Salt of thiazole derivative inhibitor, crystal form thereof, preparation method therefor and use thereof

Abstract

The present invention relates to a salt of a thiazole derivative inhibitor, a crystal form thereof, a preparation method therefor and the use thereof. In particular, the present invention relates to a salt of a compound represented by general formula (I), a crystal form thereof, a preparation method therefor, a pharmaceutical composition containing a therapeutically effective amount of the salt and / or crystal form, and the use thereof as an inhibitor in the treatment of autoimmune diseases.

Description

A salt of a thiazole derivative inhibitor, its crystal form, preparation method, and application. Technical Field

[0001] This invention belongs to the field of biomedicine, specifically relating to a salt of a thiazole derivative inhibitor, its crystal form, its preparation method, and its application. Background Technology

[0002] Human IL-17 (interleukin 17) is a large family of pro-inflammatory cytokines. Human IL-17 comprises six family members: IL-17A (also known as CTLA-8), IL-17B, IL-17C, IL-17D, IL-17E (also known as IL-25), and IL-17F. The human IL-17 receptor family comprises five family members: IL-17RA, IL-17RB, IL-17RC, IL-17RD, and IL-17RE. Human IL-17 initiates downstream signaling pathways by binding to the heterodimeric IL-17 receptor.

[0003] IL-17A is one of the most studied cytokines. It is produced by various cell types, including Th17 (helper T cells 17), Tc17 (cytotoxic T cells 17), NKT (natural killer T cells), γδT (γδT cells), and epithelial cells. IL-17A binds to its receptor on skin cells and other cells, activating the Act1 (TRAF3 interacting protein 2)-dependent MAPK and NF-κB signaling pathways. This leads to transcriptional increases in the expression levels of various cytokines (such as IL-6, TNF-α, G-CSF, GM-CSF, etc.), chemokines (such as CXCL1, CXCL2, CXCL5, CXCL8, CXCL10, etc.), antimicrobial peptides (such as Defensin, MUCSAC, S100A7, etc.), and matrix metalloproteinases (such as MMP1, etc.). IL-17A participates in regulating many important biological processes, such as bacterial and fungal infections, wound healing, and promoting inflammation.

[0004] The IL-17A pathway also plays an important role in autoimmune / inflammatory diseases. Preclinical studies have shown that IL-23 or IL-17RA knockout mice are resistant to imiquimod (IMQ)-induced psoriasis; IL-17 monoclonal antibodies can effectively inhibit IMQ or IL-23-induced psoriasis-related scores. IL-17-related therapeutic antibodies (Secukinumab, Ixekizumab, Brodalumab, Bimekizumab, etc.) have also been approved for the treatment of psoriasis, ankylosing spondylitis, and other diseases, with excellent clinical efficacy and mild, manageable side effects.

[0005] Nevertheless, IL-17-related therapeutic antibodies are expensive and require subcutaneous or intravenous injection, making them inaccessible and inconvenient for patients with autoimmune / inflammatory diseases requiring long-term medication. Developing highly active oral small-molecule inhibitors of IL-17 could significantly improve patient accessibility and convenience, possessing immense clinical and commercial value.

[0006] PCT / CN2024 / 092928 discloses a series of inhibitors containing thiazole derivatives. In subsequent research and development, in order to facilitate the handling, filtration and drying of the products, and to seek suitable crystals that are easy to store, have long-term product stability and high bioavailability, this invention has conducted a comprehensive study on the salts and crystal forms of the above-mentioned compounds. Summary of the Invention

[0007] All contents covered in PCT / CN2024 / 092928 are incorporated herein by reference.

[0008] The purpose of this invention is to provide an acid salt of a compound of general formula (I) or its stereoisomer, or its crystal form.

[0009] in:

[0010] Ring B is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0011] Ring E is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl;

[0012] M2 is selected from CH2 or NH;

[0013] R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups;

[0014] R 2-1-1 Each group is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, oxo, thio, =CF2, =CHF, =NOC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1- 6-Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Heteroalkyl, C 1-6 Deuterated heteroalkyl, C 1-6 Halogenated heteroalkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Heteroalkyl, C 1-6Deuterated heteroalkyl, C 1- 6-Hydroalkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, oxo, thio, =CF2, =CHF, =NOC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1- 6 heteroalkyl, C 1-6 Deuterated heteroalkyl, C 1-6 Halogenated heteroalkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups;

[0015] R 4-1-1 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0016] R5 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups;

[0017] x is 0, 1, 2, 3, 4 or 5;

[0018] w is 0, 1, 2, 3, 4, 5, or 6;

[0019] j can be 0, 1, 2, 3, 4 or 5;

[0020] u can be 0, 1, 2, 3, 4 or 5;

[0021] The acid is an inorganic acid or an organic acid, wherein the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, or phosphoric acid; and the organic acid is selected from 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphtholic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxyxamic acid, adipic 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, diphenyl Formicotartaric 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-toluenesulfonic acid, or L-malic acid, preferably hydrochloric acid, hydrobromic acid, or p-toluenesulfonic acid; more preferably p-toluenesulfonic acid.

