0±0.2°、21.8±0.2°、25.2±0.2°；

[0087] 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、25.2±0.2°、27.9±0.2°；

[0088] 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、18.0±0.2°、19.3±0.2°；

[0089] 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、18.0±0.2°、25.2±0.2°；

[0090] 8.8±0.2°、9.0±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、18.0±0.2°、25.2±0.2°；

[0091] 4.5±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、18.0±0.2°、19.3±0.2°、25.2±0.2°；

[0092] 4.5±0.2°、8.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、18.0±0.2°、21.8±0.2°、25.2±0.2°；

[0093] 4.5±0.2°、8.8±0.2°、10.8±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、18.0±0.2°、25.2±0.2°、27.9±0.2°；

[0094] 4.5±0.2°、8.8±0.2°、9.0±0.2°、10.8±0.2°、12.9±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、18.0±0.2°、25.2±0.2°；

[0095] 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、16.3±0.2°、17.1±0.2°、18.0±0.2°、19.3±0.2°、25.2±0.2°；

[0096] 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、17.1±0.2°、18.0±0.2°、21.8±0.2°、25.2±0.2°；

[0097] 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、18.0±0.2°、25.2±0.2°、27.9±0.2°；

[0098] 4.5±0.2°、8.8±0.2°、9.0±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、25.2±0.2°；

[0099] 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、18.0±0.2°、19.3±0.2°。

[0100] In certain embodiments of the present invention, the phosphate crystal form A, using Cu-Kα radiation, has characteristic X-ray diffraction peaks represented by 2θ angles and interplanar spacing d values ​​as shown in Table 1.

[0101] Table 1

[0102] In certain embodiments of the present invention, the phosphate crystal form A has an X-ray powder diffraction pattern substantially as shown in FIG1 ; and a DSC pattern substantially as shown in FIG2 .

[0103] In certain embodiments of the present invention, the crystalline form is N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide phosphate crystalline form B, and its X-ray powder diffraction pattern at 2θ (±0.2°) is 5.3±0.2°, 16.0±0.2° , 19.9±0.2°, 20.3±0.2°, 21.4±0.2° and 22.3±0.2° and have diffraction peaks; preferably, its X-ray powder diffraction pattern also has diffraction peaks at 2θ (±0.2°) of 12.5±0.2° and 13.0±0.2°; more preferably, its X-ray powder diffraction pattern further has diffraction peaks at 2θ (±0.2°) of 14.1±0.2° and 24.7±0.2°.

[0104] In certain embodiments of the present invention, the phosphate crystal form B, using Cu-Kα radiation, has characteristic X-ray diffraction peaks represented by 2θ angles and interplanar spacing d values ​​as shown in Table 2.

[0105] Table 2

[0106] In certain embodiments of the present invention, the phosphate crystal form B has an X-ray powder diffraction pattern substantially as shown in FIG3 ; and a DSC pattern substantially as shown in FIG4 .

[0107] In certain embodiments of the present invention, the crystalline form is N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide hydrochloride salt form A, and its X-ray powder diffraction pattern at 2θ (±0.2°) is 6.4±0.2°, 7.1±0.2 The present invention relates to a novel nanostructured ...

[0108] In certain embodiments of the present invention, the hydrochloride crystal form A, using Cu-Kα radiation, has characteristic X-ray diffraction peaks represented by 2θ angles and interplanar spacing d values ​​as shown in Table 3.

[0109] Table 3

[0110] In certain embodiments of the present invention, the hydrochloride salt form A has an X-ray powder diffraction pattern substantially as shown in FIG5 ; and a DSC pattern substantially as shown in FIG6 .

[0111] In certain embodiments of the present invention, the crystalline form is N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide hydrochloride salt form B, and its X-ray powder diffraction pattern at 2θ (±0.2°) is 9.6±0.2°, 15.8±0.2 The present invention relates to a novel nanostructured ...

[0112] In certain embodiments of the present invention, the hydrochloride crystal form B, using Cu-Kα radiation, has characteristic X-ray diffraction peaks represented by 2θ angles and interplanar spacing d values ​​as shown in Table 4.

[0113] Table 4

[0114] In certain embodiments of the present invention, the hydrochloride salt form B has an X-ray powder diffraction pattern substantially as shown in FIG7 ; and a DSC pattern substantially as shown in FIG8 .

[0115] In certain embodiments of the present invention, the crystalline form is N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide sulfate crystalline form A, and its X-ray powder diffraction pattern at 2θ (±0.2°) is 5.5±0.2°, 6.1±0.2 °, 6.3±0.2°, 16.1±0.2°, 26.1±0.2° and 26.8±0.2°; preferably, its X-ray powder diffraction pattern further has diffraction peaks at 2θ (±0.2°) of 15.7±0.2° and 22.9±0.2°; more preferably, its X-ray powder diffraction pattern further has diffraction peaks at 2θ (±0.2°) of 14.1±0.2° and 22.0±0.2°.

[0116] In certain embodiments of the present invention, the sulfate salt crystalline form A, using Cu-Kα radiation, has characteristic X-ray diffraction peaks represented by 2θ angles and interplanar spacing d values ​​as shown in Table 5.

[0117] Table 5

[0118] In certain embodiments of the present invention, the sulfate salt crystalline form A has an X-ray powder diffraction pattern substantially as shown in FIG9 ; and a DSC pattern substantially as shown in FIG10 .

[0119] In certain embodiments of the present invention, the crystalline form is N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide hydrobromide salt form A, and its X-ray powder diffraction pattern at 2θ (±0.2°) is 7.1±0.2°, 14.3±0.2 The present invention relates to a novel nanostructured ...

[0120] In certain embodiments of the present invention, the hydrobromide salt form A, using Cu-Kα radiation, has characteristic X-ray diffraction peaks represented by 2θ angles and interplanar spacing d values ​​as shown in Table 6.

[0121] Table 6

[0122] In certain embodiments of the present invention, the hydrobromide salt form A has an X-ray powder diffraction pattern substantially as shown in FIG11 ; and a DSC pattern substantially as shown in FIG12 .

[0123] In certain embodiments of the present invention, the crystalline form is N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide hydrobromide salt Form B, and its X-ray powder diffraction pattern at 2θ (±0.2°) is 6.9±0.2°, 18.5±0. The present invention relates to a novel nanostructured ...

[0124] In certain embodiments of the present invention, the hydrobromide salt form B, using Cu-Kα radiation, has characteristic X-ray diffraction peaks represented by 2θ angles and interplanar spacing d values ​​as shown in Table 7.

[0125] Table 7

[0126] In certain embodiments of the present invention, the hydrobromide salt form B has an X-ray powder diffraction pattern substantially as shown in FIG13 ; and a DSC pattern substantially as shown in FIG14 .

[0127] In certain embodiments of the present invention, the crystalline form is N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide citrate crystalline form A, and its X-ray powder diffraction pattern at 2θ (±0.2°) is 12.2±0.2°, 16.7±0. The present invention relates to a novel nanostructured ...

[0128] In certain embodiments of the present invention, the citrate salt crystalline form A, using Cu-Kα radiation, has characteristic X-ray diffraction peaks represented by 2θ angles and interplanar spacing d values ​​as shown in Table 8.

[0129] Table 8

[0130] In certain embodiments of the present invention, the citrate salt crystalline form A has an X-ray powder diffraction pattern substantially as shown in FIG15 ; and a DSC pattern substantially as shown in FIG16 .

[0131] In certain embodiments of the present invention, the crystalline form is N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide oxalate crystalline form A, and its X-ray powder diffraction pattern at 2θ (±0.2°) is 4.3±0.2°, 17.5±0.2 The present invention relates to a novel nanostructured ...

[0132] In certain embodiments of the present invention, the oxalate crystal form A, using Cu-Kα radiation, has characteristic X-ray diffraction peaks represented by 2θ angles and interplanar spacing d values ​​as shown in Table 9.

[0133] Table 9

[0134] In certain embodiments of the present invention, the oxalate salt form A has an X-ray powder diffraction pattern substantially as shown in FIG17 ; and a DSC pattern substantially as shown in FIG18 .

[0135] In certain embodiments of the present invention, the crystalline form is N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide maleate crystalline form A, and its X-ray powder diffraction pattern at 2θ (±0.2°) is 7.1±0.2°, 8.1±0.2 The present invention relates to a novel nanostructured ...

[0136] In certain embodiments of the present invention, maleate salt form A, using Cu-Kα radiation, has characteristic X-ray diffraction peaks represented by 2θ angles and interplanar spacing d values ​​as shown in Table 10.

[0137] Table 10

[0138] In certain embodiments of the present invention, the maleate salt crystalline form A has an X-ray powder diffraction pattern substantially as shown in FIG19 ; and a DSC pattern substantially as shown in FIG20 .

[0139] In certain embodiments of the present invention, the crystalline form is N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide salicylate crystalline form A, and its X-ray powder diffraction pattern at 2θ (±0.2°) is 8.3±0.2°, 16.5±0.2 The present invention relates to a novel nanostructured ...

[0140] In certain embodiments of the present invention, the salicylate crystalline form A, using Cu-Kα radiation, has characteristic X-ray diffraction peaks represented by 2θ angles and interplanar spacing d values ​​as shown in Table 11.

[0141] Table 11

[0142] In certain embodiments of the present invention, the salicylate crystalline form A has an X-ray powder diffraction pattern substantially as shown in FIG21 ; and a DSC pattern substantially as shown in FIG22 .

[0143] In certain embodiments of the present invention, the crystalline form is N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide p-hydroxybenzoate crystalline form A, and its X-ray powder diffraction pattern at 2θ (±0.2°) is 5.9±0.2°, 17.2±0 .2°, 17.5±0.2°, 18.9±0.2°, 22.3±0.2° and 25.2±0.2°; preferably, its X-ray powder diffraction pattern further has diffraction peaks at 2θ(±0.2°) of 16.1±0.2° and 22.0±0.2°; more preferably, its X-ray powder diffraction pattern further has diffraction peaks at 2θ(±0.2°) of 23.7±0.2° and 25.6±0.2°.

[0144] In certain embodiments of the present invention, the p-hydroxybenzoate crystalline form A uses Cu-Kα radiation, and the X-ray characteristic diffraction peaks represented by 2θ angles and interplanar spacing d values ​​are shown in Table 12.

[0145] Table 12

[0146] In certain embodiments of the present invention, the p-hydroxybenzoate crystalline form A has an X-ray powder diffraction pattern substantially as shown in FIG23 ; and a DSC pattern substantially as shown in FIG24 .

[0147] In certain embodiments of the present invention, the phosphate form A, phosphate form B, hydrochloride form A, hydrochloride form B, sulfate form A, hydrobromide form A, hydrobromide form B, citric acid form A of N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide The 2θ errors of the top ten diffraction peak positions with relative peak intensities in the X-ray powder diffraction patterns of salt form A, oxalate form A, maleate form A, salicylate form A, and p-hydroxybenzoate form A and the diffraction peaks corresponding to the positions in Figures 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, and 23 are ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°.

[0148] In certain embodiments of the present invention, the crystalline form is Form A of N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide, and its X-ray powder diffraction pattern at 2θ (±0.2°) is 13.0±0.2°, 14.0±0.2° , 15.9±0.2°, 19.8±0.2°, 20.2±0.2° and 22.3±0.2°; preferably, its X-ray powder diffraction pattern further has diffraction peaks at 2θ(±0.2°) of 12.4±0.2° and 24.6±0.2°; more preferably, its X-ray powder diffraction pattern further has diffraction peaks at 2θ(±0.2°) of 5.3±0.2° and 21.3±0.2°.

[0149] In certain embodiments of the present invention, Cu-Kα radiation is used, and the X-ray characteristic diffraction peaks of Form A expressed in terms of 2θ angles and interplanar spacing d values ​​are shown in Table 13.

[0150] Table 13

[0151] In certain embodiments of the present invention, Form A has an X-ray powder diffraction pattern substantially as shown in FIG25 ; and a DSC pattern as shown in FIG26 .

[0152] In certain embodiments of the present invention, the crystalline form is Form B of N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide, and its X-ray powder diffraction pattern at 2θ (±0.2°) is 11.3±0.2°, 11.6±0.2° , 17.4±0.2°, 21.9±0.2°, 22.2±0.2° and 23.3±0.2°; preferably, its X-ray powder diffraction pattern further has diffraction peaks at 2θ(±0.2°) of 12.0±0.2° and 15.5±0.2°; more preferably, its X-ray powder diffraction pattern further has diffraction peaks at 2θ(±0.2°) of 15.9±0.2° and 27.2±0.2°.

[0153] In certain embodiments of the present invention, Cu-Kα radiation is used, and the X-ray characteristic diffraction peaks of Form B expressed in terms of 2θ angles and interplanar spacing d values ​​are shown in Table 14.

[0154] Table 14

[0155] In certain embodiments of the present invention, Form B has an X-ray powder diffraction pattern substantially as shown in FIG. 27 ; and a DSC pattern substantially as shown in FIG. 28 .

[0156] In certain embodiments of the present invention, the crystalline form is Form C of N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide, and its X-ray powder diffraction pattern at 2θ (±0.2°) is 11.6±0.2°, 18.5±0.2°, and 10. The present invention relates to a novel nanostructured ...

[0157] In certain embodiments of the present invention, Cu-Kα radiation is used, and the X-ray characteristic diffraction peaks of Form C expressed in terms of 2θ angles and interplanar spacing d values ​​are shown in Table 15.

[0158] Table 15

[0159] In certain embodiments of the present invention, Form C has an X-ray powder diffraction pattern substantially as shown in FIG. 29 ; and a DSC pattern substantially as shown in FIG. 30 .

[0160] In certain embodiments of the present invention, the crystalline form is Form D of N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide, and its X-ray powder diffraction pattern at 2θ (±0.2°) is 12.2±0.2°, 16.1±0.2° , 19.7±0.2°, 21.2±0.2°, 21.9±0.2° and 24.0±0.2°; preferably, its X-ray powder diffraction pattern further has diffraction peaks at 2θ(±0.2°) of 15.9±0.2° and 21.4±0.2°; more preferably, its X-ray powder diffraction pattern further has diffraction peaks at 2θ(±0.2°) of 24.5±0.2° and 29.0±0.2°.

[0161] In certain embodiments of the present invention, Cu-Kα radiation is used, and the X-ray characteristic diffraction peaks of Form D expressed in terms of 2θ angles and interplanar spacing d values ​​are shown in Table 16.

[0162] Table 16

[0163] In certain embodiments of the present invention, Form D has an X-ray powder diffraction pattern substantially as shown in FIG31 ; and a DSC pattern substantially as shown in FIG32 .

