A salt of a pyridazine derivative, a crystal form thereof, and a preparation method and application thereof

Abstract

The present application relates to a kind of pyridazine derivative salt, crystal form and its preparation method and application.It is specifically related to a kind of compound salt with general formula (I) and crystal form, preparation method and pharmaceutical composition containing therapeutically effective amount of the crystal form, and application in preparation TYK2 inhibitor drug.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis, specifically relating to a salt, crystal form, preparation method, and application of a pyridazine derivative. Background Technology

[0002] Janus kinases (JAKs) are intracellular non-receptor tyrosine kinases that mediate the signal transduction and activation of various cytokines. The JAK kinase family is divided into four subtypes: JAK1, JAK2, JAK3, and TYK2. Each subtype mediates different types of cytokine signaling pathways. JAK-1, JAK-2, and TYK-2 are expressed in all human tissues and cells, while JAK-3 is mainly expressed in hematopoietic cells. A common characteristic of cytokine receptors is that the receptors themselves do not possess kinase activity, but their intracellular domains contain binding sites for tyrosine kinases (JAKs). When a cytokine receptor binds to its ligand, it activates receptor-coupled JAKs, leading to receptor phosphorylation. The phosphorylated tyrosine residues can bind to STAT proteins containing SH2 domains, thereby recruiting STAT to the receptor and phosphorylating it through JAKs. Subsequently, phosphotyrosine mediates STAT dimerization. The activated STAT dimers translocate into the nucleus and activate the transcription of their target genes, thereby regulating various cellular functions such as growth, activation, and differentiation.

[0003] TYK2 is the earliest discovered subtype of the JAK family, mediating the function of cytokines such as IFN-α, IL-6, IL-10, IL-12, and IL-23. Studies have shown that TYK2 deletion mutations can effectively inhibit the occurrence of immune diseases such as allergies, autoimmune diseases, and inflammation. IL-23 plays a crucial role in the development and progression of psoriasis. Recent research indicates that the pathogenesis of psoriasis involves endogenous unknown antigens activating antigen-presenting cells (APCs) to secrete IL-23. IL-23 then activates Th17 cells to secrete cytokines such as IL-17, inducing keratinocyte differentiation and proliferation and IL-23 secretion, further stimulating inflammation and keratinocyte proliferation to produce psoriasis. TYK2 and JAK2 jointly mediate the downstream signaling pathway of IL-23. Inhibiting JAK2 can lead to anemia and other blood-related side effects; therefore, targeting TYK2 to inhibit the IL-23 signaling pathway is a good strategy for treating psoriasis.

[0004] Early TYK2 inhibitors, such as tofacitinib, were non-selective JAK inhibitors and were the first oral JAK inhibitors, exhibiting significant inhibitory activity against JAK1, 2, and 3 subtypes. Inhibition of other subtypes, such as JAK1, JAK2, and JAK3, increased the efficacy of tofacitinib but also brought more serious side effects, including infection, tuberculosis, tumors, anemia, liver damage, and increased cholesterol. Since JAK2 activity is related to erythroid cell differentiation and lipid metabolism, some of the aforementioned adverse reactions, such as anemia, are thought to be related to the insufficient selectivity of tofacitinib for JAK-2, resulting from the drug's non-selective inhibition. Currently, there are no selective TYK2 inhibitors on the market. Early JAK inhibitors mainly exerted their effects by competitively binding the kinase domain to ATP, thus generally suffering from low selectivity.

[0005] Given the good efficacy and severe side effects associated with multiple target-related factors of non-selective JAK inhibitors, developing a safer TYK2 selective inhibitor for the treatment of inflammatory diseases such as psoriasis has great clinical application potential. BMS's international patent applications WO2015069310A1 and WO2018081488A1 report a TYK2 selective inhibitor. Their developed drug, BMS-986165, has achieved good efficacy in Phase II clinical trials and has entered Phase III clinical trials, demonstrating the advantages of TYK2 selective inhibitors and possessing significant clinical application value.

[0006] Jiangsu Hansoh Pharmaceutical Group Co., Ltd.'s patent applications (application numbers: CN201910080672.0, CN201910294976.7, CN201910895133.2) disclose the structures of a series of pyridazine derivative inhibitors. In subsequent research and development, in order to make the products easy to handle, filter, dry, store, maintain long-term stability, and have high bioavailability, this invention has conducted a comprehensive study on the salts and crystal forms of the above-mentioned substances, and is committed to obtaining the most suitable crystal form. Summary of the Invention

[0007] All contents relating to patent applications CN201910080672.0, CN201910294976.7 and CN201910895133.2 are incorporated herein by reference.

[0008] The object of this invention is to provide an acid salt of the compound represented by general formula (I).

[0009]

[0010] in:

[0011] R1 is selected from hydrogen, deuterium, halogen, amino, mercapto, nitro, hydroxyl, cyano, alkyl, deuterated alkyl, haloalkyl, alkoxy, or haloalkoxy;

[0012] R2 is selected from hydrogen, deuterium, halogen, amino, mercapto, nitro, hydroxyl, cyano, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, ynyl, cycloalkyl, or heterocyclic groups, wherein the amino, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, ynyl, cycloalkyl, or heterocyclic group may optionally be further substituted by one or more substituents selected from halogen, nitro, cyano, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, ynyl, cycloalkyl, or heterocyclic groups;

[0013] The acid salt is an inorganic or organic acid, wherein the inorganic acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, or phosphoric acid, and the organic acid is selected from 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphtholic acid, methanesulfonic acid, oxalic acid, hydroxyethylsulfonic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxyxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetaminobenzoic acid, 4-aminobenzoic acid, decanoic acid, hexanoic acid, caprylic acid, octanoic acid, cinnamic acid, citric acid, cyclohexanesulfonic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, etc. Tartaric acid, dodecyl sulfuric acid, dibenzoyl tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactobionic acid, gentian acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, palmitic acid, dihydroxynaphthalic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanate, undecanoic acid, trifluoroacetic acid, benzenesulfonic acid, p-methylbenzenesulfonic acid, and L-malic acid; and

[0014] x is an integer from 0 to 3.

[0015] In a further preferred embodiment of the present invention, R1 is selected from hydrogen, deuterium, halogen, amino, mercapto, nitro, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; preferably hydrogen, deuterium, or C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3The compounds are halogenated alkoxy, fluorine, chlorine, bromine, amino, mercapto, nitro, hydroxyl, or cyano; more preferably hydrogen, deuterium, fluorine, chlorine, or bromine, with hydrogen or fluorine being the most preferred.

[0016] In a further preferred embodiment of the present invention, R2 is selected from hydrogen, deuterium, halogen, amino, mercapto, nitro, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl or 3-8 membered heterocyclic groups, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, optionally further converted to halogens, nitro groups, cyano groups, C... 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 The cyclic alkyl group or one or more substituents of a 3-8 membered heterocyclic group are used for substitution; preferably hydrogen, deuterium, halogen, cyano, or C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, wherein the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, optionally further converted to halogens, nitro groups, cyano groups, C... 1-3 Alkyl, C 1-3 Deuterated alkyl, C1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 The cyclic group is substituted with one or more substituents of cycloalkyl or 3-6 membered heterocyclic groups, more preferably methyl, ethyl, propyl, or cyclopropyl, wherein the methyl, ethyl, propyl, and cyclopropyl groups may optionally be further substituted with one or more substituents of halogen, nitro, cyano, or ethynyl.

[0017] In a further preferred embodiment of the present invention, the compound of general formula (I) is selected from the following compounds:

[0018]

[0019]

[0020] In a further preferred embodiment of the present invention, the acid in the acid salt is selected from methanesulfonic acid, sulfuric acid, hydrobromic acid, phosphoric acid, benzenesulfonic acid, methanesulfonic acid, oxalic acid, hydroxyethylsulfonic acid, maleic acid, fumaric acid, adipic acid, p-toluenesulfonic acid, citric acid, malonic acid, or L-malic acid.

[0021] In a further preferred embodiment of the present invention, the compound 6-(cyclopropylcarbamate)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is an acid salt, wherein the acid in the acid salt is selected from methanesulfonic acid, sulfuric acid, hydrobromic acid, phosphoric acid, benzenesulfonic acid, methanesulfonic acid, oxalic acid, hydroxyethylsulfonic acid, maleic acid, fumaric acid, adipic acid, p-toluenesulfonic acid, citric acid, malonic acid, or L-malic acid.

[0022] In a further preferred embodiment of the present invention, the compound 6-(cyclopropylcarbamate)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is an acid salt, wherein the acid salt is selected from methanesulfonic acid, sulfuric acid, hydrobromic acid, phosphoric acid, benzenesulfonic acid, methanesulfonic acid, oxalic acid, hydroxyethylsulfonic acid, maleic acid, fumaric acid, adipic acid, p-toluenesulfonic acid, citric acid, malonic acid, or L-malic acid.

[0023] In a further preferred embodiment of the present invention, the compound 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is an acid salt, wherein the acid salt is selected from methanesulfonic acid, sulfuric acid, hydrobromic acid, phosphoric acid, benzenesulfonic acid, methanesulfonic acid, oxalic acid, hydroxyethylsulfonic acid, maleic acid, fumaric acid, adipic acid, p-toluenesulfonic acid, citric acid, malonic acid, or L-malic acid.

[0024] In a further preferred embodiment of the present invention, the number of acids is 0.2-3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3; more preferably 0.5, 1, 2 or 3.

[0025] In a further preferred embodiment of the present invention, the acid salt is a hydrate or anhydrous form, and when the acid salt is a hydrate, the number of water molecules is 0.2-3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3; more preferably 0.5, 1, 2 or 3.

[0026] In a further preferred embodiment of the present invention, the acid salt of the compound 6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is the crystal form, preferably the methanesulfonate crystal form, sulfate crystal form, hydrobromide crystal form, phosphate crystal form, benzenesulfonate crystal form, oxalate crystal form, hydroxyethylsulfonate crystal form, maleate crystal form, fumarate crystal form, adipate crystal form, p-methylbenzenesulfonate crystal form, citrate crystal form, malonate crystal form, or L-malate crystal form.

[0027] In a further preferred embodiment of the present invention, the acid salt of the compound 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is the crystal form, preferably the methanesulfonate crystal form, sulfate crystal form, hydrobromide crystal form, phosphate crystal form, benzenesulfonate crystal form, oxalate crystal form, hydroxyethylsulfonate crystal form, maleate crystal form, fumarate crystal form, adipate crystal form, p-methylbenzenesulfonate crystal form, citrate crystal form, malonate crystal form, or L-malate crystal form.

[0028] In a further preferred embodiment of the present invention, the number of acids is 0.2-3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3; more preferably 0.5, 1, 2 or 3.

[0029] In a further preferred embodiment of the present invention, the acid salt crystal form of the compound 6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is selected from:

[0030] Hydrobromic acid, crystal form A, with one acid atom, exhibits the following X-ray powder diffraction peaks: at 7.6 ± 0.2°; or at 24.7 ± 0.2°; or at 22.9 ± 0.2°; or at 14.2 ± 0.2°; or at 21.2 ± 0.2°; or at 7.0 ± 0.2°; or at 14. The diffraction peak is present at 7±0.2°; or at 17.2±0.2°; or at 13.8±0.2°; or at 10.3±0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks are included; more preferably, any 6, 7, or 8 of the above diffraction peaks are included.

[0031] The X-ray powder diffraction pattern of hydrobromic acid crystal form A contains at least one or more diffraction peaks located at 2θ of 7.6±0.2°, 24.7±0.2°, and 22.9±0.2°, preferably two, more preferably three; optionally, it may further contain at least one peak located at 2θ of 14.2±0.2°, 21.2±0.2°, 7.0±0.2°, 14.7±0.2°, and 17.2±0.2°, preferably two, three, four, or five; for example, the X-ray powder diffraction pattern of the hydrobromic acid crystal form A has diffraction peaks at the following positions at 2θ (±0.2°): 7.6, 24.7, 22.9, 14.2, 21.2, 7.0; 7.6, 24.7, 14.2, 21.2, 7.0, 14.7; 7.6, 22.9, 14.2, 21.2, 7.0, 14.7; 24.7, 22.9, 14.2, 21.2, 7.0, 14.7; 7.6, 24.7, 22.9, 14.2, 7.0, 14.7; 7.6, 24.7, 22.9, 14.2, 21.2, 14.7; 7.6, 24.7, 21.2, 7.0, 14.7, 17.2; 7.6, 22.9, 14.2, 7.0, 14.7, 17.2; 24.7, 22.9, 14.2, 21.2, 14.7, 17.2; 7.6, 24.7, 22.9, 14.2, 21.2, 7.0, 14.7; 7.6, 24.7, 22.9, 14.2, 21.2, 7.0, 17.2; 7.6, 24.7, 22.9, 14.2, 21.2, 7.0, 14.7, 17.2;

[0033] The X-ray powder diffraction pattern of hydrobromic acid crystal form A optionally includes one or more diffraction peaks located at 2θ of 13.8±0.2°, 10.3±0.2°, 26.4±0.2°, 11.3±0.2°, 27.2±0.2°, 25.6±0.2°, and 20.5±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks; for example, the X-ray powder diffraction pattern of hydrobromic acid crystal form A at 2θ (±0.2°)... 7.6, 24.7, 22.9, 14.2, 21.2, 7.0, 13.8, 10.3; 7.6, 24.7, 14.2, 21.2, 7.0, 14.7, 13.8, 10.3; 7.6, 22.9, 14.2, 21.2, 7.0, 14.7, 13.8, 10.3; 24.7, 22.9, 14.2, 21.2, 7.0, 14.7, 13.8, 10.3; 7.6, 24.7, 22.9, 21.2, 7.0, 14.7, 13.8, 10.3; 7.6, 24.7, 22.9, 14.2, 7.0, 14.7, 13.8, 10.3; 7.6, 24.7, 22.9, 14.2, 21.2, 14.7, 13.8, 10.3; 7.6, 22.9, 14.2, 7.0, 14.7, 17.2, 13.8, 10.3; 24.7, 22.9, 14.2, 21.2, 14.7, 17.2, 13.8, 10.3; 7.6, 24.7, 22.9, 14.2, 21.2, 7.0, 14.7, 13.8, 10.3; 7.6, 24.7, 22.9, 14.2, 21.2, 7.0, 17.5, 13.8, 10.3; 7.6, 24.7, 22.9, 14.2, 21.2, 7.0, 14.7, 17.2, 13.8, 10.3;

[0035] The X-ray powder diffraction pattern of hydrobromic acid crystal form A contains one or more diffraction peaks located at 2θ of 7.6±0.2°, 24.7±0.2°, 22.9±0.2°, 14.2±0.2°, 21.2±0.2°, 7.0±0.2°, 14.7±0.2°, 17.2±0.2°, 13.8±0.2°, 10.3±0.2°, 26.4±0.2°, 11.3±0.2°, 27.2±0.2°, 25.6±0.2°, and 20.5±0.2°. Preferably, it contains diffraction peaks at any of the selected 4, 5, 6, 8, or 10 of these peaks. For example, the X-ray powder diffraction pattern of hydrobromic acid crystal form A has peaks at 2θ (±0.2°). 7.6, 24.7, 22.9, 14.2; 7.6, 24.7, 22.9, 21.2; 7.6, 14.2, 21.2, 7.0, 14.7, 17.2; 24.7, 14.2, 21.2, 7.0, 14.7, 17.2; 7.6, 24.7, 14.2, 7.0, 14.7, 13.8, 10.3, 26.4; 7.6, 24.7, 22.9, 14.2, 21.2, 7.0, 14.7, 13.8, 10.3, 26.4; 7.6, 24.7, 22.9, 14.2, 21.2, 7.0, 17.2, 13.8, 10.3, 26.4;

[0037] The X-ray powder diffraction pattern of hydrobromic acid crystal form A includes values ​​at 2θ of 7.6±0.2°, 24.7±0.2°, 22.9±0.2°, 14.2±0.2°, 21.2±0.2°, 7.0±0.2°, 14.7±0.2°, 17.2±0.2°, and 13.8±0.2°. One or more diffraction peaks are found in the range of 10.3±0.2°, 26.4±0.2°, 11.3±0.2°, 27.2±0.2°, 25.6±0.2°, 20.5±0.2°, 28.6±0.2°, 24.0±0.2°, 28.8±0.2°, 23.3±0.2°, and 18.1±0.2°. Preferably, four, five, six, eight, or ten diffraction peaks are found in these peaks.

[0038] The characteristic X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d using Cu-Kα radiation are shown in Table 1.

[0039] Table 1

[0040]

[0041]

[0042]

[0043] More preferably, its XRPD spectrum is basically as shown in the attached figure. Figure 1 As shown, its DSC spectrum is basically as follows: Figure 2 As shown;

[0044] Phosphate crystal form A, with one acid atom, exhibits the following X-ray powder diffraction patterns: a diffraction peak at 2θ = 8.0 ± 0.2°; or at 14.5 ± 0.2°; or at 7.2 ± 0.2°; or at 20.0 ± 0.2°; or at 25.1 ± 0.2°; or at 14.8 ± 0.2°; or at 21.8 ± 0.2°; or at 15.9 ± 0.2°; or at 19.7 ± 0.2°; or at 15.3 ± 0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, or 5-8 of the aforementioned diffraction peaks are included. Or 6-8 locations, more preferably including any 6, 7 or 8 locations;

[0045] The X-ray powder diffraction pattern of phosphate crystal form A contains at least one or more diffraction peaks located at 2θ of 8.0±0.2°, 14.5±0.2°, and 7.2±0.2°, preferably two, more preferably three; optionally, it may further contain at least one peak located at 2θ of 20.0±0.2°, 25.1±0.2°, 14.8±0.2°, 21.8±0.2°, and 15.9±0.2°, preferably two, three, four, or five; for example, the X-ray powder diffraction pattern of phosphate crystal form A at 2θ (±0.2°) contains... 8.0, 14.5, 7.2, 20.0, 25.1, 14.8; 8.0, 14.5, 20.0, 25.1, 14.8, 21.8; 8.0, 7.2, 20.0, 25.1, 14.8, 21.8; 7.2, 14.5, 20.0, 25.1, 14.8, 21.8; 8.0, 14.5, 7.2, 20.0, 14.8, 21.8; 8.0, 14.5, 7.2, 25.1, 14.8, 21.8; 8.0, 14.5, 20.0, 14.8, 21.8, 15.9; 8.0, 7.2, 20.0, 25.1, 21.8, 15.9; 7.2, 14.5, 20.0, 25.1, 14.8, 15.9; 8.0, 14.5, 7.2, 20.0, 25.1, 14.8, 21.8; 8.0, 14.5, 7.2, 20.0, 25.1, 14.8, 15.9; 8.0, 14.5, 7.2, 20.0, 25.1, 14.8, 15.9, 21.8;

[0047] The X-ray powder diffraction pattern of phosphate crystal form A contains at least one or more diffraction peaks located at 2θ of 19.7±0.2°, 15.3±0.2°, 24.0±0.2°, 23.6±0.2°, 8.8±0.2°, 26.6±0.2°, and 22.7±0.2°; preferably, it contains at least 2-3, 4-5, or 6-7 peaks; more preferably, it contains any 2, 3, 4, 5, 6, or 7 peaks; for example, the X-ray powder diffraction pattern of phosphate crystal form A at 2θ (±0.2°) contains...

[0048] Diffraction peaks are observed at positions 8.0, 14.5, 7.2, 20.0, 25.1, 14.8, 19.7, and 15.3; diffraction peaks are observed at positions 8.0, 14.5, 20.0, 25.1, 14.8, 21.8, 19.7, and 15.3; diffraction peaks are observed at positions 7.2, 14.5, 20.0, 25.1, 14.8, 21.8, 19.7, and 15.3; diffraction peaks are observed at positions 8.0, 14.5, 7.2, 20.0, 14.8, 21.8, 19.7, and 15.3. Diffraction peaks are observed at positions 8.0, 14.5, 7.2, 20.0, 25.1, 21.8, 19.7, and 15.3; diffraction peaks are observed at positions 8.0, 14.5, 7.2, 25.1, 14.8, 21.8, 19.7, and 15.3; diffraction peaks are observed at positions 8.0, 14.5, 7.2, 25.1, 14.8, 21.8, 19.7, and 15.3; diffraction peaks are observed at positions 8.0, 14.5, 20.0, 14.8, 21.8, 15.9, 19.7, and 15.3; diffraction peaks are observed at positions 7.2, 14.5, 20.0, 25.1, 14.8, 15.9, 19.7, and 15.3; diffraction peaks are observed at positions 8.0, 14.5, 7.2, 20.0, 25.1, 21 ...7.2, 14.5, 20.0, 25.1, 1 Diffraction peaks are observed at positions 7.2, 20.0, 25.1, 14.8, 21.8, 19.7, and 15.3; diffraction peaks are observed at positions 8.0, 14.5, 7.2, 20.0, 25.1, 14.8, 15.9, 19.7, and 15.3; diffraction peaks are observed at positions 8.0, 14.5, 7.2, 20.0, 25.1, 14.8, 15.9, 21.8, 19.7, and 15.3.

[0049] The X-ray powder diffraction pattern of phosphate crystal form A contains at least one or more diffraction peaks located at 2θ of 8.0±0.2°, 14.5±0.2°, 7.2±0.2°, 20.0±0.2°, 25.1±0.2°, 14.8±0.2°, 21.8±0.2°, 15.9±0.2°, 19.7±0.2°, 15.3±0.2°, 24.0±0.2°, 23.6±0.2°, 8.8±0.2°, 26.6±0.2°, and 22.7±0.2°; preferably, it contains diffraction peaks at any of 4, 5, 6, 8, or 10 of these peaks; for example, the X-ray powder diffraction pattern of phosphate crystal form A at 2θ (±0.2°)... 8.0, 14.5, 7.2, 20.0; 8.0, 14.5, 7.2, 25.1; 8.0, 20.0, 25.1, 14.8, 21.8, 15.9; 14.5, 20.0, 25.1, 14.8, 21.8, 15.9; 8.0, 14.5, 20.0, 25.1, 14.8, 19.7, 15.3, 24.0; 8.0, 7.2, 20.0, 25.1, 14.8, 19.7, 15.3, 24.0; 8.0, 14.5, 7.2, 20.0 25.1, 14.8, 21.8, 19.7, 15.3, 24.0; 8.0, 14.5, 7.2, 20.0, 25.1, 14.8, 15.9, 19.7, 15.3, 24.0;

[0051] The X-ray powder diffraction pattern of phosphate crystal form A includes at least the following 2θ values: 8.0±0.2°, 14.5±0.2°, 7.2±0.2°, 20.0±0.2°, 25.1±0.2°, 14.8±0.2°, 21.8±0.2°, 15.9±0.2°, 19.7±0.2°, 15.3±0.2°, and 24.0±0.2°. One or more diffraction peaks are selected from the following: °, 23.6±0.2°, 8.8±0.2°, 26.6±0.2°, 22.7±0.2°, 27.0±0.2°, 22.4±0.2°, 23.3±0.2°, 25.6±0.2°, and 20.8±0.2°; preferably, 4, 5, 6, 8, or 10 diffraction peaks are selected from these.

[0052] The characteristic X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d using Cu-Kα radiation are shown in Table 2.

[0053] Table 2

[0054]

[0055]

[0056] More preferably, its XRPD spectrum is basically as shown in the attached figure. Figure 3 As shown, its DSC spectrum is basically as follows: Figure 4 As shown, its TGA spectrum is basically as follows: Figure 5 As shown;

[0057] Phosphate crystal form B, with one acid atom, exhibits the following X-ray powder diffraction patterns: a diffraction peak at 2θ = 7.8 ± 0.2°; or at 19.5 ± 0.2°; or at 8.6 ± 0.2°; or at 23.5 ± 0.2°; or at 14.6 ± 0.2°; or at 23.2 ± 0.2°; or at 25.1 ± 0.2°; or at 15.6 ± 0.2°; or at 21.6 ± 0.2°; or at 14.3 ± 0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, or 5-8 of the aforementioned diffraction peaks are included. Or 6-8 locations, more preferably including any 6, 7 or 8 locations;

[0058] The X-ray powder diffraction pattern of phosphate crystal form B contains at least one or more diffraction peaks located at 2θ of 7.8±0.2°, 19.5±0.2°, and 8.6±0.2°, preferably two, more preferably three; optionally, it may further contain at least one peak located at 2θ of 23.5±0.2°, 14.6±0.2°, 23.2±0.2°, 25.1±0.2°, and 15.6±0.2°, preferably two, three, four, or five; for example, the X-ray powder diffraction pattern of phosphate crystal form B at 2θ (±0.2°) contains...

[0059] Diffraction peaks are observed at positions 7.8, 19.5, 8.6, 23.5, 14.6, and 23.2; diffraction peaks are observed at positions 7.8, 19.5, 23.5, 14.6, 23.2, and 25.1; diffraction peaks are observed at positions 7.8, 8.6, 23.5, 14.6, 23.2, and 25.1; diffraction peaks are observed at positions 19.5, 8.6, 23.5, 14.6, 23.2, and 25.1; diffraction peaks are observed at positions 7.8, 19.5, 8.6, 23.5, 14.6 .... Diffraction peaks are observed at 14.6, 23.2, and 25.1; diffraction peaks are observed at 7.8, 19.5, 23.5, 14.6, 25.1, and 15.6.

[0060] Diffraction peaks are observed at positions 7.8, 8.6, 23.5, 14.6, 23.2, and 15.6; diffraction peaks are observed at positions 19.5, 8.6, 23.5, 23.2, 25.1, and 15.6; diffraction peaks are observed at positions 7.8, 19.5, 8.6, 23.5, 14.6, 23.2, and 15.6; diffraction peaks are observed at positions 7.8, 19.5, 8.6, 23.5, 14.6, 23.2, and 25.1; diffraction peaks are observed at positions 7.8, 19.5, 8.6, 23.5, and 23.5. The X-ray powder diffraction pattern of phosphate crystal form B has diffraction peaks at 2θ values ​​of 14.6, 23.2, 25.1, and 15.6. The pattern includes at least one or more diffraction peaks at 2θ values ​​of 21.6 ± 0.2°, 14.3 ± 0.2°, 24.7 ± 0.2°, 7.1 ± 0.2°, 21.2 ± 0.2°, 28.9 ± 0.2°, and 27.2 ± 0.2°. Preferably, it includes at least 2-3, 4-5, or 6-7 peaks. More preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks. For example, the X-ray powder diffraction pattern of phosphate crystal form B has peaks at 2θ (±0.2°).

[0061] Diffraction peaks are observed at positions 7.8, 19.5, 8.6, 23.5, 14.6, 23.2, 21.6, and 14.3; Diffraction peaks are observed at positions 7.8, 19.5, 23.5, 14.6, 23.2, 25.1, 21.6, and 14.3; Diffraction peaks are observed at positions 19.5, 8.6, 23.5, 14.6, 23.2, 25.1, 21.6, and 14.3; Diffraction peaks are observed at positions 7.8, 19.5, 8.6, 23.5, 23.2, 25.1, 21.6, and 14.3. Diffraction peaks are observed at positions 7.8, 19.5, 8.6, 23.5, 14.6, 25.1, 21.6, and 14.3; diffraction peaks are observed at positions 7.8, 19.5, 8.6, 14.6, 23.2, 25.1, 21.6, and 14.3; diffraction peaks are observed at positions 7.8, 19.5, 23.5, 14.6, 25.1, 15.6, 21.6, and 14.3; diffraction peaks are observed at positions 7.8, 19.5, 23.5, 14.6, 25.1, 15.6, 21.6, and 14.3; diffraction peaks are observed at positions 19.5, 8.6, 23.5, 23.2, 25.1, 15.6, 21.6, and 14.3; diffraction peaks are observed at positions 7.8, 19.5, 23.5, 14.6, 23.2 ...19.5, 8.6, 23.5, 23.2, 25.1, 15.6, 21.6, and 14.3; diffraction peaks are observed at positions 7.8, 19.5, 23.5, 14.6, 23.2, 15.6, 21. Diffraction peaks are observed at positions 8.6, 23.5, 14.6, 23.2, 15.6, 21.6, and 14.3; diffraction peaks are observed at positions 7.8, 19.5, 8.6, 23.5, 14.6, 23.2, 25.1, 21.6, and 14.3; diffraction peaks are observed at positions 7.8, 19.5, 8.6, 23.5, 14.6, 23.2, 25.1, 15.6, 21.6, and 14.3.

[0062] The X-ray powder diffraction pattern of phosphate crystal form B contains at least one or more diffraction peaks located at 2θ of 7.8±0.2°, 19.5±0.2°, 8.6±0.2°, 23.5±0.2°, 14.6±0.2°, 23.2±0.2°, 25.1±0.2°, 15.6±0.2°, 21.6±0.2°, 14.3±0.2°, 24.7±0.2°, 7.1±0.2°, 21.2±0.2°, 28.9±0.2°, and 27.2±0.2°; preferably, it contains diffraction peaks at any of 4, 5, 6, 8, or 10 of these peaks; for example, the X-ray powder diffraction pattern of phosphate crystal form B at 2θ (±0.2°) contains diffraction peaks at 2θ (±0.2°).

[0063] Diffraction peaks are present at positions 7.8, 19.5, 8.6, and 23.5; diffraction peaks are present at positions 7.8, 19.5, 8.6, and 14.6; diffraction peaks are present at positions 7.8, 23.5, 14.6, 23.2, 25.1, and 15.6; diffraction peaks are present at positions 19.5, 23.5, 14.6, 23.2, 25.1, and 15.6; diffraction peaks are present at positions 7.8, 19.5, 23.5, 14.6, 23.2, 21.6, 14.3, and 24.7; diffraction peaks are present at positions 7.8, 19.5, 23.5, 14.6, 23.2, 21.6, 14.3, and 24.7; diffraction peaks are present at positions 7.8, 19.5, 23.5, 14.6, 23.2, 21.6, 14.3, and 24.7; diffraction peaks are present at positions 7.8, 19.5, 23.5, 14.6, 23.2, 25.1, and 15.6; diffraction peaks are present at positions 7.8, 19.5, 23.5, 14.6, 23.2, 21.6, 14.3, and 24.7 .... Diffraction peaks are observed at positions 8.6, 23.5, 14.6, 23.2, 25.1, 21.6, 14.3, and 24.7; diffraction peaks are also observed at positions 7.8, 19.5, 8.6, 23.5, 14.6, 23.2, 15.6, 21.6, 14.3, and 24.7.

[0064] The X-ray powder diffraction pattern of phosphate crystal form B includes at least the following 2θ values: 7.8±0.2°, 19.5±0.2°, 8.6±0.2°, 23.5±0.2°, 14.6±0.2°, 23.2±0.2°, 25.1±0.2°, 15.6±0.2°, 21.6±0.2°, 14.3±0.2°, 24.7±0.2°, 7.1±0.2°, 21.2±0.2°, 28.9±0.2°, 27.2±0.2°, 22.6±0.2°, and 30.5±0.2°. One or more diffraction peaks are selected from 15.2±0.2, 30.8±0.2, and 17.4±0.2; preferably, 4, 5, 6, 8, or 10 diffraction peaks are selected from these peaks.

[0065] The characteristic X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d using Cu-Kα radiation are shown in Table 3.

[0066] Table 3

[0067]

[0068]

[0069] More preferably, its XRPD spectrum is basically as shown in the attached figure. Figure 6 As shown, its DSC spectrum is basically as follows: Figure 7 As shown, its TGA spectrum is basically as follows: Figure 8 As shown;

[0070] The benzenesulfonate crystal form A, with one acid, exhibits the following X-ray powder diffraction pattern: a diffraction peak at 2θ = 20.1 ± 0.2°; or at 5.8 ± 0.2°; or at 17.7 ± 0.2°; or at 15.2 ± 0.2°; or at 22.9 ± 0.2°; or at 14.0 ± 0.2°; or at 21.4 ± 0.2°; or at 23.1 ± 0.2°; or at 19.0 ± 0.2°; or at 17.4 ± 0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, or 5-8 of the above diffraction peaks are included. Or 6-8 locations, more preferably including any 6, 7 or 8 locations;

[0071] The X-ray powder diffraction pattern of benzenesulfonate crystal form A contains at least one or more diffraction peaks located at 2θ of 20.1±0.2°, 5.8±0.2°, and 17.7±0.2°, preferably two, more preferably three; optionally, it may further contain at least one peak located at 2θ of 15.2±0.2°, 22.9±0.2°, 14.0±0.2°, 21.4±0.2°, and 23.1±0.2°, preferably two, three, four, or five; for example, the X-ray powder diffraction pattern of benzenesulfonate crystal form A at 2θ (±0.2°) contains...

[0072] Diffraction peaks are observed at 20.1, 5.8, 17.7, 15.2, 22.9, and 14.0; diffraction peaks are observed at 20.1, 5.8, 15.2, 22.9, 14.0, and 21.4; diffraction peaks are observed at 20.1, 17.7, 15.2, 22.9, 14.0, and 21.4; diffraction peaks are observed at 20.1, 5.8 ... Diffraction peaks are present at positions 17.7, 22.9, 14.0, and 21.4; diffraction peaks are present at positions 20.1, 5.8, 15.2, 14.0, 21.4, and 23.1; diffraction peaks are present at positions 20.1, 17.7, 15.2, 22.9, 21.4, and 23.1; diffraction peaks are present at positions 5.8, 17.7, 15.2, 22.9, 14.0, and 23.1; diffraction peaks are present at positions 20.1, 5.8, 17.7, 15.2, 22.9, 14.0, and 21.4; diffraction peaks are present at positions 20.1, 5.8, 17.7, 15.2, 22.9, 14.0, and 23.1 .... Diffraction peaks are observed at 17.7, 15.2, 22.9, 14.0, 21.4, and 23.1.

[0073] The X-ray powder diffraction pattern of benzenesulfonate crystal form A contains at least one or more diffraction peaks located at 2θ of 19.0±0.2°, 17.4±0.2°, 24.5±0.2°, 24.1±0.2°, 26.0±0.2°, 18.0±0.2°, and 23.5±0.2°; preferably, it contains at least 2-3, 4-5, or 6-7 peaks; more preferably, it contains any 2, 3, 4, 5, 6, or 7 peaks; for example, the X-ray powder diffraction pattern of benzenesulfonate crystal form A at 2θ (±0.2°) contains...

[0074] Diffraction peaks are observed at 20.1, 5.8, 17.7, 15.2, 22.9, 14.0, 19.0, and 17.4. (This is repeated four times in the original text.)

[0075] Diffraction peaks are observed at 20.1, 5.8, 17.7, 15.2, 22.9, 21.4, 19.0, and 17.4; diffraction peaks are observed at 20.1, 5.8, 17.7, 22.9, 14.0, 21.4, 19.0, and 17.4; diffraction peaks are observed at 20.1, 5.8, 15.2, 14.0, 21.4, 23.1, 19.0, and 17.4; diffraction peaks are observed at 20.1, 17.7, 15.2, 22.9, 21.4, 23.1, 19.0, and 17.4; diffraction peaks are observed at 5.8, 17.7, 15.2, 22.9, 14.0, 23.1, 19.0, and 17.4. Diffraction peaks are observed at 20.1, 5.8, 17.7, 15.2, 22.9, 14.0, 21.4, 19.0, and 17.4.

[0076] The X-ray powder diffraction pattern of benzenesulfonate crystal form A contains at least one or more diffraction peaks located at 2θ of 20.1±0.2°, 5.8±0.2°, 17.7±0.2°, 15.2±0.2°, 22.9±0.2°, 14.0±0.2°, 21.4±0.2°, 23.1±0.2°, 19.0±0.2°, 17.4±0.2°, 24.5±0.2°, 24.1±0.2°, 26.0±0.2°, 18.0±0.2°, and 23.5±0.2°; preferably, it contains diffraction peaks at any of 4, 5, 6, 8, or 10 of these peaks; for example, the X-ray powder diffraction pattern of benzenesulfonate crystal form A has peaks at 2θ (±0.2°).

[0077] Diffraction peaks are observed at positions 20.1, 5.8, 17.7, and 15.2; at positions 20.1, 5.8, 17.7, and 22.9; at positions 20.1, 15.2, 22.9, 14.0, 21.4, and 23.1; at positions 5.8, 15.2, 22.9, 14.0, 21.4, and 23.1; at positions 20.1, 5.8, 15.2, 22.9, 14.0, 19.0, 17.4, and 24.5; at positions 20.1, 5.8, 15.2, 22.9, 14.0, 19.0, 17.4, and 24.5; at positions 20.1, 5.8, 17.7, and 15.2; at positions 20.8, 15.2, 22.9, 14.0, 21.4, and 23.1; at positions 20.1, 5.8, 15.2, 22.9, 14.0, 19.0, 17.4, and 24.5; at positions 20.1, 5.8, 17.7 ... Diffraction peaks are observed at 17.7, 15.2, 22.9, 14.0, 21.4, 19.0, 17.4, and 24.5; diffraction peaks are also observed at 20.1, 5.8, 17.7, 15.2, 22.9, 14.0, 23.1, 19.0, 17.4, and 24.5.

[0078] The X-ray powder diffraction pattern of benzenesulfonate crystal form A contains at least the following 2θ values: 20.1±0.2°, 5.8±0.2°, 17.7±0.2°, 15.2±0.2°, 22.9±0.2°, 14.0±0.2°, 21.4±0.2°, 23.1±0.2°. One or more diffraction peaks are found at the following values: 19.0±0.2°, 17.4±0.2°, 24.5±0.2°, 24.1±0.2°, 26.0±0.2°, 18.0±0.2°, 23.5±0.2°, 24.9±0.2°, 22.3±0.2°, 15.7±0.2°, 29.2±0.2°, and 21.1±0.2°; preferably, 4, 5, 6, 8, or 10 diffraction peaks are present.

[0079] The characteristic X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d using Cu-Kα radiation are shown in Table 4.

[0080] Table 4

[0081]

[0082]

[0083] More preferably, its XRPD spectrum is basically as shown in the attached figure. Figure 9 As shown, its DSC spectrum is basically as follows: Figure 10 As shown, its TGA spectrum is basically as follows: Figure 11 As shown.

[0084] In a further preferred embodiment of the present invention, the acid salt crystal form of compound 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is selected from:

[0085] Hydrobromide crystal form A, with one acid atom, has an X-ray powder diffraction pattern showing a diffraction peak at 25.1 ± 0.2°; or at 8.2 ± 0.2°; or at 22.7 ± 0.2°; or at 31.1 ± 0.2°; or at 18.7 ± 0.2°; or at 23.4 ± 0.2°; or at 29.1 ± 0.2°; or at 17.5 ± 0.2°; or at 13.1 ± 0.2°; or at 26.5 ± 0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, or 5-8 of the above diffraction peaks are included. Or 6-8 locations, more preferably including any 6, 7 or 8 locations;

[0086] The X-ray powder diffraction pattern of hydrobromic acid crystal form A contains at least one or more diffraction peaks located at 2θ of 25.1±0.2°, 8.2±0.2°, and 22.7±0.2°, preferably two, more preferably three; optionally, it may further contain at least one peak located at 2θ of 31.1±0.2°, 18.7±0.2°, 23.4±0.2°, 29.1±0.2°, and 17.5±0.2°, preferably two, three, four, or five; for example, the X-ray powder diffraction pattern of hydrobromic acid crystal form A contains peaks at 2θ (±0.2°) of 25.1±0.2°.

[0087] Diffraction peaks are present at positions 25.1, 8.2, 22.7, 31.1, 18.7, and 23.4; diffraction peaks are present at positions 25.1, 8.2, 31.1, 18.7, 23.4, and 29.1; diffraction peaks are present at positions 25.1, 22.7, 31.1, 18.7, 23.4, and 29.1; diffraction peaks are present at positions 8.2, 22.7, 31.1, 18.7, 23.4, and 29.1; diffraction peaks are present at positions 25.1, 8.2, 22.7, 31.1, 18.7, and 29.1; diffraction peaks are present at positions 25.1, 8.2, 22.7, 31.1, 18.7, and 29.1; diffraction peaks are present at positions 25.1, 8.2, 22.7, 31.1, 18.7, and 29.1; diffraction peaks are present at positions 25.1, 8.2, 22.7, 31.1, 18.7, and 29.1; diffraction peaks are present at positions 25.1, 8.2, 22.7, 31.1, 18.7, and 29.1. Diffraction peaks are present at positions 22.7, 18.7, 23.4, and 29.1; diffraction peaks are present at positions 25.1, 8.2, 31.1, 18.7, 23.4, and 17.5. (This text is repeated four times in the original.) Diffraction peaks are observed at 22.7, 31.1, 18.7, 23.4, 29.1, and 17.5.

[0088] The X-ray powder diffraction pattern of hydrobromic acid crystal form A optionally includes one or more diffraction peaks located at 2θ of 13.1±0.2°, 26.5±0.2°, 14.4±0.2°, 24.5±0.2°, 28.5±0.2°, 21.1±0.2°, and 20.3±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks; for example, the X-ray powder diffraction pattern of hydrobromic acid crystal form A at 2θ (±0.2°)...

[0089] Diffraction peaks are observed at positions 25.1, 8.2, 22.7, 31.1, 18.7, 23.4, 13.1, and 26.5; diffraction peaks are observed at positions 25.1, 8.2, 31.1, 18.7, 23.4, 29.1, 13.1, and 26.5; diffraction peaks are observed at positions 25.1, 8.2, 22.7, 31.1, 18.7, 23.4, 29.1, 13.1, and 26.5; diffraction peaks are observed at positions 8.2, 22.7, 31.1, 18.7, 23.4, 29.1, 13.1, and 26.5; diffraction peaks are observed at positions 25.1, 8.2, 22.7, 31.1, 23.4, 29.1, 13.1, and 26.5. Diffraction peaks are observed at positions 25.1, 8.2, 22.7, 31.1, 18.7, 29.1, 13.1, and 26.5; diffraction peaks are also observed at positions 25.1, 8.2, 22.7, 18.7, 23.4, 29.1, 13.1, and 26.5; diffraction peaks are observed at positions 25.1, 8.2, 31.1, 18.7, 23.4, and 17.5. Diffraction peaks are present at positions 13.1 and 26.5; diffraction peaks are present at positions 25.1, 22.7, 31.1, 18.7, 29.1, 17.5, 13.1, and 26.5; diffraction peaks are present at positions 8.2, 22.7, 31.1, 23.4, 29.1, 17.5, 13.1, and 26.5; diffraction peaks are present at positions 25.1, 8.2, 22.7, 31.1, 18.7, 23.4, 17.5, 13.1, and 26.5; diffraction peaks are present at positions 25.1, 8.2, 22.7, 31.1, 18.7, 23.4, 17.5, 13.1, and 26.5; diffraction peaks are present at positions 25.1, 8.2, 22.7, 31.1, 18.7, 23.4, 17.5, 13.1, and 26.5; diffraction peaks are present at positions 25.1, 8.2, 22.7, 31.1, 18.7, 23.4, 17.5, 13.1, and 26.5. Diffraction peaks are observed at 23.4, 29.1, 17.5, 13.1, and 26.5.