[0022] In some embodiments of the present invention, ring B is selected from C. 3-6 Cycloalkyl, phenyl, or 5-6-membered heteroaryl; or ring B is absent; preferably, ring B is selected from...

[0023] In some embodiments of the present invention, ring E is a 5-9 membered heterocyclic group, more preferably a 5-6 membered heterocyclic group; preferably, ring E is selected from...

[0024] In some embodiments of the present invention, R 2-1-1 Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 1-3 Heteroalkyl, C 1-3 Halogenated heteroalkyl groups, preferably methyl, ethyl, methoxy, F, -CHF2, -CH2F, -CF3, -CH2CHF2, -CHF2CH3, -CH2CF3, -CH2OCH3, -CH2OCF3, or OCF. 3。

[0025] In some embodiments of the present invention, R 4-1-1 Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-3 Alkyl, C1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy group; preferably methyl or F.

[0026] In some embodiments of the present invention, R1 is independently selected from hydrogen, deuterium, halogen, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy group; preferably methyl or F.

[0027] In some embodiments of the present invention, R5 is independently selected from methyl, ethyl, deuterated methyl, and deuterated ethyl.

[0028] In some embodiments of the present invention, the compound is shown below:

[0029] In some embodiments of the present invention, the number of acids in the acid salt 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, and even more preferably 1.

[0030] In some embodiments of the present invention, the acid salt is a hydrate or anhydrous; 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.

[0031] The crystal form is either a hydrate crystal form or an anhydrous crystal form; when the 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, and more preferably 2.

[0032] In certain embodiments of the present invention, the acid salt of the compound or its stereoisomer or its crystal form is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazo-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide p-toluenesulfonate crystal form A;

[0033] The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form A shows a diffraction peak at 2θ of 4.3 ± 0.2°; or at 5.8 ± 0.2°; or at 6.8 ± 0.2°; or at 8.1 ± 0.2°; or at 11.6 ± 0.2°; or at 12.3 ± 0.2°; or at 16.4 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 17.3±0.2°; or has diffraction peaks at 18.1±0.2°; or has diffraction peaks at 20.5±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them;

[0034] Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide p-toluenesulfonate crystal form B;

[0035] The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form B shows a diffraction peak at 2θ of 4.2 ± 0.2°; or at 6.1 ± 0.2°; or at 7.1 ± 0.2°; or at 8.4 ± 0.2°; or at 15.7 ± 0.2°; or at 16.6 ± 0.2°; or at 18.5 ± 0.2°; or at 19.1°. The diffraction peak is present at ±0.2°; or at 19.8±0.2°; or at 22.4±0.2°; or at 22.6±0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-11 of the above diffraction peaks are included; more preferably, any 6, 7, 8, 9, 10, or 11 of the above diffraction peaks are included.

[0036] Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide p-toluenesulfonate crystal form C;

[0037] The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form C has a diffraction peak at 2θ of 4.8 ± 0.2°; or at 7.3 ± 0.2°; or at 9.5 ± 0.2°; or at 14.3 ± 0.2°; or at 15.3 ± 0.2°; or at 16.2 ± 0.2°; or at 17.4 ± 0.2°; or at 22.2 ± 0.2°; or at 22.7 ± 0.2°; preferably, it includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-9 of the above diffraction peaks; more preferably, it includes any 6, 7, 8, or 9 of them;

[0038] Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide p-toluenesulfonate crystal form D;

[0039] The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form D shows a diffraction peak at 2θ of 7.1 ± 0.2°; or at 12.3 ± 0.2°; or at 14.6 ± 0.2°; or at 15.2 ± 0.2°; or at 17.2 ± 0.2°; or at 17.7 ± 0.2°; or at 19.7 ± 0.2°. It has a diffraction peak; or a diffraction peak at 20.8±0.2°; or a diffraction peak at 20.9±0.2°; or a diffraction peak at 22.4±0.2°; preferably, it includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably, it includes any 6, 7, 8, 9, or 10 of them;

[0040] Alternatively, it is N-((S)-2-((5-((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide p-toluenesulfonate crystal form E;

[0041] The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form E shows a diffraction peak at 2θ of 10.5 ± 0.2°; or at 11.0 ± 0.2°; or at 15.3 ± 0.2°; or at 17.5 ± 0.2°; or at 18.7 ± 0.2°; or at 20.3 ± 0.2°; or at 21.1 ± 0.2°. The diffraction peak is present at: 22.0 ± 0.2°; or at 24.2 ± 0.2°; or at 30.8 ± 0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks are included; more preferably, any 6, 7, 8, 9, or 10 of the above diffraction peaks are included.

[0042] Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide p-toluenesulfonate crystal form F;

[0043] The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form F shows a diffraction peak at 2θ of 4.8 ± 0.2°; or at 7.4 ± 0.2°; or at 7.6 ± 0.2°; or at 10.8 ± 0.2°; or at 12.4 ± 0.2°; or at 14.1 ± 0.2°; or at 14.6 ± 0.2°; or at 17. The diffraction peak is present at 5±0.2°; or at 19.7±0.2°; or at 20.8±0.2°; or at 22.2±0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-11 of the above diffraction peaks are included; more preferably, any 6, 7, 8, 9, 10, or 11 of the above diffraction peaks are included.