[0164] In certain embodiments of the present invention, the crystalline form is Form E of N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide, and its X-ray powder diffraction pattern at 2θ (±0.2°) is 12.3±0.2°, 16.6±0.2° , 20.0±0.2°, 21.2±0.2°, 21.6±0.2° and 24.4±0.2°; preferably, its X-ray powder diffraction pattern further has diffraction peaks at 2θ(±0.2°) of 8.1±0.2° and 24.1±0.2°; more preferably, its X-ray powder diffraction pattern further has diffraction peaks at 2θ(±0.2°) of 16.0±0.2° and 19.8±0.2°.

[0165] In certain embodiments of the present invention, Cu-Kα radiation is used, and the X-ray characteristic diffraction peaks of Form E expressed in terms of 2θ angles and interplanar spacing d values ​​are shown in Table 17.

[0166] Table 17

[0167] In certain embodiments of the present invention, Form E has an X-ray powder diffraction pattern substantially as shown in FIG33 ; and a DSC pattern substantially as shown in FIG34 .

[0168] In certain embodiments of the present invention, the crystalline form is Form F of N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide, and its X-ray powder diffraction pattern at 2θ (±0.2°) is 14.2±0.2°, 17.2±0.2° , 19.7±0.2°, 21.2±0.2°, 25.3±0.2° and 26.2±0.2°; preferably, its X-ray powder diffraction pattern further has diffraction peaks at 2θ(±0.2°) of 6.6±0.2° and 23.3±0.2°; more preferably, its X-ray powder diffraction pattern further has diffraction peaks at 2θ(±0.2°) of 15.1±0.2° and 18.1±0.2°.

[0169] In certain embodiments of the present invention, Cu-Kα radiation is used, and the X-ray characteristic diffraction peaks of Form F expressed in terms of 2θ angles and interplanar spacing d values ​​are shown in Table 18.

[0170] Table 18

[0171] In certain embodiments of the present invention, Form F has an X-ray powder diffraction pattern substantially as shown in FIG. 35 ; and a DSC pattern substantially as shown in FIG. 36 .

[0172] In certain embodiments of the present invention, the crystalline form is Form G of N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide, and its X-ray powder diffraction pattern at 2θ (±0.2°) is 10.4±0.2°, 16.3±0.2° , 18.8±0.2°, 21.3±0.2°, 22.2±0.2° and 23.9±0.2°; preferably, its X-ray powder diffraction pattern further has diffraction peaks at 2θ(±0.2°) of 9.4±0.2° and 25.7±0.2°; more preferably, its X-ray powder diffraction pattern further has diffraction peaks at 2θ(±0.2°) of 16.6±0.2° and 23.2±0.2°.

[0173] In certain embodiments of the present invention, Cu-Kα radiation is used, and the X-ray characteristic diffraction peaks of Form G expressed in 2θ angles and interplanar spacing d values ​​are shown in Table 19.

[0174] Table 19

[0175] In certain embodiments of the present invention, Form G has an X-ray powder diffraction pattern substantially as shown in FIG37 ; and a DSC pattern substantially as shown in FIG38 .

[0176] In certain embodiments of the present invention, the X-ray powder diffraction patterns of Form A, Form B, Form C, Form D, Form E, Form F, and Form G of N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide have a 2θ error of ±0.2° to ±0.5° compared to the diffraction peaks at the corresponding positions in Figures 25, 27, 29, 31, 33, 35, and 37, respectively; preferably ±0.2° to ±0.3°, and most preferably ±0.2°. The present invention also provides a method for preparing the above-mentioned acid addition salt, which is method one or method two:

[0177] Method 1 includes the following steps:

[0178] 1) dissolving the compound in an organic solvent;

[0179] 2) adding a counterion acid; the amount of the counterion acid is preferably 1.2 equivalents; the counterion acid can be dissolved in an organic solvent;

[0180] 3) stirring and mixing to evaporate the solvent;

[0181] 4) isolating the acid addition salt;

[0182] Method 2 includes the following steps:

[0183] 1) suspending the compound in an organic solvent;

[0184] 2) adding a counterion acid; the amount of the counterion acid is preferably 1.2 equivalents; the counterion acid can be dissolved in an organic solvent;

[0185] 3) Stir to dissolve, and continue stirring to precipitate;

[0186] 4) isolating the acid addition salt;

[0187] Wherein: the solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol or N,N-dimethylformamide; preferably methanol, ethanol, acetone or ethyl acetate;

[0188] The counterion 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, hexanoic 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, dodecyl sulfate, dibenzoyl Tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactosonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, niacin, 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, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, n-butyric acid, p-hydroxybenzoic acid, or L-malic acid.

[0189] The present invention also provides a method for obtaining the crystalline form of the acid addition salt, which is method 1 or method 2:

[0190] Method 1 includes the following steps:

[0191] 1) Weigh an appropriate amount of the compound and dissolve it in a benign solvent;

[0192] 2) Weigh an appropriate amount of counterion acid and dissolve it in an organic solvent; the amount of counterion acid is preferably 1.2 equivalents;

[0193] 3) Combine the above two solutions and stir to precipitate or add a poor solvent dropwise and stir to precipitate;

[0194] 4) rapidly centrifuging or standing to dry to obtain the crystal form;

[0195] Wherein: the benign solvent is selected from methanol, ethanol, acetone, ethyl acetate, 2-butanone, 3-pentanone or 1,4-dioxane; preferably acetone, 2-butanone, 3-pentanone or ethyl acetate;

[0196] The organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol or N,N-dimethylformamide; preferably methanol, ethanol, acetone or ethyl acetate; the above-mentioned benign solvent and organic solution need to be miscible when used;

[0197] The poor solvent is selected from heptane, water, methyl tert-butyl ether or isopropyl ether;

[0198] The counterion 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, hexanoic 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, dodecyl sulfate, dibenzoyl Tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactosonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalene disulfonic acid, naphthalene-2-sulfonic acid, niacin, 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, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, n-butyric acid, p-hydroxybenzoic acid, or L-malic acid;

[0199] Method 2 includes the following steps:

[0200] 1) Weigh an appropriate amount of the compound and dissolve it in a solvent;

[0201] 2) mixing with a counter-ion acid to obtain the crystalline form; the amount of the counter-ion acid is preferably 1.2 equivalents;

[0202] The solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol or N,N-dimethylformamide; preferably methanol, ethanol, acetone or ethyl acetate;

[0203] The counterion 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, hexanoic 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, dodecyl sulfuric acid, dibenzoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, Formic acid, fumaric acid, galactosonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalene disulfonic acid, naphthalene-2-sulfonic acid, niacin, 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, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, n-butyric acid, p-hydroxybenzoic acid, or L-malic acid.

[0204] In certain embodiments of the present invention, the method for preparing the phosphate crystal form A comprises the following steps:

[0205] 1) The compound is dissolved in an ester solvent;

[0206] 2) adding an alcohol solution of phosphoric acid to the solution of step 1);

[0207] 3) stirring to obtain the phosphate crystal form A;

[0208] Wherein, the ester solvent is preferably methyl formate, ethyl formate, methyl acetate or ethyl acetate, preferably ethyl acetate;

[0209] The alcohol is preferably methanol, ethanol, n-propanol, isopropanol or n-butanol, preferably methanol.

[0210] The present invention also provides a method for preparing the above-mentioned crystal form, which is method 1 or method 2:

[0211] Method 1 includes the following steps:

[0212] 1) Weigh an appropriate amount of the compound and dissolve it in a good solvent by heating;

[0213] 2) The above solution was quickly placed at room temperature and stirred until solids precipitated;

[0214] 3) The suspension was rapidly centrifuged, the supernatant was removed, and the remaining solid was dried in a vacuum drying oven at 40°C to a constant weight to obtain the target crystalline form;

[0215] Wherein: the benign solvent is selected from methanol, acetone, ethyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropyl alcohol, n-butanol, isobutyl alcohol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone, 3-pentanone, N-methylpyrrolidone, dimethyl sulfoxide; preferably tetrahydrofuran, dichloromethane, 2-methyl-tetrahydrofuran and 3-pentanone;

[0216] Method 2 includes the following steps:

[0217] 1) Weigh an appropriate amount of free base and dissolve it in a good solvent;

[0218] 2) adding an antisolvent to the above solution at a certain temperature, preferably 0-25°C, and stirring until a solid precipitates;

[0219] 3) The suspension was rapidly centrifuged, the supernatant was removed, and the remaining solid was dried in a vacuum drying oven at 40°C to a constant weight to obtain the target product;

[0220] Wherein: the benign solvent is selected from acetone, 88% acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, toluene, isopropyl alcohol, n-butanol, isobutyl alcohol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone, 3-pentanone, N-methylpyrrolidone, ethyl formate, dimethyl sulfoxide; preferably acetone, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl formate, butanone, 3-pentanone, 1,4-dioxane.

[0221] The poor solvent is selected from heptane, water, methyl tert-butyl ether and isopropyl ether.

[0222] The present invention also provides a pharmaceutical composition comprising a therapeutically effective dose of the above-mentioned acid addition salt or a crystal form thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0223] The present invention also provides the use of the above-mentioned acid addition salt, the above-mentioned crystal form, or the above-mentioned pharmaceutical composition in the preparation of EGFR inhibitor drugs.

[0224] In certain embodiments of the present invention, the EGFR is a mutated EGFR, preferably one or more mutations among Del19, L858R, T790M or C797S, more preferably L858R / T790M, Del19 / T790M, Del19 / C797S, L858R / C797S, Del19 / T790M / C797S or L858R / T790M / C797S mutated EGFR.

[0225] The present invention also provides the use of the above-mentioned acid addition salt, the above-mentioned crystal form, or the above-mentioned pharmaceutical composition in the preparation of a drug for treating cancer; preferably, the cancer is selected from ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor, thyroid cancer, bile duct cancer, endometrial cancer, renal cancer, anaplastic large cell lymphoma, multiple myeloma, melanoma or mesothelioma; more preferably, the cancer is non-small cell lung cancer; further preferably, the cancer is EGFR Non-small cell lung cancer with L858R / T790M, Del19 / T790M, Del19 / C797S, L858R / C797S, Del19 / T790M / C797S, or L858R / T790M / C797S mutations. BRIEF DESCRIPTION OF THE DRAWINGS

[0226] FIG1 is an XRPD diagram of phosphate crystal form A.

[0227] FIG2 is a DSC diagram of phosphate crystal form A.

[0228] FIG3 is an XRPD diagram of phosphate crystal form B.

[0229] FIG4 is a DSC diagram of phosphate crystal form B.

[0230] FIG5 is an XRPD diagram of hydrochloride form A.

[0231] FIG6 is a DSC diagram of hydrochloride form A.

[0232] FIG7 is an XRPD diagram of hydrochloride Form B.

[0233] FIG8 is a DSC diagram of hydrochloride form B.

[0234] FIG9 is an XRPD diagram of sulfate salt form A.

[0235] FIG10 is a DSC diagram of sulfate salt form A.

[0236] FIG11 is an XRPD diagram of hydrobromide salt Form A.

[0237] FIG12 is a DSC diagram of hydrobromide salt form A.

[0238] FIG13 is an XRPD diagram of hydrobromide salt Form B.

[0239] FIG14 is a DSC diagram of hydrobromide salt form B.

[0240] FIG15 is an XRPD diagram of Form A of the citrate salt.

[0241] FIG16 is a DSC diagram of Form A of the citrate salt.

[0242] FIG17 is an XRPD diagram of Form A of the oxalate salt.

[0243] FIG18 is a DSC diagram of oxalate salt form A.

[0244] FIG19 is an XRPD diagram of maleate salt Form A.

[0245] FIG20 is a DSC diagram of maleate salt Form A.

[0246] FIG21 is an XRPD diagram of salicylate salt Form A.

[0247] FIG22 is a DSC diagram of salicylate crystalline form A.

[0248] FIG23 is an XRPD diagram of Form A of the p-hydroxybenzoate salt.

[0249] FIG24 is a DSC diagram of p-hydroxybenzoate crystalline form A.

[0250] FIG25 is an XRPD diagram of free base Form A.

[0251] FIG26 is a DSC diagram of free base Form A.

[0252] FIG27 is an XRPD diagram of free base Form B.

[0253] FIG28 is a DSC diagram of free base Form B.

[0254] FIG29 is an XRPD diagram of free base Form C.

[0255] FIG30 is a DSC diagram of free base Form C.

[0256] FIG31 is an XRPD diagram of free base Form D.

[0257] FIG32 is a DSC diagram of free base Form D.

[0258] FIG33 is an XRPD diagram of free base Form E.

[0259] FIG34 is a DSC diagram of free base Form E.

[0260] FIG35 is an XRPD diagram of free base Form F.

[0261] FIG36 is a DSC diagram of free base Form F.

[0262] FIG37 is an XRPD diagram of free base Form G.

[0263] FIG38 is a DSC diagram of free base Form G. DETAILED DESCRIPTION

[0264] The present invention is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present invention.

[0265] 1. Compound Examples

[0266] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, using deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as the solvents, with tetramethylsilane (TMS) as the internal standard.

[0267] Liquid chromatography-mass spectrometry (LC-MS) was performed on an Agilent 1200 Infinity Series mass spectrometer. HPLC was performed on an Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150 × 4.6 mm column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C 18 150×4.6mm chromatographic column).

[0268] Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0269] The starting materials in the examples of the present invention are known and can be purchased commercially, or can be synthesized using or according to methods known in the art.

[0270] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, with dry solvents and reaction temperatures in degrees Celsius.

[0271] Intermediate 1

[0272] 3-((Methylsulfonyl)methyl)azetidine

[0273] The first step is the synthesis of tert-butyl 3-((methylthio)methyl)azetidine-1-carboxylate

[0274] Tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (2 g, 6.73 mmol) and sodium thiomethoxide (970 mg, 13.50 mmol) were dissolved in ACN (15 mL) and H₂O (5 mL) and heated to 60°C for 12 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and separated by column chromatography to obtain the target compound, tert-butyl 3-((methylthio)methyl)azetidine-1-carboxylate (1.30 g, 88.9%). MS m / z (ESI): 162.0 [M+H-56] + .

[0275] Step 2: Synthesis of tert-butyl 3-((methylsulfonyl)methyl)azetidine-1-carboxylate

[0276] Tert-butyl 3-((methylthio)methyl)azetidine-1-carboxylate (1.30 g, 5.99 mmol) was dissolved in dichloromethane (15 mL), and m-chloroperbenzoic acid (2 g, 12 mmol) was added. The mixture was stirred overnight. The reaction mixture was washed with saturated sodium thiosulfate and saturated sodium chloride solutions. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and isolated by column chromatography to yield the target compound, tert-butyl 3-((methylsulfonyl)methyl)azetidine-1-carboxylate (1.30 g, 87.1%). MS m / z (ESI): 194.0 [M+H-56] + .