[0090] The X-ray powder diffraction pattern of hydrobromic acid crystal form A contains one or more diffraction peaks located at 2θ of 25.1±0.2°, 8.2±0.2°, 22.7±0.2°, 31.1±0.2°, 18.7±0.2°, 23.4±0.2°, 29.1±0.2°, 17.5±0.2°, 13.1±0.2°, 26.5±0.2°, 14.4±0.2°, 24.5±0.2°, 28.5±0.2°, 21.1±0.2°, and 20.3±0.2°. Preferably, it contains diffraction peaks at any of the selected 4, 5, 6, 8, or 10 peaks. For example, the X-ray powder diffraction pattern of hydrobromic acid crystal form A has peaks at 2θ (±0.2°).

[0091] Diffraction peaks are present at positions 25.1, 8.2, 22.7, and 31.1; diffraction peaks are present at positions 25.1, 8.2, 22.7, and 18.7; diffraction peaks are present at positions 25.1, 31.1, 18.7, 23.4, 29.1, and 17.5; diffraction peaks are present at positions 8.2, 31.1, 18.7, 23.4, 29.1, and 17.5; diffraction peaks are present at positions 25.1, 8.2, 31.1, 18.7, 23.4, 13.1, 26.5, and 14.4; diffraction peaks are present at positions 25.1, 22.7, 31.1, 18.7, 23.4, 13.1, 26.5, and 14.4; diffraction peaks are present at positions 25.1, 8.2, and 17.5; diffraction peaks are present at positions 25.1, 8.2 ... Diffraction peaks are observed at 22.7, 31.1, 18.7, 23.4, 29.1, 13.1, 26.5, and 14.4; diffraction peaks are also observed at 25.1, 8.2, 22.7, 31.1, 18.7, 23.4, 17.5, 13.1, 26.5, and 14.4.

[0092] The X-ray powder diffraction pattern of hydrobromic acid crystal form A includes values ​​at 2θ of 25.1±0.2°, 8.2±0.2°, 22.7±0.2°, 31.1±0.2°, 18.7±0.2°, 23.4±0.2°, 29.1±0.2°, 17.5±0.2°, 13.1±0.2°, 26.5±0.2°, 14.4±0.2°, 24.5±0.2°, 28.5±0.2°, 21.1±0.2°, 20.3±0.2°, 16.2±0.2°, and 34.7±0.2°. One or more diffraction peaks are found in the range of 25.5±0.2°, 11.5±0.2°, and 13.8±0.2°. Preferably, 4, 5, 6, 8, or 10 diffraction peaks are found in these peaks.

[0093] The characteristic X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d using Cu-Kα radiation are shown in Table 5.

[0094] Table 5

[0095]

[0096]

[0097] More preferably, its XRPD spectrum is basically as shown in the attached figure. Figure 12 As shown, its DSC spectrum is basically as shown in Figure 13, and its TGA spectrum is basically as shown in Figure 14. Figure 14 As shown;

[0098] Hydrobromide crystal form B, with one acid atom, exhibits the following X-ray powder diffraction patterns: a diffraction peak at 7.0 ± 0.2°; or at 26.5 ± 0.2°; or at 21.8 ± 0.2°; or at 20.3 ± 0.2°; or at 15.4 ± 0.2°; or at 14.1 ± 0.2°; or at 24.0 ± 0.2°; or at 27.6 ± 0.2°; or at 13.7 ± 0.2°; or at 28.9 ± 0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, or 5-8 of the aforementioned diffraction peaks are included. Or 6-8 locations, more preferably including any 6, 7 or 8 locations;

[0099] The X-ray powder diffraction pattern of hydrobromic acid form B contains at least one or more diffraction peaks located at 2θ of 7.0±0.2°, 26.5±0.2°, and 21.8±0.2°, preferably two, more preferably three; optionally, it may further contain at least one peak located at 2θ of 20.3±0.2°, 15.4±0.2°, 14.1±0.2°, 24.0±0.2°, and 27.6±0.2°, preferably two, three, four, or five; for example, the X-ray powder diffraction pattern of hydrobromic acid form B at 2θ (±0.2°) contains...

[0100] Diffraction peaks are observed at 7.0, 26.5, 21.8, 20.3, 15.4, and 14.1; diffraction peaks are observed at 7.0, 26.5, 20.3, 15.4, 14.1, and 24.0; diffraction peaks are observed at 7.0, 21.8, 20.3, 15.4, 14.1, and 24.0; diffraction peaks are observed at 7.0, 26.5, 21.8, 20.3, 15.4 .... Diffraction peaks are observed at 21.8, 15.4, 14.1, and 24.0; diffraction peaks are observed at 7.0, 26.5, 20.3, 15.4, 14.1, and 27.6; diffraction peaks are observed at 7.0, 21.8, 20.3, 15.4, 14.1, and 27.6; diffraction peaks are observed at 26.5, 21.8, 20.3, 15.4, 14.1, and 27.6; diffraction peaks are observed at 7.0, 26.5, 21.8, 20.3, 15.4, 14.1, and 27.6; diffraction peaks are observed at 7.0, 26.5, 21.8, 20.3, 15.4, 14.1, and 24.0 .... Diffraction peaks are observed at 21.8, 20.3, 15.4, 14.1, 24.0, and 27.6.

[0101] The X-ray powder diffraction pattern of hydrobromic acid form B optionally includes one or more diffraction peaks located at 2θ of 13.7±0.2°, 28.9±0.2°, 21.2±0.2°, 28.1±0.2°, 15.9±0.2°, 25.8±0.2°, and 32.3±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks; for example, the X-ray powder diffraction pattern of hydrobromic acid form B at 2θ (±0.2°)...

[0102] Diffraction peaks are observed at 7.0, 26.5, 21.8, 20.3, 15.4, 14.1, 13.7, and 28.9; diffraction peaks are observed at 7.0, 26.5, 20.3, 15.4, 14.1, 24.0, 13.7, and 28.9; diffraction peaks are observed at 7.0, 26.5, 21.8, 20.3, 15.4, 14.1, 24.0, 13.7, and 28.9; diffraction peaks are observed at 26.5, 21.8, 20.3, 15.4, 14.1, 24.0, 13.7, and 28.9; diffraction peaks are observed at 7.0, 26.5, 21.8, 20.3, 14.1, 24.0, 13.7, and 28.9. Diffraction peaks are observed at 7.0, 26.5, 21.8, 20.3, 15.4, 24.0, 13.7, and 28.9; diffraction peaks are observed at 7.0, 26.5, 21.8, 15.4, 14.1, 24.0, 13.7, and 28.9; diffraction peaks are observed at 7.0, 26.5, 20.3, 15.4, 14.1, 27.6, 13.7, and 28.9; diffraction peaks are observed at 7.0, 26.5, 20.3, 15.4, 14.1, 27.6, 13.7, and 28.9; diffraction peaks are observed at 26.5, 21.8, 20.3, 15.4, 14.1, 27.6, 13.7, and 28.9; diffraction peaks are observed at 7.0, ...0.3, 15.4, 14.1, 27.6, 13.7, and 28.9; diffraction peaks are observed at 7.0, 26.5, 20.3, 15.4, 14.1, 27.6, 13.7, and 28.9; diffraction peaks are observed at 7.0, 26.5, 20.3, 15.4, 14.1, 27.6, 13. Diffraction peaks are observed at 26.5, 21.8, 20.3, 15.4, 14.1, 27.6, 13.7, and 28.9; diffraction peaks are observed at 7.0, 26.5, 21.8, 20.3, 15.4, 14.1, 24.0, 13.7, and 28.9; diffraction peaks are observed at 7.0, 26.5, 21.8, 20.3, 15.4, 14.1, 24.0, 27.6, 13.7, and 28.9.

[0103] The X-ray powder diffraction pattern of hydrobromic acid form B includes one or more diffraction peaks located at 2θ of 7.0±0.2°, 26.5±0.2°, 21.8±0.2°, 20.3±0.2°, 15.4±0.2°, 14.1±0.2°, 24.0±0.2°, 27.6±0.2°, 13.7±0.2°, 28.9±0.2°, 21.2±0.2°, 28.1±0.2°, 15.9±0.2°, 25.8±0.2°, and 32.3±0.2°. Preferably, it includes diffraction peaks at any of the selected 4, 5, 6, 8, or 10 peaks. For example, the X-ray powder diffraction pattern of hydrobromic acid form B has peaks at 2θ (±0.2°).

[0104] Diffraction peaks are observed at 7.0, 26.5, 21.8, and 20.3; at 7.0, 26.5, 21.8, and 15.4; at 7.0, 20.3, 15.4, 14.1, 24.0, and 27.6; at 26.5, 20.3, 15.4, 14.1, 24.0, and 27.6; at 7.0, 26.5, 20.3, 15.4, 14.1, 13.7, 28.9, and 21.2; at 7.0, 21.8, 20.3, 15.4, 14.1, 24.0, and 27.6; at 7.0, 26.5, 20.3, 15.4, 14.1, 24.0, and 27.6; at 7.0, 26.5, 20.3, 15.4, 14.1, 13.7, 28.9, and 21.2 ...24.0, and 27.6; at 7.0, 26.5, 20.3, 15.4, 14.1, 24.0, and 27.6; at 7.0, 26.5, 20.3, 15.4, 14.1, 13.7, 28.9, and 21.2; at 7.0, 26. Diffraction peaks are observed at 21.8, 20.3, 15.4, 14.1, 24.0, 13.7, 28.9, and 21.2; diffraction peaks are also observed at 7.0, 26.5, 21.8, 20.3, 15.4, 14.1, 27.6, 13.7, 28.9, and 21.2.

[0105] The X-ray powder diffraction pattern of hydrobromic acid crystal form B includes areas at 2θ of 7.0±0.2° and 26.5±0.2°. One or more diffraction peaks are found in the range of 21.8±0.2°, 20.3±0.2°, 15.4±0.2°, 14.1±0.2°, 24.0±0.2°, 27.6±0.2°, 13.7±0.2°, 28.9±0.2°, 21.2±0.2°, 28.1±0.2°, 15.9±0.2°, 25.8±0.2°, 32.3±0.2°, 26.9±0.2°, 35.9±0.2°, 14.9±0.2°, 18.5±0.2°, and 25.3±0.2°. Preferably, four, five, six, eight, or ten diffraction peaks are found in these peaks.

[0106] The characteristic X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d using Cu-Kα radiation are shown in Table 6.

[0107] Table 6

[0108]

[0109]

[0110] More preferably, its XRPD spectrum is basically as shown in the attached figure. Figure 15 As shown in Figure 16, its DSC spectrum is basically as shown in Figure 16.

[0111] The hydrobromide crystal form is C, with one acid atom. Its X-ray powder diffraction pattern shows a diffraction peak at 25.3±0.2°; or at 7.5±0.2°; or at 23.7±0.2°; or at 14.0±0.2°; or at 22.4±0.2°; or at 11.7±0.2°; or at 26.6±0.2°; or at 24.2±0.2°. Or it has a diffraction peak at 14.5±0.2°; or it has a diffraction peak at 15.1±0.2°; preferably it includes any 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks, more preferably it includes any 6, 7 or 8 of them;

[0112] The X-ray powder diffraction pattern of hydrobromic acid C contains at least one or more diffraction peaks located at 2θ of 25.3±0.2°, 7.5±0.2°, and 23.7±0.2°, preferably two, more preferably three; optionally, it may further contain at least one peak located at 2θ of 14.0±0.2°, 22.4±0.2°, 11.7±0.2°, 26.6±0.2°, and 24.2±0.2°, preferably two, three, four, or five; for example, the X-ray powder diffraction pattern of hydrobromic acid C at 2θ (±0.2°) contains...

[0113] Diffraction peaks are observed at 25.3, 7.5, 23.7, 14.0, 22.4, and 11.7; diffraction peaks are observed at 25.3, 7.5, 14.0, 22.4, 11.7, and 26.6; diffraction peaks are observed at 25.3, 23.7, 14.0, 22.4, 11.7, and 26.6; diffraction peaks are observed at 25.3, 7.5 ... Diffraction peaks are observed at 23.7, 22.4, 11.7, and 26.6; 25.3, 7.5, 14.0, 22.4, 11.7, and 24.2; 25.3, 23.7, 14.0, 22.4, 26.6, and 24.2; 7.5, 23.7, 14.0, 11.7, 26.6, and 24.2; 25.3, 7.5, 23.7, 14.0, 22.4, 11.7, and 24.2; 25.3, 7.5, 23.7, 14.0, 22.4, 11.7, and 26.6; 25.3, 7.5, Diffraction peaks are observed at 23.7, 14.0, 22.4, 11.7, 26.6, and 24.2.

[0114] The X-ray powder diffraction pattern of hydrobromic acid C optionally includes one or more diffraction peaks located at 2θ of 14.5±0.2°, 15.1±0.2°, 16.8±0.2°, 19.3±0.2°, 20.1±0.2°, 26.3±0.2°, and 21.8±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks; for example, the X-ray powder diffraction pattern of hydrobromic acid C at 2θ (±0.2°)...

[0115] Diffraction peaks are observed at 25.3, 7.5, 23.7, 14.0, 22.4, 11.7, 14.5, and 15.1; diffraction peaks are observed at 25.3, 7.5, 14.0, 22.4, 11.7, 26.6, 14.5, and 15.1; diffraction peaks are observed at 7.5, 23.7, 14.0, 22.4, 11.7, 26.6, 14.5, and 15.1; diffraction peaks are observed at 25.3, 7.5, 23.7, 14.0, 22.4, 26.6, 14.5, and 15.1. Diffraction peaks are observed at 25.3, 7.5, 23.7, 14.0, 11.7, 26.6, 14.5, and 15.1. Diffraction peaks are also observed at 25.3, 7.5, 23.7, 22.4, 11.7, 26.6, 14.5, and 15.1. Diffraction peaks are also observed at 25.3, 7.5, 14.0, 22.4, 11.7, 24.2, 14.5, and 15.1. Diffraction peaks are also observed at 7.5, 23.7, 14.0, 11.7, 26.6, 24.2, 14.5, and 15.1. Diffraction peaks are observed at 7.5, 23.7, 14.0, 22.4, 11.7, 24.2, 14.5, and 15.1; diffraction peaks are observed at 25.3, 7.5, 23.7, 14.0, 22.4, 11.7, 26.6, 14.5, and 15.1; diffraction peaks are observed at 25.3, 7.5, 23.7, 14.0, 22.4, 11.7, 26.6, 24.2, 14.5, and 15.1.

[0116] The X-ray powder diffraction pattern of hydrobromic acid C contains one or more diffraction peaks located at 2θ of 25.4±0.2°, 7.5±0.2°, 23.7±0.2°, 14.0±0.2°, 22.4±0.2°, 11.7±0.2°, 26.6±0.2°, 24.2±0.2°, 14.5±0.2°, 15.1±0.2°, 16.8±0.2°, 19.3±0.2°, 20.1±0.2°, 26.3±0.2°, and 21.8±0.2°. Preferably, it contains diffraction peaks at any of the selected 4, 5, 6, 8, or 10 peaks. For example, the X-ray powder diffraction pattern of hydrobromic acid C at 2θ (±0.2°) contains peaks at...

[0117] Diffraction peaks are observed at 25.3, 7.5, 23.7, and 14.0; at 25.3, 7.5, 23.7, and 22.4; at 25.3, 14.0, 22.4, 11.7, 26.6, and 24.2; at 7.5, 14.0, 22.4, 11.7, 26.6, and 24.2; at 25.3, 7.5, 14.0, 22.4, 11.7, 14.5, 15.1, and 16.8; at 25.3, 23.7, 14.0, 22.4, 11.7, 14.5, 15.1, and 16.8; at 25.3, 7.5, Diffraction peaks are observed at 23.7, 14.0, 22.4, 11.7, 26.6, 14.5, 15.1, and 16.8; diffraction peaks are also observed at 25.3, 7.5, 23.7, 14.0, 22.4, 11.7, 24.2, 14.5, 15.1, and 16.8.

[0118] The X-ray powder diffraction pattern of hydrobromic acid crystal form C includes areas located at 2θ of 25.4±0.2°, 7.5±0.2°, One or more diffraction peaks are found in the range of 23.7±0.2°, 14.0±0.2°, 22.4±0.2°, 11.7±0.2°, 26.6±0.2°, 24.2±0.2°, 14.5±0.2°, 15.1±0.2°, 16.8±0.2°, 19.3±0.2°, 20.1±0.2°, 26.3±0.2°, 21.8±0.2°, 24.9±0.2°, 21.2±0.2°, 28.0±0.2°, 18.3±0.2°, and 27.4±0.2°. Preferably, four, five, six, eight, or ten diffraction peaks are found in these peaks.

[0119] The characteristic X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d using Cu-Kα radiation are shown in Table 7.

[0120] Table 7

[0121]

[0122]

[0123] More preferably, its XRPD spectrum is basically as shown in the attached figure. Figure 17 As shown in Figure 18, its DSC spectrum is basically as shown in Figure 18.

[0124] Hydrobromide crystal form D, with an acid number of 1, exhibits the following X-ray powder diffraction peaks: at 6.5 ± 0.2°; or at 6.8 ± 0.2°; or at 21.5 ± 0.2°; or at 13.2 ± 0.2°; or at 17.0 ± 0.2°; or at 25.8 ± 0.2°; or at 26°. The diffraction peak is present at 0.6±0.2°; or at 10.2±0.2°; or at 24.6±0.2°; or at 22.6±0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks are included; more preferably, any 6, 7, or 8 of the above diffraction peaks are included.

[0125] The X-ray powder diffraction pattern of hydrobromic acid crystal form D contains at least one or more diffraction peaks located at 2θ of 6.5±0.2°, 6.8±0.2°, and 21.5±0.2°, preferably two, more preferably three; optionally, it may further contain at least one peak located at 2θ of 13.2±0.2°, 17.0±0.2°, 25.8±0.2°, 26.6±0.2°, and 10.2±0.2°, preferably two, three, four, or five; for example, the X-ray powder diffraction pattern of hydrobromic acid crystal form D at 2θ (±0.2°) contains...

[0126] Diffraction peaks are present at positions 6.5, 6.8, 21.5, 13.2, 17.0, and 25.8; diffraction peaks are present at positions 6.5, 6.8, 13.2, 17.0, 25.8, and 26.6; diffraction peaks are present at positions 6.5, 21.5, 13.2, 17.0, 25.8, and 26.6; diffraction peaks are present at positions 6.8, 21.5, 13.2, 17.0, 25.8, and 26.6; diffraction peaks are present at positions 6.5, 6.8, 21.5, 13.2, 25.8, and 26.6; diffraction peaks are present at positions 6.5, 6.8, 21.5, 17.0, and 26.6; diffraction peaks are present at positions 6.5, 6.8, 21.5, 17.0, and 26.6; diffraction peaks are present at positions 6.5, 6.8, 21.5, 17.0, and 26.6; diffraction peaks are present at positions 6.5, 6.8, 21.5, 17.0, and 26.6; diffraction peaks are present at positions 6.5, 6.8, 21.5, 17.0, and 26.6. Diffraction peaks are present at 25.8 and 26.6; diffraction peaks are present at 6.5, 6.8, 13.2, 17.0, 25.8, and 10.2; diffraction peaks are present at 6.5, 21.5, 13.2, 17.0, 26.6, and 10.2; diffraction peaks are present at 6.8, 21.5, 13.2, 25.8, 26.6, and 10.2; diffraction peaks are present at 6.5, 6.8, 21.5, 13.2, 17.0, 25.8, and 10.2; diffraction peaks are present at 6.5, 6.8, 21.5, 13.2, 17.0, 25.8, and 26.6; diffraction peaks are present at 6.5, 6.8, 21.5, 13.2, 17.0, 25.8, 26.6, and 10.2.

[0127] The X-ray powder diffraction pattern of hydrobromic acid crystal form D optionally includes one or more diffraction peaks located at 2θ of 24.6±0.2°, 22.6±0.2°, 27.0±0.2°, 14.8±0.2°, 34.2±0.2°, 15.4±0.2°, and 27.9±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks; for example, the X-ray powder diffraction pattern of hydrobromic acid crystal form D at 2θ (±0.2°)...

[0128] Diffraction peaks are observed at positions 6.5, 6.8, 21.5, 13.2, 17.0, 25.8, 24.6, and 22.6; (This last part is repeated twice in the original text.) Diffraction peaks are observed at 6.8, 21.5, 13.2, 25.8, 26.6, 24.6, and 22.6; diffraction peaks are observed at 6.5, 6.8, 21.5, 17.0, 25.8, 26.6, 24.6, and 22.6; diffraction peaks are observed at 6.5, 6.8, 13.2, 17.0, 25.8, 10.2 ...0.2, 24.6, and 22.6; diffraction peaks are observed at 6.5, 6.8, 10.2, 24.6, and 22.6; diffraction peaks are observed at 6.5, 6.8, 10.2, 24.6, and 22.6; diffraction peaks are observed at Diffraction peaks are observed at 21.5, 13.2, 17.0, 25.8, 10.2, 24.6, and 22.6; diffraction peaks are observed at 6.5, 6.8, 21.5, 13.2, 17.0, 25.8, 26.6, 24.6, and 22.6; diffraction peaks are observed at 6.5, 6.8, 21.5, 13.2, 17.0, 25.8, 26.6, 10.2, 24.6, and 22.6.

[0129] The X-ray powder diffraction pattern of hydrobromic acid crystal form D contains one or more diffraction peaks located at 2θ of 6.5±0.2°, 6.8±0.2°, 21.5±0.2°, 13.2±0.2°, 17.0±0.2°, 25.8±0.2°, 26.6±0.2°, 10.2±0.2°, 24.6±0.2°, 22.6±0.2°, 27.0±0.2°, 14.8±0.2°, 34.2±0.2°, 15.4±0.2°, and 27.9±0.2°. Preferably, it contains diffraction peaks at any of the selected 4, 5, 6, 8, or 10 peaks. For example, the X-ray powder diffraction pattern of hydrobromic acid crystal form D has peaks at 2θ (±0.2°).

[0130] Diffraction peaks are observed at 6.5, 6.8, 21.5, and 13.2; diffraction peaks are observed at 6.5, 6.8, 21.5, and 17.0.

[0131] Diffraction peaks are observed at 6.5, 13.2, 17.0, 25.8, 26.6, and 10.2; diffraction peaks are observed at 6.5, 6.8, 13.2, 17.0, 25.8, 26.6, and 10.2; diffraction peaks are observed at 6.5, 6.8, 13.2, 17.0, 25.8, 24.6, 22.6, and 27.0; diffraction peaks are observed at 6.5, 6.8, 21.5, 13.2, 17.0, 25.8, 26.6 ...5, 24.6, 22.6, and 27.0; diffraction peaks are observed at 6.5, 6.8, 21.5, 13.2, 17.0, 25.8, 26.6, 24.6, 22.6, and 27.0. Diffraction peaks are observed at 13.2, 17.0, 25.8, 10.2, 24.6, 22.6, and 27.0.

[0132] The X-ray powder diffraction pattern of hydrobromic acid crystal form D includes areas located at 2θ of 6.5±0.2° and 6.8±0.2°. One or more diffraction peaks are found in the range of 21.5±0.2°, 13.2±0.2°, 17.0±0.2°, 25.8±0.2°, 26.6±0.2°, 10.2±0.2°, 24.6±0.2°, 22.6±0.2°, 27.0±0.2°, 14.8±0.2°, 34.2±0.2°, 15.4±0.2°, 27.9±0.2°, 18.6±0.2°, 22.3±0.2°, 23.3±0.2°, 20.2±0.2°, and 24.4±0.2°. Preferably, four, five, six, eight, or ten diffraction peaks are found in these peaks.

[0133] The characteristic X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d using Cu-Kα radiation are shown in Table 8.

[0134] Table 8

[0135]

[0136]

[0137] More preferably, its XRPD spectrum is basically as shown in the attached figure. Figure 19 As shown, its DSC spectrum is basically as shown in Figure 20, and its TGA spectrum is basically as shown in Figure 20. Figure 21 As shown;

[0138] The hydrobromide crystal form is E, with one acid atom. Its X-ray powder diffraction pattern exhibits diffraction peaks at 24.5 ± 0.2°; or at 18.0 ± 0.2°; or at 25.1 ± 0.2°; or at 25.3 ± 0.2°; or at 22.7 ± 0.2°; or at 29.2 ± 0.2°; or at 23.4 ± 0.2°; or at 18.7 ± 0.2°; or at 26.6 ± 0.2°; or at 13.9 ± 0.2°. Preferably, it includes any 2-5, 3-5, 3-6, 3-8, or 5-8 of the aforementioned diffraction peaks. Or 6-8 locations, more preferably including any 6, 7 or 8 locations;

[0139] The X-ray powder diffraction pattern of hydrobromic acid crystal form E contains at least one or more diffraction peaks located at 2θ of 24.5±0.2°, 18.0±0.2°, and 25.1±0.2°, preferably two, more preferably three; optionally, it may further contain at least one peak located at 2θ of 25.3±0.2°, 22.7±0.2°, 29.2±0.2°, 23.4±0.2°, and 18.7±0.2°, preferably two, three, four, or five; for example, the X-ray powder diffraction pattern of hydrobromic acid crystal form E at 2θ (±0.2°) contains...

[0140] Diffraction peaks are observed at 24.5, 18.0, 25.1, 25.3, 22.7, and 29.2; 24.5, 18.0, 25.3, 22.7, 29.2, and 23.4; 24.5, 25.1, 25.3, 22.7, 29.2, and 23.4; 18.0, 25.1, 25.3, 22.7, 29.2, and 23.4; 24.5, 18.0, 25.1, 25.3, 22.7, and 29.4. A diffraction peak is observed at 23.4; diffraction peaks are observed at 24.5, 18.0, 25.1, 25.3, 29.2, and 23.4; diffraction peaks are observed at 24.5, 18.0, 25.1, 22.7, 29.2, and 23.4; diffraction peaks are observed at 24.5, 18.0, 25.3, 22.7, 29.2, and 18.7; diffraction peaks are observed at 24.5, 18.0, 25.3, 22.7, 23.4, and 18.7; diffraction peaks are observed at 18.0, 25.1, 25.3, 29.2, 23.4, and 18.7; diffraction peaks are observed at 24.5, 18.0, 25.1, 25.3, 22.7, 29.2, and 18.7. Diffraction peaks are observed at positions 24.5, 18.0, 25.1, 25.3, 22.7, 29.2, and 23.4; and at positions 24.5, 18.0, 25.1, 25.3, 22.7, 29.2, 23.4, and 18.7.

[0141] The X-ray powder diffraction pattern of hydrobromic acid crystal form E optionally includes one or more diffraction peaks located at 2θ of 26.6±0.2°, 13.9±0.2°, 31.1±0.2°, 17.6±0.2°, 15.8±0.2°, 14.4±0.2°, and 7.5±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks; for example, the X-ray powder diffraction pattern of hydrobromic acid crystal form E at 2θ (±0.2°)...

[0142] Diffraction peaks are observed at positions 24.5, 18.0, 25.1, 25.3, 22.7, 29.2, 26.6, and 13.9; Diffraction peaks are observed at positions 24.5, 18.0, 25.3, 22.7, 29.2, 23.4, 26.6, and 13.9; Diffraction peaks are observed at positions 18.0, 25.1, 25.3, 22.7, 29.2, 23.4, 26.6, and 13.9; Diffraction peaks are observed at positions 24.5, 18.0, 25.1, 25.3, 22.7, 23.4, 26.6, and 13.9. Diffraction peaks are observed at positions 24.5, 18.0, 25.1, 25.3, 29.2, 23.4, 26.6, and 13.9; diffraction peaks are observed at positions 24.5, 18.0, 25.1, 22.7, 29.2, 23.4, 26.6, and 13.9; diffraction peaks are observed at positions 24.5, 18.0, 25.3, 22.7, 29.2, 18.7, 26.6, and 13.9; diffraction peaks are observed at positions 24.5, 25.1, 25.3, 22.7, 23.4, 18.7, 26.6, and 13.9; diffraction peaks are observed at positions 18.0, 25.1, 25.3, 29.2, 23.4, 18.7, 26.6, and 13.9; diffraction peaks are observed at positions 24.5, 25.1, 25.3, 22.7 ... Diffraction peaks are observed at positions 18.0, 25.1, 25.3, 22.7, 29.2, 18.7, 26.6, and 13.9; diffraction peaks are observed at positions 24.5, 18.0, 25.1, 25.3, 22.7, 29.2, 23.4, 26.6, and 13.9.

[0143] The X-ray powder diffraction pattern of hydrobromic acid crystal form E includes one or more diffraction peaks located at 2θ of 24.5±0.2°, 18.0±0.2°, 25.1±0.2°, 25.3±0.2°, 22.7±0.2°, 29.2±0.2°, 23.4±0.2°, 18.7±0.2°, 26.6±0.2°, 13.9±0.2°, 31.1±0.2°, 17.6±0.2°, 15.8±0.2°, 14.4±0.2°, and 7.5±0.2°. Preferably, it includes diffraction peaks at any of the selected 4, 5, 6, 8, or 10 peaks. For example, the X-ray powder diffraction pattern of hydrobromic acid crystal form E has peaks at 2θ (±0.2°).

[0144] Diffraction peaks are observed at 24.5, 18.0, 25.1, and 25.3; 24.5, 18.0, 25.1, and 22.7; 24.5, 25.3, 22.7, 29.2, 23.4, and 18.7; 18.0, 25.3, 22.7, 29.2, 23.4, and 18.7; 24.5, 18.0, 25.3, 22.7, 29.2, 26.6, 13.9, and 31.1; 24.5, 25.1, 25.3, 22.7, 29.2, 26.6, 13.9, and 31.1; 24.5, Diffraction peaks are observed at 18.0, 25.1, 25.3, 22.7, 29.2, 23.4, 26.6, 13.9, and 31.1; diffraction peaks are also observed at 24.5, 18.0, 25.1, 25.3, 22.7, 29.2, 18.7, 26.6, 13.9, and 31.1.

[0145] The X-ray powder diffraction pattern of hydrobromic acid crystal form E includes values ​​at 2θ of 24.5±0.2°, 18.0±0.2°, 25.1±0.2°, 25.3±0.2°, 22.7±0.2°, 29.2±0.2°, 23.4±0.2°, 18.7±0.2°, 26.6±0.2°, 13.9±0.2°, and 31.1±0. One or more diffraction peaks are found in the range of 2°, 17.6±0.2°, 15.8±0.2°, 14.4±0.2°, 7.5±0.2°, 13.1±0.2°, 20.1±0.2°, 20.4±0.2°, 8.2±0.2°, and 21.1±0.2°. Preferably, 4, 5, 6, 8, or 10 diffraction peaks are found in these peaks.

[0146] The characteristic X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d using Cu-Kα radiation are shown in Table 9.

[0147] Table 9

[0148]

[0149]

[0150] More preferably, its XRPD spectrum is basically as shown in the attached figure. Figure 22 As shown in Figure 23, its DSC spectrum is basically as shown in Figure 24.

[0151] Hydrobromide crystal form F, with an acid number of 1, exhibits the following X-ray powder diffraction peaks: at 24.5 ± 0.2°; or at 25.3 ± 0.2°; or at 7.5 ± 0.2°; or at 23.8 ± 0.2°; or at 14.6 ± 0.2°; or at 20.1 ± 0.2°; or at 14... The diffraction peak is present at 0±0.2°; or at 13.3±0.2°; or at 15.8±0.2°; or at 22.4±0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks are included; more preferably, any 6, 7, or 8 of the above diffraction peaks are included.

[0152] The X-ray powder diffraction pattern of hydrobromic acid form F contains at least one or more diffraction peaks located at 2θ of 24.5±0.2°, 25.3±0.2°, and 7.5±0.2°, preferably two, more preferably three; optionally, it may further contain at least one peak located at 2θ of 23.8±0.2°, 14.6±0.2°, 20.1±0.2°, 14.0±0.2°, and 13.3±0.2°, preferably two, three, four, or five; for example, the X-ray powder diffraction pattern of hydrobromic acid form F at 2θ (±0.2°) contains...

[0153] Diffraction peaks are observed at 24.5, 25.3, 7.5, 23.8, 14.6, and 20.1; diffraction peaks are observed at 24.5, 25.3, 7.5, 23.8, 14.6, 20.1, and 14.0 ... Diffraction peaks are observed at 7.5, 14.6, 20.1, and 14.0; diffraction peaks are observed at 24.5, 25.3, 23.8, 14.6, 20.1, and 13.3; diffraction peaks are observed at 24.5, 7.5, 23.8, 14.6, 14.0, and 13.3; diffraction peaks are observed at 25.3, 7.5, 23.8, 20.1, 14.0, and 13.3; diffraction peaks are observed at 24.5, 25.3, 7.5, 23.8, 14.6, 20.1, and 13.3; diffraction peaks are observed at 24.5, 25.3, 7.5, 23.8, 14.6, 20.1, and 14.0 ... Diffraction peaks are observed at 7.5, 23.8, 14.6, 20.1, 14.0, and 13.3.

[0154] The X-ray powder diffraction pattern of hydrobromic acid form F optionally includes one or more diffraction peaks located at 2θ of 15.8±0.2°, 22.4±0.2°, 15.1±0.2°, 11.7±0.2°, 17.2±0.2°, 13.1±0.2°, and 19.0±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks; for example, the X-ray powder diffraction pattern of hydrobromic acid form F at 2θ (±0.2°)...

[0155] Diffraction peaks are observed at 24.5, 25.3, 7.5, 23.8, 14.6, 20.1, 15.8, and 22.4; diffraction peaks are observed at 24.5, 25.3, 23.8, 14.6, 20.1, 14.0, 15.8, and 22.4; diffraction peaks are observed at 24.5, 25.3, 7.5, 23.8, 14.6, 20.1, 14.0, 15.8, and 22.4; diffraction peaks are observed at 24.5, 25.3, 7.5, 23.8, 14.6, 20.1, 14.0, 15.8, and 22.4. Diffraction peaks are observed at 24.5, 25.3, 7.5, 23.8, 20.1, 14.0, 15.8, and 22.4; 24.5, 25.3, 7.5, 14.6, 20.1, 14.0, 15.8, and 22.4; 24.5, 25.3, 23.8, 14.6, 20.1, 13.3, 15.8, and 22.4; 24.5, 7.5, 23.8, 14.6, 20.1, 13.3, 15.8, and 22.4; 25.3, 7.5, 23.8, 20.1, 14.0, 13.3, 15.8, and 22.4; 24.5, Diffraction peaks are observed at 25.3, 7.5, 23.8, 14.6, 20.1, 13.3, 15.8, and 22.4; diffraction peaks are observed at 24.5, 25.3, 7.5, 23.8, 14.6, 20.1, 14.0, 15.8, and 22.4; diffraction peaks are observed at 24.5, 25.3, 7.5, 23.8, 14.6, 20.1, 14.0, 13.3, 15.8, and 22.4.

[0156] The X-ray powder diffraction pattern of hydrobromic acid form F includes one or more diffraction peaks located at 2θ of 24.5±0.2°, 25.3±0.2°, 7.5±0.2°, 23.8±0.2°, 14.6±0.2°, 20.1±0.2°, 14.0±0.2°, 13.3±0.2°, 15.8±0.2°, 22.4±0.2°, 15.1±0.2°, 11.7±0.2°, 17.2±0.2°, 13.1±0.2°, and 19.0±0.2°. Preferably, it includes diffraction peaks at any of the selected 4, 5, 6, 8, or 10 peaks. For example, the X-ray powder diffraction pattern of hydrobromic acid form F has peaks at 2θ (±0.2°).

[0157] Diffraction peaks are present at positions 24.5, 25.3, 7.5, and 23.8; 24.5, 25.3, 7.5, and 14.6; 24.5, 23.8, 14.6, 20.1, 14.0, and 13.3; 25.3, 23.8, 14.6, 20.1, 14.0, and 13.3; 24.5, 25.3, 23.8, 14.6, 20.1, 15.8, 22.4, and 15.1; 24.5, 25.3, and 23.8 have diffraction peaks at positions 24.5, 25.3, 7.5, and 14.6; 24.5, 7.5, 7.5, and 14.6 have diffraction peaks at positions 24.5, 23.8, 14.6, 20.1, 14.0, and 13.3 have diffraction peaks at positions 25.3, 23.8, 14.6, 20.1, 15.8, 22.4, and 15.1 have diffraction peaks at positions 24.5, 25.3, 7.5, and 14.6; 24.5, 25.3, and 14.6 have diffraction peaks at positions 24.5, 7 ...3.8, 14.6, 20.1, 15. Diffraction peaks are observed at 7.5, 23.8, 14.6, 20.1, 14.0, 15.8, 22.4, and 15.1; diffraction peaks are also observed at 24.5, 25.3, 7.5, 23.8, 14.6, 20.1, 13.3, 15.8, 22.4, and 15.1.

[0158] The X-ray powder diffraction pattern of hydrobromic acid crystal form F includes areas located at 2θ of 24.5±0.2° and 25.3±0.2°. One or more diffraction peaks are found in the range of 7.5±0.2°, 23.8±0.2°, 14.6±0.2°, 20.1±0.2°, 14.0±0.2°, 13.3±0.2°, 15.8±0.2°, 22.4±0.2°, 15.1±0.2°, 11.7±0.2°, 17.2±0.2°, 13.1±0.2°, 19.0±0.2°, 26.6±0.2°, 16.8±0.2°, 29.9±0.2°, 21.0±0.2°, and 28.3±0.2°. Preferably, 4, 5, 6, 8, or 10 diffraction peaks are found in these peaks.

[0159] The characteristic X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d using Cu-Kα radiation are shown in Table 10.

[0160] Table 10

[0161]

[0162]

[0163] More preferably, its XRPD spectrum is basically as shown in the attached figure. Figure 24 As shown in Figure 25, its DSC spectrum is basically as shown in Figure 25.

[0164] Phosphate crystal form A, with one acid atom, has an X-ray powder diffraction pattern showing a diffraction peak at 2θ of 9.5±0.2°; or at 6.9±0.2°; or at 7.1±0.2°; or at 8.2±0.2°; at 23.5±0.2°; at 18.2±0.2°; at 13.1±0.2°; at 25.8±0.2°; at 6.0±0.2°; at 13.8±0.2°; preferably including any 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks, more preferably including any 6, 7, or 8 of them;

[0165] The X-ray powder diffraction pattern of the phosphate crystal form A includes at least one or more diffraction peaks located at 2θ of 9.5±0.2°, 6.9±0.2°, or 7.1±0.2°, preferably two, more preferably three; optionally, it may further include at least one of 8.2±0.2°, 23.5±0.2°, 18.2±0.2°, 13.1±0.2°, or 25.8±0.2°, preferably two, three, four, or five; for example, the X-ray powder diffraction pattern of phosphate crystal form A at 2θ (±0.2°) is:

[0166] Diffraction peaks are observed at positions 9.5, 6.9, 7.1, 8.2, 23.5, and 18.2; 9.5, 6.9, 7.1, 8.2, 23.5, and 13.1; 9.5, 6.9, 7.1, 8.2, 23.5, and 5.8; 9.5, 6.9, 7.1, 8.2, 23.5, and 25.8; 9.5, 6.9, 7.1, 8.2, 23.5, and 18.2; 9.5, 6.9, 7.1, 8.2, 18.2, and 13.1; 9.5, 6.9, 8.2, 23.5, 18.2, and 13.1. Diffraction peaks are observed at the following locations: 9.5, 6.9, 8.2, 13.1, 18.2, and 25.8. (This is repeated four times in the original text.)

[0167] The X-ray powder diffraction pattern of the phosphate crystal form A optionally includes one or more diffraction peaks located at 2θ of 22.2±0.2°, 14.3±0.2°, 4.6±0.2°, 21.1±0.2°, 22.0±0.2°, 13.4±0.2°, 20.8±0.2°, or 15.6±0.2°; preferably, it includes at least 2 to 3, 4 to 5, or 6 to 7 peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks; for example, the X-ray powder diffraction pattern of phosphate crystal form A at 2θ (±0.2°) is:

[0168] Diffraction peaks are observed at positions 9.5, 6.9, 7.1, 8.2, 23.5, 13.1, 22.2, and 14.3; diffraction peaks are observed at positions 9.5, 6.9, 7.1, 8.2, 23.5, 25.8, 22.2, and 14.3; diffraction peaks are observed at positions 9.5, 6.9, 7.1, 8.2, 23.5, 25.8, 22.2, and 14.3; diffraction peaks are observed at positions 9.5, 6.9, 7.1, 8.2, 23.5, 6.0 ... Diffraction peaks are present at positions 13.1, 25.8, 22.2, and 14.3; diffraction peaks are present at positions 9.5, 6.9, 8.2, 23.5, 13.1, 25.8, 22.2, and 14.3; diffraction peaks are present at positions 9.5, 6.9, 8.2, 13.1, 25.8, 6.0, 22.2, and 14.3; diffraction peaks are present at positions 9.5, 7.1, 8.2, and 23.5. Diffraction peaks are observed at positions 13.1, 25.8, 22.2, and 14.3; at positions 9.5, 7.1, 8.2, 23.5, 13.1, 6.0, 22.2, and 14.3; at positions 6.9, 7.1, 8.2, 23.5, 13.1, 25.8, 22.2, and 14.3; at positions 6.9, 7.1, 8.2, 23.5, 13.1, 6.0, 22.2, and 14.3.

[0169] The X-ray powder diffraction pattern of the phosphate crystal form A includes one or more diffraction peaks located at 2θ of 9.5±0.2°, 6.9±0.2°, 7.1±0.2°, 8.2±0.2°, 23.5±0.2°, 18.2±0.2°, 13.1±0.2°, 25.8±0.2°, 6.0±0.2°, 13.8±0.2°, 22.2±0.2°, 14.3±0.2°, 4.6±0.2°, 21.1±0.2°, or 22.0±0.2°.