[0044] Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide p-toluenesulfonate crystal form G;

[0045] The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form G shows a diffraction peak at 2θ of 6.9 ± 0.2°; or at 7.0 ± 0.2°; or at 10.8 ± 0.2°; or at 14.7 ± 0.2°; or at 17.8 ± 0.2°; or at 19.3 ± 0.2°; or at 19.7 ± 0.2°. It has diffraction peaks; or diffraction peaks at 20.9±0.2°; or diffraction peaks at 28.0±0.2°; or diffraction peaks at 32.1±0.2°; preferably, it includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably, it includes any 6, 7, 8, 9, or 10 of them;

[0046] Alternatively, it is N-((S)-2-((5-((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide p-toluenesulfonate crystal form H;

[0047] The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form H shows a diffraction peak at 2θ of 6.8 ± 0.2°; or at 10.5 ± 0.2°; or at 11.6 ± 0.2°; or at 12.1 ± 0.2°; or at 14.4 ± 0.2°; or at 15.0 ± 0.2°; or at 17.1 ± 0.2°. It has diffraction peaks; or diffraction peaks at 19.5±0.2°; or diffraction peaks at 20.6±0.2°; or diffraction peaks at 22.2±0.2°; preferably, it includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably, it includes any 6, 7, 8, 9, or 10 of them;

[0048] Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide hydrochloride crystal form A;

[0049] The X-ray powder diffraction pattern of the hydrochloride crystal form A shows a diffraction peak at 2θ of 6.8 ± 0.2°; or at 7.3 ± 0.2°; or at 10.5 ± 0.2°; or at 12.2 ± 0.2°; or at 15.6 ± 0.2°; or at 16.3 ± 0.2°; or at 16.7 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 17.1±0.2°; or has diffraction peaks at 19.9±0.2°; or has diffraction peaks at 20.2±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them;

[0050] Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide hydrochloride crystal form B;

[0051] The X-ray powder diffraction pattern of the hydrochloride crystal form B shows a diffraction peak at 2θ of 5.0 ± 0.2°; or at 7.3 ± 0.2°; or at 8.6 ± 0.2°; or at 10.0 ± 0.2°; or at 10.4 ± 0.2°; or at 14.2 ± 0.2°; or at 16.1 ± 0.2°. The diffraction peaks are present; or diffraction peaks are present at 18.0±0.2°; or diffraction peaks are present at 19.7±0.2°; or diffraction peaks are present at 22.3±0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks are included; more preferably, any 6, 7, 8, 9, or 10 of the above diffraction peaks are included.

[0052] Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide hydrochloride crystal form C;

[0053] The X-ray powder diffraction pattern of the hydrochloride crystal form C has a diffraction peak at 2θ of 5.4±0.2°; or at 6.9±0.2°; or at 9.4±0.2°; or at 10.4±0.2°; or at 11.1±0.2°; or at 12.6±0.2°; or at 14.3±0.2°; or at 16.0±0.2°; or at 19.7±0.2°; preferably, it includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-9 of the above diffraction peaks; more preferably, it includes any 6, 7, 8, or 9 of them;

[0054] Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide hydrobromide crystal form A;

[0055] The X-ray powder diffraction pattern of the hydrobromide crystal form A exhibits a diffraction peak at 2θ of 6.5 ± 0.2°; or at 7.0 ± 0.2°; or at 11.3 ± 0.2°; or at 12.0 ± 0.2°; or at 15.2 ± 0.2°; or at 16.3 ± 0.2°; or at 20.1 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 21.0±0.2°; or has diffraction peaks at 21.5±0.2°; or has diffraction peaks at 30.3±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them;

[0056] Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide hydrobromide crystal form B;

[0057] The X-ray powder diffraction pattern of the hydrobromide crystal form B shows a diffraction peak at 2θ of 6.3 ± 0.2°; or at 7.4 ± 0.2°; or at 9.9 ± 0.2°; or at 10.4 ± 0.2°; or at 12.7 ± 0.2°; or at 17.1 ± 0.2°; or at 19.1 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 20.6±0.2°; or has diffraction peaks at 22.3±0.2°; or has diffraction peaks at 24.3±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them;

[0058] Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide hydrobromide crystal form C;

[0059] The X-ray powder diffraction pattern of the hydrobromide crystal form C exhibits diffraction peaks at 2θ of 8.8 ± 0.2°; or at 9.9 ± 0.2°; or at 10.4 ± 0.2°; or at 12.9 ± 0.2°; or at 16.1 ± 0.2°; or at 16.7 ± 0.2°; or at 19.7 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 20.7±0.2°; or has diffraction peaks at 22.3±0.2°; or has diffraction peaks at 23.6±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them;