[0277] Step 3: Synthesis of 3-((methylsulfonyl)methyl)azetidine trifluoroacetate

[0278] Tert-butyl 3-((methylsulfonyl)methyl)azetidine-1-carboxylate (1.30 g, 5.22 mmol) was dissolved in dichloromethane (15 mL), TFA (3 mL) was added, and the mixture was stirred for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain the target compound, 3-((methylsulfonyl)methyl)azetidine trifluoroacetate, as a crude product (740 mg). MS m / z (ESI): 150.0 [M+H] + .

[0279] Intermediate 2

[0280] (2R,3S)-2-Methyl-3-((methylsulfonyl)methyl)azetidine

[0281] The first step is the synthesis of (2R,3S)-1-diphenylmethyl-2-methylazetidin-3-yl methanesulfonate

[0282] (2R,3S)-1-Benzhydryl-2-methylazetidin-3-ol (10 g, 39.50 mmol) was dissolved in dichloromethane (100 mL). Triethylamine (4.80 g, 47.30 mmol) was added. The reaction solution was cooled to 0°C and methanesulfonyl chloride (5 g, 43.40 mmol) was slowly added dropwise. The reaction was allowed to react at room temperature overnight. The reaction was quenched with water, the dichloromethane and water were separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the target compound, (2R,3S)-1-Benzhydryl-2-methylazetidin-3-yl methanesulfonate (12.80 g), as a crude product. MS m / z (ESI): 332.2 [M+H] + .

[0283] Step 2: Synthesis of methyl (S)-2-((2R,3S)-1-diphenylmethyl-2-methylazetidin-3-yl)-2-(methylsulfonyl)acetate

[0284] (2R,3S)-1-Benzhydryl-2-methylazetidin-3-yl methanesulfonate (12.80 g, 38.62 mmol) and methyl 2-(methylsulfonyl)acetate (7.70 g, 50.60 mmol) were dissolved in DMF (100 mL). Sodium hydride (2.20 g, 60% in mineral oil, 55.50 mmol) was added portionwise. The mixture was allowed to react at room temperature for 15 minutes and then heated to 80°C overnight. The reaction mixture was cooled to room temperature and quenched with saturated ammonium chloride solution. The mixture was then separated by ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate and concentrated, and then separated by column chromatography to yield the target compound, methyl (S)-2-((2R,3S)-1-Benzhydryl-2-methylazetidin-3-yl)-2-(methylsulfonyl)acetate (11.60 g, 77.5%). MS m / z (ESI): 388.2 [M+H] + .

[0285] Step 3: Synthesis of (2R,3S)-1-diphenylmethyl-2-methyl-3-((methylsulfonyl)methyl)azetidine

[0286] Methyl (S)-2-((2R,3S)-1-benzhydryl-2-methylazetidin-3-yl)-2-(methylsulfonyl)acetate (11.60 g, 29.94 mmol) was dissolved in DMA (120 mL), and lithium chloride (10.50 g, 247.50 mmol) was added. The temperature was raised to 150°C and the reaction was allowed to react for 2 hours. The mixture was cooled to room temperature, separated by ethyl acetate and water, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain the target compound, (2R,3S)-1-benzhydryl-2-methyl-3-((methylsulfonyl)methyl)azetidine (9.20 g, 93.3%). MS m / z (ESI): 330.0 [M+H] + .

[0287] Step 4: Synthesis of (2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidine

[0288] (2R,3S)-1-Benzhydryl-2-methyl-3-((methylsulfonyl)methyl)azetidine (9.20 g, 27.92 mmol) was dissolved in methanol (120 mL). TFA (5 mL) and palladium hydroxide (2.80 g) were added. The mixture was evacuated and filled with hydrogen gas three times. The reaction was allowed to proceed overnight under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound, (2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidine, as a crude product (4 g). MS m / z (ESI): 164.0 [M+H] + .

[0289] Intermediate 3

[0290] 8-Bromo-3-chloro-6-fluoro-5-isopropylisoquinoline

[0291] The first step is the synthesis of 3-chloro-6-fluoroisoquinoline

[0292] 1,3-Dichloro-6-fluoroisoquinoline (7.50 g, 34.72 mmol) was dissolved in glacial acetic acid (40 mL) and hydroiodic acid (20 mL, 45% aqueous solution). Red phosphorus (2.69 g, 86.8 mmol) was added and the reaction temperature was raised to 100°C for 4 hours. The reaction solution was cooled to room temperature, concentrated, diluted with dichloromethane (100 mL), and washed with saturated aqueous sodium carbonate. The organic phase was separated and dried over anhydrous sodium sulfate. After filtration, the organic solvent was concentrated under reduced pressure and separated by column chromatography to obtain the target compound, 3-chloro-6-fluoroisoquinoline (4.90 g, 77.8%). MS m / z (ESI): 182.0 [M+H] + .

[0293] Step 2 Synthesis of 5-bromo-3-chloro-6-fluoroisoquinoline

[0294] 3-Chloro-6-fluoroisoquinoline (3.20 g, 17.62 mmol) was dissolved in concentrated sulfuric acid (20 mL), and NBS (3.45 g, 19.38 mmol) was added. The mixture was stirred at room temperature overnight. The reaction mixture was slowly added to ice water and partitioned with ethyl acetate. The organic phase was separated and dried over anhydrous sodium sulfate. After filtration, the organic solvent was concentrated under reduced pressure. The target compound, 5-bromo-3-chloro-6-fluoroisoquinoline (4.0 g, 87.1%), was isolated by column chromatography. MS m / z (ESI): 260.0 [M+H] + .

[0295] Step 3 Synthesis of 3-chloro-6-fluoro-5-(prop-1-en-2-yl)isoquinoline

[0296] 5-Bromo-3-chloro-6-fluoroisoquinoline (4.0 g, 15.36 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (2.71 g, 16.72 mmol) were dissolved in 1,4-dioxane (20 mL) and water (3 mL). 1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride (562 mg, 0.77 mmol) and cesium carbonate (10.01 g, 30.71 mmol) were added, and the mixture was heated to 80°C for 2 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and separated by column chromatography to obtain the target compound, 3-chloro-6-fluoro-5-(prop-1-en-2-yl)isoquinoline (3.0 g, 88.1%). MS m / z (ESI): 222.0 [M+H] + .

[0297] Step 4: Synthesis of 3-chloro-6-fluoro-5-isopropylisoquinoline

[0298] 3-Chloro-6-fluoro-5-(prop-1-en-2-yl)isoquinoline (3.0 g, 13.53 mmol) was dissolved in ethyl acetate (30 mL), and platinum dioxide (615 mg, 2.71 mmol) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure and then isolated by column chromatography to obtain the target compound, 3-chloro-6-fluoro-5-isopropylisoquinoline (2.10 g, 69.4%). MS m / z (ESI): 224.1 [M+H] + .

[0299] Step 5: Synthesis of 8-bromo-3-chloro-6-fluoro-5-isopropylisoquinoline

[0300] To a solution of 3-chloro-6-fluoro-5-isopropylisoquinoline (800 mg, 3.58 mmol) in concentrated sulfuric acid (5 mL) was slowly added portionwise with dibromohydantoin (1.12 g, 3.93 mmol) under ice-cooling. Stirring was continued under ice-cooling for 0.5 hour. The reaction mixture was carefully added to ice-water and partitioned with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. Column chromatography was performed to obtain the target compound, 8-bromo-3-chloro-6-fluoro-5-isopropylisoquinoline (320 mg, 29.6%). MS m / z (ESI): 302.0 [M+H] + .

[0301] Intermediate 4

[0302] N-Methyl-N-((2R,3S)-2-methylazetidin-3-yl)methanesulfonamide trifluoroacetate

[0303] The first step is the synthesis of (2R,3S)-1-diphenylmethyl-2-methylazetidin-3-yl methanesulfonate

[0304] (2R,3S)-1-Benzhydryl-2-methylazetidin-3-ol (100g, 397mmol), triethylamine (110mL, 793mmol), and anhydrous dichloromethane (1000mL) were added to a 2L reaction flask. The mixture was cooled to 5°C under a nitrogen atmosphere. Methanesulfonic anhydride (138g, 795mmol) was added portionwise and the mixture was warmed to room temperature and stirred for 2h. Water and dichloromethane were added for separation. The organic phase was separated and washed sequentially with 5% sodium carbonate solution and saturated sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target product, (2R,3S)-1-Benzhydryl-2-methylazetidin-3-yl methanesulfonate (138g), as a crude product. MS m / z (ESI): 332.1 [M+H] + .

[0305] Step 2: Synthesis of N-((2R,3S)-1-diphenylmethyl-2-methylazetidin-3-yl)-N-methylmethanesulfonamide

[0306] At room temperature, (2R,3S)-1-benzhydryl-2-methylazetidin-3-yl methanesulfonate (138 g, 0.42 mol) was dissolved in MeCN (950 mL). Cs2CO3 (273 g, 0.84 mol) and N-methylmethanesulfonamide (82 g, 0.75 mol) were added and stirred at 80°C overnight under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (0.5 L) was added, and the mixture was extracted with ethyl acetate (1 L x 2). The organic phases were combined and washed with saturated sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The organic solvent was then concentrated by column chromatography to yield the desired product, N-((2R,3S)-1-benzhydryl-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (110 g, 76.7%). MS m / z (ESI): 345.1 [M+H] + .

[0307] Step 3: Synthesis of N-methyl-N-((2R,3S)-2-methylazetidin-3-yl)methanesulfonamide trifluoroacetate

[0308] N-((2R,3S)-1-benzhydryl-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (85 g, 0.247 mol) was dissolved in a mixture of MeOH (850 mL) and TFA (52 mL). 10% Pd(OH)2 / C (28 g) was added and stirred overnight at room temperature under a H2 atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the desired product, N-methyl-N-((2R,3S)-2-methylazetidin-3-yl)methanesulfonamide trifluoroacetate (66 g), as a crude product.

[0309] 1 H NMR(400MHz,DMSO-d6)δ8.88(s,1H),4.62-4.56(m,1H),4.31-4.25(m,1H),4.10- 4.06(m,1H),3.95-3.91(m,1H),2.95(s,3H),2.83(s,3H),1.40(d,J=6.0Hz,3H);

[0310] MS m / z(ESI):179.1[M+H] + .

[0311] Intermediate 5

[0312] 2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0313] Step 1: Synthesis of 4-bromo-3-chloro-1-methyl-1H-pyrazole

[0314] 3-Chloro-1-methyl-1H-pyrazole (500 mg, 4.29 mmol) was dissolved in dichloromethane (10 mL) and cooled to 0°C. NBS (764 mg, 4.29 mmol) was added portionwise, and the mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, partitioned with dichloromethane and water, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The target compound, 4-bromo-3-chloro-1-methyl-1H-pyrazole (790 mg, 94.2%), was then isolated by column chromatography.

[0315] Step 2 Synthesis of 3-chloro-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[0316] 4-Bromo-3-chloro-1-methyl-1H-pyrazole (790 mg, 4.04 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.23 g, 4.85 mmol) were dissolved in dioxane (15 mL). Potassium phosphate (793 mg, 8.08 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (300 mg, 0.41 mmol) were added, and the mixture was heated to 95°C and stirred for 12 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Dichloromethane and water were added to separate the organic phases, which were dried over anhydrous sodium sulfate. The organic phase was filtered, the organic solvent was concentrated under reduced pressure, and then separated by column chromatography to obtain the target compound, 3-chloro-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (590 mg, 60.2%). MS m / z (ESI): 243.1 [M+H] + .

[0317] Step 3 Synthesis of 2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0318] 2-Chloropyrimidin-4-amine (259 mg, 2 mmol), 3-chloro-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (534 mg, 2.20 mmol), and potassium carbonate (829 mg, 6 mmol) were mixed in dioxane (5 mL) and water (1 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (146 mg, 0.20 mmol) was added, and the mixture was heated to 95°C and stirred for 12 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and partitioned with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The resulting mixture was then isolated by column chromatography to afford the target compound, 2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (143 mg, 34.2%). MS m / z(ESI):210.0[M+H] + .

[0319] Example 1

[0320] Preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-6-fluoro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

[0321] Step 1: Synthesis of 3-chloro-6-fluoro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline

[0322] 8-Bromo-3-chloro-6-fluoro-5-isopropylisoquinoline (500 mg, 1.65 mmol) and (2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidine (297 mg, 1.82 mmol) were dissolved in dioxane (10 mL). Cesium carbonate (1.15 g, 3.54 mmol) and Xantphos Pd G4 (164 mg, 0.17 mmol) were added, and the mixture was heated to 100°C and stirred for 12 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The reaction mixture was then separated with dichloromethane and water, and the organic phase was dried over anhydrous sodium sulfate. The organic solvent was concentrated under reduced pressure and separated by column chromatography to obtain the target compound, 3-chloro-6-fluoro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidine-1-yl)isoquinoline (418 mg, 65.8%). MS m / z(ESI):385.1[M+H] + .

[0323] Step 2: Synthesis of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-6-fluoro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

[0324] 3-Chloro-6-fluoro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline (100 mg, 0.26 mmol) and 2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (54 mg, 0.26 mmol) were dissolved in dioxane (5 mL), and cesium carbonate (274 mg, 0.84 mmol) and BrettPhos Pd G4 (24 mg, 26 μmol) were added. The temperature was raised to 100°C and stirred for 12 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The mixture was then separated by dichloromethane and water, and the organic phase was dried over anhydrous sodium sulfate. The organic solvent was concentrated under reduced pressure and then separated by column chromatography to obtain the target compound, N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-6-fluoro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine (61 mg, 42%). MS m / z (ESI): 558.2 [M+H] + .