[0170] Preferably, diffraction peaks are found at any of 4, 5, 6, 8, or 10 locations; for example, the X-ray powder diffraction pattern of the phosphate crystal form A has diffraction peaks at the following positions at 2θ (±0.2°):

[0171] Diffraction peaks are observed at positions 9.5, 6.9, 7.1, and 8.2; at positions 9.5, 6.9, 7.1, and 23.5; at positions 9.5, 6.9, 7.1, and 13.1; and at positions 9.5, 6.9, 7.1, and 25.8. A diffraction peak is observed at 18.2; diffraction peaks are observed at 9.5, 6.9, 8.2, and 23.5; diffraction peaks are observed at 9.5, 6.9, 8.2, and 13.1; diffraction peaks are observed at 9.5, 6.9, 8.2, and 25.8; diffraction peaks are observed at 9.5, 6.9, 7.1, 8.2, and 23.5; diffraction peaks are observed at 9.5, 7.1, 8.2, and 13.1; diffraction peaks are observed at 9.5, 7.1, 8.2, and 25.8; diffraction peaks are observed at 9.5, 6.9, 7.1, 8.2, 23.5, and 6.0. Diffraction peaks are present at positions 9.5, 6.9, 7.1, 8.2, 18.2, and 13.8; diffraction peaks are present at positions 9.5, 6.9, 7.1, 8.2, 23.5, and 6.0; diffraction peaks are present at positions 9.5, 6.9, 7.1, 8.2, 13.1, and 6.0; diffraction peaks are present at positions 9.5, 6.9, 7.1, 8.2, 13.1, and 13.8; diffraction peaks are present at positions 9.5, 6.9, 7.1, 8.2, 6.0 ... Diffraction peaks are observed at 6.9, 8.2, 23.5, 18.2, and 6.0; 9.5, 6.9, 8.2, 13.1, 6.0, and 13.8; 9.5, 6.9, 8.2, 13.1, 18.2, and 6.0; 9.5, 7.1, 8.2, 23.5, 18.2, and 6.0; 9.5, 7.1, 8.2, 23.5, 18.2, and 6.0; 6.9, Diffraction peaks are observed at positions 7.1, 8.2, 23.5, 18.2, and 13.8; at positions 6.9, 7.1, 8.2, 23.5, 6.0, and 13.8; at positions 9.5, 6.9, 7.1, 8.2, 23.5, 18.2, 6.0, and 13.8; at positions 9.5, 6.9, 7.1, 8.2, 23.5, 13.1, 6.0, and 13.8; at positions 9.5, 6.9, 7.1, 8.2, 23.5, 5.8, and 9.9. Diffraction peaks are present at 6.0 and 13.8; diffraction peaks are present at 9.5, 6.9, 7.1, 8.2, 23.5, 25.8, 6.0, and 13.8; diffraction peaks are present at 9.5, 6.9, 7.1, 8.2, 23.5, 18.2, 6.0, and 13.8; diffraction peaks are present at 9.5, 6.9, 7.1, 8.2, 23.5, 18.2, 13.1, 6.0, and 13.8; diffraction peaks are present at 9.5, 6.9 ....Diffraction peaks are observed at positions 2, 13.1, 18.2, 25.8, 6.0, and 13.8; diffraction peaks are observed at positions 9.5, 6.9, 8.2, 13.1, 18.2, 13.1, 6.0, and 13.8; diffraction peaks are observed at positions 9.5, 7.1, 8.2, 23.5, 18.2, 13.1, 6.0, and 13.8. Diffraction peaks are observed at the following locations: 6.9, 7.1, 8.2, 23.5, 18.2, 13.1, 6.0, and 13.8; 6.9, 7.1, 8.2, 23.5, 18.2, 25.8, 6.0, and 13.8; 9.5, 6.9, 7.1, 8.2, 23.5, 18.2, 6.0, 13.8, 22.2, and 14.3; 9.5, 6.9, 7.1, 8.2, 23.5, 13.1, 6.0, 13.8, 22.2, and 14.3; 9.5, 6.9, 7.1, 8.2, 23.5, 5.8, 6.0, 13.8, and 22.2. A diffraction peak is present at position 14.3; diffraction peaks are present at positions 9.5, 6.9, 7.1, 8.2, 23.5, 25.8, 6.0, 13.8, 22.2, and 14.3; diffraction peaks are present at positions 9.5, 6.9, 7.1, 8.2, 23.5, 18.2, 6.0, 13.8, 22.2, and 14.3; diffraction peaks are present at positions 9.5, 6.9, 7.1, 8.2, 18.2, 13.1, 6.0, 13.8, 22.2, and 14.3; diffraction peaks are present at positions 9.5, 6.9, 7.1, 8.2, 23.5 ... Diffraction peaks are observed at positions 8.2, 13.1, 18.2, 25.8, 6.0, 13.8, 22.2, and 14.3; diffraction peaks are observed at positions 9.5, 6.9, 8.2, 13.1, 18.2, 13.1, 6.0, 13.8, 22.2, and 14.3; diffraction peaks are observed at positions 9.5, 7.1, 8.2, 23.5, 18.2, 25.8, 6.0, 13.8, 22.2, and 14.3; diffraction peaks are observed at positions 9.5, 7.1, 8.2, 23.5, 18.2, 13.1, 6.0, 13.8, and 14.3; diffraction peaks are observed at positions 6.9, 7.1, 8.2, 23.5, 18.2, 13.1, 6.0, and 13.8. Diffraction peaks are observed at 22.2 and 14.3; diffraction peaks are also observed at 6.9, 7.1, 8.2, 23.5, 18.2, 25.8, 6.0, 13.8, 22.2, and 14.3.

[0172] The characteristic X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d using Cu-Kα radiation are shown in Table 11.

[0173] Table 11

[0174]

[0175]

[0176] More preferably, its XRPD spectrum is basically as shown in the attached figure. Figure 26 As shown, its DSC spectrum is basically as follows: Figure 27 As shown, its TGA spectrum is basically as follows: Figure 28 As shown;

[0177] Phosphate crystal form B, with one acid, has an X-ray powder diffraction pattern showing a diffraction peak at 2θ of 4.6 ± 0.2°; or at 9.4 ± 0.2°; or at 22.1 ± 0.2°; or at 21.0 ± 0.2°; at 12.6 ± 0.2°; at 7.9 ± 0.2°; at 17.3 ± 0.2°; at 18.8 ± 0.2°; at 15.1 ± 0.2°; at 17.7 ± 0.2°; preferably including any 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks, more preferably including any 6, 7, or 8 of them.

[0178] The X-ray powder diffraction pattern of the phosphate crystal form B contains at least one or more diffraction peaks located at 2θ of 4.6±0.2°, 9.4±0.2°, or 22.1±0.2°, preferably two, more preferably three; optionally, it may further contain at least one of 21.0±0.2°, 12.6±0.2°, 7.9±0.2°, 17.3±0.2°, or 18.8±0.2°, preferably two, three, four, or five; for example, the X-ray powder diffraction pattern of the phosphate crystal form B has diffraction peaks at the following positions at 2θ (±0.2°):

[0179] Diffraction peaks are observed at 4.6, 9.4, 22.1, 21.0, 12.6, and 7.9; 4.6, 9.4, 22.1, 21.0, 12.6, and 7.9; 4.6, 9.4, 22.1, 12.6, 7.9, and 17.3; 4.6, 9.4, 22.1, 21.0, 12.6, and 18.8; 4.6, 9.4, 21.0, 12.6, 7.9, and 17.3; 4.6, 9.4, 21.0, 12.6, 17.3, and 18.8; 4.6, 22.1, 21.0, 12.6, 7.9, and 17.3. Diffraction peaks are observed at: 4.6, 22.1, 21.0, 12.6, 7.9, and 18.8; 9.4, 22.1, 21.0, 12.6, 7.9, and 18.8; and 9.4, 22.1, 21.0, 12.6, 17.3, and 18.8.

[0180] The X-ray powder diffraction pattern of the phosphate crystal form B optionally includes one or more diffraction peaks located at 2θ of 14.2±0.2°, 16.2±0.2°, 14.8±0.2°, 19.5±0.2°, 24.1±0.2°, 25.5±0.2°, 23.1±0.2°, or 27.1±0.2°; preferably, it includes at least 2 to 3, 4 to 5, or 6 to 7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks; for example, the X-ray powder diffraction pattern of the phosphate crystal form B has diffraction peaks at the following positions at 2θ (±0.2°):

[0181] Diffraction peaks are present at 4.6, 9.4, 22.1, 21.0, 12.6, 7.9, 14.2, and 16.2 ± 0.2°; diffraction peaks are present at 4.6, 9.4, 22.1, 21.0, 12.6, 7.9, 14.2, and 16.2; diffraction peaks are present at 4.6, 9.4, 22.1, 12.6, 7.9, 17.3, 14.2, and 16.2; diffraction peaks are present at 4.6, 9.4, 22.1, 21.0, 12.6, 18.8, 14.2, and 16.2; diffraction peaks are present at 4.6, 9.4, 21.0 ...1.0, 12.6, 7.9, 17.3, 14.2, and 16.2; diffraction peaks are present at 4.6, 9.4, 22.1, 21.0, 12.6, 18.8, 14.2, and 16.2; diffraction peaks are Diffraction peaks are observed at positions 9.4, 21.0, 12.6, 17.3, 18.8, 14.2, and 16.2; diffraction peaks are observed at positions 4.6, 22.1, 21.0, 12.6, 7.9, 17.3, 14.2, and 16.2; diffraction peaks are observed at positions 4.6, 22.1, 21.0, 12.6, 7.9, 18.8, 14.2, and 16.2; diffraction peaks are observed at positions 9.4, 22.1, 21.0, 12.6, 7.9, 18.8, 14.2, and 16.2; diffraction peaks are observed at positions 9.4, 22.1, 21.0, 12.6, 17.3, 18.8, 14.2, and 16.2.

[0182] The X-ray powder diffraction pattern of the phosphate crystal form B includes one or more diffraction peaks located at 2θ of 4.6±0.2°, 9.4±0.2°, 22.1±0.2°, 21.0±0.2°, 12.6±0.2°, 7.9±0.2°, 17.3±0.2°, 18.8±0.2°, 15.1±0.2°, 17.7±0.2°, 14.2±0.2°, 16.2±0.2°, 14.8±0.2°, 19.5±0.2°, or 24.1±0.2°.

[0183] Preferably, diffraction peaks are found at any of 4, 5, 6, 8, or 10 locations; for example, the X-ray powder diffraction pattern of the phosphate crystal form B has diffraction peaks at the following positions at 2θ (±0.2°):

[0184] Diffraction peaks are present at positions 4.6, 9.4, 22.1, and 21.0; diffraction peaks are present at positions 4.6, 9.4, 22.1, and 12.6; diffraction peaks are present at positions 4.6, 9.4, 22.1, and 7.9; diffraction peaks are present at positions 4.6, 9.4, 22.1, and 17.3; diffraction peaks are present at positions 4.6, 9.4, 21.0, and 12.6; diffraction peaks are present at positions 4.6, 9.4, 21.0, and 12.6; diffraction peaks are present at positions 4.6, 9.4, 21.0, and 7.9; diffraction peaks are present at positions 4.6, 22.1, 21.0, and 12.6; diffraction peaks are present at positions 4.6, 22.1, and 21.0. A diffraction peak is observed at position 7.9; diffraction peaks are observed at positions 4.6, 22.1, 21.0, and 17.3; diffraction peaks are observed at positions 4.6, 9.4, 22.1, 21.0, 14.2, and 16.2; diffraction peaks are observed at positions 4.6, 9.4, 22.1, 12.6, 14.2, and 16.2; diffraction peaks are observed at positions 4.6, 9.4, 22.1, 7.9, 14.2, and 16.2; diffraction peaks are observed at positions 4.6, 9.4, 22.1, 17.3, 14.2, and 16.2; diffraction peaks are observed at positions 4.6, 9.4, 21.0, 12.6, 14.2, and 16.2; diffraction peaks are observed at positions 4.6, 9.4, 21.0, 12.6, 14.2, and 16.2; diffraction peaks are observed at positions 4.6, 9.4, 21.0, 12.6, 14.2, and 16.2. Diffraction peaks are observed at 12.6, 14.2, and 16.2; at 4.6, 9.4, 21.0, 7.9, 14.2, and 16.2; at 4.6, 22.1, 21.0, 12.6, 14.2, and 16.2; at 4.6, 22.1, 21.0, 7.9, 14.2, and 16.2; at 4.6, 22.1, 21.0, 17.3, 14.2, and 16.2; at 4.6, 9.4, 22.1, 21.0, 12.6, 7.9, 15.1, and 17.7; at 4.6, 9.4, 22.1, 21.0, 12.6, and 16.2. Diffraction peaks are present at positions 7.9, 15.1, and 17.7; diffraction peaks are present at positions 4.6, 9.4, 22.1, 12.6, 7.9, 17.3, 15.1, and 17.7; diffraction peaks are present at positions 4.6, 9.4, 22.1, 21.0, 12.6, 18.8, 15.1, and 17.7; diffraction peaks are present at positions 4.6, 9.4, 21.0, 12.6, 7.9, 17.3, 15.1, and 17.7; diffraction peaks are present at positions 4.6, 9.4, 21.0, 12.6, 7.9, 17.3, and 17.7; diffraction peaks are present at positions 4.6, 22.1, 21.0, 12.6, 7.9, 17.3, and 15.1. A diffraction peak is observed at 17.7; diffraction peaks are observed at 4.6, 22.1, 21.0, 12.6, 7.9, 18.8, 15.1, and 17.7; diffraction peaks are observed at 9.4, 22.1, 21.0, 12.6, 7.9, 18.8, 15.1, and 17.7; diffraction peaks are observed at 9.4 and 22.1. Diffraction peaks are observed at 21.0, 12.6, 17.3, 18.8, 15.1, and 17.7.

[0185] The characteristic X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d using Cu-Kα radiation are shown in Table 12.

[0186] Table 12

[0187]

[0188]

[0189] More preferably, its XRPD spectrum is basically as shown in the attached figure. Figure 29 As shown;

[0190] Methanesulfonate crystal form A, with one acid, has an X-ray powder diffraction pattern showing a diffraction peak at 2θ 14.9 ± 0.2°; or at 7.4 ± 0.2°; or at 24.5 ± 0.2°; or at 22.4 ± 0.2°; at 37.9 ± 0.2°; at 25.0 ± 0.2°; at 21.0 ± 0.2°; at 18.9 ± 0.2°; at 34.1 ± 0.2°; at 28.5 ± 0.2°; preferably including any 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks, more preferably including any 6, 7, or 8 of them;

[0191] The X-ray powder diffraction pattern of the methanesulfonate crystal form A contains at least one or more diffraction peaks located at 2θ of 14.9±0.2°, 7.4±0.2°, or 24.5±0.2°, preferably two, more preferably three; optionally, it may further contain at least one of 22.4±0.2°, 37.9±0.2°, 25.0±0.2°, 21.0±0.2°, or 18.9±0.2°, preferably two, three, four, or five; for example, the X-ray powder diffraction pattern of the methanesulfonate crystal form A has diffraction peaks at the following positions at 2θ (±0.2°):

[0192] Diffraction peaks are observed at 14.9, 7.4, 24.5, 22.4, 37.9, and 22.4; diffraction peaks are observed at 14.9, 7.4, 24.5, 22.4, 37.9, and 25.0; diffraction peaks are observed at 14.9, 7.4, 24.5, 22.4, 37.9, and 21.0; diffraction peaks are observed at 14.9, 7.4, 24.5, 22.4, 22.4, and 25.0; diffraction peaks are observed at 14.9, 7.4, 22.4, 37.9, 22.4, and 37.9; diffraction peaks are observed at 14.9, 24.5, and 21.0; diffraction peaks are observed at 14.9, 7.4, 24.5, 22.4, 22.4, and 25.0; diffraction peaks are observed at 14.9, 24.5, and 22.4 ... Diffraction peaks are observed at 22.4, 37.9, 22.4, and 37.9; at 14.9, 24.5, 22.4, 37.9, 22.4, and 25.0; at 7.4, 24.5, 22.4, 37.9, 22.4, and 37.9; and at 7.4, 24.5, 22.4, 37.9, 22.4, and 25.0.

[0193] The X-ray powder diffraction pattern of the methanesulfonate crystal form A optionally includes one or more diffraction peaks located at 2θ of 17.4 ± 0.2°, 21.5 ± 0.2°, 22.9 ± 0.2°, 23.8 ± 0.2°, 26.5 ± 0.2°, 29.1 ± 0.2°, 30.2 ± 0.2°, or 26.5 ± 0.2°; preferably, it includes at least 2 to 3, 4 to 5, or 6 to 7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks; for example, the X-ray powder diffraction pattern of the methanesulfonate crystal form A has diffraction peaks at the following positions at 2θ (±0.2°):

[0194] Diffraction peaks are observed at positions 14.9, 7.4, 24.5, 22.4, 37.9, 22.4, 17.4, and 21.5; diffraction peaks are observed at positions 14.9, 7.4, 24.5, 37.9, 37.9, 22.4, 17.4, and 21.5; diffraction peaks are observed at positions 14.9, 7.4, 24.5, 24.5, 37.9, 22.4, 17.4, and 21.5; diffraction peaks are observed at positions 14.9, 7.4, 24.5, 24.5, 37.9, 22.4, 17.4, and 21.5; diffraction peaks are observed at positions 14.9, 7.4, 22.4, 37.9, 37.9, 22.4, 17.4, and 21.5. Diffraction peaks are observed at positions 14.9, 7.4, 37.9, 24.5, 37.9, 22.4, 17.4, and 21.5; diffraction peaks are observed at positions 14.9, 24.5, 22.4, 37.9, 37.9, 22.4, 17.4, and 21.5; diffraction peaks are observed at positions 14.9, 24.5, 22.4, 21.0, 37.9, 22.4, 17.4, and 21.5; diffraction peaks are observed at positions 7.4, 24.5, 22.4, 37.9, 37.9, 22.4, 17.4, and 21.5; diffraction peaks are observed at positions 7.4, 24.5, 22.4, 24.5, 37.9, 22.4, 17.4, and 21.5.

[0195] The X-ray powder diffraction pattern of the methanesulfonate crystal form A includes one or more diffraction peaks located at 2θ of 14.9, 7.4, 24.5, 22.4, 37.9, 25.0, 21.0, 18.9, 34.1, 28.5, 17.4, 21.5, 22.9, 23.8, or 26.5.

[0196] Preferably, diffraction peaks are found at any of 4, 5, 6, 8, or 10 locations; for example, the X-ray powder diffraction pattern of the methanesulfonate crystal form A has diffraction peaks at the following positions at 2θ (±0.2°):

[0197] Diffraction peaks are present at positions 14.9, 7.4, 24.5, and 22.4; diffraction peaks are present at positions 14.9, 7.4, 24.5, and 37.9; diffraction peaks are present at positions 14.9, 7.4, 24.5, and 24.5; diffraction peaks are present at positions 14.9, 7.4, 24.5, and 21.0; diffraction peaks are present at positions 14.9, 7.4, 22.4, and 37.9; diffraction peaks are present at positions 14.9, 24.5, 22.4, and 37.9; diffraction peaks are present at positions 14.9, 24.5, 22.4, and 21.0; diffraction peaks are present at positions 7.4, 24.5, and 22.4. A diffraction peak is observed at 37.9; diffraction peaks are observed at 7.4, 24.5, 22.4, and 24.5; diffraction peaks are observed at 14.9, 7.4, 24.5, 22.4, 17.4, and 21.5; diffraction peaks are observed at 14.9, 7.4, 24.5, 37.9, 17.4, and 21.5; diffraction peaks are observed at 14.9, 7.4, 24.5, 24.5, 17.4, and 21.5; diffraction peaks are observed at 14.9, 7.4, 24.5, 21.0, 17.4, and 21.5; diffraction peaks are observed at 14.9, 7.4, 22.4, 37.9, 17.4, and 21.5; diffraction peaks are observed at 14.9, 7.4, 24.5, 22.4, 17.4, and 21.5. Diffraction peaks are observed at 37.9, 24.5, 17.4, and 21.5; at 14.9, 24.5, 22.4, 37.9, 17.4, and 21.5; at 14.9, 24.5, 22.4, 21.0, 17.4, and 21.5; at 7.4, 24.5, 22.4, 37.9, 17.4, and 21.5; at 7.4, 24.5, 22.4, 24.5, 17.4, and 21.5; at 14.9, 7.4, 24.5, 22.4, 37.9, 17.4, and 21.5; at 14.9, 7.4, 24.5, 22.4, 37.9, 22.4, 34.1, and 28.5; at 14.9, 7.4, 24.5, 22.4, 37.9, 22.4, 34.1, and 28.5. Diffraction peaks are observed at 24.5, 22.4, 37.9, 25.0, 34.1, and 28.5; diffraction peaks are observed at 14.9, 7.4, 24.5, 22.4, 37.9, 21.0, 34.1, and 28.5; diffraction peaks are observed at 14.9, 7.4, 24.5, 22.4, 22.4, 25.0, 34.1, and 28.5; diffraction peaks are observed at 14.9 ... Diffraction peaks are observed at 37.9, 22.4, 37.9, 34.1, and 28.5; diffraction peaks are observed at 14.9, 24.5, 22.4, 37.9, 22.4, 25.0, 34.1, and 28.5; diffraction peaks are observed at 7.4, 24.5, 22.4, and 37.Diffraction peaks are observed at positions 9, 22.4, 37.9, 34.1, and 28.5; at positions 7.4, 24.5, 22.4, 37.9, 22.4, 25.0, 34.1, and 28.5; at positions 14.9, 7.4, 24.5, 22.4, 37.9, 22.4, 34.1, 28.5, 17.4, and 21.5; at positions 14.9, 7.4, 24.5, 22.4, 37.9, 25.0, 34.1, 28.5, 17.4, and 21.5; at positions 14.9, 7.4, and 24.5... Diffraction peaks are observed at 22.4, 37.9, 21.0, 34.1, 28.5, 17.4, and 21.5; Diffraction peaks are observed at 14.9, 7.4, 24.5, 22.4, 22.4, 25.0, 34.1, 28.5, 17.4, and 21.5; Diffraction peaks are observed at 14.9, 7.4, 22.4, 37.9, 22.4, 37.9, 34.1, 28.5, 17.4, and 21.5; Diffraction peaks are observed at 14.9, 24.5, 22.4, 37.9, 22.4, 37.9, 34.1, and 21.5; Diffraction peaks are observed at 14.9, 24.5, 22.4, 37.9, 22.4, 37.9, and 34.1; Diffraction peaks are present at 28.5, 17.4, and 21.5; diffraction peaks are present at 14.9, 24.5, 22.4, 37.9, 22.4, 25.0, 34.1, 28.5, 17.4, and 21.5; diffraction peaks are present at 7.4, 24.5, 22.4, 37.9, 22.4, 37.9, 34.1, 28.5, 17.4, and 21.5.

[0198] The characteristic X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d using Cu-Kα radiation are shown in Table 13.

[0199] Table 13

[0200]

[0201]

[0202] More preferably, its XRPD spectrum is basically as shown in the attached figure. Figure 30 The DSC spectrum shown is basically as follows: Figure 31 As shown;

[0203] Methanesulfonate crystal form B, with one acid, has an X-ray powder diffraction pattern showing a diffraction peak at 2θ of 7.7 ± 0.2°; or at 18.9 ± 0.2°; or at 13.9 ± 0.2°; or at 24.9 ± 0.2°; at 17.5 ± 0.2°; at 22.7 ± 0.2°; at 9.9 ± 0.2°; at 15.9 ± 0.2°; at 24.1 ± 0.2°; at 20.3 ± 0.2°; preferably including any 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks, more preferably including any 6, 7, or 8 of them;

[0204] The X-ray powder diffraction pattern of the methanesulfonate crystal form B contains at least one or more diffraction peaks located at 2θ of 7.7±0.2°, 18.9±0.2°, or 13.9±0.2°, preferably two, more preferably three; optionally, it may further contain at least one of 24.9±0.2°, 17.5±0.2°, 22.7±0.2°, 9.9±0.2°, or 15.9±0.2°, preferably two, three, four, or five; for example, the X-ray powder diffraction pattern of the methanesulfonate crystal form B has diffraction peaks at the following positions at 2θ (±0.2°):

[0205] Diffraction peaks are present at 7.7, 18.9, 13.9, 24.9, 17.5, and 22.7; diffraction peaks are present at 7.7, 18.9, 13.9, 24.9, 17.5, and 9.9; diffraction peaks are present at 7.7, 18.9, 13.9, 24.9, 17.5, and 9.9; diffraction peaks are present at 7.7, 18.9, 24.9, 17.5, and 15.9; diffraction peaks are present at 7.7, 18.9, 24.9, 17.5, 22.7, and 22.7; diffraction peaks are present at 7.7, 18.9, 24.9, 17.5, 22.7, and 9.9; diffraction peaks are present at 7.7, 18.9, 24.9 ... Diffraction peaks are present at 17.5, 22.7, and 15.9; diffraction peaks are present at 7.7, 13.9, 24.9, 17.5, 22.7, and 22.7; diffraction peaks are present at 7.7, 13.9, 24.9, 17.5, 22.7, and 9.9; diffraction peaks are present at 7.7, 13.9, 24.9, 17.5, 22.7, and 9.9.

[0206] The X-ray powder diffraction pattern of the methanesulfonate crystal form B optionally includes one or more diffraction peaks located at 2θ of 20.0 ± 0.2°, 14.3 ± 0.2°, 7.1 ± 0.2°, 16.3 ± 0.2°, 23.6 ± 0.2°, 25.7 ± 0.2°, 26.0 ± 0.2°, or 27.0 ± 0.2°; preferably, it includes at least 2 to 3, 4 to 5, or 6 to 7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks; for example, the X-ray powder diffraction pattern of the methanesulfonate crystal form B has diffraction peaks at the following positions at 2θ (±0.2°):

[0207] Diffraction peaks are observed at 7.7, 18.9, 13.9, 24.9, 17.5, 22.7, 20.0, and 14.3; 7.7, 18.9, 13.9, 24.9, 17.5, 22.7, 20.0, and 14.3; 7.7, 18.9, 13.9, 24.9, 17.5, 9.9, 20.0, and 14.3; 7.7, 18.9, 13.9, 24.9, 17.5, 15.9, 20.0, and 14.3; 7.7, 18.9, 24.9, 17.5, 22.7, 22.7, 20.0, and 14.3. Diffraction peaks are observed at 7.7, 18.9, 24.9, 17.5, 22.7, 9.9, 20.0, and 14.3; diffraction peaks are observed at 7.7, 18.9, 24.9, 17.5, 22.7, 15.9, 20.0, and 14.3; diffraction peaks are observed at 7.7, 13.9, 24.9, 17.5, 22.7, 22.7, 20.0, and 14.3; diffraction peaks are observed at 7.7, 13.9, 24.9, 17.5, 22.7, 9.9, 20.0, and 14.3; diffraction peaks are observed at 7.7, 13.9, 24.9, 17.5, 22.7, 9.9, 20.0, and 14.3.

[0208] The X-ray powder diffraction pattern of the methanesulfonate crystal form B includes one or more diffraction peaks located at 2θ of 7.7±0.2°, 18.9±0.2°, 13.9±0.2°, 24.9±0.2°, 17.5±0.2°, 22.7±0.2°, 9.9±0.2°, 15.9±0.2°, 24.1±0.2°, 20.3±0.2°, 20.0±0.2°, 14.3±0.2°, 7.1±0.2°, 16.3±0.2°, or 23.6±0.2°.

[0209] Preferably, diffraction peaks are found at any of 4, 5, 6, 8, or 10 locations; for example, the X-ray powder diffraction pattern of the methanesulfonate crystal form B has diffraction peaks at the following positions at 2θ (±0.2°):

[0210] Diffraction peaks are observed at 7.7, 18.9, 13.9, and 24.9; diffraction peaks are also observed at 7.7, 18.9, 13.9, and 17.5.

[0211] Diffraction peaks are present at 7.7, 18.9, 13.9, and 22.7; diffraction peaks are present at 7.7, 18.9, 13.9, and 9.9.

[0212] Diffraction peaks are observed at 7.7, 18.9, 24.9, and 17.5; diffraction peaks are also observed at 7.7, 18.9, 24.9, and 22.7.

[0213] Diffraction peaks are observed at 7.7, 18.9, 24.9, and 9.9; diffraction peaks are observed at 7.7, 13.9, 24.9, and 17.5.

[0214] Diffraction peaks are observed at 7.7, 13.9, 24.9, and 22.7; diffraction peaks are observed at 7.7, 13.9, 24.9, and 9.9.

[0215] Diffraction peaks are observed at 7.7, 18.9, 13.9, 24.9, 17.5, 22.7, 24.1, and 20.3; 9.9, 24.1, and 20.3; and 7.7, 18.9, 13.9, 24.9, 17.5, 15.9, 24.1, and 20.3. Diffraction peaks are observed at the following locations: 7.7, 18.9, 24.9, 17.5, 22.7, 24.1, and 20.3; 7.7, 18.9, 24.9, 17.5, 22.7, 9.9, 24.1, and 20.3; 7.7, 18.9, 24.9, 17.5, 22.7, 15.9, 24.1, and 20.3; 7.7, 13.9, 24.9, 17.5, 22.7, and 22.7. Diffraction peaks are present at 24.1 and 20.3; diffraction peaks are present at 7.7, 13.9, 24.9, 17.5, 22.7, 9.9, 24.1, and 20.3; diffraction peaks are present at 7.7, 13.9, 24.9, 17.5, 22.7, 9.9, 24.1, and 20.3; diffraction peaks are present at 7.7, 18.9, 13.9, 24.9, 17.5, 22.7, 24.1, 20.3±0.2, 20.0, and 14.3°; diffraction peaks are present at 7.7, 18.9, 13.9, 24.9, 17.5, 22.7, 24.1, 20.3±0.2, 20.0, and 14.3°; diffraction peaks are present at 7.7, 18.9, 13.9, 24.9, 17.5, and 20.3±0.2, 20.0, and 14.3°. Diffraction peaks are present at positions 9.9, 24.1, 20.3, 20.0, and 14.3; diffraction peaks are present at positions 7.7, 18.9, 13.9, 24.9, 17.5, 15.9, 24.1, 20.3, 20.0, and 14.3; diffraction peaks are present at positions 7.7, 18.9, 24.9, 17.5, 22.7, 24.1, 20.3, 20.0, and 14.3; diffraction peaks are present at positions 7.7, 18.9, 24.9, 17.5, 22.7, 9.9, 24.1, 20.3, 20.0, and 14.3; diffraction peaks are present at positions 7.7, 18.9, 24.9, 17.5, 22.7, 15.9, 24.1, 20.3, and 20.0. A diffraction peak is observed at 14.3; diffraction peaks are observed at 7.7, 13.9, 24.9, 17.5, 22.7, 22.7, 24.1, 20.3, 20.0, and 14.3; diffraction peaks are observed at 7.7, 13.9, 24.9, 17.5, 22.7, 9.9, 24.1, 20.3, 20.0, and 14.3; diffraction peaks are observed at 7.7, 13.9, 24.9, 17.5, 22.7, 9.9, 24.1, 20.3, 20.0, and 14.Three diffraction peaks are observed.

[0216] The characteristic X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d using Cu-Kα radiation are shown in Table 14.

[0217] Table 14

[0218]

[0219]

[0220] More preferably, its XRPD spectrum is basically as shown in the attached figure. Figure 32 As shown, its DSC spectrum is basically as follows: Figure 33 As shown;

[0221] The methanesulfonate crystal form is C, with one acid atom. Its X-ray powder diffraction pattern has a diffraction peak at 2θ of 23.7 ± 0.2°; or at 23.1 ± 0.2°; or at 25.2 ± 0.2°; or at 20.6 ± 0.2°; at 7.2 ± 0.2°; at 15.1 ± 0.2°; at 17.3 ± 0.2°; at 14.8 ± 0.2°; at 15.8 ± 0.2°; at 21.4 ± 0.2°; preferably including any 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks, more preferably including any 6, 7, or 8 of them.

[0222] The X-ray powder diffraction pattern of the methanesulfonate crystal form C contains at least one or more diffraction peaks located at 2θ of 23.7±0.2°, 23.1±0.2°, or 7.2±0.2°, preferably two, more preferably three; optionally, it may further contain at least one of 25.2±0.2°, 20.6±0.2°, 15.1±0.2°, 17.3±0.2°, or 14.8±0.2°, preferably two, three, four, or five; for example, the X-ray powder diffraction pattern of the methanesulfonate crystal form C has diffraction peaks at the following positions at 2θ (±0.2°):

[0223] Diffraction peaks are present at positions 23.7, 23.1, 7.2, 25.2, 20.6, and 15.1; diffraction peaks are present at positions 23.7, 23.1, 7.2, 25.2, 20.6, and 17.3; diffraction peaks are present at positions 23.7, 23.1, 7.2, 25.2, 20.6, and 14.8; diffraction peaks are present at positions 23.7, 23.1, 7.2, 20.6, 15.1, and 17.3; diffraction peaks are present at positions 23.7, 23.1, 25.2, 20.6, 15.1, and 17.3; diffraction peaks are present at positions 23.7, 7.2, 23.1, 25.2, 20.6, 15.1, and 14.8; diffraction peaks are present at positions 23.7, 7.2, 23.1, 7.2, 20.6, 15.1, and 14.8; diffraction peaks are present at positions 23.7, 7.2, 23.1, 25 ... Diffraction peaks are observed at positions 25.2, 20.6, 15.1, and 17.3; diffraction peaks are observed at positions 23.7, 7.2, 25.2, 20.6, 15.1, and 14.8; diffraction peaks are observed at positions 23.1, 7.2, 25.2, 20.6, 15.1, and 17.3; diffraction peaks are observed at positions 23.1, 7.2, 25.2, 20.6, 15.1, and 14.8.

[0224] The X-ray powder diffraction pattern of the methanesulfonate crystal form C optionally includes one or more diffraction peaks located at 2θ of 20.9, 18.2, 20.3, 25.5, 26.3, 28.5, 24.2, or 13.7; preferably, it includes at least 2 to 3, 4 to 5, or 6 to 7 peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks; for example:

[0225] Diffraction peaks are observed at positions 23.7, 23.1, 7.2, 25.2, 20.6, 15.1, 20.9, and 18.2; diffraction peaks are observed at positions 23.7, 23.1, 7.2, 25.2, 20.6, 17.3, 20.9, and 18.2; diffraction peaks are observed at positions 23.7, 23.1, 7.2, 25.2, 20.6, 14.8, 20.9, and 18.2; diffraction peaks are observed at positions 23.7, 23.1, 7.2, 25.2, 20.6, 15.1, 17.3, 20.9, and 18.2; diffraction peaks are observed at positions 23.7, 23.1, 25.2, 20.6, 15.1, 17.3, 20.9, and 18.2. Diffraction peaks are observed at positions 23.7, 23.1, 25.2, 20.6, 15.1, 14.8, 20.9, and 18.2; diffraction peaks are observed at positions 23.7, 7.2, 25.2, 20.6, 15.1, 17.3, 20.9, and 18.2; diffraction peaks are observed at positions 23.7, 7.2, 25.2, 20.6, 15.1, 14.8, 20.9, and 18.2; diffraction peaks are observed at positions 23.1, 7.2, 25.2, 20.6, 15.1, 14.8, 20.9, and 18.2.

[0226] The X-ray powder diffraction pattern of the methanesulfonate crystal form C includes one or more diffraction peaks located at 2θ of 23.7±0.2°, 23.1±0.2°, 7.2±0.2°, 25.2±0.2°, 20.6±0.2°, 15.1±0.2°, 17.3±0.2°, 14.8±0.2°, 15.8±0.2°, 21.4±0.2°, 20.9±0.2°, 18.2±0.2°, 20.3±0.2°, 25.5±0.2°, or 26.3±0.2°.

[0227] Preferably, diffraction peaks are found at any of 4, 5, 6, 8, or 10 locations; for example, the X-ray powder diffraction pattern of the methanesulfonate crystal form C has diffraction peaks at the following positions at 2θ (±0.2°):

[0228] Diffraction peaks are present at positions 23.7, 23.1, 7.2, and 25.2; diffraction peaks are present at positions 23.7, 23.1, 7.2, and 20.6; diffraction peaks are present at positions 23.7, 23.1, 7.2, and 15.1; diffraction peaks are present at positions 23.7, 23.1, 7.2, and 17.3; diffraction peaks are present at positions 23.7, 7.2, 25.2, and 20.6; diffraction peaks are present at positions 23.7, 7.2, and 17.3; diffraction peaks are present at positions 23.7, 7.2, and 25.2; diffraction peaks are present at positions 23.7, 7.2, and 25.2; diffraction peaks are present at positions 23.7, 23.1, 7.2, and 17.3; diffraction peaks are present at positions 23.7, 7.2, and 25.2; diffraction peaks are present at positions 23.7, 23.1, 7.2, and 20.6; diffraction peaks are present at positions 23.7, 23.1, 7.2, and 15.1; diffraction peaks are present at positions 23.7, 23.1, 7.2, and 17.3; diffraction peaks are present at positions 23.7, 7.2, and 25.2; diffraction peaks are present at positions 23.7, 7.2, and 25.2; diffraction peaks are present at positions 23.7, 23.1, 7.2, and 20.6; diffr Diffraction peaks are present at positions 25.2 and 15.1; at positions 23.7, 7.2, 25.2, and 17.3; at positions 23.7, 23.1, 7.2, 25.2, 20.9, and 18.2; at positions 23.7, 23.1, 7.2, 20.6, 20.9, and 18.2; at positions 23.7, 23.1, 7.2, 15.1, 20.9, and 18.2; at positions 23.7, 23.1, 7.2, 17.3, 20.9, and 18.2; at positions 23.7, 23.1, 25.2, 20.6, 20.9, and 18.2. Diffraction peaks are observed at positions 23.7, 23.1, 25.2, 15.1, 20.9, and 18.2; diffraction peaks are observed at positions 23.7, 23.1, 25.2, 17.3, 20.9, and 18.2; diffraction peaks are observed at positions 23.7, 7.2, 25.2, 20.6, 20.9, and 18.2; diffraction peaks are observed at positions 23.7, 7.2, 25.2, 15.1, 20.9, and 18.2; diffraction peaks are observed at positions 23.7, 7.2, 25.2, 17.3, 20.9, and 18.2; diffraction peaks are observed at positions 23.7, 23.1 ...15.1, 15.8, and 21.4; diffraction peaks are observed at positions 23.7, 7.2, 25.2, 15.1, 20.9, and 18.2; diffraction peaks are observed at positions 23.7, 7.2, 25.2, 17. Diffraction peaks are observed at positions 23.1, 7.2, 25.2, 20.6, 17.3, 15.8, and 21.4; diffraction peaks are observed at positions 23.7, 23.1, 7.2, 25.2, 20.6, 14.8, 15.8, and 21.4; diffraction peaks are observed at positions 23.7, 23.1, 7.2, 25.2, 20.6, 15.1, 17.3, 15.8, and 21.4; diffraction peaks are observed at positions 23.7, 7.2, 23.1, 7.2, 25.2, 20.6, 15.1, 17.3, 15.8, and 21.4; diffraction peaks are observed at positions 23.7, 7.2, 23.1, 7.2, 25.2, 20.6, 15.1, 14.8 ...0.6, 15.1, 17.3, 15.8, and 21. Diffraction peaks are observed at 25.2, 20.6, 15.1, 17.3, 15.8, and 21.4; diffraction peaks are observed at 23.7, 7.2, 25.2, 20.6, 15.1, 14.8, 15.8, and 21.4; diffraction peaks are observed at 23.1, 7.2, 25.2, and 20.Diffraction peaks are observed at positions 6, 15.1, 17.3, 15.8, and 21.4; at positions 23.1, 7.2, 25.2, 20.6, 15.1, 14.8, 15.8, and 21.4; at positions 23.7, 23.1, 7.2, 25.2, 20.6, 15.1, 15.8, 21.4, 20.9, and 18.2; at positions 23.7, 23.1, 7.2, 25.2, 20.6, 17.3, 15.8, 21.4, 20.9, and 18.2; at positions 23.7, 23.1, 23.1, 23.2, 25.2, 20.6, 17.3, 15.8, 21.4, 20.9, and 18.2; at positions 23.7, 23.1, 23.2, 23.1, 23.2, 23.3, 23.4, 23.5, 23.6, 23.7 ... Diffraction peaks are observed at positions 7.2, 25.2, 20.6, 14.8, 15.8, 21.4, 20.9, and 18.2; diffraction peaks are observed at positions 23.7, 23.1, 7.2, 20.6, 15.1, 17.3, 15.8, 21.4, 20.9, and 18.2; diffraction peaks are observed at positions 23.7, 23.1, 25.2, 20.6, 15.1, 17.3, 15.8, 21.4, 20.9, and 18.2; diffraction peaks are observed at positions 23.7, 7.2, 25.2, 20.6, 15.1, 14.8, 15.8, 21.4, 20.9, and 18.2; diffraction peaks are observed at positions 23.7, 7.2, 25.2, 20.6, 15.1, and 17.3. Diffraction peaks are observed at 15.8, 21.4, 20.9, and 18.2; 23.7, 7.2, 25.2, 20.6, 15.1, 14.8, 15.8, 21.4, 20.9, and 18.2; 23.1, 7.2, 25.2, 20.6, 15.1, 17.3, 15.8, 21.4, 20.9, and 18.2; 23.1, 7.2, 25.2, 20.6, 15.1, 14.8, 15.8, 21.4, 20.9, and 18.2.

[0229] The characteristic X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d using Cu-Kα radiation are shown in Table 15.

[0230] Table 15

[0231]

[0232]

[0233] More preferably, its XRPD spectrum is basically as shown in the attached figure. Figure 34 As shown, its DSC spectrum is basically as shown in Figure 35;

[0234] The methanesulfonate crystal form D, with one acid, has an X-ray powder diffraction pattern showing a diffraction peak at 2θ of 20.3 ± 0.2°; or at 7.6 ± 0.2°; or at 17.7 ± 0.2°; or at 18.0 ± 0.2°; at 24.9 ± 0.2°; at 18.8 ± 0.2°; at 21.5 ± 0.2°; at 9.6 ± 0.2°; at 24.4 ± 0.2°; at 29.2 ± 0.2°; preferably including any 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks; more preferably including any 6, 7, or 8 of the above diffraction peaks.

[0235] The X-ray powder diffraction pattern of the methanesulfonate crystal form D contains at least one or more diffraction peaks located at 2θ of 20.3±0.2°, 7.6±0.2°, or 17.7±0.2°, preferably two, more preferably three; optionally, it may further contain at least one of 18.0±0.2°, 24.9±0.2°, 18.8±0.2°, 21.5±0.2°, or 9.6±0.2°, preferably two, three, four, or five; for example, the X-ray powder diffraction pattern of the methanesulfonate crystal form D has diffraction peaks at 2θ (±0.2°) positions as follows:

[0236] Diffraction peaks are observed at 20.3, 7.6, 17.7, 18.0, 24.9, and 18.8; 20.3, 7.6, 17.7, 18.0, 24.9, and 21.5; 20.3, 7.6, 17.7, 18.0, 24.9, and 9.6; 20.3, 7.6, 17.7, 18.0, 18.8, and 21.5; 20.3, 7.6, 18.0, 24.8, and 21.5; 20.3, 7.6, 18.0, 24.9, 18.8, and 9.6; 20.3, 17.7, 18.0, 24.9, 18.8, and 9.6; Diffraction peaks are observed at 18.0, 24.9, 18.8, and 21.5; at 20.3, 17.7, 18.0, 24.9, 18.8, and 9.6; at 7.6, 17.7, 18.0, 24.9, 18.8, and 21.5; at 7.6, 17.7, 18.0, 24.9, 18.8, and 9.6.