[0060] Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide hydrobromide crystal form D;

[0061] The X-ray powder diffraction pattern of the hydrobromide crystal form D shows a diffraction peak at 2θ of 10.5 ± 0.2°; or at 12.4 ± 0.2°; or at 15.3 ± 0.2°; or at 16.9 ± 0.2°; or at 17.6 ± 0.2°; or at 19.1 ± 0.2°; or at 20.0 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 20.8±0.2°; or has diffraction peaks at 22.6±0.2°; or has diffraction peaks at 24.6±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them;

[0062] Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide benzoate crystal form A;

[0063] The X-ray powder diffraction pattern of the benzoate crystal form A exhibits a diffraction peak at 2θ of 5.1 ± 0.2°; or at 8.7 ± 0.2°; or at 9.0 ± 0.2°; or at 13.1 ± 0.2°; or at 16.6 ± 0.2°; or at 17.5 ± 0.2°; or at 19.5 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 20.9±0.2°; or has diffraction peaks at 21.5±0.2°; or has diffraction peaks at 24.6±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them;

[0064] Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide benzoate crystal form B;

[0065] The X-ray powder diffraction pattern of the benzoate crystal form B exhibits a diffraction peak at 2θ of 6.6 ± 0.2°; or at 7.0 ± 0.2°; or at 7.5 ± 0.2°; or at 10.0 ± 0.2°; or at 10.5 ± 0.2°; or at 13.5 ± 0.2°; or at 15.4 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 17.0±0.2°; or has diffraction peaks at 18.2±0.2°; or has diffraction peaks at 19.7±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them;

[0066] Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide fumarate crystal form A;

[0067] The X-ray powder diffraction pattern of the fumarate crystal form A exhibits a diffraction peak at 2θ of 5.2 ± 0.2°; or at 7.0 ± 0.2°; or at 8.9 ± 0.2°; or at 11.3 ± 0.2°; or at 13.2 ± 0.2°; or at 13.7 ± 0.2°; or at 15.6 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 18.4±0.2°; or has diffraction peaks at 22.4±0.2°; or has diffraction peaks at 23.2±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them;

[0068] Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide fumarate crystal form B;

[0069] The X-ray powder diffraction pattern of the fumarate crystal form B has a diffraction peak at 2θ of 5.2 ± 0.2°; or at 6.8 ± 0.2°; or at 7.5 ± 0.2°; or at 9.3 ± 0.2°; or at 11.1 ± 0.2°; or at 15.0 ± 0.2°; or at 15.6 ± 0.2°; or at 16.4 ± 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.

[0070] Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide fumarate crystal form C;

[0071] The X-ray powder diffraction pattern of the fumarate crystal form C exhibits diffraction peaks at 2θ of 5.2 ± 0.2°; or at 7.5 ± 0.2°; or at 8.6 ± 0.2°; or at 10.5 ± 0.2°; or at 13.3 ± 0.2°; or at 14.0 ± 0.2°; or at 15.8 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 18.4±0.2°; or has diffraction peaks at 20.2±0.2°; or has diffraction peaks at 23.2±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them;

[0072] Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide maleate crystal form A;

[0073] The X-ray powder diffraction pattern of the maleate crystal form A shows a diffraction peak at 2θ of 5.9 ± 0.2°; or at 6.8 ± 0.2°; or at 7.5 ± 0.2°; or at 8.4 ± 0.2°; or at 12.7 ± 0.2°; or at 14.6 ± 0.2°; or at 15.6 ± 0.2°; or at 17.8 ± 0.2°. The diffraction peak is present at ±0.2°; or at 20.0±0.2°; or at 20.6±0.2°; or at 22.1±0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-11 of the above diffraction peaks are included; more preferably, any 6, 7, 8, 9, 10, or 11 of the above diffraction peaks are included.

[0074] Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide methanesulfonate crystal form B;

[0075] The X-ray powder diffraction pattern of the methanesulfonate crystal form B has a diffraction peak at 2θ of 5.8±0.2°; or at 7.1±0.2°; or at 12.5±0.2°; or at 13.5±0.2°; or at 16.7±0.2°; or at 18.9±0.2°; or at 20.7±0.2°; or at 23.7±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.

[0076] In some embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form A includes at least one or more diffraction peaks located at 2θ of 5.8±0.2°, 6.8±0.2°, 8.1±0.2°, and 20.5±0.2°, preferably including two such peaks, more preferably including three or four such peaks; even more preferably, it may also include at least one of 2θ of 4.3±0.2°, 11.6±0.2°, 12.3±0.2°, 16.4±0.2°, 18.1±0.2°, and 17.3±0.2°, preferably including two, three, four, five, or six such peaks;

[0077] More preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form A includes one or more diffraction peaks located at 4.3±0.2°, 5.8±0.2°, 6.8±0.2°, 8.1±0.2°, 11.6±0.2°, 12.3±0.2°, 16.4±0.2°, 17.3±0.2°, 18.1±0.2°, and 20.5±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 8, or 10 locations.