[0325] 1 H NMR (400MHz, DMSO-d6) δ10.14(s,1H),8.96(s,1H),8.53(s,1H),8.35(d,J=5.8Hz,1H),8.24(s,1H),7.19(d,J=5.8Hz,1H),6.27(d,J=14.4Hz,1 H),4.70-4.62(m,1H),4.21-4.14(m,1H),3.83(s,3H),3.72-3.64(m,1H ),3.57-3.41(m,3H),2.93(s,3H),2.87-2.77(m,1H),1.39-1.26(m,9H);

[0326] Example 2

[0327] Preparation of N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide

[0328] The first step is the synthesis of N-((2R,3S)-1-(3-chloro-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide

[0329] 8-Bromo-3-chloro-6-fluoro-5-isopropylisoquinoline (500 mg, 1.65 mmol) and N-methyl-N-((2R,3S)-2-methylazetidin-3-yl)methanesulfonamide trifluoroacetate (470 mg, 1.70 mmol) were mixed in dioxane (10 mL), and cesium carbonate (1.15 g, 3.54 mmol) and Xantphos Pd G4 (164 mg, 0.17 mmol) were added. The temperature was raised to 100°C and stirred for 5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was separated between dichloromethane and water, and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and then separated by column chromatography to obtain the target compound, N-((2R,3S)-1-(3-chloro-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (330 mg, 50.0%). MS m / z (ESI): 400.1 [M+H] + .

[0330] 1 H NMR (400MHz, DMSO-d6) δ9.08(s,1H),8.07(s,1H),6.68-6.65(m,1H),4.76-4.69(m,1H),4.59-4.55(m,1H),4.26-4. 22(m,1H),3.98-3.96(m,1H),3.67-3.59(m,1H),2.95(s,3H),2.83(s,3H),1.40(d,J=6.0Hz,3H),1.37-1.31(m,6H);

[0331] Step 2: Synthesis of N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide

[0332] N-((2R,3S)-1-(3-chloro-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (100 mg, 0.25 mmol) and 2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (55 mg, 0.25 mmol) were dissolved in dioxane (5 mL), and cesium carbonate (274 mg, 0.84 mmol) and BrettPhos Pd G4 (24 mg, 26 μmol) were added. The temperature was raised to 100 ° C and stirred for 12 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was separated by dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and then separated by column chromatography to obtain the target compound, N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (73 mg, 50.9%). MS m / z (ESI): 573.2 [M+H] + .

[0333] 1 H NMR (400MHz, DMSO-d6) δ10.21(s,1H),9.05(s,1H),8.60(s,1H),8.42(d,J=5.8Hz,1H),8.30(s,1H),7.28(d,J=6.0Hz, 1H),6.47-6.43(m,1H),4.71-4.69(m,1H),4.53-4.49(m,1H),4.23-4.18(m,1H),3.94-3.91(m,1H),3.89(s,3H),3.63 -3.58(m,1H),2.95(s,3H),2.84(s,3H),1.40(d,J=6.0Hz,6H),1.36-1.32(m,3H).

[0334] Example 3

[0335] Preparation of N-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide

[0336] The preparation method of N-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide refers to Example 1.

[0337] 1 H NMR (400MHz, DMSO-d6) δ10.18(s,1H),9.06(s,1H),8.56(s,1H),8.42(d,J=5.8Hz,1H),8.30(s,1H),7.31(d,J=5.8Hz,1H),6.28-6.25(m,1H),4.70 -4.68(m,1H),4.46-4.43(m,2H),4.32-4.29(m,2H),3.89(s,3H),3.59-3.56(m,1H),2.95-2.93(m,6H),1.38-1.36(m,6H);

[0338] MS m / z(ESI):559.2[M+H] + .

[0339] Example 4

[0340] Preparation of N-(2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-6-fluoro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

[0341] The preparation method of N-(2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-6-fluoro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was as described in Example 1.

[0342] 1 H NMR (400MHz, DMSO-d6) δ10.04(s,1H),8.96(s,1H),8.47(s,1H),8.31(d,J= 5.8Hz,1H),8.07(s,1H),7.17-7.09(m,1H),6.31-6.23(m,1H),4.66(t,J=7. 6Hz,1H),4.18(t,J=6.2Hz,1H),3.77(s,3H),3.68(t,J=7.2Hz,1H),3.56-3 .44(m,3H),2.93(s,3H),2.86-2.77(m,1H),2.44(s,3H),1.39-1.31(m,9H);

[0343] MS m / z(ESI):538.2[M+H] + .

[0344] Example 5

[0345] Preparation of N-((2R,3S)-1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide

[0346] The preparation method of N-((2R,3S)-1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide refers to Example 2.

[0347] 1 H NMR (400MHz, DMSO-d6) δ10.12(s,1H),9.05(s,1H),8.55(s,1H),8.38(d,J=5. 8Hz,1H),8.14(s,1H),7.22(d,J=5.6Hz,1H),6.47(d,J=14.3Hz,1H),4.75-4.6 7(m,1H),4.57-4.48(m,1H),4.27-4.19(m,1H),3.97-3.91(m,1H),3.84(s,3H) ,3.64-3.52(m,1H),2.95(s,3H),2.84(s,3H),2.51(s,3H),1.46-1.37(m,9H);

[0348] MS m / z(ESI):553.2[M+H] + .

[0349] Example 6

[0350] Preparation of N-(1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide

[0351] The preparation method of N-(1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide refers to Example 1.

[0352] 1H NMR (400MHz, DMSO-d6) δ10.00(s,1H),9.00(s,1H),8.43(s,1H),8.32(d,J=5.8Hz,1H),8.07(s,1H),7.21-7.17(m,1H),6.23-6.15(m,1H),4.67 -4.60(m,1H),4.39(t,J=8.2Hz,2H),4.29-4.22(m,2H),3.77(s,3H),3. 55-3.47(m,1H),2.91-2.84(m,6H),2.44(s,3H),1.34(d,J=6.6Hz,6H);

[0353] MS m / z(ESI):539.2[M+H] + .

[0354] Example 7

[0355] Preparation of N-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-(dimethylamino)-6-fluoroisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide

[0356] The preparation method of N-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-(dimethylamino)-6-fluoroisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide refers to Example 1.

[0357] MS m / z(ESI):560.2[M+H] + .

[0358] Example 8

[0359] Preparation of (R)-N-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-(1-methoxyethyl)isoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide

[0360] The preparation method of (R)-N-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-(1-methoxyethyl)isoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide refers to Example 1.

[0361] MS m / z(ESI):575.2[M+H] + .

[0362] Example 9

[0363] Preparation of (S)-N-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-(1-methoxyethyl)isoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide

[0364] The preparation method of (S)-N-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-(1-methoxyethyl)isoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide refers to Example 1.

[0365] MS m / z(ESI):575.2[M+H] + .

[0366] Example 10

[0367] Preparation of N3-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-6-fluoro-N5,N5-dimethyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline-3,5-diamine

[0368] The preparation method of N3-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-6-fluoro-N5,N5-dimethyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline-3,5-diamine refers to Example 1.

[0369] MS m / z(ESI):559.2[M+H] + .

[0370] Example 11

[0371] Preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-6-fluoro-5-((R)-1-methoxyethyl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

[0372] The preparation method of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-6-fluoro-5-((R)-1-methoxyethyl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine refers to Example 1.

[0373] MS m / z(ESI):574.2[M+H] + .

[0374] Example 12

[0375] Preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-6-fluoro-5-((S)-1-methoxyethyl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

[0376] The preparation method of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-6-fluoro-5-((S)-1-methoxyethyl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine refers to Example 1.

[0377] MS m / z(ESI):574.2[M+H] + .

[0378] Example 13

[0379] Preparation of N-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methanesulfonamide

[0380] The preparation method of N-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methanesulfonamide refers to Example 2.

[0381] 1 H NMR (400MHz, DMSO-d6) δ10.24(s,1H),9.08(s,1H),8.63(s,1H),8.48(d,J=5.2Hz,1H),8.36(s,1H),7.92(d,J=7.2Hz,1H),7.35(br s,1H),6.36(d,J=8.0Hz,1H),4.69-4.65(m,2H),4.44-4.41(m,1H),4.08-4 .04(m,2H),3.95(s,3H),3.58-3.52(m,1H),3.04(s,3H),1.44-1.33(m,6H);

[0382] MS m / z(ESI):545.2[M+H] + .

[0383] Example 14

[0384] Preparation of N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonamide

[0385] The preparation method of N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonamide refers to Example 2.

[0386] 1 H NMR (400MHz, DMSO-d6) δ10.16(s,1H),8.96(s,1H),8.54(s,1H),8.35(d,J=7.2Hz,1H),8.24(s,1H),7.71(d,J=7.6Hz,1H),7.20(br s,1H),6.36(br s,1H),4.82-4.77(m,1H),4.16-4.10(m,1H),3.88-3.83(m,4H),3.62-3.54(m,2H),2.90(s,3H),1.37-1.16(m,9H);

[0387] MS m / z(ESI):559.2[M+H] + .

[0388] 2. Biological Test Evaluation of Compounds

[0389] The present invention is further described and explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[0390] Test Example 1: Determination of the inhibitory effect of the compounds of the present invention on the kinase activity of EGFR del19 / T790M / C797S and EGFR L858R / T790M / C797S mutations

[0391] Experimental purpose: The purpose of this test example is to test the activity of the compound in inhibiting the kinase activity of EGFR del19 / T790M / C797S and EGFR L858R / T790M / C797S mutations.

[0392] Experimental instruments: Centrifuge (5810R) was purchased from Eppendorf, pipettes were purchased from Eppendorf or Rainin, and microplate reader was purchased from BioTek, USA, model SynergyH1 full-function microplate reader.

[0393] Experimental Methods: This experiment uses the Cisbio HTRF kinase assay (Cisbio #62TK0PEB). The substrate peptide TK and ATP catalyze a reaction in the presence of the tyrosine kinase EGFR del19 / T790M / C797S or EGFR L858R / T790M / C797S mutations. The substrate is phosphorylated. The activity of the kinase is characterized by measuring the amount of phosphorylated substrate generated in the reaction. The half-maximal inhibitory concentration (IC) of the compound for inhibition of the EGFR del19 / T790M / C797S or EGFR L858R / T790M / C797S mutant kinase activity is determined. 50 .

[0394] The specific experimental procedures are as follows: Kinase reactions were performed in a white 384-well plate (Perkin Elmer #6008280). 1–5 μL of compound at different concentrations diluted in 1% DMSO in ddH2O was added to each well. 1–5 μL of 1% DMSO in ddH2O was added to the positive control wells. Then, 1–5 μL of 0.5–5 nM 4× EGFR del19 / T790M / C797S or EGFR L858R / T790M / C797S mutant kinase solution diluted in Dilution buffer (5× kinase buffer, 6.65 mM MgCl2, 1.33 mM MnCl2, 1.33 mM DTT) was added to each well. 1–5 μL of Dilution buffer was added to the negative control wells. 1–5 μL of 4 μM 4× substrate TK solution prepared in 10× Dilution buffer was added to all wells. Finally, 1–5 μL of Dilution buffer was added to the negative control wells. The reaction was initiated with 24 μM 4× ATP solution diluted in buffer. After reacting at room temperature for 120 minutes, 10 μL of detection solution (TK antibody 16 nM, XL665 0.5 μM) was added to each well. The reaction was carried out in the dark at room temperature for 20 minutes, and the chemiluminescence value was detected using a BioTek Synergy H1 microplate reader.

[0395] Experimental data processing method: The percentage inhibition data of the wells treated with the compound were calculated by comparing the positive control wells (DMSO control wells) and the negative control wells (no kinase added) on the plate {% inhibition rate = 100 - [(test compound value - negative control value)] / (positive control value - negative control value) × 100}. GraphPad Prism was used to fit the different concentrations and the corresponding percentage inhibition rate data to a 4-parameter nonlinear logistic equation to calculate the IC 50 value.

[0396] Experimental results and conclusions: The examples of the present invention have a good inhibitory effect on EGFR L858R / T790M / C797S and EGFR del19 / T790M / C797S drug-resistant mutant kinases.

[0397] Test Example 2: Cell proliferation inhibition experiment

[0398] Experimental purpose: The purpose of this test case is to test the proliferation inhibitory activity of the compound against different EGFR C797S resistant mutant cell lines Ba / F3 EGFR Del19 / T790M / C797S, Ba / F3 EGFR L858R / T790M / C797S and Ba / F3 EGFR Del19 / C797S.

[0399] Experimental instruments: Centrifuge (Eppendorf 5810R) and microplate reader (BioTek Synergy H1)

[0400] Pipettes (Eppendorf or Rainin) CO2 incubator (Thermo 311)

[0401] Cell counter (Life CountessⅡ)

[0402] Experimental reagents and consumables:

[0403] Ba / F3 EGFR Del19 / T790M / C797S cells were purchased from Beijing Kangyuan Bochuang Biotechnology Co., Ltd.

[0404] Ba / F3 EGFR Del19 / C797S cells were purchased from Nanjing Kebai Biotechnology Co., Ltd.

[0405] Ba / F3 EGFR L858R / T790M / C797S cells were purchased from Nanjing Kebai Biotechnology Co., Ltd.

[0406] Cell Titer-Glo was purchased from Promega, catalog number G7573

[0407] RPMI 1640 was purchased from Gibco, catalog number 22400089;

[0408] FBS was purchased from Gibco, catalog number 10091148;

[0409] Cell culture plates were purchased from Corning, catalog number 3610.

[0410] Experimental Methods: The Cell Titer-Glo assay was used to assess the antiproliferative activity of compounds against cell lines harboring different EGFR C797S drug-resistant mutations. Each cell line was cultured in RPMI 1640 complete medium supplemented with 10% FBS at 37°C, 5% CO2. Cells were harvested by centrifugation when they reached a specific density, counted, and adjusted to the appropriate cell density. 90 μL of cells were plated per well in a white 96-well plate and incubated overnight at 37°C, 5% CO2. Compound solutions of varying concentrations were then added at 10 μL per well, along with corresponding vehicle controls. After further incubation at 37°C, 5% CO2 for 72 hours, 50 μL of Cell Titer-Glo solution was added to each well, mixed thoroughly, and incubated in the dark for 10 minutes. The plates were then read using a BioTek Synergy H1 microplate reader.

[0411] Experimental data processing method: The inhibition rate was calculated using the luminescence signal value, and the concentration and inhibition rate were fitted with a nonlinear regression curve using Graphpad Prism software to obtain the IC 50 See the table below for details.

[0412] Table 20

[0413] Table 21

[0414] Table 22

[0415] Experimental conclusion: The above scheme shows that the compound shown in the present invention shows significant proliferation inhibition activity in the proliferation inhibition activity test on different EGFR C797S drug-resistant mutant cell lines.

[0416] Test Example 3: Pharmacokinetic Evaluation Test in Rats

[0417] 1. Study purpose: SD rats were used as test animals to study the pharmacokinetic behavior of the compound of the present invention in rats (plasma) at a dose of 5 mg / kg when orally administered.

[0418] 2. Experimental plan:

[0419] 2.1 Experimental drugs: Compounds of the present invention, homemade.