[0237] The X-ray powder diffraction pattern of the methanesulfonate crystal form D optionally includes one or more diffraction peaks located at 2θ of 34.0 ± 0.2°, 27.0 ± 0.2°, 23.2 ± 0.2°, 6.6 ± 0.2°, 15.1 ± 0.2°, 16.3 ± 0.2°, 22.4 ± 0.2°, or 12.6 ± 0.2°; preferably, it includes at least 2 to 3, 4 to 5, or 6 to 7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks; for example, the X-ray powder diffraction pattern of the methanesulfonate crystal form D has diffraction peaks at the following positions at 2θ (±0.2°):

[0238] Diffraction peaks are observed at 20.3, 7.6, 17.7, 18.0, 24.9, 18.8, 34.0, and 27.0; 20.3, 7.6, 17.7, 18.0, 24.9, 21.5, 34.0, and 27.0; 20.3, 7.6, 17.7, 18.0, 24.9, 9.6, 34.0, and 27.0; 20.3, 7.6, 17.7, 18.0, 18.8, 21.5, 34.0, and 27.0; 20.3, 7.6, 18.0, 24.9, 18.8, 21.5, 34.0, and 27.0. Diffraction peaks are observed at 20.3, 7.6, 18.0, 24.9, 18.8, 9.6, 34.0, and 27.0; diffraction peaks are observed at 20.3, 17.7, 18.0, 24.9, 18.8, 21.5, 34.0, and 27.0; diffraction peaks are observed at 7.6, 17.7, 18.0, 24.9, 18.8, 21.5, 34.0, and 27.0; diffraction peaks are observed at 7.6, 17.7, 18.0, 24.9, 18.8, 9.6, 34.0, and 27.0.

[0239] The X-ray powder diffraction pattern of the methanesulfonate crystal form D includes one or more diffraction peaks located at 2θ of 20.3±0.2°, 7.6±0.2°, 17.7±0.2°, 18.0±0.2°, 24.9±0.2°, 18.8±0.2°, 21.5±0.2°, 9.6±0.2°, 34.0±0.2°, 27.0±0.2°, 23.2±0.2°, 6.6±0.2°, or 15.1±0.2°.

[0240] Preferably, diffraction peaks are found at any of 4, 5, 6, 8, or 10 locations; for example, the X-ray powder diffraction pattern of the methanesulfonate crystal form D has diffraction peaks at the following positions at 2θ (±0.2°):

[0241] Diffraction peaks are present at positions 20.3, 7.6, 17.7, and 18.0; diffraction peaks are present at positions 20.3, 7.6, 17.7, and 24.9; diffraction peaks are present at positions 20.3, 7.6, 17.7, and 18.8; diffraction peaks are present at positions 20.3, 7.6, 17.7, and 21.5; diffraction peaks are present at positions 20.3, 7.6, 18.0, and 24.9; diffraction peaks are present at positions 20.3, 7.6, 18.0, and 18.8; diffraction peaks are present at positions 20.3, 17.7, 18.0, and 24.9; diffraction peaks are present at positions 20.3, 17.7, 18.0, and 24.9; diffraction peaks are present at positions 20.3, 17.7, 18.0, and 18.8; diffraction peaks are present at positions 7.6, 17.7, and 18.0. A diffraction peak is observed at 24.9; diffraction peaks are observed at 7.6, 17.7, 18.0, and 18.8; diffraction peaks are observed at 20.3, 7.6, 17.7, 18.0, 34.0, and 27.0; diffraction peaks are observed at 20.3, 7.6, 17.7, 24.9, 34.0, and 27.0; diffraction peaks are observed at 20.3, 7.6, 17.7, 18.8 ...0, 34.0, and 27.0; diffraction peaks are observed at 20.3, 7.6, 17.7, 18.0, 34.0, and 27.0; diffraction peaks are observed at 20.3, 7.6, 17.7, 18.0, 34.0, and 27.0; diffraction peaks are observed at 20.3, 7.6, 17.7, 18.8, 34.0, and 27.0. Diffraction peaks are observed at 18.0, 18.8, 34.0, and 27.0; at 20.3, 17.7, 18.0, 24.9, 34.0, and 27.0; at 20.3, 17.7, 18.0, 18.8, 34.0, and 27.0; at 7.6, 17.7, 18.0, 24.9, 34.0, and 27.0; at 7.6, 17.7, 18.0, 18.8, 34.0, and 27.0; at 20.3, 7.6, 17.7, 18.0, 24.9, 18.8, 34.0, and 27.0; at 20.3, 7.6, 17.7, 18.0, 24.9, 18.8, 34.0, and 27.0; at 20.3, 7.6, 17.7, 18.0, 24.9, 18.8, 34.0, and 27.0; at 20.3, 7.6, 17.7, 18.0, 24.9, 18.8, 34.0, and 27.0. Diffraction peaks are observed at 17.7, 18.0, 24.9, 21.5, 34.0, and 27.0; 20.3, 7.6, 17.7, 18.0, 24.9, 9.6, 34.0, and 27.0; 20.3, 7.6, 17.7, 18.0, 18.8, 21.5, 34.0, and 27.0; 20.3, 7.6, 18.0, 24.9, 18.8, 21.5, 34.0, and 27.0; 20.3, 17.7, 18.0, 24.9, 18.8, 9.6, 34.0, and 27.0; 20.3, 17.7, 18.0, 24.9, 18.8, 9.6, 34.0, and 27.0. Diffraction peaks are observed at 24.9, 18.8, 21.5, 34.0, and 27.0; diffraction peaks are observed at 20.3, 17.7, 18.0, 24.9, 18.8, 9.6, 34.0, and 27.0; diffraction peaks are observed at 7.6, 17.7, 18.0, 24.9, and 18.Diffraction peaks are observed at 8, 21.5, 34.0, and 27.0.

[0242] Diffraction peaks are observed at 7.6, 17.7, 18.0, 24.9, 18.8, 9.6, 34.0, and 27.0; diffraction peaks are observed at 20.3, 7.6, 17.7, 18.0, 24.9, 18.8, 34.0, 27.0, 34.0, and 27.0; diffraction peaks are observed at 20.3, 7.6, 17.7, 18.0, 24.9, 9.6, 34.0, 27.0, 34.0, and 27.0; diffraction peaks are observed at 20.3, 7.6, 17.7, 18.0, 24.9, 9.6, 34.0, 27.0, 34.0, and 27.0; diffraction peaks are observed at 20.3, 7.6, 17.7, 18.0, 18.8, and 27.0. Diffraction peaks are observed at 21.5, 34.0, 27.0, 34.0, and 27.0; 20.3, 7.6, 18.0, 24.9, 18.8, 21.5, 34.0, 27.0, 34.0, and 27.0; 20.3, 7.6, 18.0, 24.9, 18.8, 9.6, 34.0, 27.0, 34.0, and 27.0; 20.3, 17.7, 18.0, 24.9, 18.8, 9.6, 34.0, 27.0, and 34.0. A diffraction peak is observed at 27.0; diffraction peaks are observed at 7.6, 17.7, 18.0, 24.9, 18.8, 21.5, 34.0, 27.0, 34.0, and 27.0; diffraction peaks are observed at 7.6, 17.7, 18.0, 24.9, 18.8, 9.6, 34.0, 27.0, 34.0, and 27.0.

[0243] The characteristic X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d using Cu-Kα radiation are shown in Table 16.

[0244] Table 16

[0245]

[0246]

[0247] More preferably, its XRPD spectrum is basically as shown in the attached figure. Figure 36 As shown, its DSC spectrum is basically as shown in Figure 37;

[0248] The methanesulfonate crystal form E, with one acid, has an X-ray powder diffraction pattern showing a diffraction peak at 2θ of 7.8 ± 0.2°; or at 18.9 ± 0.2°; or at 13.9 ± 0.2°; or at 14.3 ± 0.2°; at 22.7 ± 0.2°; at 7.1 ± 0.2°; at 24.1 ± 0.2°; at 25.8 ± 0.2°; at 17.6 ± 0.2°; at 24.9 ± 0.2°; preferably including any 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks; more preferably including any 6, 7, or 8 of the above diffraction peaks.

[0249] The X-ray powder diffraction pattern of the methanesulfonate crystal form E contains at least one or more diffraction peaks located at 2θ of 7.8±0.2°, 18.9±0.2°, or 13.9±0.2°, preferably two, more preferably three; optionally, it may further contain at least one of 14.3±0.2°, 22.7±0.2°, 7.1±0.2°, 24.1±0.2°, or 25.8±0.2°, preferably two, three, four, or five; for example, the X-ray powder diffraction pattern of the methanesulfonate crystal form E has diffraction peaks at the following positions at 2θ (±0.2°):

[0250] Diffraction peaks are present at positions 7.8, 18.9, 13.9, 14.3, 22.7, and 7.1; diffraction peaks are present at positions 7.8, 18.9, 13.9, 14.3, 22.7, and 24.1; diffraction peaks are present at positions 7.8, 18.9, 13.9, 14.3, 22.7, and 25.8; diffraction peaks are present at positions 7.8, 18.9, 14.3, 22.7, 7.1, and 24.1; diffraction peaks are present at positions 7.8, 18.9, 14.3, 22.7, 7.1, and 25.8; diffraction peaks are present at positions 7.8, 13.9, 14.3, 22.7, 7.1, and 24.1; diffraction peaks are present at positions 7.8, 13.9, 14.3, 22.7, and 24.1; diffraction peaks are present at positions 7.8, 13.9, 14.3, and 22.7. Diffraction peaks are present at 22.7, 7.1, and 25.8; diffraction peaks are present at 18.9, 13.9, 14.3, 22.7, 7.1, and 24.1; diffraction peaks are present at 18.9, 13.9, 14.3, 22.7, 7.1, and 25.8.

[0251] The X-ray powder diffraction pattern of the methanesulfonate crystal form E optionally includes one or more diffraction peaks located at 2θ of 22.5 ± 0.2°, 20.3 ± 0.2°, 21.6 ± 0.2°, 9.9 ± 0.2°, 15.9 ± 0.2°, 10.7 ± 0.2°, 12.8 ± 0.2°, or 20.0 ± 0.2°; preferably, it includes at least 2 to 3, 4 to 5, or 6 to 7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks; for example, the X-ray powder diffraction pattern of the methanesulfonate crystal form E has diffraction peaks at the following positions at 2θ (±0.2°):

[0252] Diffraction peaks are observed at positions 7.8, 18.9, 13.9, 14.3, 22.7, 7.1, 22.5, and 20.3; diffraction peaks are observed at positions 7.8, 18.9, 13.9, 14.3, 22.7, 24.1, 22.5, and 20.3; diffraction peaks are observed at positions 7.8, 18.9, 13.9, 14.3, 22.7, 25.8, 22.5, and 20.3; diffraction peaks are observed at positions 7.1, 24.1, 22.5, and 20.3; diffraction peaks are observed at positions 7.8, 18.9, 14.3, 22.7, 7.1, 25.8, 22.5, and 20.3. Diffraction peaks are observed at 7.8, 13.9, 14.3, 22.7, 7.1, 24.1, 22.5, and 20.3; diffraction peaks are observed at 7.8, 13.9, 14.3, 22.7, 7.1, 25.8, 22.5, and 20.3; diffraction peaks are observed at 18.9, 13.9, 14.3, 22.7, 7.1, 25.8, 22.5, and 20.3; diffraction peaks are observed at 18.9, 13.9, 14.3, 22.7, 7.1, 25.8, 22.5, and 20.3.

[0253] The X-ray powder diffraction pattern of the methanesulfonate crystal form E includes one or more diffraction peaks located at 2θ of 7.8±0.2°, 18.9±0.2°, 13.9±0.2°, 14.3±0.2°, 22.7±0.2°, 7.1±0.2°, 24.1±0.2°, 25.8±0.2°, 17.6±0.2°, 24.9±0.2°, 22.5±0.2°, 20.3±0.2°, 21.6±0.2°, 9.9±0.2°, or 15.9±0.2°.

[0254] Preferably, diffraction peaks are found at any of 4, 5, 6, 8, or 10 locations; for example, the X-ray powder diffraction pattern of the methanesulfonate crystal form E has diffraction peaks at the following positions at 2θ (±0.2°):

[0255] Diffraction peaks are present at positions 7.8, 18.9, 13.9, and 14.3; diffraction peaks are present at positions 7.8, 18.9, 13.9, and 22.7; diffraction peaks are present at positions 7.8, 18.9, 13.9, and 7.1; diffraction peaks are present at positions 7.8, 18.9, 13.9, and 24.1; diffraction peaks are present at positions 7.8, 18.9, 14.3, and 22.7; diffraction peaks are present at positions 7.8, 18.9, 14.3, and 7.1; diffraction peaks are present at positions 7.8, 18.9, 14.3, and 24.1; diffraction peaks are present at positions 7.8, 13.9, 14.3, and 22.7; diffraction peaks are present at positions 7.8, 13.9, and 14.3. A diffraction peak is present at position 7.1; diffraction peaks are present at positions 7.8, 13.9, 14.3, and 24.1; diffraction peaks are present at positions 7.8, 18.9, 13.9, 14.3, 2.5, and 20.3; diffraction peaks are present at positions 7.8, 18.9, 13.9, 22.7, 2.5, and 20.3; diffraction peaks are present at positions 7.1, 13.9, 14.3, 24.1, 2.5, and 20.3; diffraction peaks are present at positions 7.8, 18.9, 13.9, 24.1, 2.5, and 20.3; diffraction peaks are present at positions 7.8, 18.9, 14.3, 22.7 .... Diffraction peaks are present at positions 7.1, 2.5, and 20.3; diffraction peaks are present at positions 7.8, 18.9, 14.3, 24.1, 2.5, and 20.3; diffraction peaks are present at positions 7.8, 13.9, 14.3, 22.7, 2.5, and 20.3; diffraction peaks are present at positions 7.1, 2.5, and 20.3; diffraction peaks are present at positions 7.1, 2.5, and 20.3; diffraction peaks are present at positions 7.8, 13.9, 14.3, 24 ... and 25.8; diffraction peaks are present at positions 7.1, 18.9, 13.9, 14.3, 22.7, and 24.1; diffraction peaks are present at positions 7.1, 18.9, 13.9, 14.3, 22.7, and 24.1; diffraction peaks are present at positions 7.8, 13. Diffraction peaks are present at positions 24.1 and 25.8; diffraction peaks are present at positions 7.8, 18.9, 13.9, 14.3, 22.7, 7.1, 24.1, and 25.8; diffraction peaks are present at positions 7.8, 18.9, 14.3, 22.7, 7.1, 24.1, 24.1, and 25.8; diffraction peaks are present at positions 7.8, 18.9, 14.3, 22.7, 7.1, 25.8, 24.1, and 25.8; diffraction peaks are present at positions 7.8, 13.9, 14.3, 22.7, 7.1, 24.1, 24.1, and 25.8; diffraction peaks are present at positions 7.8, 13.9, 14.3, 22.7, 7.1, 25.8, and 24.1. A diffraction peak is present at 25.8; diffraction peaks are present at 18.9, 13.9, 14.3, 22.7, 7.1, 24.1, 24.1, and 25.8; diffraction peaks are present at 18.9, 13.9, 14.3, 22.7, 7.1, 25.8, 24.1, and 25.8; 7.Diffraction peaks are observed at positions 8, 18.9, 13.9, 14.3, 22.7, 7.1, 24.1, 25.8, 22.5, and 20.3; diffraction peaks are observed at positions 7.8, 18.9, 13.9, 14.3, 22.7, 24.1, 24.1, 25.8, 22.5, and 20.3; diffraction peaks are observed at positions 7.8, 18.9, 13.9, 14.3, 22.7, 25.8, 24.1, 25.8, 22.5, and 20.3; diffraction peaks are observed at positions 7.8, 18.9, 14.3, 22.7, 7.1, 24.1, 24.1, 25.8, 22.5, and 20.3; diffraction peaks are observed at positions 7.8, 18.9, 14.3, 22.7, 7.1, 25.8, and 20.3; diffraction peaks are observed at positions 7.8, 18.9, 14.3, 22.7, 7.1, 25.8, and 20.3. Diffraction peaks are present at positions 24.1, 25.8, 22.5, and 20.3; 7.8, 13.9, 14.3, 22.7, 7.1, 24.1, 24.1, 25.8, 22.5, and 20.3; 18.9, 13.9, 14.3, 22.7, 7.1, 24.1, 24.1, 25.8, 22.5, and 20.3; 18.9, 13.9, 14.3, 22.7, 7.1, 25.8, 24.1, 25.8, 22.5, and 20.3.

[0256] The characteristic X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d using Cu-Kα radiation are shown in Table 17.

[0257] Table 17

[0258]

[0259]

[0260]

[0261] More preferably, its XRPD spectrum is basically as shown in the attached figure. Figure 38 As shown;

[0262] The methanesulfonate crystal form F, with one acid, has an X-ray powder diffraction pattern showing a diffraction peak at 2θ of 6.8 ± 0.2°; or at 13.8 ± 0.2°; or at 22.7 ± 0.2°; or at 20.8 ± 0.2°; at 21.3 ± 0.2°; at 9.2 ± 0.2°; at 21.6 ± 0.2°; at 10.3 ± 0.2°; at 14.9 ± 0.2°; at 26.4 ± 0.2°; preferably including any 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks; more preferably including any 6, 7, or 8 of the above diffraction peaks.

[0263] The X-ray powder diffraction pattern of the methanesulfonate crystal form F contains at least one or more diffraction peaks located at 2θ of 6.8±0.2°, 13.8±0.2°, or 22.7±0.2°, preferably two, more preferably three; optionally, it may further contain at least one of 20.8±0.2°, 21.3±0.2°, 9.2±0.2°, 21.6±0.2°, or 10.3±0.2°, preferably two, three, four, or five; for example, the X-ray powder diffraction pattern of the methanesulfonate crystal form F has diffraction peaks at 2θ (±0.2°) positions as follows:

[0264] Diffraction peaks are observed at positions 6.8, 13.8, 22.7, 20.8, 21.3, and 9.2; diffraction peaks are observed at positions 6.8, 13.8, 22.7, 20.8, 21.3, and 21.6; diffraction peaks are observed at positions 6.8, 13.8, 22.7, 20.8, 21.3, and 10.3; diffraction peaks are observed at positions 6.8, 13.8, 22.7, 20.8, 9.2, and 21.6; diffraction peaks are observed at positions 6.8, 13.8, 20.8, 21.3, 9.2, and 10.3; diffraction peaks are observed at positions 6.8, 22.7 .... Diffraction peaks are present at 21.3, 9.2, and 21.6; diffraction peaks are present at 6.8, 22.7, 20.8, 21.3, 9.2, and 10.3; diffraction peaks are present at 13.8, 22.7, 20.8, 21.3, 9.2, and 21.6; diffraction peaks are present at 13.8, 22.7, 20.8, 21.3, 9.2, and 10.3.

[0265] The X-ray powder diffraction pattern of methanesulfonate crystal form F optionally includes one or more diffraction peaks located at 2θ of 16.1±0.2°, 19.8±0.2°, 25.9±0.2°, 14.6±0.2°, 23.5±0.2°, 25.0±0.2°, 29.5±0.2°, or 31.0±0.2°; preferably, it includes at least 2 to 3, 4 to 5, or 6 to 7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks; for example, the X-ray powder diffraction pattern of methanesulfonate crystal form F has diffraction peaks at the following positions at 2θ (±0.2°):

[0266] Diffraction peaks are observed at positions 6.8, 13.8, 22.7, 20.8, 21.3, 9.2, 16.1, and 19.8; diffraction peaks are observed at positions 6.8, 13.8, 22.7, 20.8, 21.3, 21.6, 16.1, and 19.8; diffraction peaks are observed at positions 6.8, 13.8, 22.7, 20.8, 21.3, 10.3, 16.1, and 19.8; diffraction peaks are observed at positions 6.8, 13.8, 22.7, 20.8, 21.3, 9.2, 21.6, 16.1, and 19.8; diffraction peaks are observed at positions 6.8, 13.8, 20.8, 21.3, 9.2, 21.6, 16.1, and 19.8. Diffraction peaks are observed at positions 6.8, 13.8, 20.8, 21.3, 9.2, 10.3, 16.1, and 19.8; diffraction peaks are observed at positions 6.8, 22.7, 20.8, 21.3, 9.2, 10.3, 16.1, and 19.8; diffraction peaks are observed at positions 13.8, 22.7, 20.8, 21.3, 9.2, 10.3, 16.1, and 19.8; diffraction peaks are observed at positions 13.8, 22.7, 20.8, 21.3, 9.2, 10.3, 16.1, and 19.8.

[0267] The X-ray powder diffraction pattern of the methanesulfonate crystal form F includes one or more diffraction peaks located at 2θ of 6.8±0.2°, 13.8±0.2°, 22.7±0.2°, 20.8±0.2°, 21.3±0.2°, 9.2±0.2°, 21.6±0.2°, 10.3±0.2°, 14.9±0.2°, 26.4±0.2°, 16.1±0.2°, 19.8±0.2°, 25.9±0.2°, 14.6±0.2°, or 23.5±0.2°.

[0268] Preferably, diffraction peaks are found at any of 4, 5, 6, 8, or 10 locations; for example, the X-ray powder diffraction pattern of the methanesulfonate crystal form F has diffraction peaks at the following positions at 2θ (±0.2°):

[0269] Diffraction peaks are present at positions 6.8, 13.8, 22.7, and 20.8; diffraction peaks are present at positions 6.8, 13.8, 22.7, and 21.3; diffraction peaks are present at positions 6.8, 13.8, 22.7, and 9.2; diffraction peaks are present at positions 6.8, 13.8, 20.8, and 21.3; diffraction peaks are present at positions 6.8, 13.8, 21.3, and 9.2; diffraction peaks are present at positions 6.8, 13.8, 20.8, and 9.2; diffraction peaks are present at positions 6.8, 22.7, 20.8, and 21.6; diffraction peaks are present at positions 6.8, 22.7, 20.8, and 9.2; diffraction peaks are present at positions 13.8, 22.7, and 20.8. A diffraction peak is observed at 21.3; diffraction peaks are observed at 13.8, 22.7, 20.8, and 9.2; diffraction peaks are observed at 6.8, 13.8, 22.7, 20.8, 14.9, and 26.4; diffraction peaks are observed at 6.8, 13.8, 22.7, 21.3, 14.9, and 26.4; diffraction peaks are observed at 6.8, 13.8, 20.8, 21.3, 14.9, and 26.4; diffraction peaks are observed at 6.8, 13.8, 20.8, 21.3, 9.2, 14.9, and 26.4; diffraction peaks are observed at 6.8, 13.8, 20.8, 21.3, 9.2, 14.9, and 26.4; diffraction peaks are observed at 6.8, 13.8, 20.8, 21.3, 9.2, 14.9, and 26.4; diffraction peaks are observed at 6.8, 13.8, 20.8, 21.3, 9.2, 14.9, and 26.4. Diffraction peaks are present at positions 9.2, 14.9, and 26.4; diffraction peaks are present at positions 6.8, 22.7, 20.8, 21.6, 14.9, and 26.4; diffraction peaks are present at positions 6.8, 22.7, 20.8, 9.2, 14.9, and 26.4; diffraction peaks are present at positions 13.8, 22.7, 20.8, 21.3, 14.9, and 26.4; diffraction peaks are present at positions 13.8, 22.7, 20.8, 9.2, 14.9, and 26.4; diffraction peaks are present at positions 6.8, 13.8, 22.7, 20.8, 21.3 ... Diffraction peaks are present at positions 21.3, 21.6, 14.9, and 26.4; diffraction peaks are present at positions 6.8, 13.8, 22.7, 20.8, 21.3, 10.3, 14.9, and 26.4; diffraction peaks are present at positions 6.8, 13.8, 22.7, 20.8, 9.2, 21.6, 14.9, and 26.4; diffraction peaks are present at positions 6.8, 13.8, 20.8, 21.3, 9.2, 21.6, 14.9, and 26.4; diffraction peaks are present at positions 6.8, 13.8, 20.8, 21.3, 9.2, 21.6, 14.9, and 26.4; diffraction peaks are present at positions 6.8, 13.8, 20.8, 21.3, 9.2, 21.6, 14.9, and 26.4. Diffraction peaks are observed at 20.8, 21.3, 9.2, 10.3, 14.9, and 26.4; 6.8, 22.7, 20.8, 21.3, 9.2, 10.3, 14.9, and 26.4; and 13.8, 22.7, 20.8, 21.3, 9.2, 21.6, 14.9, and 26.4.Diffraction peaks are observed at 4 locations; 13.8, 22.7, 20.8, 21.3, 9.2, 10.3, 14.9, and 26.4; 6.8, 13.8, 22.7, 20.8, 21.3, 9.2, 14.9, 26.4, 16.1, and 19.8; 6.8, 13.8, 22.7, 20.8, 21.3, 21.6, 14.9, 26.4, 16.1, and 19.8; 6.8, 13.8, 22.7, 20.8, 21.3, 10.3, 14.9, 26.4, 16.1, and 19.8; 6.8, 13.8, 22.7, 20.8, 9.2, and 21.6... Diffraction peaks are observed at 14.9, 26.4, 16.1, and 19.8; 6.8, 13.8, 20.8, 21.3, 9.2, 21.6, 14.9, 26.4, 16.1, and 19.8; 6.8, 22.7, 20.8, 21.3, 9.2, 10.3, 14.9, 26.4, 16.1, and 19.8; 6.8, 22.7, 20.8, 21.3, 9.2, 10.3, 14.9, 26.4, 16.1, and 19.8. Diffraction peaks are observed at the following locations: 13.8, 22.7, 20.8, 21.3, 9.2, 21.6, 14.9, 26.4, 16.1, and 19.8.

[0270] The characteristic X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d using Cu-Kα radiation are shown in Table 18.

[0271] Table 18

[0272]

[0273]

[0274] More preferably, its XRPD spectrum is basically as shown in the attached figure. Figure 39 As shown in Figure 40, its DSC spectrum is basically as shown in Figure 40.

[0275] Oxalate crystal form A, with one acid atom, has an X-ray powder diffraction pattern showing a diffraction peak at 2θ of 12.5 ± 0.2°; or at 7.1 ± 0.2°; or at 6.9 ± 0.2°; or at 23.5 ± 0.2°; or at 8.4 ± 0.2°; at 13.8 ± 0.2°; at 14.3 ± 0.2°; at 23.3 ± 0.2°; at 25.8 ± 0.2°; at 13.1 ± 0.2°; preferably including any 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks, more preferably including any 6, 7, or 8 of them;

[0276] The X-ray powder diffraction pattern of the oxalate crystal form A contains at least one or more diffraction peaks located at 2θ of 12.5±0.2°, 7.1±0.2°, or 6.9±0.2°, preferably two, more preferably three; optionally, it may further contain at least one of 23.5±0.2°, 8.4±0.2°, 13.8±0.2°, 14.3±0.2°, or 23.3±0.2°, preferably two, three, four, or five; for example, the X-ray powder diffraction pattern of the oxalate crystal form A has diffraction peaks at the following positions at 2θ (±0.2°):

[0277] Diffraction peaks are observed at positions 12.5, 7.1, 6.9, 23.5, 8.4, and 13.8; diffraction peaks are observed at positions 12.5, 7.1, 6.9, 23.5, 8.4, and 14.3; diffraction peaks are observed at positions 12.5, 7.1, 6.9, 23.5, 8.4, and 23.3; diffraction peaks are observed at positions 12.5, 7.1, 6.9, 23.5, 8.4, and 23.3; diffraction peaks are observed at positions 12.5, 6.9, 23.5, 8.4, and 14.3; diffraction peaks are observed at positions 12.5, 7.1, 6.9, 23.5, 8.4, and 13.3; diffraction peaks are observed at positions 12.5, 6.9, 23.5, 8.4, and 14 ...7.1, 6.9, 23.5, 8.4, and 13.3; diffraction peaks are observed at positions 12.5, 6.9, 23.5, 8.4, and 14.3; diffraction peaks are observed Diffraction peaks are present at positions 13.8 and 14.3; diffraction peaks are present at positions 12.5, 6.9, 23.5, 8.4, 13.8, and 23.3; diffraction peaks are present at positions 7.1, 6.9, 23.5, 8.4, 13.8, and 14.3; diffraction peaks are present at positions 7.1, 6.9, 23.5, 8.4, 13.8, and 23.3.

[0278] The X-ray powder diffraction pattern of oxalate crystal form A optionally includes one or more diffraction peaks located at 2θ of 10.7±0.2°, 16.3±0.2°, 27.5±0.2°, 26.9±0.2°, 24.9±0.2°, 17.4±0.2°, 19.2±0.2°, or 25.3±0.2°; preferably, it includes at least 2 to 3, 4 to 5, or 6 to 7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks; for example, the X-ray powder diffraction pattern of oxalate crystal form A has diffraction peaks at the following positions at 2θ (±0.2°):

[0279] Diffraction peaks are observed at positions 12.5, 7.1, 6.9, 23.5, 8.4, 13.8, 10.7, and 16.3; diffraction peaks are observed at positions 12.5, 7.1, 6.9, 23.5, 8.4, 14.3 ... Diffraction peaks are present at positions 13.8, 23.3, 10.7, and 16.3; diffraction peaks are present at positions 12.5, 6.9, 23.5, 8.4, 13.8, 14.3, 10.7, and 16.3; diffraction peaks are present at positions 12.5, 6.9, 23.5, 8.4, 13.8, 14.3, 10.7, and 16.3; diffraction peaks are present at positions 7.1, 6.9, 23.5, 8.4, 13.8, 14.3, 10.7, and 16.3.

[0280] The X-ray powder diffraction pattern of the oxalate crystal form A includes one or more diffraction peaks located at 2θ of 12.5±0.2°, 7.1±0.2°, 6.9±0.2°, 23.5±0.2°, 8.4±0.2°, 13.8±0.2°, 14.3±0.2°, 23.3±0.2°, 25.8±0.2°, 13.1±0.2°, 10.7±0.2°, 16.3±0.2°, 27.5±0.2°, 26.9±0.2°, or 24.9±0.2°.

[0281] Preferably, diffraction peaks are found at any of 4, 5, 6, 8, or 10 locations; for example, the X-ray powder diffraction pattern of the oxalate crystal form A has diffraction peaks at the following positions within 2θ (±0.2°):

[0282] Diffraction peaks are observed at 12.5, 7.1, 6.9, and 23.5; at 12.5, 7.1, 6.9, and 8.4; at 12.5, 7.1, 6.9, and 13.8; at 12.5, 7.1, 6.9, and 14.3; at 12.5, 7.1, 23.5, and 8.4; at 12.5, 7.1, 23.5, and 13.8; at 12.5, 6.9, and 23.5... A diffraction peak is observed at position 8.4; diffraction peaks are observed at positions 12.5, 6.9, 23.5, and 13.8; diffraction peaks are observed at positions 7.1, 6.9, 23.5, and 8.4; diffraction peaks are observed at positions 7.1, 6.9, 23.5, and 13.8; diffraction peaks are observed at positions 12.5, 7.1, 6.9, 23.5, 10.7, and 16.3; diffraction peaks are observed at positions 12.5, ... Diffraction peaks are observed at 6.9, 13.8, 10.7, and 16.3; 12.5, 7.1, 6.9, 14.3, 10.7, and 16.3; 12.5, 7.1, 23.5, 8.4, 10.7, and 16.3; 12.5, 7.1, 23.5, 13.8, 10.7, and 16.3; 12.5, 6.9, 23.5, 8.4, 10.7, and 16.3; 12.5, Diffraction peaks are observed at positions 6.9, 23.5, 13.8, 10.7, and 16.3; 7.1, 6.9, 23.5, 8.4, 10.7, and 16.3; 7.1, 6.9, 23.5, 13.8, 10.7, and 16.3; 12.5, 7.1, 6.9, 23.5, 8.4, 13.8, 25.8, and 13.1; and 12.5, 7.1, 6.9, 23.5, 8.4, and 14.3. Diffraction peaks are present at 25.8 and 13.1; diffraction peaks are present at 12.5, 7.1, 6.9, 23.5, 8.4, 23.3, 25.8, and 13.1; diffraction peaks are present at 12.5, 7.1, 6.9, 23.5, 13.8, 14.3, 25.8, and 13.1; diffraction peaks are present at 12.5, 7.1, 23.5, 8.4, 13.8, 14.3, 25.8, and 13.1; diffraction peaks are present at 12.5, 6.9, 23.5, 8.4, 13.8, 14.3, 25.8, and 13.1. Diffraction peaks are observed at: 12.5, 6.9, 23.5, 8.4, 13.8, 23.3, 25.8, and 13.1; 7.1, 6.9, 23.5, 8.4, 13.8, 14.3, 25.8, and 13.1; 7.1, 6.9, 23.5, and 8.Diffraction peaks are observed at positions 4, 13.8, 23.3, 25.8, and 13.1; at positions 12.5, 7.1, 6.9, 23.5, 8.4, 13.8, 25.8, 13.1, 10.7, and 16.3; at positions 12.5, 7.1, 6.9, 23.5, 8.4, 14.3, 25.8, 13.1, 10.7, and 16.3; at positions 12.5, 7.1, 6.9, 23.5, 8.4, 23.3, 25.8, 13.1, 10.7, and 16.3; at positions 12.5, 7.1, 6.9, 23.5, 8.4, 23.3, 25.8, 13.1, 10.7, and 16.3. Diffraction peaks are observed at the following locations: 12.5, 7.1, 23.5, 8.4, 13.8, 14.3, 25.8, 13.1, 10.7, and 16.3. Diffraction peaks are also observed at the following locations: 12.5, 7.1, 23.5, 8.4, 13.8, 23.3, 25.8, 13.1, 10.7, and 16.3. Diffraction peaks are also observed at the following locations: 12.5, 6.9, 23.5, 8.4, 13.8, 14.3, 25.8, 13.1, 10.7, and 16.3. Diffraction peaks are also observed at the following locations: 12.5, 6.9, 23.5, 8.4, 13.8, 23.3, 25.8, and 13.1. Diffraction peaks are also observed at the following locations: 7.1, 6.9, 23.5, 8.4, 13.8, 23.3, 25.8, and 13.1. Diffraction peaks are observed at positions 8.4, 13.8, 14.3, 25.8, and 13.1; diffraction peaks are also observed at positions 7.1, 6.9, 23.5, 8.4, 13.8, 23.3, 25.8, and 13.1.

[0283] The characteristic X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d using Cu-Kα radiation are shown in Table 19.

[0284] Table 19

[0285]

[0286]

[0287] More preferably, its XRPD spectrum is basically as shown in the attached figure. Figure 41 As shown, its DSC spectrum is basically as shown in Figure 42, and its TGA spectrum is basically as shown in Figure 42. Figure 43 As shown;

[0288] Hydroxyethyl sulfonate crystal form A, with one acid, has an X-ray powder diffraction pattern showing a diffraction peak at 2θ of 5.7 ± 0.2°; or at 18.1 ± 0.2°; or at 12.4 ± 0.2°; or at 14.6 ± 0.2°; at 23.9 ± 0.2°; at 16.4 ± 0.2°; at 23.5 ± 0.2°; at 10.5 ± 0.2°; at 21.2 ± 0.2°; preferably including any 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks, more preferably including any 6, 7, or 8 of them;

[0289] The X-ray powder diffraction pattern of the hydroxyethyl sulfonate crystal form A contains at least one or more diffraction peaks located at 2θ of 5.7 ± 0.2°, 18.1 ± 0.2°, or 12.4 ± 0.2°, preferably two, more preferably three; optionally, it may further contain at least one of 14.6 ± 0.2°, 23.9 ± 0.2°, 16.4 ± 0.2°, 23.5 ± 0.2°, or 10.5 ± 0.2°, preferably two, three, four, or five; for example, the X-ray powder diffraction pattern of the hydroxyethyl sulfonate crystal form A has diffraction peaks at 2θ (± 0.2°) at the following positions:

[0290] Diffraction peaks are present at positions 5.7, 18.1, 12.4, 14.6, 23.9, and 16.4; diffraction peaks are present at positions 5.7, 18.1, 12.4, 14.6, 23.9, and 23.5; diffraction peaks are present at positions 5.7, 18.1, 12.4, 14.6, 23.9, and 10.5; diffraction peaks are present at positions 5.7, 18.1, 12.4, 14.6, 16.4, and 23.5; diffraction peaks are present at positions 5.7, 12.4, 18.1, 12.4, 14.6, 23.9, and 16.4; diffraction peaks are present at positions 5.7, 18.1, 12.4, 14.6, 23.9, 16.4, and 23.5; diffraction peaks are present at positions 5.7, 12.4, 18.1, 18.1, 18.6, 23.9, 16.4, and 10.5; diffraction peaks are present at positions 5.7, 18.1, 18.1, 14 .... Diffraction peaks are observed at positions 14.6, 23.9, 16.4, and 23.5; at positions 5.7, 12.4, 14.6, 23.9, 16.4, and 10.5; at positions 18.1, 12.4, 14.6, 23.9, 16.4, and 23.5; at positions 18.1, 12.4, 14.6, 23.9, 16.4, and 10.5.

[0291] The X-ray powder diffraction pattern of hydroxyethyl sulfonate crystal form A optionally includes one or more diffraction peaks located at 2θ of 25.5 ± 0.2°, 11.6 ± 0.2°, 20.7 ± 0.2°, 25.0 ± 0.2°, 13.0 ± 0.2°, 22.9 ± 0.2°, or 28.4 ± 0.2°; preferably, it includes at least 2 to 3, 4 to 5, or 6 to 7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks; for example, the X-ray powder diffraction pattern of the hydroxyethyl sulfonate crystal form A has diffraction peaks at the following positions at 2θ (±0.2°):

[0292] Diffraction peaks are observed at positions 5.7, 18.1, 12.4, 14.6, 23.9, 16.4, 25.5, and 11.6; diffraction peaks are observed at positions 5.7, 18.1, 12.4, 14.6, 23.9, 23.5, 25.5, and 11.6; diffraction peaks are observed at positions 5.7, 18.1, 12.4, 14.6, 23.9, 10.5, 25.5, and 11.6; diffraction peaks are observed at positions 5.7, 18.1, 12.4, 14.6, 16.4, 23.5, 25.5, and 11.6; diffraction peaks are observed at positions 5.7, 18.1, 14.6, 23.9, 16.4, 23.5, 25.5, and 11.6. Diffraction peaks are observed at positions 5.7, 18.1, 14.6, 23.9, 16.4, 10.5, 25.5, and 11.6; diffraction peaks are observed at positions 5.7, 12.4, 14.6, 23.9, 16.4, 23.5, 25.5, and 11.6; diffraction peaks are observed at positions 18.1, 12.4, 14.6, 23.9, 16.4, 10.5, 25.5, and 11.6; diffraction peaks are observed at positions 18.1, 12.4, 14.6, 23.9, 16.4, 10.5, 25.5, and 11.6.

[0293] The X-ray powder diffraction pattern of the hydroxyethyl sulfonate crystal form A includes one or more diffraction peaks located at 2θ of 5.7±0.2°, 18.1±0.2°, 12.4±0.2°, 14.6±0.2°, 23.9±0.2°, 16.4±0.2°, 23.5±0.2°, 10.5±0.2°, 10.5±0.2°, 21.2±0.2°, 25.5±0.2°, 11.6±0.2°, 20.7±0.2°, 25.0±0.2°, or 13.0±0.2°.

[0294] Preferably, diffraction peaks are present at any of 4, 5, 6, 8, or 10 locations; for example, the X-ray powder diffraction pattern of the hydroxyethyl sulfonate crystal form A has diffraction peaks at the following positions at 2θ (±0.2°):

[0295] Diffraction peaks are present at positions 5.7, 18.1, 12.4, and 14.6; diffraction peaks are present at positions 5.7, 18.1, 12.4, and 23.9; diffraction peaks are present at positions 5.7, 18.1, 12.4, and 16.4; diffraction peaks are present at positions 5.7, 18.1, 12.4, and 23.5; diffraction peaks are present at positions 5.7, 18.1, 14.6, and 23.9; diffraction peaks are present at positions 5.7, 18.1, 14.6, and 16.4; diffraction peaks are present at positions 5.7, 12.4, 14.6, and 23.9; diffraction peaks are present at positions 5.7, 12.4, 14.6, and 16.4; diffraction peaks are present at positions 18.1, 12.4, and 14.6. A diffraction peak is observed at position 23.9; diffraction peaks are observed at positions 18.1, 12.4, 14.6, and 16.4; diffraction peaks are observed at positions 5.7, 18.1, 12.4, 14.6, 25.5, and 11.6; diffraction peaks are observed at positions 5.7, 18.1, 12.4, 23.9, 25.5, and 11.6; diffraction peaks are observed at positions 5.7, 18.1, 12.4, 16.4, 25.5, and 11.6; diffraction peaks are observed at positions 5.7, 18.1, 12.4, 23.5, 25.5, and 11.6; diffraction peaks are observed at positions 5.7, 18.1, 14.6, 23.9 .... Diffraction peaks are observed at positions 14.6, 16.4, 25.5, and 11.6; at positions 5.7, 12.4, 14.6, 23.9, 25.5, and 11.6; at positions 5.7, 12.4, 14.6, 16.4, 25.5, and 11.6; at positions 18.1, 12.4, 14.6, 23.9, 25.5, and 11.6; at positions 18.1, 12.4, 14.6, 16.4, 25.5, and 11.6; at positions 5.7, 18.1, 12.4, 14.6, 23.9, 25.5, and 11.6; at positions 5.7, 18.1, 12.4, 14.6, 23.9, 16.4, 10.5, and 21.2; at positions 5.7, 18.1, 12.4, 14.6, 23.9, 16.4, 10.5, and 21.2. Diffraction peaks are observed at positions 12.4, 14.6, 23.9, 23.5, 10.5, and 21.2; diffraction peaks are observed at positions 5.7, 18.1, 12.4, 14.6, 23.9, 10.5, 10.5, and 21.2; diffraction peaks are observed at positions 5.7, 18.1, 12.4, 14.6, 23.9, 16.4, 23.5, 10.5, and 21.2; diffraction peaks are observed at positions 5.7, 18.1, 12.4, 14.6, 23.9, 16.4, 10 ...2.4, 14.6, 23.9, 16.4, 10.5, 10.5, and 21.2; diffraction peaks are observed at positions 5.7, 12.4, 14.6, 23.9, 16.4, 10.5, 10.5, and 21.2; diffraction peaks are observed at positions 5.7, 12.4, 14.6, 23.9, 16.4, 10.5, 10.5, and 21.2. Diffraction peaks are observed at 23.9, 16.4, 23.5, 10.5, and 21.2; diffraction peaks are observed at 5.7, 12.4, 14.6, 23.9, 16.4, 10.5, 10.5, and 21.2; and diffraction peaks are observed at 18.1, 12.4, 14.6, 23.9, and 16.Diffraction peaks are observed at positions 4, 23.5, 10.5, and 21.2; at positions 18.1, 12.4, 14.6, 23.9, 16.4, 10.5, 10.5, and 21.2; at positions 5.7, 18.1, 12.4, 14.6, 23.9, 16.4, 10.5, 21.2, 25.5, and 11.6; at positions 5.7, 18.1, 12.4, 14.6, 23.9, 23.5, 10.5, 21.2, 25.5, and 11.6; at positions 5.7, 18.1, 12.4, and 21.2. Diffraction peaks are observed at positions 14.6, 23.9, 10.5, 10.5, 21.2, 25.5, and 11.6; Diffraction peaks are observed at positions 5.7, 18.1, 12.4, 14.6, 16.4, 23.5, 10.5, 21.2, 25.5, and 11.6; Diffraction peaks are observed at positions 5.7, 18.1, 14.6, 23.9, 16.4, 23.5, 10.5, 21.2, 25.5, and 11.6; Diffraction peaks are observed at positions 5.7, 18.1, 14.6, 23.9, 16.4, 10.5, and 11.6. Diffraction peaks are observed at positions 10.5, 21.2, 25.5, and 11.6; 5.7, 12.4, 14.6, 23.9, 16.4, 23.5, 10.5, 21.2, 25.5, and 11.6; 18.1, 12.4, 14.6, 23.9, 16.4, 23.5, 10.5, 21.2, 25.5, and 11.6; 18.1, 12.4, 14.6, 23.9, 16.4, 10.5, 10.5, 21.2, 25.5, and 11.6. It exhibits diffraction peaks.