[0078] More preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form A may also include one or more diffraction peaks with 2θ values ​​of 15.3±0.2°, 15.7±0.2°, 19.2±0.2°, 22.2±0.2°, 23.4±0.2°, and 27.0±0.2°; preferably, it includes at least 2-3, 4-5, or 5-6 peaks; more preferably, it includes any 2, 3, 4, 5, or 6 peaks.

[0079] For example, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form A has diffraction peaks at the following positions with a 2θ value:

[0080] 5.8±0.2°, 6.8±0.2°, 8.1±0.2°, 11.6±0.2°, 17.3±0.2°, 18.1±0.2°, 20.5±0.2°;

[0081] 4.3±0.2°, 5.8±0.2°, 6.8±0.2°, 8.1±0.2°, 11.6±0.2°, 17.3±0.2°, 18.1±0.2°, 20.5±0.2°;

[0082] 5.8±0.2°, 6.8±0.2°, 8.1±0.2°, 11.6±0.2°, 15.7±0.2°, 17.3±0.2°, 18.1±0.2°, 20.5±0.2°;

[0083] 5.8±0.2°, 6.8±0.2°, 8.1±0.2°, 11.6±0.2°, 17.3±0.2°, 18.1±0.2°, 19.2±0.2°, 20.5±0.2°;

[0084] 5.8±0.2°, 6.8±0.2°, 8.1±0.2°, 11.6±0.2°, 17.3±0.2°, 18.1±0.2°, 20.5±0.2°, 23.4±0.2°;

[0085] 5.8±0.2°, 6.8±0.2°, 8.1±0.2°, 11.6±0.2°, 17.3±0.2°, 18.1±0.2°, 20.5±0.2°, 27.0±0.2°;

[0086] 4.3±0.2°, 5.8±0.2°, 6.8±0.2°, 8.1±0.2°, 11.6±0.2°, 15.7±0.2°, 17.3±0.2°, 18.1±0.2°, 20.5±0.2°;

[0087] 4.3±0.2°, 5.8±0.2°, 6.8±0.2°, 8.1±0.2°, 11.6±0.2°, 15.7±0.2°, 17.3±0.2°, 18.1±0.2°, 20.5±0.2°, 23.4±0.2°;

[0088] 4.3±0.2°, 5.8±0.2°, 6.8±0.2°, 8.1±0.2°, 11.6±0.2°, 15.7±0.2°, 17.3±0.2°, 18.1±0.2°, 20.5±0.2°, 23.4±0.2°, 27.0±0.2°;

[0089] Most preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form A is basically as shown in Figure 1; the TGA-DSC pattern is shown in Figure 2;

[0090] The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form B includes at least one or more diffraction peaks located at 2θ of 4.2±0.2°, 6.1±0.2°, 7.1±0.2°, 15.7±0.2°, 22.4±0.2°, and 22.6±0.2°, preferably two, more preferably three; and even more preferably, it may also include at least one of 2θ of 8.4±0.2°, 16.6±0.2°, 18.5±0.2°, 19.1±0.2°, and 19.8±0.2°, preferably two, three, four, or five.

[0091] More preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form B includes one or more diffraction peaks located at 2θ of 4.2±0.2°, 6.1±0.2°, 7.1±0.2°, 8.4±0.2°, 15.7±0.2°, 16.6±0.2°, 18.5±0.2°, 19.1±0.2°, 19.8±0.2°, 22.4±0.2°, and 22.6±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 7, 8, 10, or 11 locations.

[0092] For example, the X-ray powder diffraction pattern of p-toluenesulfonate crystal form B shows diffraction peaks at the following positions with a 2θ value:

[0093] 4.2±0.2°, 6.1±0.2°, 7.1±0.2°, 15.7±0.2°, 22.4±0.2°, 22.6±0.2°;

[0094] 4.2±0.2°, 6.1±0.2°, 7.1±0.2°, 8.4±0.2°, 15.7±0.2°, 22.4±0.2°, 22.6±0.2°;

[0095] 4.2±0.2°, 6.1±0.2°, 7.1±0.2°, 8.4±0.2°, 15.7±0.2°, 16.6±0.2°, 22.4±0.2°, 22.6±0.2°;

[0096] Most preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form B is shown in Figure 3; the DSC pattern is shown in Figure 4; and the TGA pattern is shown in Figure 5.

[0097] The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form C includes at least one or more diffraction peaks located at 2θ of 4.8±0.2°, 7.3±0.2°, 9.5±0.2°, and 22.2±0.2°, preferably two, more preferably three; and even more preferably, it may also include at least one of 2θ of 14.3±0.2°, 15.3±0.2°, 16.2±0.2°, 17.4±0.2°, and 22.7±0.2°, preferably two, three, four, or five.