[0420] 2.2 Experimental animals: 3 male SD rats per group, Shanghai Jiesijie Experimental Animal Co., Ltd., animal production license number (SCXK (Shanghai) 2013-0006 No. 311620400001794).

[0421] 2.3 Preparation prescription:

[0422] Oral administration preparation: 20% solutol HS15 in 0.5% MC (methylcellulose)

[0423] Weigh 20g of Solutol HS15 solid and 0.5g of MC solid powder and dissolve them in 80mL of purified water. Vortex, mix, and sonicate to obtain a clear solution of 20% Solutol HS15 in 0.5% MC. Weigh the example compound into a 20mL glass vial, add this solution, and sonicate for 10 minutes to obtain a clear solution at a concentration of 0.5mg / mL.

[0424] 2.4 Administration: Three male SD rats were fasted overnight and administered orally; the orally dose was 5 mg / kg, and the administration volume was 10 mL / kg.

[0425] 2.5 Sample collection:

[0426] Blood collection: 0.2 mL of blood was collected from the jugular vein of rats before administration and 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after administration. The blood was placed in an EDTA-K2 anticoagulant tube, centrifuged at 6000 rpm for 6 min at 4°C to separate the plasma, and stored at -80°C. The rats were fed 4 h after administration.

[0427] 2.6 Sample processing:

[0428] 1) 40 μL of plasma sample was added to 160 μL of acetonitrile for precipitation, mixed, and centrifuged at 3500×g for 5-20 minutes.

[0429] 2) The supernatant solution after treatment was subjected to LC / MS / MS analysis to determine the concentration of the test compound. The LC / MS / MS analysis instrument was AB Sciex API 4000Qtrap.

[0430] 2.7 Liquid phase analysis:

[0431] Liquid phase conditions: Shimadzu LC-20AD pump

[0432] Chromatographic column: Agilent ZORBAX XDB-C18 (50×2.1mm, 3.5μm) Mobile phase: Liquid A is 0.1% formic acid in water, Liquid B is acetonitrile

[0433] Flow rate: 0.4 mL / min

[0434] Elution time: 0-4.0 minutes, eluent is as follows:

[0435] 3. Test results and analysis: The main pharmacokinetic parameters were calculated using WinNonlin 6.1. The results of the rat pharmacokinetic test are shown in Table 23 below.

[0436] Table 23

[0437] 3.4 Experimental Conclusion: The data in the table show that in the pharmacokinetic evaluation experiment in rats, the example compounds of the present invention showed a higher exposure after oral administration.

[0438] Test Example 4: In vivo pharmacodynamic study of the compound in a subcutaneous transplanted tumor model of nude mice bearing the mouse proto-B cell line Ba / F3 EGFR Del19 / C797S

[0439] 1.1 Experimental purpose: To evaluate the in vivo efficacy of the compound in the subcutaneous transplanted tumor model of nude mice bearing the mouse original B cell line Ba / F3 EGFR Del19 / C797S.

[0440] 1.2 Experimental instruments and reagents

[0441] 1.2.1 Instruments

[0442] 1. Refrigerator (BCD-268TN, Haier)

[0443] 2. Biological Safety Cabinet (BSC-1300II A2, Shanghai Boxun Industrial Co., Ltd. Medical Equipment Factory)

[0444] 3. Clean bench (CJ-2F, Suzhou Fengshi Experimental Animal Equipment Co., Ltd.)

[0445] 4. Electronic pipette assistant (Easypet 3, Eppendorf)

[0446] 5. Constant temperature water bath (HWS-12, Shanghai Yiheng Science)

[0447] 6. CO2 incubator (Thermo-311, Thermo)

[0448] 7. Centrifuge (Centrifuge 5720R, Eppendorf)

[0449] 8. Automated cell counter (Countess II, Life Technologies)

[0450] 9. Vernier caliper (CD-6" AX, Mitutoyo, Japan)

[0451] 10. Cell culture flask (T25 / T75 / T225, Corning)

[0452] 11. Electronic balance (CPA2202S, Sartorius)

[0453] 12. Electronic balance (BSA2202S-CW, Sartorius)

[0454] 13. Ultrasonic cleaner (115F0032, Shanghai Kedao)

[0455] 14. Water Purifier (Pacific TII, Thermo) 15. Magnetic Stirrer (08-2G, Chijiu)

[0456] 1.2.2 Reagents

[0457] 1. RPMI-1640 medium (22400-089, Gibco)

[0458] 2. Fetal bovine serum (FBS) (10099-141C, Gibco)

[0459] 3. Phosphate buffered saline (PBS) (10010-023, Gibco)

[0460] 4. Kolliphor HS15 (42966-1KG, Sigma-Aldrich)

[0461] 5. Methylcellulose M450 (69016482, Sinopharm Reagent)

[0462] 1.3 Experimental operation and data processing

[0463] 1.3.1 Animals: BALB / c nude mice, 6-8 weeks old, purchased from the Experimental Animal Management Department of Shanghai Institute of Family Planning Science.

[0464] 1.3.2 Cell culture and cell suspension preparation

[0465] a. A strain of Ba / F3 EGFR Del19 / C797S cells was taken from the cell bank and revived with RPMI-1640 medium (RPMI-1640 + 10% FBS). The revived cells were cultured in a CO2 incubator (incubator temperature: 37°C, CO2 concentration: 5%).

[0466] b. Subculture the cells every three days and continue to culture them in a CO2 incubator. Repeat this process until the cell count meets the in vivo efficacy requirement.

[0467] c. Collect cells in the exponential growth phase, count them using an automatic cell counter, and resuspend them in PBS to 2×10 7 cells / mL and placed in an ice box until use.

[0468] 1.3.3 Cell seeding

[0469] a, Nude mice were marked with disposable ear tags for both mice and rats before inoculation.

[0470] b. Mix the cell suspension thoroughly during inoculation, draw out 0.1-1 mL of cell suspension with a 1 mL syringe, remove any bubbles, and place the syringe on an ice pack until ready to use.

[0471] c. Secure the nude mouse with your left hand and disinfect the right side of the nude mouse's back near the right shoulder (inoculation site) with a 75% alcohol cotton ball. Start inoculation 30 seconds later.

[0472] d. The experimental nude mice were inoculated sequentially (0.1 mL of cell suspension per mouse).

[0473] 1.3.4 Tumor measurement, grouping, and drug administration in tumor-bearing mice

[0474] a, Tumors were measured and their sizes were calculated on days 9-12 after inoculation, depending on tumor growth.

[0475] Tumor volume calculation: Tumor volume (mm 3 ) = length (mm) × width (mm) × width (mm) / 2

[0476] b, Tumor-bearing mice were randomly divided into groups according to their weight and tumor size;

[0477] c. According to the grouping results, the test drug was started to be administered (administration method: oral administration; administration volume: 10 mL / kg; administration frequency: once / day or twice / day; administration cycle: 14 days; solvent: 10% Solutol HS15 / 0.5% MC).

[0478] d, Tumors were measured and weighed twice a week after the start of the test drug administration.

[0479] e, Animals were euthanized after the experiment.

[0480] f. Data were processed using Excel or other software. Calculation of compound tumor inhibition rate (TGI) (%): If tumors did not regress, TGI (%) = [1 - (average tumor volume at the end of dosing in a given treatment group - average tumor volume at the start of dosing in that treatment group) / (average tumor volume at the end of treatment in the solvent control group - average tumor volume at the start of treatment in the solvent control group)] × 100%. If tumors regressed, TGI (%) = [1 - (average tumor volume at the end of dosing in a given treatment group - average tumor volume at the start of dosing in that treatment group) / average tumor volume at the start of dosing in that treatment group] × 100%.

[0481] 1.4 Experimental results and conclusions:

[0482] The key example compounds of the present invention exhibited excellent tumor inhibition effects in the model. When administered orally at 50 mpk QD, excellent tumor inhibition effects were demonstrated, with a tumor inhibition rate TGI (%) greater than 80%, and the tumor inhibition rate TGI (%) of the key preferred compounds greater than 100%. When administered orally at 75 mpk QD, excellent tumor inhibition effects were demonstrated, with a tumor inhibition rate TGI (%) greater than 100%, and the tumor inhibition rate TGI (%) of the key preferred compounds greater than 150%. When administered orally at 120 mpk QD, excellent tumor inhibition effects were demonstrated, with a tumor inhibition rate TGI (%) greater than 150%, and the tumor inhibition rate TGI (%) of the key preferred compounds greater than 190%, without significant weight loss.

[0483] 3. Example 2 Salt Crystal Form Study

[0484] 1.1 Experimental Instruments

[0485] 1.1.1 Some parameters of physical and chemical testing instruments

[0486] 1.2 Instruments and liquid analysis conditions

[0487] 1.2.1 Instruments and Equipment

[0488] 1.2.2 Chromatographic conditions

[0489] 1.2.3 Chromatographic conditions

[0490] 1. Preparation of compound salt crystal form

[0491] 1. Phosphate crystal form A

[0492] Weigh 20 mg of the free base amorphous form, add 0.2 mL of ethyl acetate to dissolve at room temperature, add 0.042 mL of 1 M phosphoric acid in methanol to the system. The system remains clear after the addition of the acid. After stirring for a certain period of time, a large amount of yellow solid precipitates. React at room temperature for 2 hours, and centrifuge and dry the solid to obtain phosphate crystal form A.

[0493] 2. Phosphate crystal form B

[0494] Weigh 20 mg of the free base amorphous form and add 0.1 mL of acetone to dissolve at room temperature. Then, add 0.3 mL of methanol. Add 0.042 mL of a 1 M solution of phosphoric acid in methanol. The solution becomes turbid after the addition of the acid. After stirring for a period of time, a yellow solid precipitates. React at room temperature for 3 hours. Centrifuge and dry the solid to obtain Form B, the phosphate salt.

[0495] 3. Hydrochloride Form A

[0496] 20 mg of the free base amorphous form was weighed, 0.1 mL of ethanol was added, and the amorphous form was stirred at 50°C to crystallize into a suspension. 0.042 mL of a 1 M hydrochloric acid solution in methanol was added to the system. After the addition of the acid, the system became a red solution. After cooling to room temperature and stirring for a certain period of time, a large amount of solid precipitated. The solid was centrifuged and dried to obtain the hydrochloride salt form A.

[0497] 4. Hydrochloride Form B

[0498] Weigh 20 mg of the free base amorphous form, add 0.2 mL of ethyl acetate and dissolve at room temperature, add 0.042 mL of a 1 M hydrochloric acid solution in methanol to the system. After the addition of the acid, the system becomes a red solution. Add some seed crystals A of the hydrochloride crystal form A to the system until the system becomes turbid. Stir for a certain period of time to precipitate a large amount of solid. Continue the reaction at room temperature for 48 hours, then centrifuge and dry the solid to obtain the hydrochloride crystal form B.

[0499] 5. Sulfate crystal form A

[0500] 20 mg of the free base amorphous form was weighed, 0.1 mL of ethanol was added, and stirred at 50°C until the amorphous form crystallized into a suspension. 0.042 mL of a 1 M sulfuric acid solution in methanol was added to the system. After the addition of the acid, the system became a red solution. After cooling to room temperature and stirring for a certain period of time, a large amount of solid precipitated. The solid was centrifuged and dried to obtain sulfate salt Form A.

[0501] 6. Hydrobromide Form A

[0502] 20 mg of the free base amorphous form was weighed, 0.1 mL of ethanol was added, and the amorphous form was stirred at 50°C to crystallize into a suspension. 0.042 mL of a 1 M methanol solution of hydrobromic acid was added to the system. After the addition of the acid, the system turned into a red solution. After cooling to room temperature and stirring for a certain period of time, a large amount of solid precipitated. The solid was centrifuged and dried to obtain the hydrobromide salt form A.

[0503] 7. Hydrobromide Form B

[0504] 20 mg of the free base amorphous form was weighed and 0.2 mL of ethyl acetate was added to dissolve it at room temperature. 0.042 mL of a 1 M methanol solution of hydrobromic acid was added to the system. The system remained clear after the addition of the acid. After stirring for a certain period of time, a large amount of orange-yellow solid precipitated. The reaction was carried out at room temperature for 2 hours. The solid was centrifuged and dried to obtain hydrobromide salt Form B.

[0505] 8. Citrate Form A

[0506] Weigh 20 mg of the amorphous free base and 8.079 mg of citric acid monohydrate, mix them, add 0.3 mL of ethyl acetate, and react at 40°C. After a certain period of time, a beige solid precipitates. After cooling to room temperature and stirring for 2 hours, the solid is centrifuged and dried to obtain citrate salt Form A.

[0507] 9. Oxalate Form A

[0508] Weigh 20 mg of the amorphous free base and 4.8 mg of oxalic acid dihydrate, mix them, add 0.3 mL of ethyl acetate, and react at 40°C. After a certain period of time, a colloidal solid precipitates. After cooling to room temperature and stirring for 2 hours, the solid is centrifuged and dried to obtain oxalate salt Form A.

[0509] 10. Maleate Crystalline Form A

[0510] Weigh 20 mg of the amorphous free base and 4.56 mg of maleic acid, mix them, add 0.3 mL of ethyl acetate, and react at 40°C. After a period of time, a pale yellow solid precipitates. After cooling to room temperature and stirring for 2 hours, the solid is centrifuged and dried to obtain maleate salt Form A.

[0511] 11. Salicylate Crystal Form A

[0512] Weigh 20 mg of the amorphous free base and 5.3 mg of salicylic acid, mix them, add 0.3 mL of ethyl acetate, and react at 40°C. After a certain period of time, a yellow solid precipitates. After cooling to room temperature and stirring for 2 hours, the solid is centrifuged and dried to obtain salicylate salt Form A.

[0513] 12. Parahydroxybenzoate Crystalline Form A

[0514] Weigh 20 mg of the amorphous free base and 5.3 mg of p-hydroxybenzoic acid, mix them, add 0.3 mL of ethyl acetate, and react at 40°C for 1 hour. No solid precipitates. After cooling to room temperature and stirring for a period of time, a pale yellow solid precipitates. The solid is centrifuged and dried to obtain p-hydroxybenzoate Form A.

[0515] 2. Hygroscopicity test

[0516] 2.1 Experimental purpose: To investigate the hygroscopicity of different salt crystal forms of the compound under different relative humidity conditions, and to provide a basis for the screening and storage of compound salt crystal forms.

[0517] 2.2 Experimental plan: Place the compound salt crystal form in saturated water vapor at different relative humidity to allow the compound and water vapor to reach dynamic equilibrium, and calculate the percentage of moisture absorption and weight gain of the compound salt crystal form after equilibrium.