[0296] The characteristic X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d using Cu-Kα radiation are shown in Table 20.

[0297] Table 20

[0298]

[0299]

[0300] More preferably, its XRPD spectrum is basically as shown in the attached figure. Figure 44 As shown, its DSC spectrum is basically as shown in Figure 45;

[0301] Hydroxyethyl sulfonate crystal form B, with one acid, has an X-ray powder diffraction pattern showing a diffraction peak at 2θ of 18.8 ± 0.2°; or at 7.6 ± 0.2°; or at 24.1 ± 0.2°; or at 24.7 ± 0.2°; at 13.7 ± 0.2°; at 17.5 ± 0.2°; at 26.9 ± 0.2°; at 25.7 ± 0.2°; at 22.5 ± 0.2°; at 25.9 ± 0.2°; preferably including any 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks, more preferably including any 6, 7, or 8 of them.

[0302] The X-ray powder diffraction pattern of the hydroxyethyl sulfonate crystal form B contains at least one or more diffraction peaks located at 2θ of 18.8 ± 0.2°, 7.6 ± 0.2°, or 24.1 ± 0.2°, preferably two, more preferably three; optionally, it may further contain at least one of 24.7 ± 0.2°, 13.7 ± 0.2°, 17.5 ± 0.2°, 26.9 ± 0.2°, or 25.7 ± 0.2°, preferably two, three, four, or five; for example, the X-ray powder diffraction pattern of the hydroxyethyl sulfonate crystal form B has diffraction peaks at 2θ (± 0.2°) at the following positions:

[0303] Diffraction peaks are observed at positions 18.8, 7.6, 24.1, 24.7, 13.7, and 17.5; diffraction peaks are observed at positions 18.8, 7.6, 24.1, 24.7, 13.7, and 26.9; diffraction peaks are observed at positions 18.8, 7.6, 24.1, 24.7, 13.7, and 25.7; diffraction peaks are observed at positions 18.8, 7.6, 24.1, 24.7, 17.5, and 26.9; diffraction peaks are observed at positions 18.8, 24.1, 24.7, 13.7, and 25.7; diffraction peaks are observed at positions 18.8, 24.1, 17.5, and 26.9 ... Diffraction peaks are observed at 24.7, 13.7, 17.5, and 26.9; at 18.8, 24.1, 24.7, 13.7, 17.5, and 25.7; at 7.6, 24.1, 24.7, 13.7, 17.5, and 26.9; and at 7.6, 24.1, 24.7, 13.7, 17.5, and 25.7.

[0304] The X-ray powder diffraction pattern of hydroxyethyl sulfonate crystal form B optionally includes one or more diffraction peaks located at 2θ of 28.1 ± 0.2°, 22.3 ± 0.2°, 12.6 ± 0.2°, 15.8 ± 0.2°, 10.7 ± 0.2°, 9.8 ± 0.2°, 28.6 ± 0.2°, or 21.6 ± 0.2°; preferably, it includes at least 2 to 3, 4 to 5, or 6 to 7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks; for example, the X-ray powder diffraction pattern of the hydroxyethyl sulfonate crystal form B has diffraction peaks at the following positions at 2θ (±0.2°):

[0305] Diffraction peaks are observed at positions 18.8, 7.6, 24.1, 24.7, 13.7, 17.5, 28.1, and 22.3; Diffraction peaks are observed at positions 18.8, 7.6, 24.1, 24.7, 13.7, 26.9, 28.1, and 22.3; Diffraction peaks are observed at positions 18.8, 7.6, 24.1, 24.7, 13.7, 25.7, 28.1, and 22.3; Diffraction peaks are observed at positions 18.8, 7.6, 24.1, 24.7, 17.5, 26.9, 28.1, and 22.3; Diffraction peaks are observed at positions 18.8, 7.6, 24.7, 13.7, 17.5, 26.9, 28.1, and 22.3. Diffraction peaks are observed at positions 18.8, 7.6, 24.7, 13.7, 17.5, 25.7, 28.1, and 22.3; Diffraction peaks are observed at positions 18.8, 24.1, 24.7, 13.7, 17.5, 25.7, 28.1, and 22.3; Diffraction peaks are observed at positions 7.6, 24.1, 24.7, 13.7, 17.5, 25.7, 28.1, and 22.3; Diffraction peaks are observed at positions 7.6, 24.1, 24.7, 13.7, 17.5, 25.7, 28.1, and 22.3.

[0306] The X-ray powder diffraction pattern of the hydroxyethyl sulfonate crystal form B includes one or more diffraction peaks located at 2θ of 18.8±0.2°, 7.6±0.2°, 24.1±0.2°, 24.7±0.2°, 13.7±0.2°, 17.5±0.2°, 26.9±0.2°, 25.7±0.2°, 28.1±0.2°, 22.3±0.2°, 12.6±0.2°, or 15.8±0.2°.

[0307] Preferably, diffraction peaks are present at any of 4, 5, 6, 8, or 10 locations; for example, the X-ray powder diffraction pattern of the hydroxyethyl sulfonate crystal form B has diffraction peaks at the following positions at 2θ (±0.2°):

[0308] Diffraction peaks are present at positions 18.8, 7.6, 24.1, and 24.7; 18.8, 7.6, 24.1, and 13.7; 18.8, 7.6, 24.1, and 17.5; 18.8, 7.6, 24.1, and 26.9; 18.8, 7.6, 24.7, and 13.7; 18.8, 7.6, 24.7, and 17.5; 18.8, 24.1, 24.7, and 13.7; 18.8, 24.1, 24.7, and 13.7; 18.8, 24.1, 24.7, and 17.5; 7.6, 24.1, 24.7, and 24.7. A diffraction peak is found at 13.7; diffraction peaks are found at 7.6, 24.1, 24.7, and 17.5; diffraction peaks are found at 18.8, 7.6, 24.1, 24.7, 28.1, and 22.3; diffraction peaks are found at 18.8, 7.6, 24.1, 13.7, 28.1, and 22.3; diffraction peaks are found at 18.8, 7.6, 24.1, 17.5, 28.1, and 22.3; diffraction peaks are found at 18.8, 7.6, 24.1, 26.9, 28.1, and 22.3; diffraction peaks are found at 18.8, 7.6, 24.7, 13.7, 28.1, and 22.3; diffraction peaks are found at 18.8, 7.6, 24.1, 13.7, 28.1, and 22.3; diffraction peaks are found at 18.8, 7.6, 24.1, 17.5, 18.8, 7.6, 24.1, 24.7, 28.1, and 22.3; diffraction peaks are found at 18.8, 7.6, 24.1, 13.7, 28.1, and 22.3; diffraction peaks are found at 18.8, 7.6, 24.1, 24.7, 13.7, 28.1, and 22.3; diffraction peaks are found at 18.8, 7.6, 24.1, 24 Diffraction peaks are present at positions 24.7, 17.5, 28.1, and 22.3; diffraction peaks are present at positions 18.8, 24.1, 24.7, 13.7, 28.1, and 22.3; diffraction peaks are present at positions 18.8, 24.1, 24.7, 17.5, 28.1, and 22.3; diffraction peaks are present at positions 7.6, 24.1, 24.7, 13.7, 28.1, and 22.3; diffraction peaks are present at positions 7.6, 24.1, 24.7, 17.5, 28.1, and 22.3; diffraction peaks are present at positions 18.8, 7.6, 24.1, 24.7, 13 ...28.1, and 22.3; diffraction peaks are present at positions 18.8, 7.6, 24.1, 24.7, 13.7, 28.1, and 22.3; diffraction peaks are present at positions 1 Diffraction peaks are observed at positions 24.1, 24.7, 13.7, 26.9, 28.1, and 22.3; diffraction peaks are observed at positions 18.8, 7.6, 24.1, 24.7, 13.7, 25.7, 28.1, and 22.3; diffraction peaks are observed at positions 18.8, 7.6, 24.1, 24.7, 13.7, 17.5, 26.9, 28.1, and 22.3; diffraction peaks are observed at positions 18.8, 24.1, 24.7, 17.5, 26.9, 28.1, and 22.3; diffraction peaks are observed at positions 18.8, 24.1, 24.7, 13.7, 17.5, 25.7 ...7, 24.7, 24.7, 13.7, 17.5, 25.7, 28.1, and 22.3; diffraction peaks are observed at positions 18.8, 24.1, 24.7, 24.7, 24.7, 24.7, 24.7, 24.7, 24.7, 24.7, 24.7, 24.7, 24.7, 24.7, 24.7, 24.7, Diffraction peaks are observed at 13.7, 17.5, 26.9, 28.1, and 22.3; diffraction peaks are observed at 18.8, 24.1, 24.7, 13.7, 17.5, 25.7, 28.1, and 22.3; diffraction peaks are observed at 7.6, 24.1, 24.7, and 13.Diffraction peaks are observed at positions 7, 17.5, 26.9, 28.1, and 22.3; at positions 7.6, 24.1, 24.7, 13.7, 17.5, 25.7, 28.1, and 22.3; at positions 18.8, 7.6, 24.1, 24.7, 13.7, 17.5, 28.1, 22.3, 28.1, and 22.3; at positions 18.8, 7.6, 24.1, 24.7, 13.7, 26.9, 28.1, 22.3, 28.1, and 22.3; at positions 18.8, 7.6, 24.1, and 22.3. Diffraction peaks are observed at 24.7, 13.7, 25.7, 28.1, 22.3, 28.1, and 22.3; diffraction peaks are observed at 18.8, 7.6, 24.1, 24.7, 17.5, 26.9, 28.1, 22.3, 28.1, and 22.3; diffraction peaks are observed at 18.8, 7.6, 24.7, 13.7, 17.5, 26.9, 28.1, 22.3, 28.1, and 22.3; diffraction peaks are observed at 18.8, 24.1, 24.7, 13.7, 17.5, 26.9, and 28.1; diffraction peaks are observed at 18.8, 24.1, 24.7, 13.7, 17.5, 26.9, and 28.1. Diffraction peaks are present at positions 22.3, 28.1, and 22.3; diffraction peaks are present at positions 18.8, 24.1, 24.7, 13.7, 17.5, 25.7, 28.1, 22.3, 28.1, and 22.3; diffraction peaks are present at positions 7.6, 24.1, 24.7, 13.7, 17.5, 25.7, 28.1, 22.3, 28.1, and 22.3.

[0309] The characteristic X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d using Cu-Kα radiation are shown in Table 21.

[0310] Table 21

[0311]

[0312]

[0313]

[0314] More preferably, its XRPD spectrum is basically as shown in the attached figure. Figure 46 As shown in Figure 47, its DSC spectrum is basically as shown in Figure 47.

[0315] In a further preferred embodiment of the present invention, the acid salt crystal form is a hydrate or anhydrous form. When the acid salt crystal form is a hydrate, the number of water molecules is 0.2-3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3. Furthermore, the water in the hydrate is pipe water or crystal water or a combination of both.

[0316] The present invention also provides a method for preparing an acid salt of the compound shown in general formula (I), comprising the following steps:

[0317] 1) Weigh an appropriate amount of free alkali and dissolve it in a good solvent;

[0318] 2) Weigh an appropriate amount of the counterionic acid and dissolve it in an organic solvent; the amount of the counterionic acid is preferably 1.2 equivalents;

[0319] 3) Combine the two solutions mentioned above and stir to precipitate, or add a poor solvent and stir to precipitate;

[0320] 4) Obtain the salt of the compound by rapid centrifugation or standing.

[0321] in:

[0322] The beneficial solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, acetonitrile, 2-butanone, 3-pentanone, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, or N-methylpyrrolidone; preferably methanol or ethanol.

[0323] 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, or acetonitrile.

[0324] The unsuitable solvent is selected from heptane, water, methyl tert-butyl ether, toluene, isopropyl ether, ethyl acetate, acetone, or acetonitrile; preferably water, methyl tert-butyl ether, or isopropyl ether.

[0325] The aforementioned counterionic 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-naphtholic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxyxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetaminobenzoic acid, 4-aminobenzoic acid, decanoic acid, hexanoic acid, octanoic acid, cinnamic acid, citric acid, cyclohexanesulfonic 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, galactobionic acid, gentic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, hydroxyethyl sulfonic 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, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, dihydroxynaphthalic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanate, undecanoic acid, trifluoroacetic acid, benzenesulfonic acid, p-methylbenzenesulfonic acid, or L-malic acid; preferably hydrochloric acid, phosphoric acid, ethanesulfonic acid, benzenesulfonic acid, methanesulfonic acid, fumaric acid, hydroxyethyl sulfonic acid, oxalic acid, or hydrobromic acid.

[0326] The present invention also provides a method for preparing an acid salt of the compound shown in general formula (I), comprising the following steps:

[0327] 1) Weigh an appropriate amount of free alkali and dissolve it in a good solvent;

[0328] 2) Weigh an appropriate amount of the counterionic acid and dissolve it in an organic solvent; the amount of the counterionic acid is preferably 1.2 equivalents;

[0329] 3) Mix the solutions obtained in steps 1) and 2) thoroughly and then evaporate them. After the solvent has evaporated completely, add the unsuitable solvent and stir until the solid precipitates.

[0330] 4) Obtain the salt of the compound by rapid centrifugation or standing.

[0331] in:

[0332] The beneficial solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, acetonitrile, 2-butanone, 3-pentanone, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, or N-methylpyrrolidone; preferably methanol or ethanol.

[0333] 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, or acetonitrile; the above-mentioned benign solvents and organic solutions must be miscible when used.

[0334] The unsuitable solvent is selected from ethyl acetate, acetone, dichloromethane, acetonitrile, tetrahydrofuran, 2-butanone, 3-pentanone, and 1,4-dioxane; preferably ethyl acetate, acetone, and acetonitrile.

[0335] The aforementioned counterionic 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-naphtholic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxyxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetaminobenzoic acid, 4-aminobenzoic acid, decanoic acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfonic 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, galactobionic acid, gentian acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid. Hydroxyethylsulfonic 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, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, dihydroxynaphthalic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanate, undecanoic acid, trifluoroacetic acid, benzenesulfonic acid, p-methylbenzenesulfonic acid, or L-malic acid; preferably hydrochloric acid, phosphoric acid, ethanesulfonic acid, benzenesulfonic acid, methanesulfonic acid, fumaric acid, hydroxyethylsulfonic acid, oxalic acid, or hydrobromic acid.

[0336] The present invention also provides a method for preparing the crystal form of the acid salt of the compound shown in general formula (I), comprising the following steps:

[0337] 1) Weigh an appropriate amount of the compound salt and suspend it in a poor solvent;

[0338] 2) Shake the above suspension;

[0339] 3) Centrifuge the above suspension, remove the supernatant, and dry the remaining solid to constant weight to obtain the target product;

[0340] in:

[0341] The undesirable solvent is selected from one or more of methanol, ethanol, dichloromethane, 1,4-dioxane, acetonitrile, chlorobenzene, benzene, toluene, acetone, ethyl acetate, water, 88% acetone, isopropyl acetate, 3-pentanone, ethyl formate, tetrahydrofuran, 2-methyl-tetrahydrofuran, isopropanol, n-butanol, isobutanol, n-propanol, tert-butanol, or 2-butanone.

[0342] Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of an acid salt or crystal form of the above-described compound, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0343] The present invention also aims to provide the use of the above-described acid salt or its crystal form and the above-described pharmaceutical composition in the preparation of a drug for the prevention and / or treatment of diseases related to TYK2 inhibitors.

[0344] The present invention also aims to provide the use of the above-described acid salt or its crystal form and the above-described pharmaceutical composition in the preparation of a treatment for inflammatory diseases and autoimmune diseases; wherein the inflammatory diseases and autoimmune diseases are selected from rheumatoid arthritis, dermatitis, psoriasis or inflammatory bowel disease.

[0345] Detailed description of the invention

[0346] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0347] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3- Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3- Ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and their various branched isomers, etc. More preferably, lower alkyl groups containing 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point. The substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester groups. The present invention preferably uses methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuteralkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl.

[0348] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and most preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0349] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, but excluding the ring portions of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms; most preferably, it contains 3 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include oxobutyl, thiobutyl, pyrrolyl, pyrrolidone, imidazolyl, tetrahydrofuranyl, tetrahydrothiophene, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably oxobutyl, pyrrolidone, tetrahydrofuranyl, pyrrolidone, morpholinyl, piperazinyl, and pyranyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups; wherein the spirocyclic, fused-ring, and bridged-ring heterocyclic groups involved may optionally be connected to other groups by single bonds, or may be further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring.

[0350] The heterocyclic group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0351] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. Phenyl is more preferred.

[0352] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0353] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered, more preferably 5- or 6-membered, such as imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, pyrroleyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thiophene, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, and thiazolyl; more preferably triazolyl, pyrroleyl, thiophene, thiazolyl, pyridinyl, and pyrimidinyl.

[0354] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0355] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0356] "Halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0357] "Haloalkoxy" refers to an alkoxy group that has been substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0358] "Hydroxyalkyl" refers to an alkyl group that has been replaced by a hydroxyl group, where the alkyl group is as defined above.

[0359] "Alkenyl" refers to an alkenyl group, also known as an olefinic group. The alkenyl group can be further replaced by other related groups, such as: alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0360] "Alkyne" refers to (CH≡C-), wherein the alkynyl group can be further substituted by other related groups, such as: alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0361] "Hydroxy" refers to the -OH group.

[0362] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0363] "Amino" refers to -NH2.

[0364] “Cyano” refers to -CN.

[0365] "Nitro" refers to -NO2.

[0366] "Carboxyl group" refers to -C(O)OH.

[0367] "THF" refers to tetrahydrofuran.

[0368] “EtOAc” refers to ethyl acetate.

[0369] “MeOH” refers to methanol.

[0370] "DMF" refers to N,N-dimethylformamide.

[0371] "DIPEA" refers to diisopropylethylamine.

[0372] "TFA" refers to trifluoroacetic acid.

[0373] “MeCN” refers to Yi Qing.

[0374] “DMA” stands for N,N-dimethylacetamide.

[0375] “Et2O” refers to diethyl ether.

[0376] “DCE” refers to 1,2-dichloroethane.

[0377] "DIPEA" refers to N,N-diisopropylethylamine.

[0378] “Pd2(dba)3” refers to tris(dibenzylacetone)dipalladium.

[0379] “HATU” refers to 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate.

[0380] "LiHMDS" refers to lithium bis(trimethylsilyl)amine.

[0381] "DMAP" refers to 4-dimethylaminopyridine.

[0382] “SEM-Cl” refers to chloromethyltrimethylsilylethyl ether.

[0383] “Xantphos” refers to 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene.

[0384] "DCM" refers to dichloromethane.

[0385] The different expressions such as "X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", and "X is A, B, and C" all express the same meaning, that is, X can be any one or more of A, B, and C.

[0386] In the table of this invention, " / " represents "not detected".

[0387] All hydrogen atoms described in this invention can be replaced by their isotope deuterium, and any hydrogen atom in the compounds of the embodiments of this invention can also be replaced by a deuterium atom.

[0388] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0389] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0390] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0391] "Medicinal salts" refers to salts of the compounds of this invention that are safe and effective when used in mammals and have the appropriate biological activity. Attached Figure Description

[0392] Figure 1 XRPD diagram of crystal form A of 6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carbamate hydrobromide.

[0393] Figure 2 DSC illustration of crystal form A of 6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide hydrobromide.

[0394] Figure 3 XRPD diagram of crystal form A of 6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide phosphate.

[0395] Figure 4 DSC illustration of crystal form A of 6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide phosphate.

[0396] Figure 5 TGA illustration of crystal form A of 6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide phosphate.

[0397] Figure 6 XRPD illustration of 6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide phosphate crystal form B.

[0398] Figure 7 DSC illustration of crystal form B of 6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide phosphate.

[0399] Figure 8TGA illustration of crystal form B of 6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide phosphate.

[0400] Figure 9 XRPD illustration of crystal form A of 6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carbamate benzenesulfonate.

[0401] Figure 10 DSC illustration of crystal form A of 6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carbamate benzenesulfonate.

[0402] Figure 11 TGA illustration of crystal form A of 6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carbamate benzenesulfonate.

[0403] Figure 12 XRPD diagram of crystal form A of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide hydrobromide.

[0404] Figure 13 DSC illustration of crystal form A of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide hydrobromide.

[0405] Figure 14 TGA illustration of crystal form A of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide hydrobromide.

[0406] Figure 15 XRPD illustration of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide hydrobromide crystal form B.

[0407] Figure 16 DSC illustration of crystal form B of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide hydrobromide.

[0408] Figure 17 XRPD diagram of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide hydrobromide crystal form C.

[0409] Figure 18 DSC illustration of crystal form C of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide hydrobromide.

[0410] Figure 19 XRPD diagram of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide hydrobromide crystal form D.

[0411] Figure 20 DSC illustration of crystal form D of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide hydrobromide.

[0412] Figure 21 TGA illustration of crystal form D of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide hydrobromide.

[0413] Figure 22 XRPD illustration of crystal form E of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide hydrobromide.

[0414] Figure 23DSC illustration of crystal form E of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide hydrobromide.

[0415] Figure 24 XRPD illustration of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide hydrobromide crystal form F.

[0416] Figure 25 DSC illustration of crystal form F of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide hydrobromide.

[0417] Figure 26 XRPD diagram of crystal form A of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide phosphate.

[0418] Figure 27 DSC illustration of crystal form A of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide phosphate.

[0419] Figure 28 TGA illustration of crystal form A of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide phosphate.

[0420] Figure 29 XRPD diagram of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide phosphate crystal form B.

[0421] Figure 30XRPD illustration of crystal form A of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide methanesulfonate.

[0422] Figure 31 DSC illustration of crystal form A of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide methanesulfonate.

[0423] Figure 32 XRPD illustration of crystal form B of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide methanesulfonate.

[0424] Figure 33 DSC illustration of crystal form B of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide methanesulfonate.

[0425] Figure 34 XRPD illustration of crystal form C of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide methanesulfonate.

[0426] Figure 35 DSC illustration of crystal form C of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide methanesulfonate.

[0427] Figure 36 XRPD illustration of crystal form D of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide methanesulfonate.

[0428] Figure 37DSC illustration of crystal form D of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide methanesulfonate.

[0429] Figure 38 XRPD illustration of crystal form E of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide methanesulfonate.

[0430] Figure 39 XRPD illustration of crystal form F of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide methanesulfonate.

[0431] Figure 40 DSC illustration of crystal form F of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide methanesulfonate.

[0432] Figure 41 XRPD illustration of crystal form A of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide oxalate.

[0433] Figure 42 DSC illustration of crystal form A of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide oxalate.

[0434] Figure 43 TGA illustration of crystal form A of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide oxalate.

[0435] Figure 44XRPD illustration of crystal form A of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide hydroxyethyl sulfonate.

[0436] Figure 45 DSC illustration of crystal form A of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide hydroxyethyl sulfonate.

[0437] Figure 46 XRPD illustration of crystal form B of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide hydroxyethyl sulfonate.

[0438] Figure 47 DSC illustration of crystal form B of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide hydroxyethyl sulfonate.

[0439] Figure 48 XRPD diagram of free base crystal form A of 6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.

[0440] Figure 49 DSC illustration of free base crystal form A of 6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.

[0441] Figure 50 TGA illustration of the free base crystal form A of 6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.

[0442] Figure 51XRPD diagram of free base crystal form A of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.

[0443] Figure 52 DSC illustration of free base crystal form A of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.

[0444] Figure 53 TGA illustration of free base crystal form A of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.

[0445] Figure 54 XRPD illustration of the free base crystal form B of 6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.

[0446] Figure 55 DSC illustration of the free base crystal form B of 6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.

[0447] Figure 56 TGA illustration of the free base crystal form B of 6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.

[0448] Figure 57 PASI scores were obtained in a mouse psoriasis model induced by imiquimod at different doses of the compound. Detailed Implementation

[0449] The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present invention.

[0450] I. Preparation of Compounds

[0451] Example

[0452] The structures of the compounds of this invention were 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 with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0453] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1200 Infinity Series mass spectrometer. High-performance liquid chromatography (HPLC) was performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C18 150×4.6 mm column).

[0454] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The standard size for TLC is 0.15mm to 0.20mm, while the standard size for TLC separation and purification is 0.4mm to 0.5mm. Column chromatography typically uses 200-300 mesh Yantai Huanghai silica gel as the carrier.

[0455] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using methods known in the art.

[0456] Unless otherwise specified, all reactions in this invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature is expressed in degrees Celsius.

[0457] Example 1

[0458] Preparation of 6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0459]

[0460] Step 1: Preparation of 2-methoxy-3-nitrobenzamide

[0461]

[0462] At room temperature, methyl 2-methoxy-3-nitrobenzoic acid ester (5 g, 23.7 mmol) was dissolved in ammonia-methanol solution (100 mL, 7 M), and ammonia water (28 wt%, 50 mL) was added. The mixture was stirred overnight at room temperature, diluted with ethyl acetate (300 mL), and then the organic phase was washed successively with saturated NaHCO3 aqueous solution (300 mL × 2) and saturated brine. The organic phase was separated and dried over anhydrous sodium sulfate. After concentrating the organic solvent under reduced pressure, column chromatography was used to obtain the title compound 2-methoxy-3-nitrobenzoamide (4.3 g, 92%).

[0463] MS m / z (ESI): 197.1 [M+H] + .

[0464] Step 2: Preparation of 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole

[0465]

[0466] 2-Methoxy-3-nitrobenzamide (4.2 g, 21.4 mmol) was dissolved in DMF-DMA (28.6 mL), and the mixture was heated to 95 °C and reacted for 1 hour. After concentration under reduced pressure, crude DMF-DMA addition product was obtained and dissolved in ethanol (20 mL) for later use. In an ice bath, ethanol (70 mL) and acetic acid (21 mL) were added to a reaction flask. After stirring for 5 minutes, hydrazine hydrate (80 wt.%, 10.5 mL) was slowly added dropwise while stirring for another 15 minutes. Then, the ethanol solution of the crude DMF-DMA addition product was added dropwise. The mixture was slowly brought to room temperature and stirred for another 4 hours at room temperature. After the reaction solution was concentrated under reduced pressure, it was diluted with ethyl acetate (300 mL). The organic phase was washed successively with saturated NaHCO3 aqueous solution (300 mL × 2) and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain the title compound 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (4.5 g, 95%).

[0467] MS m / z(ESI): 221.1 [M+H] + .

[0468] Step 3: Preparation of 1-cyclopropyl-3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole

[0469]

[0470] 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (200 mg, 0.91 mmol), copper acetate (198 mg, 1.1 mmol), 2,2'-bipyridine (170 mg, 1.1 mmol), and sodium carbonate (192 mg, 1.8 mmol) were mixed in 1,2-dichloroethane (5 mL). Cyclopropylboronic acid (234 mg, 2.72 mmol) was added at room temperature, and the mixture was heated to 85 °C and stirred overnight. After cooling the reaction solution to room temperature, it was diluted with a large amount of ethyl acetate. The organic phase was washed several times with saturated brine, then separated and dried over anhydrous sodium sulfate. After concentrating the organic solvent under reduced pressure, column chromatography was used to obtain the title compound 1-cyclopropyl-3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (125 mg, 53%).

[0471] 1 H NMR (400MHz, CDCl3) δ1.15-1.21(m,2H),1.24-1.29(m,2H),3.70-3.79 (m,1H),3.94(s,3H),7.23-7.31(m,1H),7.78-7.81(m,1H),8.20-8.23(m,1H),8.36 (s,1H);

[0472] MS m / z(ESI): 261.1 [M+H] + .

[0473] Step 4: Preparation of 3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyaniline

[0474]

[0475] Palladium / carbon (30 mg) was added to a methanol (5 mL) solution of 1-cyclopropyl-3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (120 mg, 0.46 mmol). The reaction was carried out under a hydrogen atmosphere at ambient temperature and pressure for 12 hours. The catalyst was then removed by filtration with diatomaceous earth. The organic solvent was concentrated under reduced pressure to obtain the title compound 3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyaniline (102 mg), which was used directly in the next reaction.

[0476] MS m / z(ESI): 231.1 [M+H] + .

[0477] Step 5: Preparation of lithium 4,6-dichloropyridazine-3-carboxylate

[0478]

[0479] Methyl 4,6-dichloropyridazine-3-carboxylic acid ester (2.07 g, 10 mmol) and lithium bromide (2.6 g, 30 mmol) were dissolved in acetonitrile (20 mL) and water (2 mL). The mixture was cooled to 0 °C, and DIPEA (5.2 mL, 30 mmol) was added dropwise. The mixture was allowed to rise naturally to room temperature for 1 hour. The reaction mixture was filtered, and the filter cake was washed with acetonitrile (2 mL × 4). The filter cake was collected and dried to give the title compound, lithium 4,6-dichloropyridazine-3-carboxylic acid (1.73 g, 87%).

[0480] MS m / z (ESI): 193.1 [M+H] + .

[0481] Step 6: Preparation of zinc 6-chloro-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxylate

[0482]

[0483] 3-(1-Cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyaniline (100 mg, 0.4 mmol), lithium 4,6-dichloropyridazine-3-carboxylate (103.7 mg, 0.5 mmol), and zinc acetate (95.6 mg, 0.5 mmol) were mixed in isopropanol (0.5 mL) and water (3.5 mL) and heated to 80 °C overnight. The reaction mixture was cooled to room temperature, and water (3 mL) was added. The mixture was stirred for 1 h. The reaction solution was filtered, and the filter cake was washed with water (3 mL × 2) and THF (2 mL). The filter cake was collected and dried to give the title compound 6-chloro-4-((3-(1-Cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxylate zinc (130 mg, 78%).

[0484] MS m / z (ESI): 387.1 [M+H] + .

[0485] Step 7: Preparation of zinc 6-(cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxylate

[0486]

[0487] 6-Chloro-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxylic acid zinc (130 mg, 0.31 mmol), cyclopropionamide (86 mg, 1.0 mmol), DBU (61 mg, 0.4 mmol), and potassium carbonate (110 mg, 0.8 mmol) were mixed in toluene (1.2 mL) and acetonitrile (0.6 mL). Palladium acetate (4.5 mg, 0.02 mmol) and (R)-(-)-1-[(S)-2-(dicyclohexylphosphine)ferrocene]ethyl di-tert-butylphosphine (22 mg, 0.04 mmol) were added. The reaction system was purged with nitrogen three times and heated to 75 °C overnight. The reaction was cooled to room temperature, and water (4 mL) and acetic acid (2 mL) were added. The mixture was washed with petroleum ether (6 mL × 2), and then the aqueous phase was separated. Water (2 mL) was added to the aqueous phase, and the mixture was extracted with CH2Cl2 (5 mL × 3). The organic phases were combined, washed with saturated NaCl aqueous solution, and the organic phase was dried over anhydrous sodium sulfate. The organic solvent was concentrated under reduced pressure to give the title compound 6-(cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxylic acid zinc (109 mg, 75%).

[0488] MS m / z (ESI): 436.1 [M+H] + .

[0489] Step 8: Preparation of 6-(cyclopropylcarbamate)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0490]

[0491] 6-(cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxylic acid zinc (90 mg, 0.19 mmol), deuterated methylamine hydrochloride (71 mg, 1.0 mmol), and DIPEA (258 mg, 2.0 mmol) were mixed in DMF (1 mL), and HATU (380 mg, 1.0 mmol) was added. The mixture was reacted overnight at 50 °C. The reaction was cooled to room temperature, separated by saturated sodium bicarbonate aqueous solution and CH2Cl2, the organic phase was washed with saturated NaCl aqueous solution, dried with anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure before column chromatography to give the title compound 6-(cyclopropylcarbamate)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (35 mg, 38%).

[0492] 1 H NMR(400MHz, CDCl3)δ0.86-0.99(m,2H),1.07-1.18(m,4H),1.22-1.26 (m,2H),1.73-1.82(m,1H),3.65-3.72(m,1H),3.81(s,3H),7.27-7.29(m,1H), 7.48-7.52(m,1H),7.81-7.84(m,1H),7.96(s,1H),8.17-8.24(m,2H),9.87(s,1H),11.27(s,1H);

[0493] MS m / z (ESI): 452.2 [M+H] + .

[0494] Example 2

[0495] 6-(cyclopropylcarbamate)-4-((5-fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0496]

[0497] The preparation method of 6-(cyclopropylcarbamoyl)-4-((5-fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0498] 1 H NMR (400MHz, CDCl3) δ0.89-0.94(m,2H),1.11-1.15(m,2H),1.78-1.84 (m,1H),3.81(s,3H),4.01(s,3H),7.23-7.26(m,1H),7.53-7.56(m,1H),8.04(s,1H),8.11(s,1H),8.30(s,1H),9.73(s,1H),11.17(s,1H);

[0499] MS m / z (ESI): 444.2 [M+H] + .

[0500] Example 3

[0501] 6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0502]

[0503] Step 1: Preparation of 3-(5-fluoro-2-methoxyphenyl)-1H-1,2,4-triazole

[0504]

[0505] 5-Fluoro-2-methoxybenzamide (3.5 g, 20.7 mmol) was dissolved in DMF-DMA (25 mL), heated to 95 °C and reacted for 1 hour. After concentration under reduced pressure, crude DMF-DMA addition product was obtained and dissolved in ethanol (20 mL) for later use. In an ice bath, ethanol (56 mL) and acetic acid (17 mL) were added to a reaction flask. After stirring for 5 minutes, hydrazine hydrate (80 wt.%, 8.4 mL) was added dropwise, and stirring continued for 15 minutes. Then, the ethanol solution of the crude DMF-DMA addition product was added dropwise. The mixture was slowly raised to room temperature and stirred for 4 hours at room temperature. After the reaction solution was concentrated under reduced pressure, it was diluted with ethyl acetate (300 mL), washed with saturated NaHCO3 aqueous solution (300 mL × 2), the organic phase was separated and washed with saturated brine, dried with anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography to obtain the title compound 3-(5-fluoro-2-methoxyphenyl)-1H-1,2,4-triazole (3.1 g, 77%).

[0506] MS m / z (ESI): 194.2 [M+H] + .

[0507] Step 2: Preparation of 3-(5-fluoro-2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole

[0508]

[0509] 3-(5-fluoro-2-methoxyphenyl)-1H-1,2,4-triazole (1.1 g, 5.69 mmol) was dissolved in concentrated sulfuric acid (10 mL). Nitric acid (68 wt.%, 1.05 g, 11.39 mmol) was added dropwise under ice bath conditions. After the addition was complete, the mixture was stirred under ice bath conditions for 2 hours. The reaction mixture was poured into ice water, and ammonia was slowly added dropwise to adjust the pH to approximately 9. The mixture was extracted with ethyl acetate, and the organic phase was separated and dried. After concentrating the organic solvent under reduced pressure, crude 3-(5-fluoro-2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (1.26 g) was obtained and used directly in the next reaction step.

[0510] MS m / z(ESI): 239.2 [M+H] + .

[0511] Step 3: Preparation of 1-cyclopropyl-3-(5-fluoro-2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole

[0512]

[0513] 3-(5-fluoro-2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (600 mg, 2.52 mmol), copper acetate (688 mg, 3.8 mmol), 2,2'-bipyridine (590 mg, 3.8 mmol), and sodium carbonate (534 mg, 5.0 mmol) were mixed in 1,2-dichloroethane (5 mL). Cyclopropylboronic acid (865 mg, 10.0 mmol) was added at room temperature, and the mixture was heated to 85 °C and stirred overnight. After cooling the reaction solution to room temperature, it was diluted with a large amount of ethyl acetate. The organic phase was washed several times with saturated brine, then dried over anhydrous sodium sulfate. After concentrating the organic solvent under reduced pressure, column chromatography was used to obtain the title compound 1-cyclopropyl-3-(5-fluoro-2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (260 mg, 38%).

[0514] 1 H NMR (400MHz, CDCl3) δ1.16-1.20(m,2H),1.24-1.27(m,2H),3.64-3.73 (m,1H),3.94(s,3H),7.52-7.54(m,1H),7.98-8.01(m,1H),8.23(s,1H);

[0515] MS m / z(ESI): 279.0 [M+H] + .

[0516] Step 4: Preparation of 3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyaniline

[0517]

[0518] Palladium / carbon (60 mg) was added to a methanol (5 mL) solution of 1-cyclopropyl-3-(5-fluoro-2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (260 mg, 0.93 mmol). After reacting for 8 hours under a hydrogen atmosphere at ambient temperature and pressure, the catalyst was removed by filtration with diatomaceous earth. The organic solvent was concentrated under reduced pressure to obtain the title compound 3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyaniline (230 mg), which was used directly in the next reaction.

[0519] MS m / z(ESI): 249.2 [M+H] +.

[0520] Step 5: Preparation of 6-chloro-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0521]

[0522] At room temperature, a tetrahydrofuran solution of LiHMDS (1M, 2.78mL, 2.78mmol) was added dropwise to a tetrahydrofuran solution of 3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyaniline (230mg, 0.93mmol) and 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (194mg, 0.93mmol). After stirring the reaction solution at room temperature for 2 hours, it was quenched with a saturated ammonium chloride aqueous solution. The reaction solution was diluted with dichloromethane, the organic phase was washed several times with saturated brine, and then the organic phase was separated, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain the title compound 6-chloro-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (290 mg, 74%).

[0523] MS m / z(ESI): 421.2 [M+H] + .

[0524] Step 6: Preparation of 6-(cyclopropylcarbamate)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0525]

[0526] 6-Chloro-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (155 mg, 0.37 mmol), cyclopropylamide (62 mg, 0.74 mmol), and cesium carbonate (360 mg, 1.1 mmol) were mixed in dioxane (5 mL), and tris(dibenzylideneacetone)dipalladium (101 mg, 0.11 mmol) and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (127 mg, 0.22 mmol) were added. The mixture was deoxygenated under nitrogen for 5 minutes and then microwaved at 145 °C for 2 hours. The reaction solution was diluted with dichloromethane, the organic phase was washed several times with saturated brine, and then the organic phase was separated, dried with anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure and separated by column chromatography to obtain the title compound 6-(cyclopropylcarbamate)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (116 mg, 67%).

[0527] 1 H NMR(400MHz, CDCl3)δ0.90-0.95(m,2H),1.11-1.16(m,4H),1.21-1.26 (m,2H),1.74-1.80(m,1H),3.65-3.71(m,1H),3.80(s,3H),7.22-7.25(m,1H),7.5 1-7.54(m,1H),8.03(s,1H),8.19(s,1H),8.29(s,1H),9.59(s,1H),11.21(s,1H);

[0528] MS m / z (ESI): 470.2 [M+H] + .

[0529] Example 4

[0530] 6-(cyclopropylcarbamate)-4-((2-methoxy-5-methyl-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0531]

[0532] The preparation method of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-5-methyl-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0533] MS m / z (ESI): 440.2 [M+H] + .

[0534] Example 5

[0535] 4-((3-(1-allyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarbamate)-N-(methyl-d3)pyridazine-3-carboxamide

[0536]

[0537] Step 1: Preparation of 3-(2-methoxy-3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole

[0538]

[0539] At -20°C, a 10 mL solution of SEM-Cl (0.964 mL, 5.45 mmol) in dichloromethane was slowly added dropwise to a 20 mL solution of 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (1.00 g, 4.54 mmol), DMAP (55.0 mg, 0.454 mmol), and DIPEA (1.05 mL, 6.36 mmol). After the addition was complete, the temperature was slowly raised to -10°C and stirred overnight at this temperature. The reaction mixture was washed with saturated brine, the organic phase was separated and dried, filtered, and the organic solvent was concentrated under reduced pressure. The crude product 3-(2-methoxy-3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole was used directly in the next reaction step.

[0540] MS m / z (ESI): 351.2 [M+H] + .

[0541] Step 2: Preparation of 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)aniline

[0542]

[0543] The crude product was dissolved in a mixture of ethanol (30 mL) and water (5 mL), and then ammonium chloride solid (1.60 g, 30.0 mmol) and reduced iron powder (1.67 g, 30.0 mmol) were added sequentially. The mixture was stirred at 50 °C for 2 hours, and then the reaction system was cooled. The insoluble matter was filtered off with diatomaceous earth. After the filtrate was concentrated, the residue was dissolved in dichloromethane and washed with saturated brine. After separating the organic phase, the residue was dried with a drying agent, filtered, and the organic solvent was concentrated under reduced pressure. Column chromatography was used to separate the title compound 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)aniline (650 mg, two-step yield: 45%).

[0544] MS m / z(ESI): 321.2 [M+H] + .

[0545] Step 3: Preparation of 6-chloro-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0546]

[0547] At 0°C, LiHMDS (1M in THF, 5.00mL) was added dropwise to a THF solution (20mL) of 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)aniline (640mg, 2.00mmol) and 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (417mg, 2.00mmol). After the addition was complete, the temperature was slowly raised to room temperature and stirred at room temperature for 2 hours. The solution was quenched with saturated brine, then extracted twice with DCM. The organic phases were combined, dried, and the organic solvent was concentrated under reduced pressure. The solution was then separated by column chromatography to obtain the title compound 6-chloro-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (780 mg, 79%).

[0548] MS m / z(ESI): 493.2 [M+H] + .