[0098] For example, the X-ray powder diffraction pattern of p-toluenesulfonate crystal form C shows diffraction peaks at the following positions with a 2θ value:

[0099] 4.8±0.2°, 7.3±0.2°, 9.5±0.2°, 22.2±0.2°, 14.3±0.2°, 17.4±0.2° and 22.7±0.2°;

[0100] 4.8±0.2°, 7.3±0.2°, 9.5±0.2°, 22.2±0.2°, 14.3±0.2°, 16.2±0.2°, 17.4±0.2° and 22.7±0.2°;

[0101] 4.8±0.2°, 7.3±0.2°, 9.5±0.2°, 22.2±0.2°, 14.3±0.2°, 15.3±0.2°, 17.4±0.2° and 22.7±0.2°;

[0102] Most preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form C is shown in Figure 6; the DSC pattern is shown in Figure 7; and the TGA pattern is shown in Figure 8.

[0103] The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form D includes at least one or more diffraction peaks located at 2θ of 7.1±0.2°, 14.6±0.2°, 20.8±0.2°, and 20.9±0.2°, preferably two, more preferably three; and even more preferably, it may also include at least one of 2θ of 12.3±0.2°, 15.2±0.2°, 17.2±0.2°, 17.7±0.2°, 19.7±0.2°, and 22.4±0.2°, preferably two, three, four, five, or six.

[0104] More preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form D includes one or more of the following 2θ values: 7.1±0.2°, 14.6±0.2°, 12.3±0.2°, 15.2±0.2°, 17.2±0.2°, 17.7±0.2°, 19.7±0.2°, 20.8±0.2°, 20.9±0.2°, and 22.4±0.2°. The diffraction peaks are located at 4, 5, 6, 7, 8, or 10 locations; more preferably, the diffraction peaks are located at at least one of the following 2θ values: 10.7±0.2°, 13.0±0.2°, 22.8±0.2°, 23.1±0.2°, 24.3±0.2°, or 28.0±0.2°, and more preferably at 2, 3, 4, 5, or 6 locations.

[0105] For example, the X-ray powder diffraction pattern of p-toluenesulfonate crystal form D shows diffraction peaks at the following positions with a 2θ value:

[0106] 7.1±0.2°, 12.3±0.2°, 14.6±0.2°, 19.7±0.2°, 20.8±0.2°, 20.9±0.2°, 22.4±0.2°;

[0107] 7.1±0.2°, 12.3±0.2°, 14.6±0.2°, 15.2±0.2°, 19.7±0.2°, 20.9±0.2°, 22.4±0.2°;

[0108] 7.1±0.2°, 12.3±0.2°, 14.6±0.2°, 15.2±0.2°, 19.7±0.2°, 20.8±0.2°, 20.9±0.2°, 22.4±0.2°;

[0109] 7.1±0.2°, 10.7±0.2°, 12.3±0.2°, 14.6±0.2°, 19.7±0.2°, 20.8±0.2°, 20.9±0.2°, 22.4±0.2°;

[0110] Most preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form D is basically as shown in Figure 9;

[0111] The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form E includes at least one or more diffraction peaks located at 2θ of 11.0±0.2°, 18.7±0.2°, 21.1±0.2°, and 22.0±0.2°, preferably two, more preferably three; and even more preferably, it may also include at least one of 2θ of 10.5±0.2°, 15.3±0.2°, 17.5±0.2°, 20.3±0.2°, 24.2±0.2°, and 30.8±0.2°, preferably two, three, four, five, or six.

[0112] More preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form E includes one or more of the following 2θ values: 10.5±0.2°, 11.0±0.2°, 15.3±0.2°, 17.5±0.2°, 18.7±0.2°, 20.3±0.2°, 21.1±0.2°, 22.0±0.2°, 24.2±0.2°, and 30.8±0.2°. The diffraction peaks are located at 4, 5, 6, 7, 8, or 10 locations; more preferably, the diffraction peaks are located at at least one of the following 2θ values: 10.6±0.2°, 12.7±0.2°, 13.2±0.2°, 15.0±0.2°, 18.1±0.2°, and 25.7±0.2°, preferably 2, 3, 4, 5, or 6 locations.

[0113] For example, the X-ray powder diffraction pattern of p-toluenesulfonate crystal form E shows diffraction peaks at the following positions with a 2θ value:

[0114] 10.5±0.2°, 11.0±0.2°, 18.7±0.2°, 20.3±0.2°, 21.1±0.2°, 22.0±0.2°, 24.2±0.2°;

[0115] 11.0±0.2°, 15.3±0.2°, 17.5±0.2°, 18.7±0.2°, 20.3±0.2°, 21.1±0.2°, 22.0±0.2°;

[0116] 10.5±0.2°, 11.0±0.2°, 18.7±0.2°, 20.3±0.2°, 21.1±0.2°, 22.0±0.2°, 30.8±0.2°;

[0117] 10.5±0.2°, 11.0±0.2°, 17.5±0.2°, 18.7±0.2°, 20.3±0.2°, 21.1±0.2°, 22.0±0.2°;

[0118] 11.0±0.2°, 15.3±0.2°, 18.7±0.2°, 20.3±0.2°, 21.1±0.2°, 22.0±0.2°, 30.8±0.2°;