[0518] 2.3 Experimental results:

[0519] 2.3.1 Hygroscopicity of salt crystals

[0520] 1) Phosphate Form A absorbed moisture at 80% relative humidity and gained 0.533% weight, indicating slight hygroscopicity. After one cycle of moisture absorption and desorption at 0-95% relative humidity, the XRPD pattern of Phosphate Form A remained unchanged, indicating no crystal form transformation.

[0521] 2) Hydrochloride Form B absorbed moisture at 80% relative humidity and gained 1.157% in weight, indicating slight hygroscopicity. Furthermore, after one cycle of moisture absorption and desorption at 0-95% relative humidity, the XRPD pattern of Hydrochloride Form B remained unchanged, indicating no crystal form transformation.

[0522] 3) The sulfate salt Form A absorbed moisture at 80% relative humidity and gained 4.616% in weight, indicating hygroscopicity. Furthermore, after one cycle of moisture absorption and desorption at 0-95% relative humidity, the XRPD pattern of the sulfate salt Form A remained unchanged, indicating no crystal form transformation.

[0523] 4) Citrate Form A absorbed moisture at 80% relative humidity and gained 0.573% in weight, indicating slight hygroscopicity. Furthermore, after one cycle of moisture absorption and desorption at 0-95% relative humidity, the XRPD pattern of Citrate Form A remained unchanged, indicating no crystal form transformation.

[0524] 5) Oxalate Form A absorbed moisture at 80% relative humidity and gained 1.707% in weight, indicating slight hygroscopicity. Furthermore, after one cycle of moisture absorption and desorption at 0-95% relative humidity, the XRPD pattern of Form A remained unchanged, indicating no crystal form transformation.

[0525] 6) The maleate salt Form A absorbed moisture at 80% relative humidity and gained 2.050% in weight, indicating hygroscopicity. Furthermore, after one cycle of moisture absorption and desorption at 0-95% relative humidity, the XRPD pattern of the maleate salt Form A remained unchanged, indicating no crystal form transformation.

[0526] 7) Salicylate Form A absorbed moisture at 80% relative humidity and gained 0.1374% in weight, indicating slight hygroscopicity. Furthermore, after one cycle of moisture absorption and desorption at 0-95% relative humidity, the XRPD pattern of Salicylate Form A remained unchanged, indicating no crystal form transformation.

[0527] 2.4 Experimental conclusion: The above-mentioned crystal form did not undergo crystal transformation under different relative humidity conditions, which is beneficial to the stability and long-term storage of the sample.

[0528] 3. Solid stability test

[0529] 3.1 Experimental purpose: To investigate the physicochemical stability of compounds with different salt crystal forms at high temperature (60°C) and high humidity (RH) = 92.5% (GS) and high temperature (50°C) and high humidity (RH) = 75% (JS), in order to provide a basis for salt crystal form screening and storage of compound salt crystal forms.

[0530] 3.2 Experimental Plan: Accurately weigh different salt forms (hydrochloride Form A, sulfate Form A, citrate Form A, oxalate Form A, maleate Form A, and salicylate Form A) and examine their stability at 60°C (GW), 92.5% RH (room temperature, GS), and 50°C / 75% RH (JS) for 7 and 14 days. Changes in related substances in the salts were calculated using the chromatographic peak area normalization method. (Chromatographic conditions are as described in 1.2.2.)

[0531] 3.3 Experimental results: See Table 24 below.

[0532] Table 24

[0533] 3.4 Experimental conclusion: Judging from the stability data, citrate crystal form A and oxalate crystal form A are relatively stable under high temperature, high humidity, and high temperature and high humidity conditions, with no significant increase in impurities, and can well meet the requirements of late-stage drug development. Maleate crystal form A and salicylate crystal form A are relatively stable under high temperature and high humidity conditions, with no significant increase in impurities, indicating that maleate crystal form A and salicylate crystal form A are not sensitive to changes in temperature and humidity and can meet the storage requirements of late-stage drugs. Hydrochloride crystal form A and sulfate crystal form A can remain stable after being placed under various conditions for a period of time, with no significant increase in impurities, indicating that hydrochloride crystal form A and sulfate crystal form A can effectively increase the operating space for late-stage drug formulation development.

[0534] 4. Solubility experiments in different media

[0535] 4.1 Experimental purpose: To compare the solubility of phosphate form A, hydrochloride form A, sulfate form A, citrate form A, oxalate form A, maleate form A and salicylate form A in artificial simulated gastric fluid (FaSSGF), fasting artificial simulated intestinal fluid (FaSSIF) and non-fasting artificial simulated intestinal fluid (FeSSIF), so as to provide a basis for the evaluation of the drugability of the salt form.

[0536] 4.2 Experimental plan: About 2 mg of the compound was suspended in different media for 24 hours, and the thermodynamic solubility of the compound at 37°C was determined by HPLC using the external standard method.

[0537] 4.3 Experimental results: See the table below.

[0538] Table 25

[0539] 4.4 Experimental conclusion: The above salt crystal forms have good solubility in various media and meet the requirements for drugability.

[0540] 5. Solid stability test

[0541] 5.1 Experimental purpose: To investigate the stability comparison of phosphate crystal form A under three conditions: high temperature 60°C (GW, closed), 50°C / 75% RH (JS, open), and room temperature / 92.5% RH (GS, open), to provide a basis for salt crystal form screening and compound salt storage.

[0542] 5.2 Experimental Plan: Approximately 2 mg of phosphate Form A was weighed into a 2 mL, dry, clean glass vial. The vial was incubated at 60°C (GW, closed), 50°C / 75% RH (JS, open), and room temperature / 92.5% RH (GS, open) for 5, 10, 20, and 30 days. Samples were taken at different time points and analyzed by HPLC to determine changes in content and related substances. (Chromatographic conditions are as described in 1.2.3).

[0543] 5.3 Experimental results: See the table below.

[0544] Table 26

[0545] 5.4 Experimental conclusion: Phosphate crystal form A is relatively stable under high temperature, high humidity, and high temperature and high humidity conditions, with no significant increase in impurities, and can well meet the requirements of later long-term storage and formulation process.

[0546] Example 2: Study on the free base crystal form

[0547] 1. Preparation of different free base crystal forms

[0548] (1) Preparation of Form A: Weigh approximately 20 mg of the free base amorphous form into a 2 mL glass bottle, add 200 μL of methanol or ethanol, and stir at room temperature for 2 hours to precipitate a solid. Centrifuge the sample at 10,000 rpm for 3 minutes, remove the supernatant, and dry it in a vacuum oven at 40°C. The vacuum-dried sample was characterized by XRD analysis. Form A was obtained. After testing and analysis, it has the following XRPD pattern as shown in Figure 25 and the DSC pattern as shown in Figure 26.

[0549] (2) Preparation of Form B: Approximately 20 mg of the free base amorphous form was weighed into a 2 mL glass vial, 200 μL of acetonitrile was added, and the mixture was stirred at room temperature for 2 hours until a solid precipitated. The sample was centrifuged at 10,000 rpm for 3 min, the supernatant removed, and the mixture was vacuum dried in a vacuum drying oven at 40°C. The vacuum-dried sample was characterized by XRD analysis. Form C was obtained. After testing and analysis, it had the following XRPD pattern as shown in Figure 27 and the DSC pattern as shown in Figure 28.

[0550] (3) Preparation of Form C: Approximately 20 mg of the free base amorphous form was weighed into a 2 mL glass vial, 200 μL of 1,4-dioxane was added, and the mixture was stirred at room temperature for 2 hours until a solid precipitated. The sample was centrifuged at 10,000 rpm for 3 minutes, the supernatant was removed, and the mixture was vacuum dried in a vacuum drying oven at 40°C. The vacuum-dried sample was characterized by XRD analysis. Form B was obtained. After testing and analysis, it had the following XRPD pattern as shown in Figure 29 and the DSC pattern as shown in Figure 30.

[0551] (4) Preparation of Form D: Approximately 20 mg of the free base amorphous form was weighed into a 2 mL glass vial, 200 μL of water was added, and the mixture was stirred at room temperature for 2 hours until a solid precipitated. The sample was centrifuged at 10,000 rpm for 3 min, the supernatant removed, and the mixture was vacuum dried in a vacuum drying oven at 40°C. The vacuum-dried sample was characterized by XRD analysis. Form D was obtained. Analysis revealed the following XRPD pattern, as shown in Figure 31, and the following DSC pattern, as shown in Figure 32.

[0552] (5) Preparation of Form E: Approximately 10 mg of the free base amorphous form was weighed into a 2 mL glass vial. 100 μL of ethyl formate was added to completely dissolve the mixture. A certain amount of water or n-heptane was then added and stirred at room temperature for 24 hours until a solid precipitated. The sample was centrifuged at 10,000 rpm for 3 min, the supernatant removed, and the mixture was vacuum dried in a vacuum drying oven at 40°C. The vacuum-dried sample was characterized by XRD analysis. Form E was obtained. Upon analysis, the XRPD pattern shown in FIG33 and the DSC pattern shown in FIG34 were obtained.

[0553] (6) Preparation of Form F: Approximately 20 mg of the free base amorphous form was weighed into a 2 mL glass vial, 200 μL of ethyl formate was added, and the mixture was stirred at room temperature for 2 hours until a solid precipitated. The sample was centrifuged at 10,000 rpm for 3 min, the supernatant removed, and the mixture was vacuum dried in a vacuum drying oven at 40°C. The vacuum-dried sample was characterized by XRD analysis. Form F was obtained. Analysis revealed the following XRPD pattern, as shown in FIG35 , and the following DSC pattern, as shown in FIG36 .

[0554] (7) Preparation of Form G: Approximately 20 mg of the free base amorphous form was weighed into a 2 mL glass vial, 200 μL of N,N-dimethylacetamide was added, and the mixture was stirred at room temperature for 2 hours until a solid precipitated. The sample was centrifuged at 10,000 rpm for 3 min, the supernatant removed, and the mixture was vacuum dried in a vacuum drying oven at 40°C. The vacuum-dried sample was characterized by XRD analysis. Form G was obtained. Analysis revealed the following XRPD pattern, as shown in FIG37 , and the following DSC pattern, as shown in FIG38 .

[0555] 2. Free base crystal solid stability test

[0556] 2.1 Experimental purpose: To investigate the physicochemical stability of the free base crystal form A at high temperature of 60°C, room temperature and high humidity RH = 92.5% and 50°C RH = 75% for 5 days, 10 days, 20 days and 30 days, so as to provide a basis for the storage of the compound.

[0557] 2.2 Experimental Plan: Approximately 2 mg of free base Form A was oven-dried at 60°C, room temperature, and high humidity (RH = 92.5%) for 5, 10, 20, and 30 days. The content was determined by HPLC using the external standard method, and changes in related substances were calculated using the chromatographic peak area normalization method. (Chromatographic conditions are as described in 1.2.3.)

[0558] 2.3 Experimental results: The physicochemical stability results of free base crystal form A under different conditions are shown in Table 27 below

[0559] Table 27

[0560] Experimental conclusion: Free base crystal form A is very stable under various conditions and can well meet the requirements of later long-term storage and formulation process.

[0561] 3. Hygroscopicity test

[0562] 3.1 Experimental purpose: To investigate the hygroscopicity of the compound free base crystal form A under different relative humidity conditions, and to provide a basis for the screening and storage of the compound crystal form.

[0563] 3.2 Experimental plan: The free base crystal form A of the compound is placed in saturated water vapor at different relative humidity to allow the compound and the water vapor to reach dynamic equilibrium, and the percentage of moisture absorption and weight gain of the compound after equilibrium is calculated.

[0564] 3.3 Experimental Results: Free base Form A absorbed moisture at 80% relative humidity and gained approximately 0.1719% weight, indicating slight hygroscopicity. After one cycle of moisture absorption and desorption at 0-95% relative humidity, the XRPD pattern of free base Form A remained unchanged, indicating no crystal form transformation, which is beneficial for sample stability and long-term storage.

[0565] 4. Solubility experiments in different media

[0566] 4.1 Experimental purpose: To test the solubility of free base form A in media such as pH 1 buffer, artificial simulated gastric fluid (FaSSGF), fasting artificial simulated intestinal fluid (FaSSIF) and non-fasting artificial simulated intestinal fluid (FeSSIF), so as to provide a basis for the evaluation of drugability.

[0567] 4.2 Experimental plan: Weigh approximately 1.0 mg of free base form A and place it in a 2 mL glass bottle. Add 1 mL of pH 1 buffer, fasting artificial simulated intestinal fluid (FaSSIF), non-fasting artificial simulated intestinal fluid (FeSSIF) and fasting simulated gastric fluid (FaSSGF) respectively. Place it on a micromixer and shake overnight at 37°C. Filter the 24 h sample solution with a 0.45 μm nylon filter membrane and take the filtrate. Use the external standard method and HPLC to test its concentration.

[0568] 4.3 Experimental results: as shown in Table 28

[0569] Table 28

[0570] Conclusion: The free base crystal form A has good solubility in different media and meets the requirements of drugability.

Claims

1. A compound represented by general formula (I) or a crystalline form of its stereoisomer or an acid addition salt thereof, in: M1 is independently selected from a bond, NR4 or CR5R6; R1 is selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl or deuterated C 1-6 alkyl; R 2-1 , R 2-2 , R 2-3 and R 2-4 are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl or deuterated C 1-6 alkyl; R 2-5 Selected from amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl or deuterated C 1-6 Alkyl, the amino, C 1- 6 Alkyl, halogenated C 1-6 Alkyl or deuterated C 1-6 The alkyl group may be further optionally substituted with deuterium, halogen, cyano, hydroxyl, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl and deuterated C 1-6 one or more substitutions in the alkyl group; R 3-1 , R 3-2 and R 3-3 are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl or deuterated C 1-6 alkyl; R4 is selected from hydrogen, deuterium, C 1-6 Alkyl, halogenated C 1-6 Alkyl or deuterated C 1-6 alkyl; R5 and R6 are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl or deuterated C 1- 6 alkyl; The acid in the acid addition salt is selected from an inorganic acid or an organic acid; wherein the inorganic acid is selected from 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, 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 , dodecyl sulfuric acid, dibenzoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactosonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalene disulfonic 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, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, n-butyric acid, p-hydroxybenzoic acid, or L-malic acid; Preferably, the acid in the acid addition salt is selected from phosphoric acid, hydrochloric acid, sulfuric acid, hydrobromic acid, citric acid, oxalic acid, maleic acid, salicylic acid or p-hydroxybenzoic acid.