[0549] Step 4: Preparation of 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0550]

[0551] 6-Chloro-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (850 mg, 1.73 mmol), cyclopropionamide (372 mg, 4.38 mmol) and cesium carbonate (2.14 g, 6.57 mmol) were mixed in 1,4-dioxane (20 mL), and the reaction solution was eluted with nitrogen to remove oxygen for 5 minutes. Then Pd2(dba)3 (400 mg, 0.438 mmol) and Xantphos (506 mg, 0.876 mmol) were added sequentially. Under nitrogen protection, the reaction was heated at 130°C in the microwave for 90 minutes, cooled to room temperature, and the organic solvent was concentrated under reduced pressure before column chromatography to obtain the title compound 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (680 mg, 73%).

[0552] MS m / z (ESI): 542.3 [M+H] + .

[0553] Step 5: Preparation of 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0554]

[0555] At 0 °C, TFA (6.0 mL) was added to a DCM solution of 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazin-3-carboxamide (630 mg, 1.16 mmol), and the mixture was stirred overnight at room temperature. The next day, the organic solvent was concentrated under reduced pressure, the residue was dissolved in DCM, and then washed successively with saturated sodium bicarbonate aqueous solution and saturated brine. After drying the organic phase, it was concentrated under reduced pressure and separated by column chromatography to obtain the title compound 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazin-3-carboxamide (270 mg, 57%).

[0556] 1H NMR (400MHz, CDCl3) δ0.99-1.03(m,2H),1.10-1.14(m,2H),1.80-1.88 (m,1H),3.71(s,3H),7.29-7.38(m,1H),7.42-7.50(m,1H),7.98-8.10(m,4H),11.37(br s,1H);

[0557] MS m / z(ESI): 412.2 [M+H] + .

[0558] Step 6: Preparation of 4-((3-(1-allyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarbamate)-N-(methyl-d3)pyridazine-3-carboxamide

[0559]

[0560] 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazin-3-carboxamide (30 mg, 0.073 mmol), allyl bromide (8.7 mg, 0.073 mmol), and potassium carbonate (20 mg, 0.15 mmol) were mixed in MeCN (3 mL) and stirred at 0 °C for 2 days. The reaction mixture was concentrated under reduced pressure and separated by column chromatography to obtain the title compound 4-((3-(1-allyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarbamate)-N-(methyl-d3)pyridazin-3-carboxamide (12 mg, 39%).

[0561] 1 H NMR(400MHz, CDCl3)δ0.88-0.92(m,2H),1.10-1.12(m,2H),1.80-1.85 (m,1H),3.80(s,3H),4.86-4.88(m,2H),5.35-5.38(m,2H),6.03-6.11(m,1H) ,7.27-7.31(m,1H),7.52(d,J=8.0Hz,1H),7.80(d,J=8.0Hz,1H),8.03(s,1H), 8.15(s,1H),8.24(s,1H),9.88(br s,1H),11.05(s,1H);

[0562] MS m / z (ESI): 452.2 [M+H] + .

[0563] Example 6

[0564] 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0565]

[0566] Step 1: Preparation of 3-(2-methoxy-3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole

[0567]

[0568] At -20°C, a 10 mL solution of SEM-Cl (0.964 mL, 5.45 mmol) in dichloromethane was slowly added dropwise to a 20 mL solution of 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (1.00 g, 4.54 mmol), DMAP (55.0 mg, 0.454 mmol), and DIPEA (1.05 mL, 6.36 mmol). After the addition was complete, the temperature was slowly raised to -10°C and stirred overnight at this temperature. The reaction mixture was washed with saturated brine, the organic phase was separated and dried, filtered, and the organic solvent was concentrated under reduced pressure. The crude product 3-(2-methoxy-3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole was used directly in the next reaction step.

[0569] MS m / z (ESI): 351.2 [M+H] + .

[0570] Step 2: Preparation of 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)aniline

[0571]

[0572] The crude product was dissolved in a mixture of ethanol (30 mL) and water (5 mL), and then ammonium chloride solid (1.60 g, 30.0 mmol) and reduced iron powder (1.67 g, 30.0 mmol) were added sequentially. The mixture was stirred at 50 °C for 2 hours, and then the reaction system was cooled. The insoluble matter was filtered off with diatomaceous earth. After the filtrate was concentrated, the residue was dissolved in dichloromethane and washed with saturated brine. After separating the organic phase, the residue was dried with a drying agent, filtered, and the organic solvent was concentrated under reduced pressure. Column chromatography was used to separate the title compound 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)aniline (650 mg, two-step yield: 45%).

[0573] MS m / z(ESI): 321.2 [M+H] + .

[0574] Step 3: Preparation of 6-chloro-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0575]

[0576] At 0°C, LiHMDS (1M in THF, 5.00mL) was added dropwise to a THF solution (20mL) of 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)aniline (640mg, 2.00mmol) and 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (417mg, 2.00mmol). After the addition was complete, the temperature was slowly raised to room temperature and stirred at room temperature for 2 hours. The solution was quenched with saturated brine, then extracted twice with DCM. The organic phases were combined, dried, and the organic solvent was concentrated under reduced pressure. The solution was then separated by column chromatography to obtain the title compound 6-chloro-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (780 mg, 79%).

[0577] MS m / z(ESI): 493.2 [M+H] + .

[0578] Step 4: Preparation of 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0579]

[0580] 6-Chloro-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (850 mg, 1.73 mmol), cyclopropionamide (372 mg, 4.38 mmol) and cesium carbonate (2.14 g, 6.57 mmol) were mixed in 1,4-dioxane (20 mL), and the reaction solution was eluted with nitrogen to remove oxygen for 5 minutes. Then Pd2(dba)3 (400 mg, 0.438 mmol) and Xantphos (506 mg, 0.876 mmol) were added sequentially. Under nitrogen protection, the reaction was heated at 130°C in the microwave for 90 minutes, cooled to room temperature, and the organic solvent was concentrated under reduced pressure before column chromatography to obtain the title compound 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (680 mg, 73%).

[0581] MS m / z (ESI): 542.3 [M+H] + .

[0582] Step 5: Preparation of 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0583]

[0584] At 0 °C, TFA (6.0 mL) was added to a 20 mL solution of 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazin-3-carboxamide (630 mg, 1.16 mmol) in DCM, and the mixture was stirred overnight at room temperature. The next day, the organic solvent was concentrated under reduced pressure, the residue was dissolved in DCM, and then washed successively with saturated sodium bicarbonate aqueous solution and saturated brine. After drying the organic phase, it was concentrated under reduced pressure and separated by column chromatography to obtain the title compound 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazin-3-carboxamide (270 mg, 57%).

[0585] 1H NMR(400MHz, CDCl3)δ0.99-1.03(m,2H),1.10-1.14(m,2H),1.80-1.88 (m,1H),3.71(s,3H),7.29-7.38(m,1H),7.42-7.50(m,1H),7.98-8.10(m,4H),11.37 (br s,1H);

[0586] MS m / z(ESI): 412.2 [M+H] + .

[0587] Step 6: Preparation of 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0588]

[0589] 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazin-3-carboxamide (30 mg, 0.073 mmol), bromopropyne (8.7 mg, 0.073 mmol), and potassium carbonate (20 mg, 0.15 mmol) were mixed in MeCN (3 mL) and stirred at 0 °C for 2 days. The reaction mixture was concentrated under reduced pressure and separated by column chromatography to obtain the title compound 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazin-3-carboxamide (10 mg, 31%).

[0590] 1 H NMR(400MHz, CDCl3)δ0.88-0.93(m,2H),1.10-1.14(m,2H),1.75-1.82 (m,1H),2.62(s,1H),3.81(s,3H),5.07(s,2H),7.26-7.30(m,1H),7.52(d,J=8.0 Hz,1H),7.82(d,J=8.0Hz,1H),8.00(s,1H),8.23(s,1H),8.38(s,1H),9.88(br s,1H),11.13(s,1H);

[0591] MS m / z (ESI): 450.2 [M+H] + .

[0592] Example 7

[0593] 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-(3-methyloxobutylcyclo-3-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0594]

[0595] The preparation method of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(3-methyloxobutylcyclo-3-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0596] 1 H NMR(400MHz, CDCl3)δ0.91-0.93(m,2H),1.08-1.13(m,2H),1.72-1.75 (m,1H),2.07(s,3H),3.86(s,3H),4.71(d,J=6.6Hz,2H),5.25(d,J=6.4Hz,2H),7 .28-7.30(m,1H),7.52-7.55(m,1H),7.82-7.85(m,1H)8.05(s,1H),8.23-8.25(m, 2H),9.31(s,1H),11.16(s,1H);

[0597] MS m / z(ESI): 482.2 [M+H] + .

[0598] Example 8

[0599] 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(oxobutylcyclo-3-ylmethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0600]

[0601] The preparation method of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(oxobutylcyclo-3-ylmethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 6.

[0602] 1H NMR(400MHz, CDCl3)δ0.91-0.94(m,2H),1.08-1.14(m,2H),3.55-3.62 (m,1H),3.81(s,3H),4.54-4.59(m,4H),4.80-4.90(m,2H),7.27-7.29(m,1H),7.5 0-7.52(m,1H),7.80-7.82(m,1H),8.06(s,1H),8.13(s,1H),8.20(s,1H),9.14(s, 1H),11.09(s,1H);

[0603] MS m / z(ESI): 482.2 [M+H] + .

[0604] Example 9

[0605] 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0606]

[0607] Step 1: Preparation of 3-(2-methoxy-3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole

[0608]

[0609] At -20°C, a 10 mL solution of SEM-Cl (0.964 mL, 5.45 mmol) in dichloromethane was slowly added dropwise to a 20 mL solution of 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (1.00 g, 4.54 mmol), DMAP (55.0 mg, 0.454 mmol), and DIPEA (1.05 mL, 6.36 mmol). After the addition was complete, the temperature was slowly raised to -10°C and stirred overnight at this temperature. The reaction mixture was washed with saturated brine, the organic phase was separated and dried, filtered, and the organic solvent was concentrated under reduced pressure. The crude product 3-(2-methoxy-3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole was used directly in the next reaction step.

[0610] MS m / z (ESI): 351.2 [M+H] + .

[0611] Step 2: Preparation of 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)aniline

[0612]

[0613] The crude product was dissolved in a mixture of ethanol (30 mL) and water (5 mL), and then ammonium chloride solid (1.60 g, 30.0 mmol) and reduced iron powder (1.67 g, 30.0 mmol) were added sequentially. The mixture was stirred at 50 °C for 2 hours, and then the reaction system was cooled. The insoluble matter was filtered off with diatomaceous earth. After the filtrate was concentrated, the residue was dissolved in dichloromethane and washed with saturated brine. After separating the organic phase, the residue was dried with a drying agent, filtered, and the organic solvent was concentrated under reduced pressure. Column chromatography was used to separate the title compound 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)aniline (650 mg, two-step yield: 45%).

[0614] MS m / z(ESI): 321.2 [M+H] + .

[0615] Step 3: Preparation of 6-chloro-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0616]

[0617] At 0°C, LiHMDS (1M in THF, 5.00mL) was added dropwise to a THF solution (20mL) of 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)aniline (640mg, 2.00mmol) and 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (417mg, 2.00mmol). After the addition was complete, the temperature was slowly raised to room temperature and stirred at room temperature for 2 hours. The solution was quenched with saturated brine, then extracted twice with DCM. The organic phases were combined, dried, and the organic solvent was concentrated under reduced pressure. The solution was then separated by column chromatography to obtain the title compound 6-chloro-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (780 mg, 79%).

[0618] MS m / z(ESI): 493.2 [M+H] + .

[0619] Step 4: Preparation of 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0620]

[0621] 6-Chloro-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (850 mg, 1.73 mmol), cyclopropionamide (372 mg, 4.38 mmol) and cesium carbonate (2.14 g, 6.57 mmol) were mixed in 1,4-dioxane (20 mL), and the reaction solution was eluted with nitrogen to remove oxygen for 5 minutes. Then Pd2(dba)3 (400 mg, 0.438 mmol) and Xantphos (506 mg, 0.876 mmol) were added sequentially. Under nitrogen protection, the reaction was carried out at 130°C in a microwave oven for 90 minutes. After cooling to room temperature and concentrating the organic solvent under reduced pressure, column chromatography was used to separate the title compound 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (680 mg, 73%).

[0622] MS m / z (ESI): 542.3 [M+H] + .

[0623] Step 5: Preparation of 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0624]

[0625] At 0 °C, TFA (6.0 mL) was added to a DCM solution of 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazin-3-carboxamide (630 mg, 1.16 mmol), and the mixture was stirred overnight at room temperature. The next day, the organic solvent was concentrated under reduced pressure, the residue was dissolved in DCM, and then washed successively with saturated sodium bicarbonate aqueous solution and saturated brine. After drying the organic phase, it was concentrated under reduced pressure and separated by column chromatography to obtain the title compound 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazin-3-carboxamide (270 mg, 57%).

[0626] 1 H NMR(400MHz, CDCl3)δ0.99-1.03(m,2H),1.10-1.14(m,2H),1.80-1.88 (m,1H),3.71(s,3H),7.29-7.38(m,1H),7.42-7.50(m,1H),7.98-8.10(m,4H),11.37(br s,1H);

[0627] MS m / z(ESI): 412.2 [M+H] + .

[0628] Example 10

[0629] 6-(cyclopropylcarbamoyl)-4-((5-fluoro-2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0630]

[0631] The preparation method of 6-(cyclopropylcarbamoyl)-4-((5-fluoro-2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 6.

[0632] 1H NMR(400MHz,DMSO-d6)δ0.84-0.87(m,2H),1.23-1.34(m,2H), 2.09-2.12(m,1H),3.60(s,1H),3.75(s,3H),5.24(s,2H),7.39-7.47(m,2H),8.26(s, 1H),8.72(s,1H),9.19(s,1H),11.20(s,1H),11.41(s,1H);

[0633] MS m / z (ESI): 468.2 [M+H] + .

[0634] Example 11

[0635] 6-(cyclopropylcarbamoyl)-4-((3-(1-(cyclopropylmethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0636]

[0637] The preparation method of 6-(cyclopropylcarbamoyl)-4-((3-(1-(cyclopropylmethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0638] 1 H NMR(400MHz, CDCl3)δ0.44-0.48(m,2H),0.70-0.76(m,2H),0.86-0.93 (m,2H),1.08-1.11(m,2H),1.33-1.40(m,1H),1.82-1.89(m,1H),3.82(s,3H),4.10 (d,J=7.2Hz,2H),7.25-7.30(m,1H),7.50-7.54(m,1H),7.80-7.83(m,1H),8.02(s,1H),8.23-8.25(m,2H),9.98(s,1H),11.04(s,1H);

[0639] MS m / z (ESI): 466.2 [M+H] + .

[0640] II. Evaluation of Compound Biological Testing

[0641] The present invention will be further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present invention.

[0642] Test Example 1: Determination of the inhibitory effect of the compounds of this invention on the TYK2 signaling pathway in cells.

[0643] Experimental objective: The purpose of this test case is to test the activity of the compound in inhibiting the TYK2 signaling pathway in cells.

[0644] Experimental apparatus:

[0645] The centrifuge (5702R) was purchased from Eppendorf.

[0646] The pipette was purchased from Eppendorf.

[0647] The microplate reader was purchased from BioTek Inc. in the United States, model SynergyH1 full-function microplate reader.

[0648] Experimental Methods: This experiment used the U266 cell line expressing TYK2. The TYK2 signaling pathway was activated by INF-α stimulation. The inhibitory activity of the compound on the phosphorylation of downstream STAT3 was detected, and the half-maximal inhibitory concentration (IC50) of the compound on the activity of the TYK2 signaling pathway was determined. 50 .

[0649] The specific experimental procedure is as follows:

[0650] 3-12 μL of U266 cells were seeded into each well of a 384-well plate (100-300 cells per well). 2 μL of serially diluted compound solution was added, and the plate was incubated in a CO2 incubator for 2 hours. After 2 hours, 2 μL of INF-α (final concentration 1000 U / mL) was added, and the plate was shaken at room temperature for 20 minutes. 2-5 μL of (5X) LANCE Ultra Lysis Buffer 2 solution was added, and the plate was shaken at room temperature for 2 hours. After 2 hours, 5 μL of LANCE Ultra Eu-labeled Anti-STAT5 (Y694 / Y699) Antibody (PerkinElmer) solution (final concentration 2 nM) and LANCE Ultra U Light-labeled Anti-STAT5 Antibody (PerkinElmer) solution (final concentration 20 nM) were added, and the plate was incubated overnight at room temperature. The fluorescence signal value at 665 nm was measured using a microplate reader. The inhibition rate was calculated from the fluorescence signal value, and the IC50 of the compound was obtained by curve fitting based on the inhibition rate at different concentrations. 50 .

[0651] Experimental data processing methods:

[0652] The percentage inhibition data for the wells treated with the compound were calculated using positive control wells (DMSO control wells) and negative control wells (no cells) on a plate: {% inhibition rate = 100 - [(test compound value - negative control value)] / (positive control value - negative control value) × 100}. The IC50 was calculated using a GraphPad Prism approximation to fit different concentrations and corresponding percentage inhibition rate data to a 4-parameter nonlinear logic formula. 50 value.

[0653] Experimental conclusion:

[0654] The activity data of the compounds in the embodiments of the present invention in inhibiting the TYK2 signaling pathway in cells, obtained through the above methods, are shown in the table below:

[0655] Compound numbering Cell viability U266 pSTAT3 (nM) Example 1 1.41 Example 2 2.43 Example 3 0.83 Example 4 4.95 Example 5 0.34 Example 6 0.13 Example 7 0.90 Example 8 1.88 Example 9 4.60 Example 10 2.10 Example 11 3.43

[0656] Experimental conclusion: The cellular activity IC50 of the compounds in the embodiments of this invention is [not specified]. 50 Less than 5 nM, exhibiting excellent activity.

[0657] Test Example 2: Determination of the inhibitory effect of the compounds of the present invention on the JAK2 signaling pathway in cells.

[0658] Experimental objective: The purpose of this test case is to test the activity of the compound of the present invention in inhibiting the JAK2 signaling pathway in cells.

[0659] Experimental apparatus:

[0660] The centrifuge (5702R) was purchased from Eppendorf.

[0661] The pipette was purchased from Eppendorf.

[0662] The microplate reader was purchased from BioTek Inc. in the United States, model SynergyH1 full-function microplate reader.

[0663] Experimental Methods: This experiment used the TF-1 cell line. The JAK2 signaling pathway was activated by IL-6 stimulation. The inhibitory activity of the compound on downstream STAT3 phosphorylation was detected, and the half-maximal inhibitory concentration (IC50) of the compound on the JAK2 signaling pathway activity was determined. 50 .

[0664] The specific experimental procedure is as follows:

[0665] 3-12 μL of TF-1 cells were seeded into each well of a 384-well plate (100-300 cells per well). 2 μL of serially diluted compound solution was added, and the plate was incubated in a CO2 incubator for 2 hours. After 2 hours, 2 μL of IL-6 (30 ng / mL) was added, and the plate was shaken at room temperature for 20 minutes. 2-5 μL of (5X) LANCE Ultra Lysis Buffer 2 solution was added, and the plate was shaken at 4°C for 2 hours. After 2 hours, 5 μL of LANCE Ultra Eu-labeled Anti-STAT3 (Tyr705) Antibody (PerkinElmer) solution (final concentration 2 nM) and LANCE Ultra U Light-labeled Anti-STAT3 Antibody (PerkinElmer) solution (final concentration 20 nM) were added, and the plate was incubated overnight at room temperature. The fluorescence signal value at 665 nm was measured using a microplate reader. The inhibition rate was calculated from the fluorescence signal value, and the IC50 of the compound was obtained by curve fitting based on the inhibition rate at different concentrations. 50 .

[0666] Experimental data processing methods:

[0667] The percentage inhibition data for the wells treated with the compound were calculated using positive control wells (DMSO control wells) and negative control wells (no cells) on a plate: {% inhibition rate = 100 - [(test compound value - negative control value)] / (positive control value - negative control value) × 100}. The IC50 was calculated using a GraphPad Prism approximation to fit different concentrations and corresponding percentage inhibition rate data to a 4-parameter nonlinear logic formula. 50 value.

[0668] Experimental conclusion:

[0669] The activity data of the compound shown in the embodiments of the present invention in inhibiting the JAK2 signaling pathway in cells, obtained through the above methods, are shown in the table below:

[0670]

[0671] Experimental conclusion: As can be seen from the data in the table, the compounds in the examples showed higher selectivity for JAK2 cell activity compared to TYK2 cell activity.

[0672] Test Example 3: Plasma Protein Binding Rate Test in Mice

[0673] 1. Research Objective:

[0674] The purpose of this experiment was to evaluate the protein binding rate of the compound (5 μM) in mouse plasma using the balanced dialysis method.

[0675] 2. Compounds and experimental materials:

[0676] 1) Prepare a 10 mM stock solution of the test compound using DMSO and store it at -20°C until use;

[0677] 2) Frozen plasma and dialysate of the required species (100mM phosphate buffer (Lot#SLBS7904 and Lot#SLBR3106V), pH 7.4).

[0678] 3. Experimental Apparatus

[0679] 96-well plate (Lot#07917415), detection membrane device (Lot#SD2369421), liquid chromatography-tandem mass spectrometry (LC-MS / MS) (LC-20AD, API4000), centrifuge (Eppendorf 5804R / 5424R), vortex apparatus (IKA VORTEXGENIUS 3), pipettes (Eppendorf 10~100μL (PIP-100-002), Eppendorf 100~1000μL (PIP-1000-002), RAININ 0.5~10μL (PIP-10-002)), water bath (Shanghai Hengke).

[0680] 4. Experimental Procedure

[0681] 4.1 Preparation of dialysis solution

[0682] Take 4.01 mL of 1M K2HPO4 (AR grade) and 0.99 mL of 1M KH2PO4 (AR grade), dilute with ultrapure water to 50 mL, and prepare 100 mM phosphate buffer (pH = 7.4) as dialysate.

[0683] 4.2 Preparation of plasma

[0684] Thaw the frozen plasma at room temperature or in a 37°C water bath, centrifuge at 3500 rpm for 5 min, and collect the supernatant.

[0685] 4.3 Preparation of the reaction termination solution

[0686] Use acetonitrile (or other suitable solution) containing an internal standard as the stop solution and store it in a refrigerator at 2-8°C. The specific concentration of the internal standard can be found in the final report.

[0687] 4.4 Preparation of compound working solutions

[0688] Preparation of working solution for compound: Dilute stock solution with DMSO to a final concentration of 1 mM.

[0689] 4.5 Preparation of plasma solution

[0690] Add 4 μL of the compound working solution to 796 μL of blank plasma to a final concentration of 5 μM, and vortex to mix.

[0691] 4.6 Balanced Dialysis

[0692] 1) Prepare the equilibrium dialysis apparatus and place the detection membrane device into the equilibrium dialysis 96-well plate;

[0693] 2) Add 200 μL of the prepared plasma solution to the membrane, n = 2;

[0694] 3) Take another 4 μL of plasma solution, dilute it 10 times with 36 μL of blank plasma of the same species, add 160 μL of acetonitrile stop solution containing internal standard, and store it in a -20℃ freezer to obtain T0 (Total) sample;

[0695] 4) Add 350 μL of dialysis buffer (100 mM phosphate buffer) outside the membrane;

[0696] 5) Seal the dialysis plate and incubate it in a 37°C water bath for 6 hours;

[0697] 6) After dialysis, take 4 μL from the inner sample well and dilute it 10 times with 36 μL of blank plasma of the same species; take 40 μL of dialysate from the outer sample well and add 160 μL of acetonitrile stop solution with internal standard to obtain T6 (Total) sample and F6 (Total) sample.

[0698] 7) Collect the supernatant after centrifuging samples T0 (Total) and T6 (Total);

[0699] 8) LC-MS analysis.

[0700] 5. Experimental Results

[0701]

[0702]

[0703] Test Example 4: Pharmacokinetic Determination in Balb / C Mice

[0704] 1. Research Objective:

[0705] Using Balb / C mice as test animals, the pharmacokinetic behavior of the compounds in the compound examples in mouse plasma after oral administration at a dose of 5 mg / kg was studied.

[0706] 2. Test Plan

[0707] 2.1 Test Drugs:

[0708] The compounds used in this invention embodiment are self-made.

[0709] CMC-Na, Sigma-C9481-500G.

[0710] The pharmaceutical preparation is 0.5% CMC-Na (1% Tween 80), prepared in-house.

[0711] 2.2 Experimental animals:

[0712] Balb / C mice (6 mice per example), male, purchased from Shanghai Jiesijie Experimental Animal Co., Ltd., Animal Production License No. (SCXK (Hu) 2013-0006 No. 311620400001794).

[0713] 2.3 Administration:

[0714] Male Balb / C mice; after overnight fasting, the pharmaceutical preparation 0.5% CMC-Na (1% Tween 80) was orally administered (p.o.) separately at a dose of 5 mg / kg, with an administration volume of 10 mL / kg.

[0715] 2.4 Sample collection:

[0716] Before and after administration, 0.1 mL of blood was collected from the orbital vein of mice at 0, 0.5, 1, 2, 4, 6, 8 and 24 hours, placed in EDTA-K₂ tubes, centrifuged at 6000 rpm at 4°C for 6 min to separate plasma, and stored at -80°C.

[0717] 2.5 Sample processing:

[0718] 1) Add 160 μL of acetonitrile to 40 uL of plasma sample for precipitation, and centrifuge at 3500×g for 5 to 20 minutes after mixing.

[0719] 2) Take 100 μL of the treated supernatant for LC / MS / MS analysis to determine the concentration of the test compound.

[0720] 2.6 Liquid phase analysis

[0721] ·Liquid phase conditions: Shimadzu LC-20AD pump

[0722] ·Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer

[0723] ·Chromatographic column: phenomenex Gemini 5um C18 50×4.6mm

[0724] ·Mobile phase: Mobile phase A is 0.1% formic acid aqueous solution, mobile phase B is acetonitrile

[0725] ·Flow rate: 0.8mL / min

[0726] ·Elution time: 0-4.0 min, the eluent is as follows:

[0727]

[0728]

[0729] 3. Test Results and Analysis

[0730] Main pharmacokinetic parameters were calculated by WinNonlin 6.1, and the pharmacokinetic test results in mice are shown in the following table:

[0731] compound <![CDATA[t max (h)]]> <![CDATA[C max (ng / mL)]]> <![CDATA[AUC 0-t (ng / mL*h)]]> <![CDATA[AUC 0-∞ (ng / mL*h)]]> <![CDATA[t 1 / 2 (h)]]> <![CDATA[MRT 0-∞ (h)]]> BMS-986165 1.0 696 1987 2038 1.4 2.3 Example 1 0.5 3930 13590 14473 1.9 3.0 Example 2 0.5 2043 6250 6348 1.3 2.3 Example 3 1.0 2190 20991 21001 2.1 5.6 Example 6 1.0 939 2466 2637 2.0 2.8

[0732] Experimental conclusion: It can be seen from the data in the table that the in vivo pharmacokinetic exposure AUC of the example compound in mice 0-t (ng / mL*h) is superior to that of the reference compound BMS-986165.

[0733] Test Example 5 Pharmacokinetics at Different Doses in Balb / C Mice

[0734] 1. Research Objective:

[0735] Using Balb / C mice as test animals, the pharmacokinetic behavior in plasma of Example compound and reference compound BMS-986165 after oral administration at different doses in mice was studied.

[0736] 2. Test Protocol

[0737] 2.1 Test Drugs

[0738] The compound of the example of the present invention is self-made.

[0739] The pharmaceutical formulation is 0.5% CMC-Na (1% Tween80), self-made.

[0740] 2.2 Test Animals

[0741] Balb / C Mouse, male, supplied by Shanghai Jiesijie Experimental Animal Co., Ltd., Animal Production License No. (SCXK(Shanghai)2013-0006N0.311620400001794).

[0742] 2.3 Administration

[0743] Balb / C mice (3 animals per group), male; after overnight fasting, were administered p.o. respectively with 0.5% CMC-Na (1% Tween80) pharmaceutical formulation at doses of 1 mg / kg, 3 mg / kg and 10 mg / kg, respectively, with an administration volume of 10 mL / kg.

[0744] 2.4 Sample Collection:

[0745] Before and after drug administration, 0.1 mL of blood was collected from the orbital cavity of mice at 0, 0.5, 1, 2, 4, 6, 8 and 24 hours. The plasma was separated by centrifugation at 6000 rpm for 6 min at 4℃ and stored at -80℃.

[0746] 2.5 Sample preparation:

[0747] 3) Add 160 μL of acetonitrile to 40 μL of plasma sample to precipitate, mix, and centrifuge at 3500×g for 5–20 minutes.

[0748] 4) Take 100 μL of the supernatant solution after treatment and analyze the concentration of the analyte compound by LC / MS / MS.

[0749] 2.6 Liquid Chromatography Analysis

[0750] • Liquid phase conditions: Shimadzu LC-20AD pump

[0751] Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer

[0752] • Column: phenomenex Gemiu 5um C18 50×4.6mm

[0753] • Mobile phase: Solution A is a 0.1% formic acid aqueous solution, and solution B is acetonitrile.

[0754] • Flow rate: 0.8 mL / min

[0755] • Elution time: 0-4.0 minutes, eluent as follows:

[0756]

[0757] 3. Experimental Results and Analysis

[0758] The results of pharmacokinetic studies in mice at different doses of Example 1 and the reference compound BMS-986165 are shown in the table below:

[0759]

[0760] Experimental conclusion: As can be seen from the data in the table, the AUC of the pharmacokinetics in mice in Example 1 was [data missing]. 0-t (ng / mL*h) showed a dose-dependent effect and was superior to the reference compound BMS-986165 at the same dose.

[0761] Test Example 6: Determination of the efficacy of the compounds of the present invention at different doses against an imiquimod-induced mouse psoriasis-like model.

[0762] 1. Experimental Objective

[0763] The efficacy of the compound at different doses in an imiquimod-induced mouse psoriasis-like model was evaluated.

[0764] 2. Main instruments and reagents for the experiment

[0765] 2.1 Instruments

[0766] Instrument and equipment name model factory Electronic balance SQP type SECURA225D-1CN Sartorius Electronic balance MP5002 Shanghai Sunny Hengping

[0767] 2.2 Reagents

[0768] name batch number Brand / Item Number Imiquimod Cream GTH110C Aldara CMC-Na SLBV9664 C9481-500G

[0769] 3. Experimental Procedure

[0770] 3.1 Modeling

[0771] Day 0: Shave the test area on the animal's back. Days 1-6: Apply 62.5 mg imiquimod to the test area on the animal's back once daily.

[0772] 3.2 Administration

[0773] From Day 1 to Day 7, animals in each group were administered drugs according to the experimental protocol. The experimental design for the imiquimod-induced mouse psoriasis-like model is shown in the table below:

[0774]

[0775] Prescription: 0.5% CMC-Na (1% Tween 80)

[0776] 3.3 Severity Index Score for Dermatitis Skin Damage

[0777] From Day 1 to Day 7, the redness, scaling, and thickening of the test area on the animal's back were scored from 0 to 4. 0: No damage; 1: Slight; 2: Moderate; 3: Obvious; 4: Very obvious. The total score indicates the severity of the damage.

[0778] 3.4 Plot PASI-time and calculate the area under the curve (AUC). PASI score AUC (total score curve) change percentage % = (AUC of the treated group - AUC of the model group) / AUC of the model group * 100%.

[0779] 4. Experimental Data

[0780] 4.1 The comparison results of PASI scores in a mouse psoriasis model induced by imiquimod at different doses of the compound are shown in the table below:

[0781]

[0782]

[0783] 4.2 PASI scores of different doses of the compound in an imiquimod-induced mouse psoriasis model are as follows: Figure 57 As shown, the data points represent the mean AUC of the PASI score-time curve within the group, N=8. The One-way ANOVA was used to compare the vehicle group, and ***p<0.001.

[0784] 5. Experimental Results

[0785] As can be seen from the above results, Example 1 of the present invention can effectively improve psoriasis symptoms in the imiquimod-induced mouse psoriasis-like model, and has a highly significant difference compared with the Vehicle group (P<0.001). Example 1, at a dose of 1 mg / kg, achieved comparable improvement in psoriasis symptoms to the reference compound BMS-986165 at a dose of 3 mg / kg.

[0786] III. Study on the salts and crystal forms of compounds

[0787] As is well known to those skilled in the art, when the compounds of the above embodiments are shown to have significant pharmacological and pharmacodynamic activity against JAK1 / 2 / 3 / TYK2 kinases, their pharmaceutically acceptable salts often possess the same pharmacological and pharmacodynamic activity. Based on this, the inventors further investigated the physicochemical properties of the salt forms and crystal forms of the corresponding compounds. However, the specific preparation and characterization of the salt forms or crystal forms described below do not constitute a limitation on the scope of protection of this invention. Those skilled in the art can use this invention as a basis to obtain more salt forms and crystals of the compounds of this invention through conventional salt-forming or crystallization methods. These salt forms and crystals are all protected by this invention. Specifically, as follows:

[0788] 1. Experimental apparatus

[0789] 1.1. Some parameters of physicochemical testing instruments

[0790]

[0791]

[0792] 2. Research on the salt form of compounds

[0793] 2.1 Salt type screening of compounds in Example 1

[0794] 2.1.1 Experimental Objective:

[0795] Screening for the salt forms of compounds.

[0796] 2.1.2 Experimental Procedure:

[0797] 1) Instruments and equipment

[0798] name model source Analytical balance BSA224S-CW Sartorius Ultrasonic cleaner SK5200LHC Shanghai Kedao Ultrasonic Instruments pipette Eppendorf (50 mL, 1000 μL) Eppendorf

[0799] 2) Operating Procedures

[0800] ① Natural evaporation method using dichloromethane as solvent

[0801] Weigh 10 mg of the compound, add 700 μL of DCM, sonicate to dissolve, add 22 μL of the corresponding acid, and slowly evaporate at room temperature; for each portion that evaporates into an oil, add 0.1 ml of ethyl acetate, slurry at 50 °C, and centrifuge if solids precipitate, and dry under vacuum at 50 °C to obtain the salt of the compound.

[0802]

[0803]

[0804] ② Salt preparation using the dissolution-crystallization method

[0805] Take 25 mg of the compound, add 1 ml of organic solvent to make a concentration of 25 mg / ml, stir at 50 °C, add the corresponding counterionic acid at a molar ratio of 1:1.2, stir overnight, and observe the phenomenon.

[0806]

[0807]

[0808] Weigh 15 mg of free base, add 300 μL of solvent, stir at 50 °C, add the corresponding acid at a molar ratio of 1:1.2, continue stirring overnight, and observe the phenomenon.

[0809]

[0810]

[0811]

[0812]

[0813]

[0814]

[0815]

[0816] 2.1.3 Experimental Results

[0817] Salt type screening experiments revealed that the compounds that can form salts with free bases are benzenesulfonic acid, hydrobromide, phosphate, p-methylbenzenesulfonate, hydroxyethylsulfonate, and ethanesulfonic acid.

[0818] As described above, those skilled in the art can obtain more medicinal salts using conventional methods based on the present invention.

[0819] 2.2 Salt type screening of compounds in Example 6

[0820] 2.2.1 Experimental Objective:

[0821] Different counterionic acids were selected to detect which counterionic acids could form compound salts.

[0822] 2.2.2 Experimental Procedure:

[0823] 1) Instruments and equipment

[0824] name model source Analytical balance BSA224S-CW Sartorius Ultrasonic cleaner SK5200LHC Shanghai Kedao Ultrasonic Instruments pipette Eppendorf (50 mL, 1000 μL) Eppendorf

[0825] 2) Operating Procedures

[0826] ① Salt formation by natural evaporation using dichloromethane as solvent

[0827] Weigh 10 mg of free base, add 0.8 ml of dichloromethane to dissolve it, add different counterionic acids according to the base:acid molar ratio of 1:1.1, mix well, let stand at room temperature, and wait for the solvent to evaporate.

[0828]

[0829]

[0830] ② Preparation of methanesulfonates by dissolution with different solvents

[0831] Weigh 20 mg of free base and add 0.4 ml of ethyl acetate, acetonitrile, acetone, toluene, methanol, 2-butanone, and dioxane, respectively. Stir at 50 °C and add a 1.0 M methanol solution of methanesulfonic acid at a base: acid ratio of 1:1.1.

[0832]

[0833] ③ Preparation of hydrobromide by dissolution in different solvents

[0834] Weigh 10 mg of free base and add it to different solvents to make a concentration of 50 mg / ml. Stir at 50°C and add 1 M hydrobromic acid ethanol solution at a ratio of 1:1.1. Observe the phenomenon.

[0835]

[0836]

[0837] 2.2.3 Experimental Results

[0838] Salt type screening experiments revealed that the acids capable of forming salts are hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, oxalic acid, p-toluenesulfonic acid, benzenesulfonic acid, and hydroxyethylsulfonic acid. As described above, those skilled in the art can obtain more pharmaceutically usable salts based on this invention and using conventional methods.

[0839] 3. Study on the crystal form of compound salts

[0840] 3.1 Crystal form study of the salt of the compound in Example 1

[0841] 3.1.1 Experimental Objective:

[0842] Screening for salts that form the crystal form of compounds.

[0843] 3.1.2 Experimental Procedure:

[0844] 1) Instruments and equipment

[0845] name model source Analytical balance BSA224S-CW Sartorius Ultrasonic cleaner SK5200LHC Shanghai Kedao Ultrasonic Instruments pipette Eppendorf (50 mL, 1000 μL) Eppendorf

[0846] 2) Operating Procedures

[0847] ① Natural evaporation method using dichloromethane as solvent

[0848] Weigh 10 mg of free base, add 700 μL of DCM, sonicate to dissolve, add 22 μL of the corresponding acid, and slowly evaporate at room temperature; for each portion that evaporates into oil, add 0.1 ml of ethyl acetate, slurry at 50 °C, and centrifuge if solids precipitate, dry under vacuum at 50 °C, and measure its XRD.

[0849]

[0850]

[0851] ② Salt crystallization is achieved using the dissolution method or suspension reaction.

[0852] Take 25 mg of free base, add 1 ml of organic solvent to make its concentration 25 mg / ml, stir at 50 °C, add the corresponding counterion acid at a molar ratio of 1:1.2, stir overnight, and observe the phenomenon.

[0853]

[0854]

[0855] Weigh 15 mg of free base, add 300 μL of solvent, stir at 50 °C, add the corresponding acid at a molar ratio of 1:1.2, continue stirring overnight, and observe the phenomenon.

[0856]

[0857]

[0858] 3.1.3 Experimental Results

[0859] Through experiments studying the crystal forms of the salts of this compound, the following crystalline salt forms were obtained: hydrobromide, sulfate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, hydroxyethylsulfonate, phosphate, and ethanesulfonate.

[0860] 3.2 Crystal form screening of the salt in Example 1

[0861] 3.2.1 Experimental Objective:

[0862] Screening the crystal form of the salt in Example 1.

[0863] 3.2.2 Experimental Procedure:

[0864] 1) Instruments and equipment

[0865] name model source Analytical balance BSA224S-CW Sartorius Ultrasonic cleaner SK5200LHC Shanghai Kedao Ultrasonic Instruments pipette Eppendorf (50 mL, 1000 μL) Eppendorf

[0866] 2) Operating Procedures

[0867] ① Preparation of benzenesulfonate crystal form A

[0868] Weigh 25 mg of free base, add 1 mL of toluene, stir at 50 °C, and slowly add 60.9 μL of 1 M benzenesulfonic acid methanol solution while stirring. After adding acid, the solution dissolves completely. Let it stand overnight, and a solid precipitates. Centrifuge, discard the supernatant, and dry under vacuum at 50 °C to constant weight to obtain benzenesulfonate crystal form A. Analysis shows that it has the following properties: Figure 9 The XRPD diagram shown is as follows: Figure 10 The DSC diagram shown and as follows Figure 11 The TGA diagram shown.

[0869] ② Preparation of phosphate crystal form A

[0870] Weigh 15 mg of free base and add 300 μL of dimethyltetrahydrofuran. Stir at 50 °C, and slowly add 36.3 μL of 1 M phosphoric acid in methanol while stirring. If the solution does not dissolve completely after acid addition, stir for 4 hours, centrifuge, discard the supernatant, and dry under vacuum at 50 °C to constant weight to obtain phosphate crystal form A. Analysis shows that it has the following properties: Figure 3 The XRPD diagram shown is as follows: Figure 4 The DSC diagram shown and as follows Figure 5 The TGA diagram shown.

[0871] ③ Preparation of phosphate crystal form B

[0872] Weigh 15 mg of free base and add 300 μL of ethyl acetate. Stir at 50 °C, and slowly add 36.3 μL of 1 M phosphoric acid in methanol while stirring. If the solution does not dissolve completely after acid addition, stir for 4 hours, centrifuge, discard the supernatant, and dry under vacuum at 50 °C to constant weight to obtain phosphate crystal form B. Analysis shows that it has the following properties: Figure 6 The XRPD diagram shown is as follows: Figure 7 The DSC diagram shown and as follows Figure 8 The TGA diagram shown.

[0873] ④ Preparation of hydrobromide crystal form A

[0874] Weigh 15 mg of free base, add 300 μL of ethanol, and stir at 50 °C. While stirring, slowly add 36.3 μL of 1 M hydrobromic acid in methanol. If the solution does not dissolve completely after acid addition, stir for 4 hours, centrifuge, discard the supernatant, and dry under vacuum at 50 °C to constant weight to obtain hydrobromide crystal form A. Analysis shows that it possesses the following properties: Figure 1 The XRPD diagram shown and as follows Figure 2 The DSC diagram shown.

[0875] ④ Preparation of free alkali crystal form A

[0876] 10.0 g of 6-(cyclopropylcarbamate)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide was added to a 250 ml reaction flask, followed by N-methylpyrrolidone (3V, 30 ml). The mixture was heated to 95°C, and the reaction solution was a clear brown liquid. Isopropanol (6V, 60 ml) was added dropwise. After the addition was complete, the mixture was kept warm and stirred for 1 hour. The heating was then turned off, and the mixture was allowed to cool naturally to room temperature, resulting in the precipitation of a large amount of solid. The mixture was cooled in an ice bath and stirred for 1 hour. After filtration, the solid was washed with isopropanol (10 ml) and dried to obtain 8.1 g of a yellow solid. Analysis showed that the solid exhibited the following properties: Figure 48 The XRPD map shown is as follows: Figure 49 The DSC spectrum shown is as follows: Figure 50 The TGA spectrum shown.

[0877] ⑤ Preparation of free alkali crystal form B

[0878] 2.0 g of 6-(cyclopropylcarbamate)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide was added to a 100 mL reaction flask, along with ethyl acetate (1V, 2.5 mL) and n-heptane (10V, 25 mL). The mixture was stirred and homogenized at room temperature for 24 hours. After filtration, the resulting solid was washed with n-heptane (5 mL) and dried to obtain 1.9 g of a yellow solid. Analysis revealed the following properties: Figure 54 The XRPD pattern shown is as follows: Figure 55 The DSC spectrum shown is as follows: Figure 56 The TGA spectrum shown.