[0119] 10.5±0.2°, 11.0±0.2°, 18.1±0.2°, 18.7±0.2°, 21.1±0.2°, 22.0±0.2°, 30.8±0.2°;

[0120] 10.5±0.2°, 11.0±0.2°, 15.0±0.2°, 18.7±0.2°, 21.1±0.2°, 22.0±0.2°, 30.8±0.2°;

[0121] 10.5±0.2°, 11.0±0.2°, 15.3±0.2°, 17.5±0.2°, 18.7±0.2°, 20.3±0.2°, 21.1±0.2°, 30.8±0.2°;

[0122] 10.5±0.2°, 11.0±0.2°, 18.7±0.2°, 20.3±0.2°, 21.1±0.2°, 22.0±0.2°, 24.2±0.2°, 30.8±0.2°;

[0123] 10.5±0.2°, 11.0±0.2°, 18.1±0.2°, 18.7±0.2°, 20.3±0.2°, 21.1±0.2°, 22.0±0.2°, 24.2±0.2°;

[0124] 10.5±0.2°, 11.0±0.2°, 18.1±0.2°, 18.7±0.2°, 21.1±0.2°, 22.0±0.2°, 24.2±0.2°, 30.8±0.2°;

[0125] Most preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form E is basically as shown in Figure 10; the TGA-DSC pattern is shown in Figure 11.

[0126] The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form F includes at least one or more diffraction peaks located at 2θ of 14.8±0.2°, 14.1±0.2°, 14.6±0.2°, and 20.8±0.2°, preferably two, more preferably three; and even more preferably, it may also include at least one of 2θ of 7.4±0.2°, 7.6±0.2°, 10.8±0.2°, 12.4±0.2°, 17.5±0.2°, 19.7±0.2°, and 22.2±0.2°, preferably two, three, four, five, six, or seven.

[0127] More preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form F includes one or more diffraction peaks located at 2θ of 7.4±0.2°, 7.6±0.2°, 10.8±0.2°, 12.4±0.2°, 14.8±0.2°, 14.1±0.2°, 14.6±0.2°, 17.5±0.2°, 19.7±0.2°, 20.8±0.2°, and 22.2±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 7, 8, or 10 locations.

[0128] For example, the X-ray powder diffraction pattern of p-toluenesulfonate crystal form F shows diffraction peaks at the following positions with a 2θ value:

[0129] 7.4±0.2°, 14.8±0.2°, 14.1±0.2°, 14.6±0.2°, 17.5±0.2°, 20.8±0.2° and 22.2±0.2°;

[0130] 12.4±0.2°, 14.8±0.2°, 14.1±0.2°, 14.6±0.2°, 17.5±0.2°, 20.8±0.2° and 22.2±0.2°;

[0131] 7.4±0.2°, 12.4±0.2°, 14.8±0.2°, 14.1±0.2°, 14.6±0.2°, 17.5±0.2°, 20.8±0.2° and 22.2±0.2°;

[0132] Most preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form F is basically as shown in Figure 12;

[0133] The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form G includes at least one or more diffraction peaks located at 2θ of 7.0±0.2°, 10.8±0.2°, 14.7±0.2°, and 20.9±0.2°, preferably two, more preferably three; and even more preferably, it may also include at least one of 2θ of 6.9±0.2°, 17.8±0.2°, 19.3±0.2°, 19.7±0.2°, 28.0±0.2°, and 32.1±0.2°, preferably two, three, four, five, or six.

[0134] More preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form G includes one or more diffraction peaks located at 2θ of 6.9±0.2°, 7.0±0.2°, 10.8±0.2°, 14.7±0.2°, 17.8±0.2°, 19.3±0.2°, 19.7±0.2°, 20.9±0.2°, 28.0±0.2°, and 32.1±0.2°; preferably, it includes 4, 5, 6, 7, 8, or 10 diffraction peaks; more preferably, it may also include at least one at 2θ of 11.8±0.2°, 15.3±0.2°, 22.5±0.2°, 24.4±0.2°, and 26.8±0.2°, preferably 2, 3, 4, or 5 such peaks;

[0135] For example, the X-ray powder diffraction pattern of p-toluenesulfonate crystal form G shows diffraction peaks at the following positions with a 2θ value:

[0136] 7.0±0.2°, 10.8±0.2°, 14.7±0.2°, 17.8±0.2°, 19.3±0.2°, 19.7±0.2° and 20.9±0.2°;

[0137] 7.0±0.2°, 10.8±0.2°, 14.7±0.2°, 17.8±0.2°, 19.3±0.2°, 19.7±0.2° and 32.1±0.2°;

[0138] 7.0±0.2°, 10.8±0.2°, 14.7±0.2°, 17.8±0.2°, 19.3±0.2°, 19.7±0.2°, 20.9±0.2° and 32.1±0.2°;

[0139] Most preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form G is basically as shown in Figure 13;

[0140] The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form H includes at least one or more diffraction peaks located at 2θ of 10.5±0.2°, 12.1±0.2°, 14.4±0.2°, and 20.6±0.2°, preferably two, more preferably three; and even more preferably, it may also include at least one of 6.8±0.2°, 11.6±0.2°, 15.0±0.2°, 17.1±0.2°, 19.5±0.2°, and 22.2±0.2°, preferably two, three, four, five, or six.