2. The crystalline form or acid addition salt thereof according to claim 1, characterized in that: R1 is selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, halogenated C 1-3 Alkyl or deuterated C 1-3 alkyl; R 2-1 , R 2-2 , R 2-3 and R 2-4 are each independently selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, halogenated C 1-3 Alkyl or deuterated C 1-3 alkyl; R 2-5 Selected from amino, C 1-3 Alkyl, halogenated C 1-3 Alkyl or deuterated C 1-3 Alkyl, the amino, C 1- 3 Alkyl, halogenated C 1-3 Alkyl or deuterated C 1-3 The alkyl group may be further optionally substituted with deuterium, halogen, cyano, hydroxyl, nitro, C 1-3 Alkyl, halogenated C 1-3 Alkyl and deuterated C 1-3 one or more substitutions in the alkyl group; R 3-1 , R 3-2 and R 3-3 are each independently selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, halogenated C 1-3 Alkyl or deuterated C 1-3 alkyl; R4 is selected from hydrogen, deuterium, C 1-3 Alkyl, halogenated C 1-3 Alkyl or deuterated C 1-3 alkyl; R5 and R6 are each independently selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, halogenated C 1-3 Alkyl or deuterated C 1- 3 Alkyl.

3. The crystalline form or acid addition salt thereof according to claim 1, characterized in that: The compound is any one of the following:

4. The crystalline form or acid addition salt thereof according to any one of claims 1 to 3, characterized in that: The number of acids in the acid addition salt is 1, 2 or 3.

5. The crystalline form or acid addition salt thereof according to any one of claims 1 to 4, characterized in that: The acid addition salt is a hydrate or an anhydrate; the anhydrate is preferred.

6. A crystalline form of N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidine-3-yl)-N-methylmethanesulfonamide, characterized in that the crystalline form is phosphate crystalline form A, phosphate crystalline form B, hydrochloride crystalline form A, hydrochloride crystalline form B, sulfate crystalline form A, hydrobromide crystalline form A, hydrobromide crystalline form B, citrate crystalline form A, oxalate crystalline form A, maleate crystalline form A, salicylate crystalline form A or p-hydroxybenzoate crystalline form A; wherein, The X-ray powder diffraction spectrum of the phosphate crystal form A has a diffraction peak at 2θ of 4.5±0.2°; or a diffraction peak at 8.8±0.2°; or a diffraction peak at 10.8±0.2°; or a diffraction peak at 12.9±0.2°; or a diffraction peak at 14.4±0.2°; or a diffraction peak at 15.3±0.2°; or a diffraction peak at 16.3±0.2°. or having a diffraction peak at 17.1±0.2°; or having a diffraction peak at 17.9±0.2°; or having a diffraction peak at 25.2±0.2°; preferably including any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, or 8-10 of the above diffraction peaks; more preferably including any 6, 7, 8, 9 or 10 thereof; The X-ray powder diffraction pattern of the phosphate crystal form B has diffraction peaks at 2θ (±0.2°) of 5.3±0.2°, 16.0±0.2°, 19.9±0.2°, 20.3±0.2°, 21.4±0.2° and 22.3±0.2°; preferably, the X-ray powder diffraction pattern of the phosphate crystal form B also has diffraction peaks at 2θ (±0.2°) of 12.5±0.2° and 13.0±0.2°; more preferably, the X-ray powder diffraction pattern of the phosphate crystal form B further has diffraction peaks at 2θ (±0.2°) of 14.1±0.2° and 24.7±0.2°; The X-ray powder diffraction pattern of the hydrochloride salt form A has diffraction peaks at 2θ (±0.2°) of 6.4±0.2°, 7.1±0.2°, 14.2±0.2°, 19.3±0.2°, 24.6±0.2° and 25.1±0.2°; preferably, the X-ray powder diffraction pattern of the hydrochloride salt form A also has diffraction peaks at 2θ (±0.2°) of 9.3±0.2° and 12.7±0.2°; more preferably, the X-ray powder diffraction pattern of the hydrochloride salt form A further has diffraction peaks at 2θ (±0.2°) of 11.2±0.2° and 15.5±0.2°; The X-ray powder diffraction pattern of the hydrochloride salt form B has diffraction peaks at 2θ (±0.2°) of 9.6±0.2°, 15.8±0.2°, 16.9±0.2°, 25.7±0.2°, 27.5±0.2° and 27.9±0.2°; preferably, the X-ray powder diffraction pattern of the hydrochloride salt form B also has diffraction peaks at 2θ (±0.2°) of 15.1±0.2° and 23.4±0.2°; more preferably, the X-ray powder diffraction pattern of the hydrochloride salt form B further has diffraction peaks at 2θ (±0.2°) of 19.1±0.2° and 26.2±0.2°; The X-ray powder diffraction pattern of the sulfate salt crystal form A has diffraction peaks at 2θ (±0.2°) of 5.5±0.2°, 6.1±0.2°, 6.3±0.2°, 16.1±0.2°, 26.1±0.2° and 26.8±0.2°; preferably, the X-ray powder diffraction pattern of the sulfate salt crystal form A also has diffraction peaks at 2θ (±0.2°) of 15.7±0.2° and 22.9±0.2°; more preferably, the X-ray powder diffraction pattern of the sulfate salt crystal form A further has diffraction peaks at 2θ (±0.2°) of 14.1±0.2° and 22.0±0.2°; The X-ray powder diffraction pattern of the hydrobromide salt form A has diffraction peaks at 2θ (±0.2°) of 7.1±0.2°, 14.3±0.2°, 21.6±0.2°, 22.1±0.2°, 25.1±0.2° and 27.0±0.2°; preferably, the X-ray powder diffraction pattern of the hydrobromide salt form A also has diffraction peaks at 2θ (±0.2°) of 11.3±0.2° and 21.2±0.2°; more preferably, the X-ray powder diffraction pattern of the hydrobromide salt form A further has diffraction peaks at 2θ (±0.2°) of 26.7±0.2° and 30.5±0.2°; The X-ray powder diffraction pattern of the hydrobromide salt form B has diffraction peaks at 2θ (±0.2°) of 6.9±0.2°, 18.5±0.2°, 19.4±0.2°, 22.8±0.2°, 24.9±0.2° and 25.3±0.2°; preferably, the X-ray powder diffraction pattern of the hydrobromide salt form B also has diffraction peaks at 2θ (±0.2°) of 7.1±0.2° and 19.7±0.2°; more preferably, the X-ray powder diffraction pattern of the hydrobromide salt form B further has diffraction peaks at 2θ (±0.2°) of 15.3±0.2° and 22.6±0.2°; The X-ray powder diffraction pattern of the citrate salt crystalline form A has diffraction peaks at 2θ (±0.2°) of 12.2±0.2°, 16.7±0.2°, 18.7±0.2°, 19.4±0.2°, 21.9±0.2° and 22.3±0.2°; preferably, the X-ray powder diffraction pattern also has diffraction peaks at 2θ (±0.2°) of 16.2±0.2° and 23.5±0.2°; more preferably, the X-ray powder diffraction pattern further has diffraction peaks at 2θ (±0.2°) of 11.7±0.2° and 15.6±0.2°; The X-ray powder diffraction pattern of the oxalate crystalline form A has diffraction peaks at 2θ (±0.2°) of 4.3±0.2°, 17.5±0.2°, 17.8±0.2°, 18.2±0.2°, 20.7±0.2° and 25.8±0.2°; preferably, the X-ray powder diffraction pattern of the oxalate crystalline form A also has diffraction peaks at 2θ (±0.2°) of 8.4±0.2° and 16.8±0.2°; more preferably, the X-ray powder diffraction pattern of the oxalate crystalline form A further has diffraction peaks at 2θ (±0.2°) of 21.0±0.2° and 27.4±0.2°; The X-ray powder diffraction pattern of the maleate salt crystalline form A has diffraction peaks at 2θ (±0.2°) of 7.1±0.2°, 8.1±0.2°, 17.0±0.2°, 19.0±0.2°, 25.7±0.2° and 26.9±0.2°; preferably, the X-ray powder diffraction pattern of the maleate salt crystalline form A also has diffraction peaks at 2θ (±0.2°) of 9.0 ±0.2° and 22.9±0.2°; more preferably, the X-ray powder diffraction pattern of the maleate salt form A further has diffraction peaks at 2θ (±0.2°) of 13.4±0.2° and 20.6±0.2°; The X-ray powder diffraction pattern of the salicylate crystalline form A has diffraction peaks at 2θ (±0.2°) of 8.3±0.2°, 16.5±0.2°, 18.5±0.2°, 20.4±0.2°, 22.3±0.2° and 24.4±0.2°; preferably, the X-ray powder diffraction pattern of the salicylate crystalline form A also has diffraction peaks at 2θ (±0.2°) of 22.0±0.2° and 28.0±0.2°; more preferably, the X-ray powder diffraction pattern of the salicylate crystalline form A further has diffraction peaks at 2θ (±0.2°) of 16.3±0.2° and 21.0±0.2°; The X-ray powder diffraction pattern of the p-hydroxybenzoate crystalline form A has diffraction peaks at 2θ (±0.2°) of 5.9±0.2°, 17.2±0.2°, 17.5±0.2°, 18.9±0.2°, 22.3±0.2° and 25.2±0.2°; preferably, the X-ray powder diffraction pattern of the p-hydroxybenzoate crystalline form A also has diffraction peaks at 2θ (±0.2°) of 16.1±0.2° and 22.0±0.2°; more preferably, the X-ray powder diffraction pattern of the p-hydroxybenzoate crystalline form A further has diffraction peaks at 2θ (±0.2°) of 23.7±0.2° and 25.6±0.2°.

7. The crystal form according to claim 6, characterized in that The X-ray powder diffraction spectrum of the phosphate crystal form A at least includes one or more diffraction peaks located at 2θ of 4.5±0.2°, 8.8±0.2°, and 10.8±0.2°, preferably includes 2 of them, and more preferably includes 3 of them; optionally, it may further include at least one of 2θ of 12.9±0.2°, 14.4±0.2°, 16.3±0.2°, and 17.1±0.2°; preferably includes 2, 3, 4 or 5 of them; Preferably, the X-ray powder diffraction pattern of the phosphate crystal form A optionally further comprises one or more diffraction peaks located at 2θ of 9.0±0.2°, 15.3±0.2°, 18.0±0.2°, 19.3±0.2°, 21.8±0.2°, 25.2±0.2°, 27.9±0.2°; preferably, at least any 2-3, or 4-5 of them; further preferably, any 2, 3, 4, or 5 of them are included; Further preferably, the X-ray powder diffraction pattern of the phosphate crystal form A comprises diffraction peaks at 2θ of 4.5±0.2° and 8.8±0.2°; preferably, further comprises diffraction peaks at 10.8±0.2° and 17.1±0.2°; more preferably, further comprises diffraction peaks at 12.9±0.2° and 14.4±0.2°; further preferably, further comprises diffraction peaks at 15.3±0.2° and 16.3±0.2°; further preferably, further comprises diffraction peaks at 18.0±0.2° and 25.2±0.2°; For example, the X-ray powder diffraction pattern of the phosphate crystal form A has diffraction peaks at 2θ of the following positions: 8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、17.1±0.2°； 4.5±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、17.1±0.2°； 4.5±0.2°、8.8±0.2°、12.9±0.2°、14.4±0.2°、17.1±0.2°； 4.5±0.2°、8.8±0.2°、10.8±0.2°、14.4±0.2°、17.1±0.2°； 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、17.1±0.2°； 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°； 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、17.1±0.2°； 8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、17.1±0.2°； 4.5±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、16.3±0.2°、17.1±0.2°； 4.5±0.2°、8.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、17.1±0.2°； 4.5±0.2°、8.8±0.2°、10.8±0.2°、14.4±0.2°、16.3±0.2°、17.1±0.2°； 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、15.3±0.2°、17.1±0.2°； 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、16.3±0.2°； 8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°； 4.5±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°； 4.5±0.2°、8.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°； 4.5±0.2°、8.8±0.2°、10.8±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°； 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°； 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、16.3±0.2°、17.1±0.2°； 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、17.1±0.2°； 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°； 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°； 8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、18.0±0.2°； 4.5±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、25.2±0.2°； 4.5±0.2°、8.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、18.0±0.2°； 4.5±0.2°、8.8±0.2°、10.8±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、25.2±0.2°； 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、18.0±0.2°； 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、16.3±0.2°、17.1±0.2°、25.2±0.2°； 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、17.1±0.2°、18.0±0.2°； 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、25.2±0.2°； 8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、18.0±0.2°、25.2±0.2°； 4.5±0.2°、9.0±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、18.0±0.2°、25.2±0.2°； 4.5±0.2°、8.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、18.0±0.2°、19.3±0.2°、25.2±0.2°； 4.5±0.2°、8.8±0.2°、10.8±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、18.0±0.2°、21.8±0.2°、25.2±0.2°； 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、18.0±0.2°、25.2±0.2°、27.9±0.2°； 4.5±0.2°、8.8±0.2°、9.0±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、16.3±0.2°、17.1±0.2°、18.0±0.2°、25.2±0.2°； 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、17.1±0.2°、18.0±0.2°、19.3±0.2°、25.2±0.2°； 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、18.0±0.2°、21.8±0.2°、25.2±0.2°； 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、25.2±0.2°、27.9±0.2°； 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、18.0±0.2°、19.3±0.2°； 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、18.0±0.2°、25.2±0.2°； 8.8±0.2°、9.0±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、18.0±0.2°、25.2±0.2°； 4.5±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、18.0±0.2°、19.3±0.2°、25.2±0.2°； 4.5±0.2°、8.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、 17.1±0.2°、18.0±0.2°、21.8±0.2°、25.2±0.2°； 4.5±0.2°、8.8±0.2°、10.8±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、18.0±0.2°、25.2±0.2°、27.9±0.2°； 4.5±0.2°、8.8±0.2°、9.0±0.2°、10.8±0.2°、12.9±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、18.0±0.2°、25.2±0.2°； 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、16.3±0.2°、17.1±0.2°、18.0±0.2°、19.3±0.2°、25.2±0.2°； 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、17.1±0.2°、18.0±0.2°、21.8±0.2°、25.2±0.2°； 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、18.0±0.2°、25.2±0.2°、27.9±0.2°； 4.5±0.2°、8.8±0.2°、9.0±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、25.2±0.2°； 4.5±0.2°、8.8±0.2°、10.8±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、16.3±0.2°、17.1±0.2°、18.0±0.2°、19.3±0.2°； Further preferably, the X-ray powder diffraction spectrum of the phosphate crystal form A is substantially as shown in FIG1 ; further preferably, the DSC spectrum of the phosphate crystal form A is substantially as shown in FIG2 ; The X-ray powder diffraction pattern of the phosphate crystal form B is substantially as shown in FIG3 ; More preferably, the DSC spectrum of the phosphate crystal form B is substantially as shown in FIG4 ; The X-ray powder diffraction pattern of the hydrochloride salt form A is substantially as shown in FIG5 ; More preferably, the DSC spectrum of the hydrochloride salt form A is substantially as shown in Figure 6; The X-ray powder diffraction pattern of the hydrochloride salt form B is substantially as shown in FIG7 ; More preferably, the DSC spectrum of the hydrochloride salt form B is substantially as shown in FIG8 ; The X-ray powder diffraction pattern of the sulfate crystal form A is substantially as shown in FIG9 ; More preferably, the DSC spectrum of the sulfate crystal form A is substantially as shown in FIG10 ; The X-ray powder diffraction pattern of the hydrobromide salt form A is substantially as shown in FIG11 ; More preferably, the DSC spectrum of the hydrobromide salt form A is substantially as shown in Figure 12; The X-ray powder diffraction pattern of the hydrobromide salt form B is substantially as shown in FIG13 ; More preferably, the DSC spectrum of the hydrobromide salt form B is substantially as shown in FIG14 ; The X-ray powder diffraction pattern of the citrate salt form A is substantially as shown in FIG15 ; More preferably, the DSC spectrum of the citrate salt form A is substantially as shown in FIG16 ; The X-ray powder diffraction pattern of the oxalate crystal form A is substantially as shown in FIG17 ; More preferably, the DSC spectrum of the oxalate crystal form A is substantially as shown in Figure 18; The X-ray powder diffraction pattern of the maleate salt form A is substantially as shown in FIG19 ; More preferably, the DSC spectrum of the maleate salt form A is substantially as shown in Figure 20; The X-ray powder diffraction pattern of the salicylate crystalline form A is substantially as shown in FIG21 ; More preferably, the DSC spectrum of the salicylate crystalline form A is substantially as shown in Figure 22; The X-ray powder diffraction pattern of the p-hydroxybenzoate crystalline form A is substantially as shown in FIG23 ; More preferably, the DSC spectrum of the para-hydroxybenzoate crystalline form A is substantially as shown in Figure 24.