[0879] 3.3 Crystal form study of the salt of the compound in Example 6

[0880] 3.3.1 Experimental Objective:

[0881] Different counterionic acids were selected to screen the crystal forms of the compound salts.

[0882] 3.3.2 Experimental Procedure:

[0883] 1) Instruments and equipment

[0884] name model source Analytical balance BSA224S-CW Sartorius Ultrasonic cleaner SK5200LHC Shanghai Kedao Ultrasonic Instruments pipette Eppendorf (50 mL, 1000 μL) Eppendorf

[0885] 2) Operating Procedures

[0886] ① Salt formation by natural evaporation using dichloromethane as solvent

[0887] Weigh 10 mg of free base, add 0.8 ml of dichloromethane to dissolve it, add different counterionic acids according to the base:acid molar ratio of 1:1.1, mix well, let stand at room temperature, and wait for the solvent to evaporate.

[0888]

[0889]

[0890] ② Crystal forms of methanesulfonate prepared by dissolution and crystallization in different solvents

[0891] Weigh 20 mg of free base and add 0.4 ml of ethyl acetate, acetonitrile, acetone, toluene, methanol, 2-butanone, and dioxane, respectively. Stir at 50 °C and add a 1.0 M methanol solution of methanesulfonic acid at a base: acid ratio of 1:1.1.

[0892] Serial Number solvent Phenomena after adding acid Properties after centrifugation XRD results 1 Ethyl acetate Partially dissolved, quickly precipitated yellowish-white solid Crystal form 2 Acetonitrile Dissolve oily Crystal form 3 acetone Dissolve Yellow solid Crystal form 4 Toluene Dissolve Yellow solid Crystal form 5 methanol Dissolve clarify / 6 2-Butanone Dissolve Yellow solid Crystal form 7 Dioxane Dissolve before adding acid Yellow solid Crystal form

[0893] ③ Crystal forms of hydrobromide prepared by dissolution and crystallization in different solvents

[0894] Weigh 10 mg of free base and add it to different solvents to make a concentration of 50 mg / ml. Stir at 50°C and add 1.0 M hydrobromic acid ethanol solution at a ratio of 1:1.1. Observe the phenomenon.

[0895] Serial Number solvent Properties after centrifugation XRD results 1 Acetonitrile Yellow solid Crystal form 2 methanol Yellow solid Crystal form 3 chlorobenzene Yellow solid Crystal form 4 Isopropanol Yellow solid Crystal form 5 2-Butanone Yellow solid Crystal form 6 Isopropyl acetate Yellow solid Crystal form 7 3-Pentanone Yellow solid Crystal form 8 xylene Yellow solid Crystal form

[0896] 3.3.3 Experimental Results

[0897] Through salt type screening experiments, the crystalline salt types were found to be hydrobromic acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, oxalic acid, acetic acid, 1,5-naphthalenedisulfonic acid, and hydroxyethylsulfonic acid.

[0898] 3.4 Crystal form screening of salt in Example 6

[0899] 3.4.1 Experimental Objective:

[0900] Based on the screening results of the crystalline salts, a suitable crystallization method was selected to screen the crystal form of the salt in Example 6.

[0901] 3.4.2 Experimental Procedure:

[0902] 1) Instruments and equipment

[0903] name model source Analytical balance BSA224S-CW Sartorius Ultrasonic cleaner SK5200LHC Shanghai Kedao Ultrasonic Instruments pipette Eppendorf (50 mL, 1000 μL) Eppendorf

[0904] 2) Operating Procedures

[0905] Preparation of Hydrobromide Crystal Form A

[0906] Weigh 100 mg of free base, add 2 ml of ethanol, stir at 50 °C, add 242 μL of 1 M HBr ethanol solution, slowly dissolve until clear, transfer to room temperature and stir overnight, filter, and dry under vacuum at 50 °C to obtain hydrobromide crystal form A. Analysis showed that it possessed the following properties: Figure 12 The XRPD diagram shown is as follows: Figure 13 The DSC diagram shown and as follows Figure 14 The TGA diagram shown.

[0907] Preparation of II hydrobromide crystal form B

[0908] Weigh 10 mg of free base and add 200 μL of toluene. Stir at 50 °C, and while stirring, add 24.2 μL of 1 M hydrobromic acid in ethanol. The solution dissolves completely during acid addition, and a solid precipitates. Continue stirring for 2 hours, centrifuge, and dry under vacuum at 50 °C to obtain hydrobromide crystal form B. Analysis shows that it possesses the following properties: Figure 15 The XRPD diagram shown and as follows Figure 16 The DSC diagram shown.

[0909] Preparation of III hydrobromide crystal form C

[0910] Weigh 10 mg of free base and add 200 μL of tetrahydrofuran. Stir at 50 °C, and while stirring, add 24.2 μL of 1 M hydrobromic acid in ethanol. The solution dissolves completely during acid addition, and a solid precipitates. Continue stirring for 2 hours, centrifuge, and dry under vacuum at 50 °C to obtain hydrobromide crystal form C. Analysis shows that it possesses the following properties: Figure 17 The XRPD diagram shown and as follows Figure 18 The DSC diagram shown.

[0911] Preparation of IV hydrobromide crystal form D

[0912] Weigh 500 mg of free base, add 10 ml of ethanol, stir at 50 °C, and while stirring, add 1210 μL of 1 M hydrobromic acid in ethanol solution. The solution dissolves completely during acid addition. Transfer to room temperature and stir overnight. A solid precipitates. Filter and dry under vacuum at 50 °C to obtain hydrobromide crystal form D. Analysis shows that it has the following properties: Figure 19 The XRPD diagram shown is as follows: Figure 20 The DSC diagram shown and as follows Figure 21 The TGA diagram shown.

[0913] Preparation of V hydrobromide crystal form E

[0914] Weigh 10 mg of free base and add 200 μL of xylene. Stir at 50 °C, and while stirring, add 24.2 μL of 1 M hydrobromic acid in ethanol. The solution dissolves completely during acid addition. Transfer to room temperature and stir overnight. A solid precipitates. Centrifuge and dry under vacuum at 50 °C to obtain hydrobromide crystal form E. Analysis shows that it possesses the following properties: Figure 22 The XRPD diagram shown and as follows Figure 23 The DSC diagram shown.

[0915] Preparation of VI hydrobromide crystal form F

[0916] Weigh 10 mg of free base and add 200 μL of isopropyl acetate. Stir at 50 °C, and while stirring, add 24.2 μL of 1 M hydrobromic acid in ethanol. The solution dissolves completely during acid addition. Transfer to room temperature and stir overnight. A solid precipitates. Centrifuge and dry under vacuum at 50 °C to obtain hydrobromide crystal form F. Analysis shows that it possesses the following properties: Figure 24 The XRPD diagram shown and as follows Figure 25 The DSC diagram shown.

[0917] Preparation of VII phosphate crystal form A

[0918] Weigh 10 mg of free base, add 800 μL of dichloromethane, dissolve completely, then add 24.2 μL of 1 M phosphoric acid in ethanol solution; the solution becomes turbid. After the solvent evaporates, dry under vacuum at 50 °C for 2 hours to obtain phosphate crystal form A. Analysis shows that it has the following properties: Figure 26 The XRPD diagram shown is as follows: Figure 27 The DSC diagram shown and as follows Figure 28 The TGA diagram shown.

[0919] Preparation of VIII phosphate crystal form B

[0920] Weigh 10 mg of free base, add 200 μL of tetrahydrofuran, and if it does not dissolve completely, add 24 μL of 1 M phosphoric acid ethanol solution, and if it dissolves completely, stir for 30 minutes until turbidity appears. Centrifuge and dry under vacuum at 50 °C to obtain phosphate crystal form B. Analysis shows that it has the following properties: Figure 29 The XRPD diagram shown.

[0921] Preparation of IX methanesulfonic acid crystal form A

[0922] Weigh 200 mg of free base, add 4 mL of toluene, stir at 50 °C. If not completely dissolved, add 480 μL of 1 M methanesulfonic acid in methanol solution. If dissolved, continue stirring, and a solid precipitates. Filter, discard the supernatant, and dry under vacuum at 50 °C to obtain methanesulfonate crystal form A. Analysis shows that it has the following properties: Figure 30 The XRPD diagram shown and as follows Figure 31 The DSC diagram shown.

[0923] Preparation of X-methanesulfonic acid crystal form B

[0924] Weigh 20 mg of free base and add 400 μL of toluene. Stir at 50 °C. If no solution is found, add 48 μL of 1 M methanesulfonic acid in methanol and stir overnight. Centrifuge, discard the supernatant, and dry under vacuum at 50 °C to obtain methanesulfonate crystal form B. Analysis shows that it has the following properties: Figure 32 The XRPD diagram shown and as follows Figure 33 The DSC diagram shown.

[0925] Preparation of XI methanesulfonic acid crystal form C

[0926] Weigh 20 mg of free base and add 400 μL of ethyl acetate. Stir at 50 °C. If no solution is found, add 48 μL of 1 M methanesulfonic acid in methanol and stir overnight. Centrifuge, discard the supernatant, and dry under vacuum at 50 °C to obtain methanesulfonate crystal form C. Analysis shows that it has the following properties: Figure 34 The XRPD diagram shown and as follows Figure 35 The DSC diagram shown.

[0927] Preparation of XII methanesulfonic acid crystal form D

[0928] Weigh 20 mg of free base, add 400 μL of dioxane, stir at 50 °C until dissolved, add 48 μL of 1 M methanesulfonic acid in methanol, stir overnight, centrifuge, discard the supernatant, and dry under vacuum at 50 °C to obtain methanesulfonate crystal form D. Analysis showed that it possessed the following properties: Figure 36 The XRPD diagram shown and as follows Figure 37 The DSC diagram shown.

[0929] Preparation of XIII methanesulfonic acid crystal form E

[0930] Weigh 20 mg of free base, add 400 μL of acetonitrile, stir at 50 °C. If no solution is found, add 48 μL of 1 M methanesulfonic acid in methanol, stir overnight, centrifuge, discard the supernatant, and dry under vacuum at 50 °C to obtain methanesulfonate crystal form E. Analysis shows that it has the following properties: Figure 38 The XRPD diagram shown.

[0931] Preparation of XIV methanesulfonic acid crystal form F

[0932] Weigh 100 mg of free base, add 2 mL of tetrahydrofuran, and slowly add 240 μL of 1 M methanesulfonic acid methanol solution while stirring. After dissolving completely, continue stirring overnight, filter, and dry the solid under vacuum at 50 °C to obtain methanesulfonate crystal form F. Analysis showed that it possessed the following properties: Figure 39 The XRPD diagram shown and as follows Figure 40 The DSC diagram shown.

[0933] Preparation of XV free base crystal form A

[0934] Weigh 10 mg of 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide into a 2 ml glass bottle, add 100 μL of toluene, and stir at 50 °C for 5 days. Centrifuge, discard the supernatant, and dry the remaining solid in a vacuum drying oven at 50 °C to constant weight to obtain 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide crystal form A, which has the following properties: Figure 51 The XRPD map shown is as follows: Figure 52 The DSC spectrum shown is as follows: Figure 53 The TGA spectrum shown.

[0935] 4. Solid stability test

[0936] 4.1 Solid stability test of the compound in Example 1

[0937] 4.1.1 Experimental Objective:

[0938] The study investigated the physicochemical stability of compound salts under high temperature, high humidity, high temperature and high humidity, and light conditions, providing a basis for salt form screening and compound salt storage.

[0939] 4.1.2 Instrument and Liquid Chromatography Analysis Conditions

[0940] Instruments and equipment:

[0941] Instrument Name model Analytical balance Sartorius BSA224S-CW Pure water machine Milli-Q Plus, Millipore High Performance Liquid Chromatography Agilent 1260 pump Agilent G1311B Injector G1329B Column oven G1316A detector G1315D

[0942] Chromatographic conditions:

[0943] Chromatographic column: ZORBAX (SB-C8, 3.5μm, 4.6*75mm)

[0944] Flow rate: 1 mL / min

[0945] Column temperature: 40℃

[0946] Detection wavelength: 240nm

[0947] Injection volume: 5.0 μL

[0948] Running time: 20 minutes

[0949] Diluent: DMSO

[0950] Mobile phase: A: Water (0.05% trifluoroacetic acid); B: Acetonitrile (0.05% trifluoroacetic acid)

[0951] T(min) A(％) B(％) 0.00 90 10 17.00 10 90 17.01 90 10 20.00 90 10

[0952] 4.1.3 Experimental Procedure:

[0953] Take about 2 mg of free alkali or different salts and place them in 60℃, 95%RH, 50℃ 75%RH and light chamber (5000lx±500lx) for 30 days. Determine the salt content by HPLC and external standard method, and calculate the changes of salt-related substances by chromatographic peak area normalization method.

[0954] 4.1.4 Experimental Results:

[0955] 1) Results of the physicochemical stability of the crystal form of the compound salt:

[0956]

[0957] Phosphate crystal form A, benzenesulfonate crystal form A, and hydrobromide crystal form A are all relatively stable under various conditions.

[0958] 4.2 Solid stability test of the compound in Example 6

[0959] 4.2.1 Experimental Objective:

[0960] The study investigates the physicochemical stability of the compound's free alkali crystal form A or its salt form under high temperature, high humidity, high temperature and high humidity, and light conditions, providing a basis for salt form screening and compound salt storage.

[0961] 4.2.2 Instrument and Liquid Chromatography Analysis Conditions

[0962] Instruments and equipment:

[0963] Instrument Name model Analytical balance Sartorius BSA224S-CW Pure water machine Milli-Q Plus, Millipore High Performance Liquid Chromatography Thermo U3000 pump LPG-3400SDN Injector WPS-3000TSL Column oven TCC-3000SD detector DAD-3000

[0964] Chromatographic conditions:

[0965] Chromatographic column: Waters Xbridge C18 (4.6mm*150mm, 3.5μm)

[0966] Flow rate: 1 mL / min

[0967] Column temperature: 35℃

[0968] Detection wavelength: 252nm

[0969] Injection volume: 10.0 μL

[0970] Running time: 13min

[0971] Diluent: ACN-water (v / v, 1:1)

[0972] Mobile phase: A: 50 μM phosphate buffer (pH 2.0); B: methanol

[0973] T(min) A(％) B(％) 0.00 85.0 15.0 7.00 30.0 70.0 10.00 30.0 70.0 10.01 85.0 15.0 13.00 85.0 15.0

[0974] 4.2.3 Experimental Scheme:

[0975] Take about 2 mg of free alkali or different salts and place them in 60℃, 95%RH, 50℃ 75%RH and light chamber (5000lx±500lx) for 10 days. Determine the salt content by HPLC and external standard method, and calculate the changes of salt-related substances by chromatographic peak area normalization method.

[0976] 4.2.4 Experimental Results:

[0977] 1) Results on the physicochemical stability of free base and salt:

[0978]

[0979] The data above show that the free alkali crystal form A, methanesulfonate crystal form F, hydrobromide crystal form A, and phosphate crystal form B are all relatively stable under various conditions.

[0980] 5. Hygroscopicity test

[0981] 5.1 Hygroscopicity test of the compound in Example 1

[0982] 5.1.1 Experimental Objective

[0983] The hygroscopicity of different salts of compounds under different relative humidity conditions was investigated to provide a basis for the screening and storage of compound salts.

[0984] 5.1.2 Experimental Procedure:

[0985] The compound salt was placed in saturated water vapor at different relative humidities to allow the compound to reach dynamic equilibrium with the water vapor, and the percentage of the compound's weight gain due to moisture absorption after equilibrium was calculated.

[0986] 5.1.3 Experimental Results:

[0987]

[0988]

[0989] Benzenesulfonate crystal form A gained 0.37% weight by absorbing moisture under RH 80% conditions, and after one cycle of moisture absorption and desorption under 0-95% relative humidity, the XRPD spectrum of benzenesulfonate crystal form A did not change, that is, the crystal form did not change.

[0990] 5.1.4 Experimental Conclusions

[0991] Benzenesulfonate crystal form A is slightly hygroscopic.

[0992] 5.2 Hygroscopicity test of the compound in Example 6

[0993] 5.2.1 Experimental Objective

[0994] The hygroscopicity of different salts of compounds under different relative humidity conditions was investigated to provide a basis for the screening and storage of compound salts.

[0995] 5.2.2 Experimental Procedure:

[0996] The compound salt was placed in saturated water vapor at different relative humidities to allow the compound to reach dynamic equilibrium with the water vapor, and the percentage of the compound's weight gain due to moisture absorption after equilibrium was calculated.

[0997] 5.2.3 Experimental Results:

[0998] ① Results of dynamic humidification experiment for hydrobromide crystal form A

[0999]

[1000]

[1001] Hydrobromide crystal form A gains 0.26% weight upon moisture absorption at 80% RH, indicating hygroscopicity. Furthermore, after one cycle of moisture absorption and desorption at 0-95% relative humidity, the XRPD spectrum of hydrobromide crystal form A remains unchanged, indicating no crystal form transformation.

[1002] ② Results of dynamic humidification experiment of hydroxyethyl sulfonate crystal form B

[1003]

[1004] Hydroxyethyl sulfonate crystal form B gains 1.79% weight upon moisture absorption at 80% RH, indicating hygroscopicity. Furthermore, after one cycle of moisture absorption and desorption at 0-95% relative humidity, the XRPD spectrum of hydroxyethyl sulfonate crystal form B remained unchanged, indicating no crystal form transformation.

[1005] ③ Results of dynamic humidification experiment for oxalate crystal form A

[1006]

[1007]

[1008] Oxalate crystal form A gains 0.88% weight upon moisture absorption at 80% RH, indicating hygroscopicity. Furthermore, after one cycle of moisture absorption and desorption at 0-95% relative humidity, the XRPD spectrum of oxalate crystal form A remains unchanged, meaning the crystal form does not transform.

[1009] ④ Results of dynamic humidification experiment for phosphate crystal form B

[1010]

[1011] Phosphate crystal form B gains 4.09% weight upon moisture absorption at 80% RH, indicating hygroscopicity. Furthermore, after one cycle of moisture absorption and desorption at 0-95% relative humidity, the XRPD spectrum of phosphate crystal form B remained unchanged, meaning the crystal form did not transform.

[1012] 5.2.4 Experimental Conclusions

[1013] Hydrobromide crystal form A, hydroxyethyl sulfonate crystal form B, oxalate crystal form A, and phosphate crystal form B did not change their crystal forms after one cycle of moisture absorption and desorption under relative humidity of 0-95%.

[1014] 6. Solubility experiments in different media

[1015] 6.1 Solubility experiment of compound in different media in Example 1

[1016] 6.1.1 Experimental Objective

[1017] Comparing the solubility of free base crystal form A, benzenesulfonate crystal form A, phosphate crystal form A, and hydrobromide crystal form A in different pH media, water, artificial gastric juice (FaSSGF), fasting artificial intestinal juice (FaSSIF), and non-fasting artificial intestinal juice (FeSSIF) provides a basis for assessing the druggability of salts.

[1018] 6.1.2 Instrument and Liquid Chromatography Analysis Conditions

[1019] Instruments and equipment:

[1020] Instrument Name model Analytical balance Sartorius BSA224S-CW Pure water machine Milli-Q Plus, Millipore High Performance Liquid Chromatography Agilent 1260 pump Agilent G1311B Injector G1329B Column oven G1316A detector G1315D

[1021] Chromatographic conditions:

[1022] Chromatographic column: ZORBAX (SB-C8, 3.5μm, 4.6*75mm)

[1023] Flow rate: 1 mL / min

[1024] Column temperature: 40℃

[1025] Detection wavelength: 240nm

[1026] Injection volume: 5.0 μL

[1027] Running time: 20 minutes

[1028] Diluent: DMSO

[1029] Mobile phase: A: Water (0.05% trifluoroacetic acid); B: Acetonitrile (0.05% trifluoroacetic acid)

[1030] T(min) A(％) B(％) 0.00 90 10 17.00 10 90 17.01 90 10 20.00 90 10

[1031] 6.1.3 Experimental Procedure:

[1032] Approximately 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.

[1033] 6.1.4 Experimental Results: As shown in the table.

[1034]

[1035] 6.1.5 Experimental Conclusions

[1036] After salt formation, the solubility of the compound in aqueous medium is significantly increased.

[1037] 6.2 Solubility Experiment of Compound 6 in Different Media in Example 6

[1038] 6.2.1 Experimental Objective

[1039] Comparing the solubility of free alkali crystal form A, hydrobromide crystal form A, hydroxyethyl sulfonic acid crystal form B, methanesulfonic acid crystal form F, and phosphate crystal form B in water, artificial simulated gastric juice (FaSSGF), fasting artificial simulated intestinal juice (FaSSIF), and non-fasting artificial simulated intestinal juice (FeSSIF) provides a basis for assessing the druggability of salts.

[1040] 6.2.2 Instrument and Liquid Chromatography Analysis Conditions

[1041] Instruments and equipment:

[1042] Instrument Name model Analytical balance Sartorius BSA224S-CW Pure water machine Milli-Q Plus, Millipore High Performance Liquid Chromatography Thermo U3000 pump LPG-3400SDN Injector WPS-3000TSL Column oven TCC-3000SD detector DAD-3000

[1043] Chromatographic conditions:

[1044] Chromatographic column: Waters Xbridge C18 (4.6mm*150mm, 3.5μm)

[1045] Flow rate: 1 mL / min

[1046] Column temperature: 35℃

[1047] Detection wavelength: 252nm

[1048] Injection volume: 10.0 μL

[1049] Running time: 13min

[1050] Diluent: ACN-water (v / v, 1:1)

[1051] Mobile phase: A: 50 μM phosphate buffer (pH 2.0); B: methanol

[1052] T(min) A(％) B(％) 0.00 85.0 15.0 7.00 30.0 70.0 10.00 30.0 70.0 10.01 85.0 15.0 13.00 85.0 15.0

[1053] 6.2.3 Experimental Procedure:

[1054] Approximately 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.

[1055] 6.2.4 Experimental Results (mg / mL):

[1056]

[1057]

[1058] 6.2.5 Experimental Conclusions

[1059] After salt formation, the solubility of the compound in aqueous medium is significantly increased.

[1060] 7. Thermodynamic stability experiment

[1061] 7.1 Polymorph Screening and Thermodynamic Stability Confirmation Experiments of Compounds in Example 1

[1062] 7.1.1 Experimental Objective:

[1063] Thermodynamically stable benzenesulfonate crystals were obtained through polycrystalline screening.

[1064] 7.1.2 Experimental Procedure:

[1065] Select an organic solvent and water with a certain solubility, suspend the compound in the solvent system, stir and slurry at room temperature for 1 week, centrifuge, discard the supernatant, dry the solid under vacuum at 40℃ (-0.1Mpa) overnight, determine the XRPD of the solid, and compare it with the XRPD of the raw material compound salt.

[1066] 7.1.3 Experimental Results:

[1067] By pulping and changing the crystallization solvent and crystallization method, only one crystal form of benzenesulfonate, namely benzenesulfonate crystal form A, can be obtained.

[1068] 7.2 Polymorph Screening and Thermodynamic Stability Confirmation Experiments of Compounds in Example 6

[1069] 7.2.1 Experimental Objective:

[1070] Thermodynamically stable hydrobromide crystals were obtained through polycrystalline screening.

[1071] 7.2.2 Experimental Procedure:

[1072] Select an organic solvent and water with a certain solubility, suspend the compound in the solvent system, stir and slurry at room temperature for 1 week, centrifuge, discard the supernatant, dry the solid under vacuum at 50°C (-0.1 MPa) overnight, determine the XRPD of the solid, and compare it with the XRPD of the raw material compound salt.

[1073] 7.2.3 Experimental Results:

[1074] By pulping and changing the crystallization solvent and crystallization method, only six crystal forms of hydrobromide were obtained: crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, and crystal form F. Comparing the DSC spectra of the six crystal forms, it can be determined that crystal form A of hydrobromide is the thermodynamically stable crystal form.

Claims

1. An acidic salt of a compound, characterized in that, The compound is selected from the following compounds: The acid in the acid salt is selected from inorganic or organic acids, wherein the inorganic acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, or phosphoric acid, and the organic acid is selected from 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphtholic acid, methanesulfonic acid, oxalic acid, hydroxyethylsulfonic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxyxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetaminobenzoic acid, 4-aminobenzoic acid, decanoic acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfonic acid, camphorsulfonic acid, aspartic acid, gluconic acid, glucuronic acid, glutamic acid, and isocyanate. Ascorbic acid, lactic acid, L-malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecyl sulfate, dibenzoyl tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactobionic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, lactobionic acid, ascorbic acid, lauric acid, camphoric acid, maleic acid, malonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, palmitic acid, dihydroxynaphthalic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanate, undecanoic acid, trifluoroacetic acid, and p-toluenesulfonic acid.

2. The acid salt of the compound according to claim 1, characterized in that, The acid in the acid salt is selected from sulfuric acid, hydrobromic acid, phosphoric acid, benzenesulfonic acid, methanesulfonic acid, oxalic acid, hydroxyethylsulfonic acid, maleic acid, fumaric acid, adipic acid, p-toluenesulfonic acid, citric acid, malonic acid, or L-malic acid.

3. The acid salt of the compound according to claim 1, characterized in that, The acid salt is the acid salt of compound 6-(cyclopropylcarbamate)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, wherein the acid in the acid salt is selected from methanesulfonic acid, sulfuric acid, hydrobromic acid, phosphoric acid, benzenesulfonic acid, oxalic acid, hydroxyethylsulfonic acid, maleic acid, fumaric acid, adipic acid, p-toluenesulfonic acid, citric acid, malonic acid, or L-malic acid; Alternatively, it is an acid salt of compound 6-(cyclopropylcarbamate)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, wherein the acid in the acid salt is selected from methanesulfonic acid, sulfuric acid, hydrobromic acid, phosphoric acid, benzenesulfonic acid, oxalic acid, hydroxyethylsulfonic acid, maleic acid, fumaric acid, adipic acid, p-toluenesulfonic acid, citric acid, malonic acid, or L-malic acid; Alternatively, it is an acid salt of compound 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, wherein the acid in the acid salt is selected from methanesulfonic acid, sulfuric acid, hydrobromic acid, phosphoric acid, benzenesulfonic acid, oxalic acid, hydroxyethylsulfonic acid, maleic acid, fumaric acid, adipic acid, p-toluenesulfonic acid, citric acid, malonic acid, or L-malic acid.

4. The acid salt of the compound according to any one of claims 1-3, characterized in that, The number of acids is 0.2-3.

5. The acid salt of the compound according to claim 4, characterized in that, The number of acids is 0.2, 0.5, 1, 1.5, 2, 2.5 or 3.

6. An acidic salt crystal form of 6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, characterized in that, The crystal form is: Hydrobromic acid crystal form A, wherein the X-ray powder diffraction pattern of hydrobromic acid crystal form A has diffraction peaks at any 7 locations among 2θ values ​​of 7.6±0.2°, 24.7±0.2°, 22.9±0.2°, 14.2±0.2°, 21.2±0.2°, 7.0±0.2°, 14.7±0.2°, 17.2±0.2°, 13.8±0.2°, and 10.3±0.2°; Phosphate crystal form A, wherein the X-ray powder diffraction pattern of phosphate crystal form A has diffraction peaks at any 7 locations among 2θ values ​​of 8.0±0.2°, 14.5±0.2°, 7.2±0.2°, 20.0±0.2°, 25.1±0.2°, 14.8±0.2°, 21.8±0.2°, 15.9±0.2°, 19.7±0.2°, and 15.3±0.2°; Phosphate crystal form B, wherein the X-ray powder diffraction pattern of phosphate crystal form B has diffraction peaks at any 7 of the following 2θ values: 7.8±0.2°, 19.5±0.2°, 8.6±0.2°, 23.5±0.2°, 14.6±0.2°, 23.2±0.2°, 25.1±0.2°, 15.6±0.2°, 21.6±0.2°, and 14.3±0.2°. Alternatively, benzenesulfonate crystal form A, wherein the X-ray powder diffraction pattern of benzenesulfonate crystal form A has diffraction peaks at any 7 locations among 2θ values ​​of 20.1±0.2°, 5.8±0.2°, 17.7±0.2°, 15.2±0.2°, 22.9±0.2°, 14.0±0.2°, 21.4±0.2°, 23.1±0.2°, 19.0±0.2°, and 17.4±0.2°.

7. The acid salt crystal form of a compound 6-(cyclopropylcarbamate)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, characterized in that, The crystal form is: Hydrobromic acid crystal form A, wherein the X-ray powder diffraction pattern of hydrobromic acid crystal form A has diffraction peaks at any 8 locations among 2θ values ​​of 7.6±0.2°, 24.7±0.2°, 22.9±0.2°, 14.2±0.2°, 21.2±0.2°, 7.0±0.2°, 14.7±0.2°, 17.2±0.2°, 13.8±0.2°, and 10.3±0.2°; Phosphate crystal form A, wherein the X-ray powder diffraction pattern of phosphate crystal form A has diffraction peaks at any 8 locations with 2θ values ​​of 8.0±0.2°, 14.5±0.2°, 7.2±0.2°, 20.0±0.2°, 25.1±0.2°, 14.8±0.2°, 21.8±0.2°, 15.9±0.2°, 19.7±0.2°, and 15.3±0.2°; Phosphate crystal form B, wherein the X-ray powder diffraction pattern of phosphate crystal form B has diffraction peaks at any 8 locations among 2θ values ​​of 7.8±0.2°, 19.5±0.2°, 8.6±0.2°, 23.5±0.2°, 14.6±0.2°, 23.2±0.2°, 25.1±0.2°, 15.6±0.2°, 21.6±0.2°, and 14.3±0.2°; Alternatively, benzenesulfonate crystal form A, wherein the X-ray powder diffraction pattern of benzenesulfonate crystal form A has diffraction peaks at any 8 locations within the range of 2θ: 20.1±0.2°, 5.8±0.2°, 17.7±0.2°, 15.2±0.2°, 22.9±0.2°, 14.0±0.2°, 21.4±0.2°, 23.1±0.2°, 19.0±0.2°, and 17.4±0.2°.

8. The crystal form according to claim 6, characterized in that: The X-ray powder diffraction pattern of the hydrobromic acid crystal form A includes three diffraction peaks located at 2θ of 7.6±0.2°, 24.7±0.2°, and 22.9±0.2°; and further includes four more peaks located at 2θ of 14.2±0.2°, 21.2±0.2°, 7.0±0.2°, 14.7±0.2°, and 17.2±0.2°. The X-ray powder diffraction pattern of the phosphate crystal form A includes three diffraction peaks located at 2θ of 8.0±0.2°, 14.5±0.2°, and 7.2±0.2°; and further includes four more peaks located at 2θ of 20.0±0.2°, 25.1±0.2°, 14.8±0.2°, 21.8±0.2°, and 15.9±0.2°. The X-ray powder diffraction pattern of the phosphate crystal form B includes three diffraction peaks located at 2θ of 7.8±0.2°, 19.5±0.2°, and 8.6±0.2°, and further includes four more peaks located at 2θ of 23.5±0.2°, 14.6±0.2°, 23.2±0.2°, 25.1±0.2°, and 15.6±0.2°. The X-ray powder diffraction pattern of the benzenesulfonate crystal form A includes three diffraction peaks located at 2θ of 20.1±0.2°, 5.8±0.2°, and 17.7±0.2°; and further includes four peaks located at 2θ of 15.2±0.2°, 22.9±0.2°, 14.0±0.2°, 21.4±0.2°, and 23.1±0.2°.

9. The crystal form according to claim 7, characterized in that: The X-ray powder diffraction pattern of the hydrobromic acid crystal form A includes three diffraction peaks located at 2θ of 7.6±0.2°, 24.7±0.2°, and 22.9±0.2°; and further includes five diffraction peaks located at 2θ of 14.2±0.2°, 21.2±0.2°, 7.0±0.2°, 14.7±0.2°, and 17.2±0.2°. The X-ray powder diffraction pattern of the phosphate crystal form A includes three diffraction peaks located at 2θ of 8.0±0.2°, 14.5±0.2°, and 7.2±0.2°; and further includes five diffraction peaks located at 2θ of 20.0±0.2°, 25.1±0.2°, 14.8±0.2°, 21.8±0.2°, and 15.9±0.2°. The X-ray powder diffraction pattern of the phosphate crystal form B includes three diffraction peaks located at 2θ of 7.8±0.2°, 19.5±0.2°, and 8.6±0.2°; and further includes five diffraction peaks located at 2θ of 23.5±0.2°, 14.6±0.2°, 23.2±0.2°, 25.1±0.2°, and 15.6±0.2°. The X-ray powder diffraction pattern of the benzenesulfonate crystal form A includes three diffraction peaks located at 2θ of 20.1±0.2°, 5.8±0.2°, and 17.7±0.2°; and further includes five diffraction peaks located at 2θ of 15.2±0.2°, 22.9±0.2°, 14.0±0.2°, 21.4±0.2°, and 23.1±0.2°.

10. The crystal form according to any one of claims 6-9, characterized in that: The X-ray powder diffraction pattern of the hydrobromic acid crystal form A also includes any two diffraction peaks located at 2θ of 13.8±0.2°, 10.3±0.2°, 26.4±0.2°, 11.3±0.2°, 27.2±0.2°, 25.6±0.2°, and 20.5±0.2°. The X-ray powder diffraction pattern of the phosphate crystal form A also includes any two diffraction peaks located at 2θ of 19.7±0.2°, 15.3±0.2°, 24.0±0.2°, 23.6±0.2°, 8.8±0.2°, 26.6±0.2°, and 22.7±0.2°. The X-ray powder diffraction pattern of the phosphate crystal form B also includes any two diffraction peaks located at 2θ of 21.6±0.2°, 14.3±0.2°, 24.7±0.2°, 7.1±0.2°, 21.2±0.2°, 28.9±0.2°, and 27.2±0.2°. The X-ray powder diffraction pattern of the benzenesulfonate crystal form A also includes any two diffraction peaks located at 2θ of 19.0±0.2°, 17.4±0.2°, 24.5±0.2°, 24.1±0.2°, 26.0±0.2°, 18.0±0.2°, and 23.5±0.2°.

11. The crystal form according to any one of claims 6-9, characterized in that: The X-ray powder diffraction pattern of the hydrobromic acid crystal form A includes 10 diffraction peaks selected from 2θ values ​​of 7.6±0.2°, 24.7±0.2°, 22.9±0.2°, 14.2±0.2°, 21.2±0.2°, 7.0±0.2°, 14.7±0.2°, 17.2±0.2°, 13.8±0.2°, 10.3±0.2°, 26.4±0.2°, 11.3±0.2°, 27.2±0.2°, 25.6±0.2°, and 20.5±0.2°. The X-ray powder diffraction pattern of the phosphate crystal form A includes 10 diffraction peaks selected from 2θ values ​​of 8.0±0.2°, 14.5±0.2°, 7.2±0.2°, 20.0±0.2°, 25.1±0.2°, 14.8±0.2°, 21.8±0.2°, 15.9±0.2°, 19.7±0.2°, 15.3±0.2°, 24.0±0.2°, 23.6±0.2°, 8.8±0.2°, 26.6±0.2°, and 22.7±0.2°. The X-ray powder diffraction pattern of the phosphate crystal form B includes 10 diffraction peaks located at 2θ values ​​of 7.8±0.2°, 19.5±0.2°, 8.6±0.2°, 23.5±0.2°, 14.6±0.2°, 23.2±0.2°, 25.1±0.2°, 15.6±0.2°, 21.6±0.2°, 14.3±0.2°, 24.7±0.2°, 7.1±0.2°, 21.2±0.2°, 28.9±0.2°, and 27.2±0.2°. The X-ray powder diffraction pattern of the benzenesulfonate crystal form A includes 10 diffraction peaks selected from 2θ values ​​of 20.1±0.2°, 5.8±0.2°, 17.7±0.2°, 15.2±0.2°, 22.9±0.2°, 14.0±0.2°, 21.4±0.2°, 23.1±0.2°, 19.0±0.2°, 17.4±0.2°, 24.5±0.2°, 24.1±0.2°, 26.0±0.2°, 18.0±0.2°, and 23.5±0.2°.

12. The crystal form according to any one of claims 6-9, characterized in that: The X-ray powder diffraction pattern of the hydrobromic acid crystal form A is shown in Figure 1; The X-ray powder diffraction pattern of the phosphate crystal form A is shown in Figure 3; The X-ray powder diffraction pattern of the phosphate crystal form B is shown in Figure 6. The X-ray powder diffraction pattern of the benzenesulfonate crystal form A is shown in Figure 9.

13. The crystal form according to claim 6, characterized in that, The 2θ error between the positions of the top ten diffraction peaks with the highest relative peak intensities in the X-ray powder diffraction patterns of hydrobromic acid crystal form A, phosphate crystal form A, phosphate crystal form B, and benzenesulfonate crystal form A and the corresponding positions of the diffraction peaks in the attached figure is ±0.2°.

14. The crystal form according to claim 6, characterized in that, The melting point of hydrobromic acid crystal form A is 230°C to 240°C; The melting point of the phosphate crystal form A is 220°C to 230°C; The melting point of the phosphate crystal form B is 225°C to 230°C; The melting point of the benzenesulfonate crystal form A is 205°C to 210°C.

15. The crystal form according to claim 6, characterized in that, The hydrobromic acid crystal form A has the DSC spectrum shown in Figure 2; The phosphate crystal form A has a DSC pattern as shown in Figure 4, or a TGA pattern as shown in Figure 5; The phosphate crystal form B has a DSC pattern as shown in Figure 7, or a TGA pattern as shown in Figure 8; The benzenesulfonate crystal form A has a DSC spectrum as shown in Figure 10, or a TGA spectrum as shown in Figure 11.

16. An acidic salt crystal form of a compound 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, characterized in that, The crystal form is: Hydrobromic acid crystal form A, wherein the X-ray powder diffraction pattern of hydrobromic acid crystal form A has diffraction peaks at any 7 locations among 25.1±0.2°, 8.2±0.2°, 22.7±0.2°, 31.1±0.2°, 18.7±0.2°, 23.4±0.2°, 29.1±0.2°, 17.5±0.2°, 13.1±0.2°, and 26.5±0.2°; Hydrobromic acid crystal form B, wherein the X-ray powder diffraction pattern of hydrobromic acid crystal form B has diffraction peaks at any 7 of the following positions: 7.0±0.2°, 26.5±0.2°, 21.8±0.2°, 20.3±0.2°, 15.4±0.2°, 14.1±0.2°, 24.0±0.2°, 27.6±0.2°, 13.7±0.2°, and 28.9±0.2°. Hydrobromic acid crystal form C, wherein the X-ray powder diffraction pattern of hydrobromic acid crystal form C has diffraction peaks at any 7 locations among 25.3±0.2°, 7.5±0.2°, 23.7±0.2°, 14.0±0.2°, 22.4±0.2°, 26.6±0.2°, 24.2±0.2°, 14.5±0.2°, and 15.1±0.2°; Hydrobromic acid crystal form D, wherein the X-ray powder diffraction pattern of hydrobromic acid crystal form D has diffraction peaks at any 7 locations among 6.5±0.2°, 6.8±0.2°, 21.5±0.2°, 13.2±0.2°, 17.0±0.2°, 25.8±0.2°, 26.6±0.2°, 10.2±0.2°, 24.6±0.2°, and 22.6±0.2°; Hydrobromic acid crystal form E, wherein the X-ray powder diffraction pattern of hydrobromic acid crystal form E has diffraction peaks at any 7 locations among 24.5±0.2°, 18.0±0.2°, 25.1±0.2°, 25.3±0.2°, 22.7±0.2°, 29.2±0.2°, 23.4±0.2°, 18.7±0.2°, 26.6±0.2°, and 13.9±0.2°; Hydrobromic acid crystal form F, wherein the X-ray powder diffraction pattern of said hydrobromic acid crystal form F has diffraction peaks at any 7 locations among 24.5±0.2°, 25.3±0.2°, 7.5±0.2°, 23.8±0.2°, 14.6±0.2°, 20.1±0.2°, 14.0±0.2°, 13.3±0.2°, 15.8±0.2°, and 22.4±0.2°; Phosphate crystal form A, with one acid atom, exhibits diffraction peaks in any seven of the following X-ray powder diffraction patterns at 2θ values ​​of 9.5±0.2°, 6.9±0.2°, 7.1±0.2°, 8.2±0.2°, 23.5±0.2°, 18.2±0.2°, 13.1±0.2°, 25.8±0.2°, 6.0±0.2°, and 13.8±0.2°. Phosphate crystal form B, with one acid atom, exhibits X-ray powder diffraction peaks at any seven locations within the range of 2θ: 4.6±0.2°, 9.4±0.2°, 22.1±0.2°, 21.0±0.2°, 12.6±0.2°, 7.9±0.2°, 17.3±0.2°, 18.8±0.2°, 15.1±0.2°, and 17.7±0.2°. Methanesulfonate crystal form A, with one acid atom, exhibits X-ray powder diffraction peaks at any seven 2θ values: 14.9±0.2°, 7.4±0.2°, 24.5±0.2°, 22.4±0.2°, 37.9±0.2°, 25.0±0.2°, 21.0±0.2°, 18.9±0.2°, 34.1±0.2°, and 28.5±0.2°. Methanesulfonate crystal form B, with one acid atom, exhibits X-ray powder diffraction peaks at any seven locations within the range of 2θ: 7.7±0.2°, 18.9±0.2°, 13.9±0.2°, 24.9±0.2°, 17.5±0.2°, 22.7±0.2°, 9.9±0.2°, 15.9±0.2°, 24.1±0.2°, and 20.3±0.2°. The methanesulfonate crystal form is C, with one acid atom. Its X-ray powder diffraction pattern shows diffraction peaks at any seven locations within the range of 2θ: 23.7±0.2°, 23.1±0.2°, 25.2±0.2°, 20.6±0.2°, 7.2±0.2°, 15.1±0.2°, 17.3±0.2°, 14.8±0.2°, 15.8±0.2°, and 21.4±0.2°. The methanesulfonate crystal form is D, with one acid atom. Its X-ray powder diffraction pattern shows diffraction peaks at any 7 locations within the range of 2θ: 20.3±0.2°, 7.6±0.2°, 17.7±0.2°, 18.0±0.2°, 24.9±0.2°, 18.8±0.2°, 21.5±0.2°, 9.6±0.2°, 24.4±0.2°, and 29.2±0.2°. The methanesulfonate crystal form is E, with one acid group. Its X-ray powder diffraction pattern shows diffraction peaks at any seven locations within the range of 2θ: 7.8±0.2°, 18.9±0.2°, 13.9±0.2°, 14.3±0.2°, 22.7±0.2°, 7.1±0.2°, 24.1±0.2°, 25.8±0.2°, 17.6±0.2°, and 24.9±0.2°. The methanesulfonate crystal form F, with one acid atom, exhibits X-ray powder diffraction peaks at any seven locations within the range of 2θ: 6.8±0.2°, 13.8±0.2°, 22.7±0.2°, 20.8±0.2°, 21.3±0.2°, 9.2±0.2°, 21.6±0.2°, 10.3±0.2°, 14.9±0.2°, and 26.4±0.2°. Oxalate crystal form A, with one acid atom, exhibits diffraction peaks in its X-ray powder diffraction pattern at any seven locations within the range of 2θ: 12.5±0.2°, 7.1±0.2°, 6.9±0.2°, 23.5±0.2°, 8.4±0.2°, 13.8±0.2°, 14.3±0.2°, 23.3±0.2°, 25.8±0.2°, and 13.1±0.2°. Hydroxyethyl sulfonate crystal form A, with one acid, exhibits X-ray powder diffraction peaks at any seven of the following 2θ values: 5.7±0.2°, 18.1±0.2°, 12.4±0.2°, 14.6±0.2°, 23.9±0.2°, 16.4±0.2°, 23.5±0.2°, 10.5±0.2°, and 21.2±0.2°. Hydroxyethyl sulfonate crystal form B, with one acid, exhibits X-ray powder diffraction peaks at any seven locations within the range of 2θ: 18.8±0.2°, 7.6±0.2°, 24.1±0.2°, 24.7±0.2°, 13.7±0.2°, 17.5±0.2°, 26.9±0.2°, 25.7±0.2°, 22.5±0.2°, and 25.9±0.2°.