8. The crystal form according to any one of claims 6 to 7, characterized in that: Phosphate Form A, Phosphate Form B, Hydrochloride Form A, Hydrochloride Form B, Sulfate Form A, Hydrobromide Form A, Hydrobromide Form B, Citrate Form A, and Hydrochloride Form B of N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide The positions of the diffraction peaks with the top ten relative peak intensities in the X-ray powder diffraction patterns of the salt form A, the maleate form A, the salicylate form A, and the p-hydroxybenzoate form A are respectively compared with the 2θ errors of the diffraction peaks at the corresponding positions in Figures 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, and 23, respectively; preferably ±0.2° to ±0.3°; and most preferably ±0.2°.

9. The crystalline form or acid addition salt thereof according to claim 1, characterized in that: The crystalline form is crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F or crystalline form G of N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidine-3-yl)-N-methylmethanesulfonamide; wherein, The X-ray powder diffraction pattern of the crystalline form A has diffraction peaks at 2θ (±0.2°) of 13.0±0.2°, 14.0±0.2°, 15.9±0.2°, 19.8±0.2°, 20.2±0.2° and 22.3±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form A also has diffraction peaks at 2θ (±0.2°) of 12.4±0.2° and 24.6±0.2°; more preferably, the X-ray powder diffraction pattern of the crystalline form A further has diffraction peaks at 2θ (±0.2°) of 5.3±0.2° and 21.3±0.2°; The X-ray powder diffraction spectrum of the crystalline form B has diffraction peaks at 2θ (±0.2°) of 11.3±0.2°, 11.6±0.2°, 17.4±0.2°, 21.9±0.2°, 22.2±0.2° and 23.3±0.2°; Preferably, the X-ray powder diffraction pattern of the crystalline form B also has diffraction peaks at 2θ (± 0.2°) of 12.0 ± 0.2° and 15.5 ± 0.2°; More preferably, the X-ray powder diffraction pattern of the crystalline form B further has diffraction peaks at 2θ (± 0.2°) of 15.9 ± 0.2° and 27.2 ± 0.2°; The X-ray powder diffraction pattern of the crystalline form C has diffraction peaks at 2θ (±0.2°) of 11.6±0.2°, 18.5±0.2°, 19.3±0.2°, 21.5±0.2°, 23.2±0.2° and 23.4±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form C also has diffraction peaks at 2θ (±0.2°) of 7.2±0.2° and 18.8±0.2°; more preferably, the X-ray powder diffraction pattern of the crystalline form C further has diffraction peaks at 2θ (±0.2°) of 8.6±0.2° and 22.3±0.2°; The X-ray powder diffraction pattern of the crystalline form D has diffraction peaks at 2θ (±0.2°) of 12.2±0.2°, 16.1±0.2°, 19.7±0.2°, 21.2±0.2°, 21.9±0.2° and 24.0±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form D also has diffraction peaks at 2θ (±0.2°) of 15.9±0.2° and 21.4±0.2°; more preferably, the X-ray powder diffraction pattern of the crystalline form D further has diffraction peaks at 2θ (±0.2°) of 24.5±0.2° and 29.0±0.2°; The X-ray powder diffraction pattern of the crystalline form E has diffraction peaks at 2θ (±0.2°) of 12.3±0.2°, 16.6±0.2°, 20.0±0.2°, 21.2±0.2°, 21.6±0.2° and 24.4±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form E also has diffraction peaks at 2θ (±0.2°) of 8.1±0.2° and 24.1±0.2°; more preferably, its X-ray powder diffraction pattern further has diffraction peaks at 2θ (±0.2°) of 16.0±0.2° and 19.8±0.2°; The X-ray powder diffraction pattern of the crystalline form F has diffraction peaks at 2θ (±0.2°) of 14.2±0.2°, 17.2±0.2°, 19.7±0.2°, 21.2±0.2°, 25.3±0.2° and 26.2±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form F also has diffraction peaks at 2θ (±0.2°) of 6.6±0.2° and 23.3±0.2°; more preferably, the X-ray powder diffraction pattern of the crystalline form F further has diffraction peaks at 2θ (±0.2°) of 15.1±0.2° and 18.1±0.2°; The X-ray powder diffraction pattern of the crystalline form G has diffraction peaks at 2θ (±0.2°) of 10.4±0.2°, 16.3±0.2°, 18.8±0.2°, 21.3±0.2°, 22.2±0.2° and 23.9±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form G also has diffraction peaks at 2θ (±0.2°) of 9.4±0.2° and 25.7±0.2°; more preferably, the X-ray powder diffraction pattern of the crystalline form G further has diffraction peaks at 2θ (±0.2°) of 16.6±0.2° and 23.2±0.2°.

10. The crystalline form or acid addition salt thereof according to claim 9, characterized in that: The X-ray powder diffraction pattern of the crystalline form A is substantially as shown in FIG25 ; More preferably, the DSC spectrum of the crystalline form A is shown in Figure 26; The X-ray powder diffraction pattern of the crystalline form B is substantially as shown in FIG27 ; More preferably, the DSC spectrum of the crystalline form B is substantially as shown in Figure 28; The X-ray powder diffraction pattern of the crystalline form C is substantially as shown in FIG29 ; More preferably, the DSC spectrum of the crystalline form C is substantially as shown in Figure 30; The X-ray powder diffraction pattern of the crystalline form D is substantially as shown in FIG31 ; More preferably, the DSC spectrum of the crystalline form D is substantially as shown in Figure 32; The X-ray powder diffraction pattern of the crystalline form E is substantially as shown in FIG33 ; More preferably, the DSC spectrum of the crystalline form E is substantially as shown in Figure 34; The X-ray powder diffraction pattern of the crystalline form F is substantially as shown in FIG35 ; More preferably, the DSC spectrum of the crystalline form F is substantially as shown in Figure 36; The X-ray powder diffraction pattern of the crystalline form G is substantially as shown in FIG37 ; More preferably, the DSC spectrum of the crystal form G is substantially as shown in Figure 38.

11. The crystalline form or acid addition salt thereof according to any one of claims 9 to 10, characterized in that: The 2θ errors of the top ten diffraction peak positions with relative peak intensity in the X-ray powder diffraction patterns of Form A, Form B, Form C, Form D, Form E, Form F, and Form G of N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidine-3-yl)-N-methylmethanesulfonamide and the diffraction peaks at the corresponding positions in Figures 25, 27, 29, 31, 33, 35, and 37, respectively, are ±0.2° to ±0.5°; preferably ±0.2° to ±0.3°, and most preferably ±0.2°.

12. A method for preparing the crystalline form or acid addition salt thereof according to any one of claims 1 to 5, characterized in that: It is either method one or method two: Method 1 includes the following steps: 1) dissolving the compound in an organic solvent; 2) adding a counter ion acid; the amount of the counter ion acid is preferably 1.2 equivalents; the counter ion acid can be dissolved in an organic solvent; 3) stirring and mixing to evaporate the solvent; 4) isolating the acid addition salt; Method 2 includes the following steps: 1) suspending the compound in an organic solvent; 2) adding a counter ion acid; the amount of the counter ion acid is preferably 1.2 equivalents; the counter ion acid can be dissolved in an organic solvent; 3) Stir to dissolve, and continue stirring to precipitate; 4) isolating the acid addition salt; Wherein: the solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol or N,N-dimethylformamide; preferably methanol, ethanol, acetone or ethyl acetate; The counter ion 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-acetylaminobenzoic 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, dodecyl sulfuric acid, dibenzoyl Tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactosonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalene disulfonic 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, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, n-butyric acid, p-hydroxybenzoic acid, or L-malic acid.

13. A method for preparing the crystal form according to any one of claims 6 to 8, characterized in that: It is either method one or method two: Method 1 includes the following steps: 1) Weigh an appropriate amount of the compound and dissolve it in a benign solvent; 2) Weigh an appropriate amount of counter ion acid and dissolve it in an organic solvent; the amount of the counter ion acid is preferably 1.2 equivalents; 3) combining the above two solutions, stirring to precipitate or adding a poor solvent dropwise and stirring to precipitate; 4) rapidly centrifuging or standing to dry to obtain the crystal form; Wherein: the benign solvent is selected from methanol, ethanol, acetone, ethyl acetate, 2-butanone, 3-pentanone or 1,4-dioxane; preferably acetone, 2-butanone, 3-pentanone or ethyl acetate; The organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol or N,N-dimethylformamide; preferably methanol, ethanol, acetone or ethyl acetate; the above benign solvent and organic solution need to be miscible when used; The poor solvent is selected from heptane, water, methyl tert-butyl ether or isopropyl ether; The counter ion 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-acetylaminobenzoic 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, dodecyl sulfuric acid, dibenzoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactosonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalene disulfonic acid, naphthalene-2-sulfonic acid, niacin, 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, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, n-butyric acid, p-hydroxybenzoic acid, or L-malic acid; Method 2 includes the following steps: 1) Weigh an appropriate amount of the compound and dissolve it in a solvent; 2) mixing with a counter ion acid to obtain the crystalline form; the amount of the counter ion acid is preferably 1.2 equivalents; The solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, ethylene dichloride, tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol or N,N-dimethylformamide; preferably methanol, ethanol, acetone or ethyl acetate; The counter ion 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-acetylaminobenzoic 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, dodecyl sulfuric acid, dibenzoyl Tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactosonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalene disulfonic 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, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, n-butyric acid, p-hydroxybenzoic acid, or L-malic acid.

14. A method for preparing the crystalline form or acid addition salt thereof according to any one of claims 1 to 5 or 9 to 11, characterized in that: It is either method one or method two: Method 1 includes the following steps: 1) Weighing an appropriate amount of the compound and heating and dissolving it in a good solvent; 2) The above solution was quickly placed at room temperature and stirred until solids precipitated; 3) The above suspension was quickly centrifuged, the supernatant was removed, and the remaining solid was placed in a vacuum drying oven at 40° C. and dried to constant weight to obtain the target crystal form; in: The benign solvent is selected from methanol, acetone, ethyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone, 3-pentanone, N-methylpyrrolidone, dimethyl sulfoxide; preferably tetrahydrofuran, dichloromethane, 2-methyl-tetrahydrofuran furan and 3-pentanone; Method 2 includes the following steps: 1) Weigh an appropriate amount of free base and dissolve it in a good solvent; 2) adding an anti-solvent to the above solution at a certain temperature, stirring until a solid precipitates, the temperature is preferably 0 to 25°C; 3) The above suspension was quickly centrifuged, the supernatant was removed, and the remaining solid was placed in a 40° C. vacuum drying oven and dried to constant weight to obtain the target product; Wherein: the benign solvent is selected from acetone, 88% acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone, 3-pentanone, N-methylpyrrolidone, ethyl formate, dimethyl sulfoxide; preferably acetone, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl formate, butanone, 3-pentanone, 1,4-dioxane; The poor solvent is selected from heptane, water, methyl tert-butyl ether and isopropyl ether.

15. A pharmaceutical composition comprising a therapeutically effective dose of the crystalline form or its acid addition salt according to any one of claims 1 to 5 or 9 to 11, the crystalline form according to any one of claims 6 to 8, and one or more pharmaceutically acceptable carriers, diluents or excipients.

16. Use of the crystal form or the acid addition salt thereof according to any one of claims 1 to 5 or 9 to 11, the crystal form according to any one of claims 6 to 8, or the pharmaceutical composition according to claim 15 in the preparation of an EGFR inhibitor.

17. The use according to claim 16, wherein the EGFR is a mutant EGFR, preferably one or more mutations of Del19, L858R, T790M or C797S, more preferably L858R / T790M, Del19 / T790M, Del19 / C797S, L858R / C797S, Del19 / T790M / C797S or L858R / T790M / C797S mutant EGFR.

18. Use of the crystalline form or its acid addition salt according to any one of claims 1 to 5 or 9 to 11, the crystalline form according to any one of claims 6 to 8, or the pharmaceutical composition according to claim 15 in the preparation of a drug for treating cancer; preferably, the cancer is selected from ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor, thyroid cancer, bile duct cancer, endometrial cancer, renal cancer, anaplastic large cell lymphoma, multiple myeloma, melanoma or mesothelioma; more preferably, the cancer is non-small cell lung cancer; further preferably, the cancer is EGFR Non-small cell lung cancer with L858R / T790M, Del19 / T790M, Del19 / C797S, L858R / C797S, Del19 / T790M / C797S, or L858R / T790M / C797S mutations.

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