17. An acidic salt crystal form of a compound 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, characterized in that, The crystal form is: Hydrobromic acid crystal form A, wherein the X-ray powder diffraction pattern of hydrobromic acid crystal form A has diffraction peaks at any 8 locations among 25.1±0.2°, 8.2±0.2°, 22.7±0.2°, 31.1±0.2°, 18.7±0.2°, 23.4±0.2°, 29.1±0.2°, 17.5±0.2°, 13.1±0.2°, and 26.5±0.2°; Hydrobromic acid crystal form B, wherein the X-ray powder diffraction pattern of hydrobromic acid crystal form B has diffraction peaks at any 8 locations selected from 7.0±0.2°, 26.5±0.2°, 21.8±0.2°, 20.3±0.2°, 15.4±0.2°, 14.1±0.2°, 24.0±0.2°, 27.6±0.2°, 13.7±0.2°, and 28.9±0.2°; Hydrobromic acid crystal form C, wherein the X-ray powder diffraction pattern of hydrobromic acid crystal form C has diffraction peaks at any 8 locations among 25.3±0.2°, 7.5±0.2°, 23.7±0.2°, 14.0±0.2°, 22.4±0.2°, 26.6±0.2°, 24.2±0.2°, 14.5±0.2°, and 15.1±0.2°; Hydrobromic acid crystal form D, wherein the X-ray powder diffraction pattern of hydrobromic acid crystal form D has diffraction peaks at any 8 locations among 6.5±0.2°, 6.8±0.2°, 21.5±0.2°, 13.2±0.2°, 17.0±0.2°, 25.8±0.2°, 26.6±0.2°, 10.2±0.2°, 24.6±0.2°, and 22.6±0.2°; Hydrobromic acid crystal form E, wherein the X-ray powder diffraction pattern of hydrobromic acid crystal form E has diffraction peaks at any 8 locations among 24.5±0.2°, 18.0±0.2°, 25.1±0.2°, 25.3±0.2°, 22.7±0.2°, 29.2±0.2°, 23.4±0.2°, 18.7±0.2°, 26.6±0.2°, and 13.9±0.2°; Hydrobromic acid crystal form F, wherein the X-ray powder diffraction pattern of said hydrobromic acid crystal form F has diffraction peaks at any 8 locations among 24.5±0.2°, 25.3±0.2°, 7.5±0.2°, 23.8±0.2°, 14.6±0.2°, 20.1±0.2°, 14.0±0.2°, 13.3±0.2°, 15.8±0.2°, and 22.4±0.2°; Phosphate crystal form A, with one acid atom, exhibits diffraction peaks in any 8 locations at 2θ values ​​of 9.5±0.2°, 6.9±0.2°, 7.1±0.2°, 8.2±0.2°, 23.5±0.2°, 18.2±0.2°, 13.1±0.2°, 25.8±0.2°, 6.0±0.2°, and 13.8±0.2°. Phosphate crystal form B, with one acid atom, exhibits diffraction peaks in any eight locations at 2θ values ​​of 4.6±0.2°, 9.4±0.2°, 22.1±0.2°, 21.0±0.2°, 12.6±0.2°, 7.9±0.2°, 17.3±0.2°, 18.8±0.2°, 15.1±0.2°, and 17.7±0.2°. Methanesulfonate crystal form A, with one acid atom, exhibits X-ray powder diffraction peaks at any eight locations with 2θ values ​​of 14.9±0.2°, 7.4±0.2°, 24.5±0.2°, 22.4±0.2°, 37.9±0.2°, 25.0±0.2°, 21.0±0.2°, 18.9±0.2°, 34.1±0.2°, and 28.5±0.2°. Methanesulfonate crystal form B, with one acid atom, exhibits X-ray powder diffraction peaks at any 8 locations within the range of 2θ: 7.7±0.2°, 18.9±0.2°, 13.9±0.2°, 24.9±0.2°, 17.5±0.2°, 22.7±0.2°, 9.9±0.2°, 15.9±0.2°, 24.1±0.2°, and 20.3±0.2°. The methanesulfonate crystal form is C, with one acid atom. Its X-ray powder diffraction pattern shows diffraction peaks at any 8 locations within the range of 2θ: 23.7±0.2°, 23.1±0.2°, 25.2±0.2°, 20.6±0.2°, 7.2±0.2°, 15.1±0.2°, 17.3±0.2°, 14.8±0.2°, 15.8±0.2°, and 21.4±0.2°. The methanesulfonate crystal form is D, with one acid atom. Its X-ray powder diffraction pattern shows diffraction peaks at any 8 locations within the range of 2θ: 20.3±0.2°, 7.6±0.2°, 17.7±0.2°, 18.0±0.2°, 24.9±0.2°, 18.8±0.2°, 21.5±0.2°, 9.6±0.2°, 24.4±0.2°, and 29.2±0.2°. The methanesulfonate crystal form is E, with one acid group. Its X-ray powder diffraction pattern shows diffraction peaks at any 8 locations within the range of 2θ: 7.8±0.2°, 18.9±0.2°, 13.9±0.2°, 14.3±0.2°, 22.7±0.2°, 7.1±0.2°, 24.1±0.2°, 25.8±0.2°, 17.6±0.2°, and 24.9±0.2°. The methanesulfonate crystal form F, with one acid atom, exhibits X-ray powder diffraction peaks at any eight locations within the range of 2θ: 6.8±0.2°, 13.8±0.2°, 22.7±0.2°, 20.8±0.2°, 21.3±0.2°, 9.2±0.2°, 21.6±0.2°, 10.3±0.2°, 14.9±0.2°, and 26.4±0.2°. Oxalate crystal form A, with one acid group, exhibits diffraction peaks in any eight locations at 2θ values ​​of 12.5±0.2°, 7.1±0.2°, 6.9±0.2°, 23.5±0.2°, 8.4±0.2°, 13.8±0.2°, 14.3±0.2°, 23.3±0.2°, 25.8±0.2°, and 13.1±0.2° in its X-ray powder diffraction pattern. Hydroxyethyl sulfonate crystal form A, with one acid, exhibits diffraction peaks in its X-ray powder diffraction pattern at any eight locations within the range of 2θ: 5.7±0.2°, 18.1±0.2°, 12.4±0.2°, 14.6±0.2°, 23.9±0.2°, 16.4±0.2°, 23.5±0.2°, 10.5±0.2°, and 21.2±0.2°. Hydroxyethyl sulfonate crystal form B, with one acid, exhibits diffraction peaks in any eight locations at 2θ values ​​of 18.8±0.2°, 7.6±0.2°, 24.1±0.2°, 24.7±0.2°, 13.7±0.2°, 17.5±0.2°, 26.9±0.2°, 25.7±0.2°, 22.5±0.2°, and 25.9±0.2°.

18. The crystal form according to claim 16, characterized in that: The X-ray powder diffraction pattern of the hydrobromic acid crystal form A includes three diffraction peaks located at 2θ of 25.1±0.2°, 8.2±0.2°, and 22.7±0.2°, and further includes at least four diffraction peaks located at 2θ of 31.1±0.2°, 18.7±0.2°, 23.4±0.2°, 29.1±0.2°, and 17.5±0.2°. The X-ray powder diffraction pattern of the hydrobromic acid crystal form B includes three diffraction peaks located at 2θ of 7.0±0.2°, 26.5±0.2°, and 21.8±0.2°; and further includes four more peaks located at 2θ of 20.3±0.2°, 15.4±0.2°, 14.1±0.2°, 24.0±0.2°, and 27.6±0.2°. The X-ray powder diffraction pattern of the hydrobromic acid crystal form C includes three diffraction peaks located at 2θ of 25.3±0.2°, 7.5±0.2°, and 23.7±0.2°; and further includes four more peaks located at 2θ of 14.0±0.2°, 22.4±0.2°, 11.7±0.2°, 26.6±0.2°, and 24.2±0.2°. The X-ray powder diffraction pattern of the hydrobromic acid crystal form D includes three diffraction peaks located at 2θ of 6.5±0.2°, 6.8±0.2°, and 21.5±0.2°; and further includes four more peaks located at 2θ of 13.2±0.2°, 17.0±0.2°, 25.8±0.2°, 26.6±0.2°, and 10.2±0.2°. The X-ray powder diffraction pattern of the hydrobromic acid crystal form E includes three diffraction peaks located at 2θ of 24.5±0.2°, 18.0±0.2°, and 25.1±0.2°; and further includes four more peaks located at 2θ of 25.3±0.2°, 22.7±0.2°, 29.2±0.2°, 23.4±0.2°, and 18.7±0.2°. The X-ray powder diffraction pattern of the hydrobromic acid crystal form F includes three diffraction peaks located at 2θ of 24.5±0.2°, 25.3±0.2°, and 7.5±0.2°; and further includes four more peaks located at 2θ of 23.8±0.2°, 14.6±0.2°, 20.1±0.2°, 14.0±0.2°, and 13.3±0.2°. The X-ray powder diffraction pattern of the phosphate crystal form A includes three diffraction peaks located at 2θ of 9.5±0.2°, 6.9±0.2°, and 7.1±0.2°; and further includes four peaks located at 2θ of 8.2±0.2°, 23.5±0.2°, 18.2±0.2°, 13.1±0.2°, or 25.8±0.2°. The X-ray powder diffraction pattern of the phosphate crystal form B includes three diffraction peaks located at 2θ of 4.6±0.2°, 9.4±0.2°, and 22.1±0.2°; and further includes four peaks located at 2θ of 21.0±0.2°, 12.6±0.2°, 7.9±0.2°, 17.3±0.2°, or 18.8±0.2°. The X-ray powder diffraction pattern of the methanesulfonate crystal form A includes three diffraction peaks located at 2θ of 14.9±0.2°, 7.4±0.2°, and 24.5±0.2°; and further includes four peaks located at 2θ of 22.4±0.2°, 37.9±0.2°, 25.0±0.2°, 21.0±0.2°, or 18.9±0.2°. The X-ray powder diffraction pattern of the methanesulfonate crystal form B includes three diffraction peaks located at 2θ of 7.7±0.2°, 18.9±0.2°, and 13.9±0.2°; and further includes four peaks located at 2θ of 24.9±0.2°, 17.5±0.2°, 22.7±0.2°, 9.9±0.2°, or 15.9±0.2°. The X-ray powder diffraction pattern of the methanesulfonate crystal form C includes three diffraction peaks located at 2θ of 23.7±0.2°, 23.1±0.2°, and 7.2±0.2°; and further includes four peaks located at 2θ of 25.2±0.2°, 20.6±0.2°, 15.1±0.2°, 17.3±0.2°, or 14.8±0.2°. The X-ray powder diffraction pattern of the methanesulfonate crystal form D includes three diffraction peaks located at 2θ of 20.3±0.2°, 7.6±0.2°, and 17.7±0.2°; and further includes four peaks located at 2θ of 18.0±0.2°, 24.9±0.2°, 18.8±0.2°, 21.5±0.2°, or 9.6±0.2°. The X-ray powder diffraction pattern of the methanesulfonate crystal form E includes three diffraction peaks located at 2θ of 7.8±0.2°, 18.9±0.2°, and 13.9±0.2°; and further includes four peaks located at 2θ of 14.3±0.2°, 22.7±0.2°, 7.1±0.2°, 24.1±0.2°, or 25.8±0.2°. The X-ray powder diffraction pattern of the methanesulfonate crystal form F includes three diffraction peaks located at 2θ of 6.8±0.2°, 13.8±0.2°, and 22.7±0.2°; and further includes four peaks located at 2θ of 20.8±0.2°, 21.3±0.2°, 9.2±0.2°, 21.6±0.2°, or 10.3±0.2°. The X-ray powder diffraction pattern of the oxalate crystal form A includes three diffraction peaks located at 2θ of 12.5±0.2°, 7.1±0.2°, or 6.9±0.2°; and further includes four peaks located at 2θ of 23.5±0.2°, 8.4±0.2°, 13.8±0.2°, 14.3±0.2°, or 23.3±0.2°. The X-ray powder diffraction pattern of the hydroxyethyl sulfonate crystal form A includes three diffraction peaks located at 2θ of 5.7±0.2°, 18.1±0.2°, and 12.4±0.2°; and further includes four peaks located at 2θ of 14.6±0.2°, 23.9±0.2°, 16.4±0.2°, 23.5±0.2°, or 10.5±0.2°. The X-ray powder diffraction pattern of the hydroxyethyl sulfonate crystal form B includes three diffraction peaks located at 2θ of 18.8±0.2°, 7.6±0.2°, or 24.1±0.2°; and further includes four peaks located at 2θ of 24.7±0.2°, 13.7±0.2°, 17.5±0.2°, 26.9±0.2°, or 25.7±0.2°.

19. The crystal form according to claim 17, characterized in that: The X-ray powder diffraction pattern of the hydrobromic acid crystal form A includes three diffraction peaks located at 2θ of 25.1±0.2°, 8.2±0.2°, and 22.7±0.2°, and further includes five diffraction peaks located at 2θ of 31.1±0.2°, 18.7±0.2°, 23.4±0.2°, 29.1±0.2°, and 17.5±0.2°. The X-ray powder diffraction pattern of the hydrobromic acid crystal form B includes three diffraction peaks located at 2θ of 7.0±0.2°, 26.5±0.2°, and 21.8±0.2°; and further includes five diffraction peaks located at 2θ of 20.3±0.2°, 15.4±0.2°, 14.1±0.2°, 24.0±0.2°, and 27.6±0.2°. The X-ray powder diffraction pattern of the hydrobromic acid crystal form C includes three diffraction peaks located at 2θ of 25.3±0.2°, 7.5±0.2°, and 23.7±0.2°; and further includes five diffraction peaks located at 2θ of 14.0±0.2°, 22.4±0.2°, 11.7±0.2°, 26.6±0.2°, and 24.2±0.2°. The X-ray powder diffraction pattern of the hydrobromic acid crystal form D includes three diffraction peaks located at 2θ of 6.5±0.2°, 6.8±0.2°, and 21.5±0.2°; and further includes five diffraction peaks located at 2θ of 13.2±0.2°, 17.0±0.2°, 25.8±0.2°, 26.6±0.2°, and 10.2±0.2°. The X-ray powder diffraction pattern of the hydrobromic acid crystal form E includes three diffraction peaks located at 2θ of 24.5±0.2°, 18.0±0.2°, and 25.1±0.2°; and further includes five diffraction peaks located at 2θ of 25.3±0.2°, 22.7±0.2°, 29.2±0.2°, 23.4±0.2°, and 18.7±0.2°. The X-ray powder diffraction pattern of the hydrobromic acid crystal form F includes three diffraction peaks located at 2θ of 24.5±0.2°, 25.3±0.2°, and 7.5±0.2°; and further includes five diffraction peaks located at 2θ of 23.8±0.2°, 14.6±0.2°, 20.1±0.2°, 14.0±0.2°, and 13.3±0.2°. The X-ray powder diffraction pattern of the phosphate crystal form A includes three diffraction peaks located at 2θ of 9.5±0.2°, 6.9±0.2°, and 7.1±0.2°; and further includes five diffraction peaks at 8.2±0.2°, 23.5±0.2°, 18.2±0.2°, 13.1±0.2°, or 25.8±0.2°. The X-ray powder diffraction pattern of the phosphate crystal form B includes three diffraction peaks located at 2θ of 4.6±0.2°, 9.4±0.2°, and 22.1±0.2°; and further includes five diffraction peaks at 21.0±0.2°, 12.6±0.2°, 7.9±0.2°, 17.3±0.2°, or 18.8±0.2°. The X-ray powder diffraction pattern of the methanesulfonate crystal form A includes three diffraction peaks located at 2θ of 14.9±0.2°, 7.4±0.2°, and 24.5±0.2°; and further includes five diffraction peaks at 22.4±0.2°, 37.9±0.2°, 25.0±0.2°, 21.0±0.2°, or 18.9±0.2°. The X-ray powder diffraction pattern of the methanesulfonate crystal form B includes three diffraction peaks located at 2θ of 7.7±0.2°, 18.9±0.2°, and 13.9±0.2°; and further includes five diffraction peaks at 24.9±0.2°, 17.5±0.2°, 22.7±0.2°, 9.9±0.2°, or 15.9±0.2°. The X-ray powder diffraction pattern of the methanesulfonate crystal form C includes three diffraction peaks located at 2θ of 23.7±0.2°, 23.1±0.2°, and 7.2±0.2°; and further includes five diffraction peaks at 25.2±0.2°, 20.6±0.2°, 15.1±0.2°, 17.3±0.2°, or 14.8±0.2°. The X-ray powder diffraction pattern of the methanesulfonate crystal form D includes three diffraction peaks located at 2θ of 20.3±0.2°, 7.6±0.2°, and 17.7±0.2°; and further includes five diffraction peaks at 18.0±0.2°, 24.9±0.2°, 18.8±0.2°, 21.5±0.2°, or 9.6±0.2°. The X-ray powder diffraction pattern of the methanesulfonate crystal form E includes three diffraction peaks at 2θ of 7.8±0.2°, 18.9±0.2°, and 13.9±0.2°; and further includes five diffraction peaks at 14.3±0.2°, 22.7±0.2°, 7.1±0.2°, 24.1±0.2°, or 25.8±0.2°. The X-ray powder diffraction pattern of the methanesulfonate crystal form F includes three diffraction peaks located at 2θ of 6.8±0.2°, 13.8±0.2°, and 22.7±0.2°; and further includes five diffraction peaks at 20.8±0.2°, 21.3±0.2°, 9.2±0.2°, 21.6±0.2°, or 10.3±0.2°. The X-ray powder diffraction pattern of the oxalate crystal form A includes three diffraction peaks located at 2θ of 12.5±0.2°, 7.1±0.2°, and 6.9±0.2°; and further includes five diffraction peaks at 23.5±0.2°, 8.4±0.2°, 13.8±0.2°, 14.3±0.2°, or 23.3±0.2°. The X-ray powder diffraction pattern of the hydroxyethyl sulfonate crystal form A includes three diffraction peaks located at 2θ of 5.7±0.2°, 18.1±0.2°, and 12.4±0.2°; and further includes five diffraction peaks at 14.6±0.2°, 23.9±0.2°, 16.4±0.2°, 23.5±0.2°, or 10.5±0.2°. The X-ray powder diffraction pattern of the hydroxyethyl sulfonate crystal form B includes three diffraction peaks located at 2θ of 18.8±0.2°, 7.6±0.2°, and 24.1±0.2°; and further includes five diffraction peaks at 24.7±0.2°, 13.7±0.2°, 17.5±0.2°, 26.9±0.2°, or 25.7±0.2°.

20. The crystal form according to any one of claims 16-19, characterized in that: The X-ray powder diffraction pattern of the hydrobromic acid crystal form A also includes any two diffraction peaks located at 2θ of 13.1±0.2°, 26.5±0.2°, 14.4±0.2°, 24.5±0.2°, 28.5±0.2°, 21.1±0.2°, and 20.3±0.2°. The X-ray powder diffraction pattern of the hydrobromic acid crystal form B also includes any two diffraction peaks located at 2θ of 13.7±0.2°, 28.9±0.2°, 21.2±0.2°, 28.1±0.2°, 15.9±0.2°, 25.8±0.2°, and 32.3±0.2°. The X-ray powder diffraction pattern of the hydrobromic acid crystal form C also includes any two diffraction peaks located at 2θ of 14.5±0.2°, 15.1±0.2°, 16.8±0.2°, 19.3±0.2°, 20.1±0.2°, 26.3±0.2°, and 21.8±0.2°. The X-ray powder diffraction pattern of the hydrobromic acid crystal form D also includes any two diffraction peaks located at 2θ of 24.6±0.2°, 22.6±0.2°, 27.0±0.2°, 14.8±0.2°, 34.2±0.2°, 15.4±0.2°, and 27.9±0.2°. The X-ray powder diffraction pattern of the hydrobromic acid crystal form E also includes any two diffraction peaks located at 2θ of 26.6±0.2°, 13.9±0.2°, 31.1±0.2°, 17.6±0.2°, 15.8±0.2°, 14.4±0.2°, and 7.5±0.2°. The X-ray powder diffraction pattern of the hydrobromic acid crystal form F also includes any two diffraction peaks located at 2θ of 15.8±0.2°, 22.4±0.2°, 15.1±0.2°, 11.7±0.2°, 17.2±0.2°, 13.1±0.2°, and 19.0±0.2°. The X-ray powder diffraction pattern of the phosphate crystal form A also includes any two diffraction peaks located at 2θ of 22.2±0.2°, 14.3±0.2°, 4.6±0.2°, 21.1±0.2°, 22.0±0.2°, 13.4±0.2°, 20.8±0.2° or 15.6±0.2°; The X-ray powder diffraction pattern of the phosphate crystal form B also includes any two diffraction peaks located at 2θ of 14.2±0.2°, 16.2±0.2°, 14.8±0.2°, 19.5±0.2°, 24.1±0.2°, 25.5±0.2°, 23.1±0.2° or 27.1±0.2°; The X-ray powder diffraction pattern of the methanesulfonate crystal form A also includes any two diffraction peaks located at 2θ of 17.4±0.2°, 21.5±0.2°, 22.9±0.2°, 23.8±0.2°, 26.5±0.2°, 29.1±0.2°, 30.2±0.2° or 26.5±0.2°; The X-ray powder diffraction pattern of the methanesulfonate crystal form B also includes any two diffraction peaks located at 2θ of 20.0±0.2°, 14.3±0.2°, 7.1±0.2°, 16.3±0.2°, 23.6±0.2°, 25.7±0.2°, 26.0±0.2° or 27.0±0.2°; The X-ray powder diffraction pattern of the methanesulfonate crystal form C also includes any two diffraction peaks located at 2θ of 20.9±0.2°, 18.2±0.2°, 20.3±0.2°, 25.5±0.2°, 26.3±0.2°, 28.5±0.2°, 24.2±0.2° or 13.7±0.2°; The X-ray powder diffraction pattern of the methanesulfonate crystal form D also includes any two diffraction peaks located at 2θ of 34.0±0.2°, 27.0±0.2°, 23.2±0.2°, 6.6±0.2°, 15.1±0.2°, 16.3±0.2°, 22.4±0.2° or 12.6±0.2°; The X-ray powder diffraction pattern of the methanesulfonate crystal form E also includes any two diffraction peaks located at 2θ of 22.5±0.2°, 20.3±0.2°, 21.6±0.2°, 9.9±0.2°, 15.9±0.2°, 10.7±0.2°, 12.8±0.2° or 20.0±0.2°; The X-ray powder diffraction pattern of the methanesulfonate crystal form F also includes any two diffraction peaks located at 2θ of 16.1±0.2°, 19.8±0.2°, 25.9±0.2°, 14.6±0.2°, 23.5±0.2°, 25.0±0.2°, 29.5±0.2° or 31.0±0.2°; The X-ray powder diffraction pattern of the oxalate crystal form A also includes any two diffraction peaks located at 2θ of 10.7±0.2°, 16.3±0.2°, 27.5±0.2°, 26.9±0.2°, 24.9±0.2°, 17.4±0.2°, 19.2±0.2°, or 25.3±0.2°. The X-ray powder diffraction pattern of the hydroxyethyl sulfonate crystal form A also includes any two diffraction peaks located at 2θ of 25.5±0.2°, 11.6±0.2°, 20.7±0.2°, 25.0±0.2°, 13.0±0.2°, 22.9±0.2° or 28.4±0.2°; The X-ray powder diffraction pattern of the hydroxyethyl sulfonate crystal form B also includes any two diffraction peaks located at 2θ of 28.1±0.2°, 22.3±0.2°, 12.6±0.2°, 15.8±0.2°, 10.7±0.2°, 9.8±0.2°, 28.6±0.2° or 21.6±0.2°.

21. The crystal form according to any one of claims 16-19, characterized in that: The X-ray powder diffraction pattern of the hydrobromic acid crystal form A includes 10 diffraction peaks selected from 2θ values ​​of 25.1±0.2°, 8.2±0.2°, 22.7±0.2°, 31.1±0.2°, 18.7±0.2°, 23.4±0.2°, 29.1±0.2°, 17.5±0.2°, 13.1±0.2°, 26.5±0.2°, 14.4±0.2°, 24.5±0.2°, 28.5±0.2°, 21.1±0.2°, and 20.3±0.2°. The X-ray powder diffraction pattern of the hydrobromic acid crystal form B includes 10 diffraction peaks selected from 2θ values ​​of 7.0±0.2°, 26.5±0.2°, 21.8±0.2°, 20.3±0.2°, 15.4±0.2°, 14.1±0.2°, 24.0±0.2°, 27.6±0.2°, 13.7±0.2°, 28.9±0.2°, 21.2±0.2°, 28.1±0.2°, 15.9±0.2°, 25.8±0.2°, and 32.3±0.2°. The X-ray powder diffraction pattern of the hydrobromic acid crystal form C includes 10 diffraction peaks selected from 2θ values ​​of 25.4±0.2°, 7.5±0.2°, 23.7±0.2°, 14.0±0.2°, 22.4±0.2°, 11.7±0.2°, 26.6±0.2°, 24.2±0.2°, 14.5±0.2°, 15.1±0.2°, 16.8±0.2°, 19.3±0.2°, 20.1±0.2°, 26.3±0.2°, and 21.8±0.2°. The X-ray powder diffraction pattern of the hydrobromic acid crystal form D includes 10 diffraction peaks selected from 2θ values ​​of 6.5±0.2°, 6.8±0.2°, 21.5±0.2°, 13.2±0.2°, 17.0±0.2°, 25.8±0.2°, 26.6±0.2°, 10.2±0.2°, 24.6±0.2°, 22.6±0.2°, 27.0±0.2°, 14.8±0.2°, 34.2±0.2°, 15.4±0.2°, and 27.9±0.2°. The X-ray powder diffraction pattern of the hydrobromic acid crystal form E includes 10 diffraction peaks selected from 2θ values ​​of 24.5±0.2°, 18.0±0.2°, 25.1±0.2°, 25.3±0.2°, 22.7±0.2°, 29.2±0.2°, 23.4±0.2°, 18.7±0.2°, 26.6±0.2°, 13.9±0.2°, 31.1±0.2°, 17.6±0.2°, 15.8±0.2°, 14.4±0.2°, and 7.5±0.2°. The X-ray powder diffraction pattern of the hydrobromic acid crystal form F includes 10 diffraction peaks selected from 2θ values ​​of 24.5±0.2°, 25.3±0.2°, 7.5±0.2°, 23.8±0.2°, 14.6±0.2°, 20.1±0.2°, 14.0±0.2°, 13.3±0.2°, 15.8±0.2°, 22.4±0.2°, 15.1±0.2°, 11.7±0.2°, 17.2±0.2°, 13.1±0.2°, and 19.0±0.2°. The X-ray powder diffraction pattern of the phosphate crystal form A includes 10 diffraction peaks located at 2θ values ​​of 9.5±0.2°, 6.9±0.2°, 7.1±0.2°, 8.2±0.2°, 23.5±0.2°, 18.2±0.2°, 13.1±0.2°, 25.8±0.2°, 6.0±0.2°, 13.8±0.2°, 22.2±0.2°, 14.3±0.2°, 4.6±0.2°, 21.1±0.2°, or 22.0±0.2°. The X-ray powder diffraction pattern of the phosphate crystal form B includes 10 diffraction peaks located at 2θ values ​​of 4.6±0.2°, 9.4±0.2°, 22.1±0.2°, 21.0±0.2°, 12.6±0.2°, 7.9±0.2°, 17.3±0.2°, 18.8±0.2°, 15.1±0.2°, 17.7±0.2°, 14.2±0.2°, 16.2±0.2°, 14.8±0.2°, 19.5±0.2°, or 24.1±0.2°. The X-ray powder diffraction pattern of the methanesulfonate crystal form A includes 10 diffraction peaks located at 2θ values ​​of 14.9±0.2°, 7.4±0.2°, 24.5±0.2°, 22.4±0.2°, 37.9±0.2°, 25.0±0.2°, 21.0±0.2°, 18.9±0.2°, 34.1±0.2°, 28.5±0.2°, 17.4±0.2°, 21.5±0.2°, 22.9±0.2°, 23.8±0.2°, or 26.5±0.2°. The X-ray powder diffraction pattern of the methanesulfonate crystal form B includes 10 diffraction peaks located at 2θ values ​​of 7.7±0.2°, 18.9±0.2°, 13.9±0.2°, 24.9±0.2°, 17.5±0.2°, 22.7±0.2°, 9.9±0.2°, 15.9±0.2°, 24.1±0.2°, 20.3±0.2°, 20.0±0.2°, 14.3±0.2°, 7.1±0.2°, 16.3±0.2°, or 23.6±0.2°. The X-ray powder diffraction pattern of the methanesulfonate crystal form C includes 10 diffraction peaks located at 2θ values ​​of 23.7±0.2°, 23.1±0.2°, 7.2±0.2°, 25.2±0.2°, 20.6±0.2°, 15.1±0.2°, 17.3±0.2°, 14.8±0.2°, 15.8±0.2°, 21.4±0.2°, 20.9±0.2°, 18.2±0.2°, 20.3±0.2°, 25.5±0.2°, or 26.3±0.2°. The X-ray powder diffraction pattern of the methanesulfonate crystal form D includes 10 diffraction peaks located at 2θ of any one of the following: 20.3±0.2°, 7.6±0.2°, 17.7±0.2°, 18.0±0.2°, 24.9±0.2°, 18.8±0.2°, 21.5±0.2°, 9.6±0.2°, 34.0±0.2°, 27.0±0.2°, 23.2±0.2°, 6.6±0.2°, or 15.1±0.2°. The X-ray powder diffraction pattern of the methanesulfonate crystal form E includes 10 diffraction peaks located at 2θ values ​​of 7.8±0.2°, 18.9±0.2°, 13.9±0.2°, 14.3±0.2°, 22.7±0.2°, 7.1±0.2°, 24.1±0.2°, 25.8±0.2°, 17.6±0.2°, 24.9±0.2°, 22.5±0.2°, 20.3±0.2°, 21.6±0.2°, 9.9±0.2°, or 15.9±0.2°. The X-ray powder diffraction pattern of the methanesulfonate crystal form F includes 10 diffraction peaks located at 2θ of 6.8±0.2°, 13.8±0.2°, 22.7±0.2°, 20.8±0.2°, 21.3±0.2°, 9.2±0.2°, 21.6±0.2°, 10.3±0.2°, 14.9±0.2°, 26.4±0.2°, 16.1±0.2°, 19.8±0.2°, 25.9±0.2°, 14.6±0.2°, or 23.5±0.2°. The X-ray powder diffraction pattern of the oxalate crystal form A includes 10 diffraction peaks located at 2θ values ​​of 12.5±0.2°, 7.1±0.2°, 6.9±0.2°, 23.5±0.2°, 8.4±0.2°, 13.8±0.2°, 14.3±0.2°, 23.3±0.2°, 25.8±0.2°, 13.1±0.2°, 10.7±0.2°, 16.3±0.2°, 27.5±0.2°, 26.9±0.2°, or 24.9±0.2°. The X-ray powder diffraction pattern of the hydroxyethyl sulfonate crystal form A includes 10 diffraction peaks located at 2θ values ​​of 5.7±0.2°, 18.1±0.2°, 12.4±0.2°, 14.6±0.2°, 23.9±0.2°, 16.4±0.2°, 23.5±0.2°, 10.5±0.2°, 21.2±0.2°, 25.5±0.2°, 11.6±0.2°, 20.7±0.2°, 25.0±0.2°, or 13.0±0.2°. The X-ray powder diffraction pattern of the hydroxyethyl sulfonate crystal form B includes 10 diffraction peaks located at 2θ of any of the following values: 18.8±0.2°, 7.6±0.2°, 24.1±0.2°, 24.7±0.2°, 13.7±0.2°, 17.5±0.2°, 26.9±0.2°, 25.7±0.2°, 28.1±0.2°, 22.3±0.2°, 12.6±0.2°, or 15.8±0.2°.

22. The crystal form according to any one of claims 16-19, characterized in that: The X-ray powder diffraction pattern of the hydrobromic acid crystal form A is shown in Figure 12. The X-ray powder diffraction pattern of the hydrobromide crystal form B is shown in Figure 15. The X-ray powder diffraction pattern of the hydrobromide crystal form C is shown in Figure 17. The X-ray powder diffraction pattern of the hydrobromide crystal form D is shown in Figure 19. The X-ray powder diffraction pattern of the hydrobromide crystal form E is shown in Figure 22. The X-ray powder diffraction pattern of the hydrobromide crystal form F is shown in Figure 24. The X-ray powder diffraction pattern of the phosphate crystal form A is shown in Figure 26. The X-ray powder diffraction pattern of the phosphate crystal form B is shown in Figure 29. The X-ray powder diffraction pattern of the methanesulfonate crystal form A is shown in Figure 30. The X-ray powder diffraction pattern of the methanesulfonate crystal form B is shown in Figure 32. The X-ray powder diffraction pattern of the methanesulfonate crystal form C is shown in Figure 34. The X-ray powder diffraction pattern of the methanesulfonate crystal form D is shown in Figure 36. The X-ray powder diffraction pattern of the methanesulfonate crystal form E is shown in Figure 38. The X-ray powder diffraction pattern of the methanesulfonate crystal form F is shown in Figure 39. The X-ray powder diffraction pattern of the oxalate crystal form A is shown in Figure 41. The X-ray powder diffraction pattern of the hydroxyethyl sulfonate crystal form A is shown in Figure 44. The X-ray powder diffraction pattern of the hydroxyethyl sulfonate crystal form B is shown in Figure 46.

23. The crystal form according to claim 16, characterized in that, The 2θ error between the positions of the top ten diffraction peaks with relative peak intensities in the X-ray powder diffraction patterns of hydrobromic acid crystal forms A, B, C, D, E, F, A, B, C, D, E, F, A, B, C, D, E, F, F, A, B, C, D, E, F, F, A, B, C, D, E, F, F, A, B, C, D, E, F, F, A, B, C, D, E, F, F, F, C, D, C, F, D, E, F ...

24. The crystal form according to claim 16, characterized in that, The melting point of hydrobromic acid crystal form A is 200°C to 215°C; The melting point of the hydrobromic acid crystal form B is 205°C to 220°C; The melting point of the hydrobromic acid crystal form C is 205°C to 215°C; The melting point of the hydrobromic acid crystal form D is 170°C to 190°C; The melting point of the hydrobromic acid crystal form E is 195°C to 205°C; The melting point of the hydrobromic acid crystal form F is 195°C to 205°C; The melting point of the phosphate crystal form A is 200°C to 210°C; The melting point of the methanesulfonate crystal form A is 240°C to 250°C; The melting point of the methanesulfonate crystal form B is 245°C to 250°C; The melting point of the methanesulfonate crystal form C is 240°C to 250°C; The melting point of the methanesulfonate crystal form D is 235°C to 250°C; The melting point of the methanesulfonate crystal form F is 205°C to 215°C; The melting point of the oxalate crystal form A is 215°C to 220°C; The melting point of the hydroxyethyl sulfonate crystal form A is 205°C to 220°C; The melting point of the hydroxyethyl sulfonate crystal form B is 220°C to 225°C.

25. The crystal form according to claim 16, characterized in that, The hydrobromic acid crystal form A has a DSC spectrum as shown in Figure 13, or a TGA spectrum as shown in Figure 14; The hydrobromic acid crystal form B has the DSC spectrum shown in Figure 16; The hydrobromic acid crystal form C has the DSC spectrum shown in Figure 18; The hydrobromic acid crystal form D has a DSC spectrum as shown in Figure 20, or a TGA spectrum as shown in Figure 21; The hydrobromic acid crystal form E has the DSC spectrum shown in Figure 23; The hydrobromic acid crystal form F has the DSC spectrum shown in Figure 25; The phosphate crystal form A has a DSC pattern as shown in Figure 27, or a TGA pattern as shown in Figure 28; The methanesulfonate crystal form A has the DSC spectrum shown in Figure 31; The methanesulfonate crystal form B has the DSC spectrum shown in Figure 33; The methanesulfonate crystal form C has the DSC spectrum shown in Figure 35; The methanesulfonate crystal form D has the DSC spectrum shown in Figure 37; The methanesulfonate crystal form F has the DSC spectrum shown in Figure 40; The oxalate crystal form A has a DSC pattern as shown in Figure 42, or a TGA pattern as shown in Figure 43; The hydroxyethyl sulfonate crystal form A has the DSC spectrum shown in Figure 45; The hydroxyethyl sulfonate crystal form B has the DSC spectrum shown in Figure 47.

26. A method for preparing the acid salt according to any one of claims 1-5, Method 1 includes the following steps: 1) Weigh out an appropriate amount of free alkali and dissolve it in a good solvent; 2) Weigh an appropriate amount of the counterionic acid and dissolve it in an organic solvent; 3) Combine the two solutions mentioned above and stir to precipitate, or add a poor solvent and stir to precipitate; 4) Obtain the salt of the compound by rapid centrifugation or standing. in: The benign solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, acetonitrile, 2-butanone, 3-pentanone, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, or N-methylpyrrolidone. 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; The unsuitable solvent is selected from heptane, water, methyl tert-butyl ether, toluene, isopropyl ether, ethyl acetate, acetone, or acetonitrile; The aforementioned counterionic acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphtholic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxyxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetaminobenzoic acid, 4-aminobenzoic acid, decanoic acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfonic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, mandelic acid, pyroglutamic acid, tartaric acid, and dodecanoic acid. Alkyl sulfuric acid, dibenzoyl tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactobionic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, hydroxyethyl sulfonic acid, lactobionic acid, ascorbic acid, lauric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, dihydroxynaphthalic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanate, undecanoic acid, trifluoroacetic acid, p-toluenesulfonic acid, or L-malic acid; or, Method 2 includes the following steps: 1) Weigh out an appropriate amount of free alkali and dissolve it in a good solvent; 2) Weigh an appropriate amount of the counterionic acid and dissolve it in an organic solvent; the amount of the counterionic acid is 1.2 equivalents. 3) Mix the solutions obtained in steps 1) and 2) thoroughly and then evaporate them. After the solvent has evaporated completely, add the unsuitable solvent and stir until the solid precipitates. 4) Obtain the salt of the compound by rapid centrifugation or standing. in: The benign solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, acetonitrile, 2-butanone, 3-pentanone, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, or N-methylpyrrolidone. 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; the above-mentioned benign solvents and organic solvents must be miscible when used. The unsuitable solvents are selected from ethyl acetate, acetone, dichloromethane, acetonitrile, tetrahydrofuran, 2-butanone, 3-pentanone, and 1,4-dioxane; The aforementioned counterionic acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphtholic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxyxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetaminobenzoic acid, 4-aminobenzoic acid, decanoic acid, hexanoic acid, caprylic acid, octanoic acid, cinnamic acid, citric acid, cyclohexanesulfonic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, mandelic acid, pyroglutamic acid, tartaric acid. Dodecyl sulfuric acid, dibenzoyl tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactobionic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, hydroxyethyl sulfonic acid, lactobionic acid, ascorbic acid, lauric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, dihydroxynaphthalic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanate, undecanoic acid, trifluoroacetic acid, p-toluenesulfonic acid, or L-malic acid.

27. The method for preparing acid salts as described in claim 26, characterized in that, In Method 1, the benign solvent is selected from methanol and ethanol; the organic solvent is selected from methanol, ethanol, or acetonitrile; the undesirable solvent is selected from water, methyl tert-butyl ether, and isopropyl ether; and the counterionic acid is selected from hydrochloric acid, phosphoric acid, ethanesulfonic acid, benzenesulfonic acid, methanesulfonic acid, fumaric acid, hydroxyethylsulfonic acid, oxalic acid, or hydrobromic acid. and / or In Method 2, the benign solvent is selected from methanol and ethanol; the organic solvent is selected from methanol, ethanol, or acetonitrile; the undesirable solvent is selected from ethyl acetate, acetone, or acetonitrile; and the counterionic acid is selected from hydrochloric acid, phosphoric acid, ethanesulfonic acid, benzenesulfonic acid, methanesulfonic acid, fumaric acid, hydroxyethylsulfonic acid, oxalic acid, or hydrobromic acid.

28. A method for preparing the crystal form according to any one of claims 6-25, comprising the following steps: 1) Weigh an appropriate amount of the compound salt and suspend it in a poor solvent; 2) Shake the above suspension; 3) Centrifuge the above suspension, remove the supernatant, and dry the remaining solid to constant weight to obtain the target product; in: The undesirable solvent is selected from one or more of methanol, ethanol, dichloromethane, 1,4-dioxane, acetonitrile, chlorobenzene, benzene, toluene, acetone, ethyl acetate, water, isopropyl acetate, 3-pentanone, ethyl formate, tetrahydrofuran, 2-methyl-tetrahydrofuran, isopropanol, n-butanol, isobutanol, n-propanol, tert-butanol, or 2-butanone.

29. A pharmaceutical composition comprising a therapeutically effective amount of an acid salt of the compound according to any one of claims 1-5, and one or more pharmaceutically acceptable carriers or excipients.

30. A pharmaceutical composition comprising a therapeutically effective amount of the crystal form according to any one of claims 6-25, and one or more pharmaceutically acceptable carriers or excipients.

31. The use of the acid salt according to any one of claims 1-5 or the crystal form according to any one of claims 6-25, and the pharmaceutical composition according to claim 29 or 30 in the preparation of a medicament for inhibiting TYK2.

32. The use of the acid salt according to any one of claims 1-5 or the crystal form according to any one of claims 6-25 and the pharmaceutical composition according to claim 29 or 30 in the preparation of a treatment for inflammatory diseases and autoimmune diseases; wherein the inflammatory diseases and autoimmune diseases are selected from rheumatoid arthritis, dermatitis, psoriasis or inflammatory bowel disease.

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