[0141] More preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form H includes one or more of the following 2θ values: 6.8±0.2°, 10.5±0.2°, 11.6±0.2°, 12.1±0.2°, 14.4±0.2°, 15.0±0.2°, 17.1±0.2°, 19.5±0.2°, 20.6±0.2°, and 22.2±0.2°. The diffraction peaks are located at 4, 5, 6, 7, 8, or 10 locations; more preferably, the diffraction peaks are located at at least one of the following 2θ values: 10.0±0.2°, 12.8±0.2°, 17.6±0.2°, 22.6±0.2°, 24.1±0.2°, or 24.7±0.2°, preferably 2, 3, 4, 5, or 6 locations.

[0142] For example, the X-ray powder diffraction pattern of p-toluenesulfonate crystal form H shows diffraction peaks at the following positions with a 2θ value:

[0143] 6.8±0.2°, 11.6±0.2°, 14.4±0.2°, 15.0±0.2°, 17.1±0.2°, 20.6±0.2°, 22.2±0.2°;

[0144] 6.8±0.2°, 12.8±0.2°, 14.4±0.2°, 15.0±0.2°, 17.1±0.2°, 20.6±0.2°, 22.2±0.2°;

[0145] 6.8±0.2°, 11.6±0.2°, 14.4±0.2°, 15.0±0.2°, 17.6±0.2°, 20.6±0.2°, 22.2±0.2°;

[0146] 6.8±0.2°, 11.6±0.2°, 14.4±0.2°, 15.0±0.2°, 17.1±0.2°, 17.6±0.2°, 20.6±0.2°, 22.2±0.2°;

[0147] 6.8±0.2°, 11.6±0.2°, 12.8±0.2°, 14.4±0.2°, 15.0±0.2°, 17.1±0.2°, 20.6±0.2°, 22.2±0.2°;

[0148] Most preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form H is basically as shown in Figure 14; the TGA-DSC pattern is shown in Figure 15.

[0149] The X-ray powder diffraction pattern of the hydrochloride crystal form A includes at least one or more diffraction peaks located at 2θ of 7.3±0.2°, 10.5±0.2°, 16.7±0.2°, and 19.9±0.2°, preferably two, more preferably three; and even more preferably, it may also include at least one of 6.8±0.2°, 12.2±0.2°, 15.6±0.2°, 16.3±0.2°, 17.1±0.2°, and 20.2±0.2°, preferably two, three, four, five, or six.

[0150] More preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form A includes one or more diffraction peaks located at 2θ of 6.8±0.2°, 7.3±0.2°, 10.5±0.2°, 12.2±0.2°, 15.6±0.2°, 16.3±0.2°, 16.7±0.2°, 17.1±0.2°, 19.9±0.2°, and 20.2±0.2°; preferably, it includes 4, 5, 6, 7, 8, or 10 diffraction peaks; more preferably, it may also include at least one at 2θ of 8.1±0.2°, 8.8±0.2°, 10.0±0.2°, 18.0±0.2°, 22.3±0.2°, and 24.7±0.2°, preferably 2, 3, 4, 5, or 6 peaks.

[0151] For example, the X-ray powder diffraction pattern of hydrochloride crystal form A shows diffraction peaks at the following positions with a 2θ value:

[0152] 6.8±0.2°, 7.3±0.2°, 10.5±0.2°, 16.7±0.2°, 17.1±0.2°, 19.9±0.2°, 20.2±0.2°;

[0153] 7.3±0.2°, 10.5±0.2°, 12.2±0.2°, 15.6±0.2°, 16.7±0.2°, 19.9±0.2°, 20.2±0.2°;

[0154] 7.3±0.2°, 10.5±0.2°, 12.2±0.2°, 16.7±0.2°, 17.1±0.2°, 19.9±0.2°, 20.2±0.2°;

[0155] 7.3±0.2°, 10.5±0.2°, 12.2±0.2°, 15.6±0.2°, 16.7±0.2°, 17.1±0.2°, 19.9±0.2°, 20.2±0.2°;

[0156] 7.3±0.2°, 10.5±0.2°, 12.2±0.2°, 15.6±0.2°, 16.7±0.2°, 19.9±0.2°, 20.2±0.2°;

[0157] 6.8±0.2°, 7.3±0.2°, 10.5±0.2°, 12.2±0.2°, 16.7±0.2°, 19.9±0.2°, 20.2±0.2°;

[0158] 7.3±0.2°, 10.0±0.2°, 10.5±0.2°, 12.2±0.2°, 16.7±0.2°, 19.9±0.2°, 20.2±0.2°;

[0159] 6.8±0.2°, 7.3±0.2°, 10.0±0.2°, 10.5±0.2°, 12.2±0.2°, 16.7±0.2°, 19.9±0.2°, 20.2±0.2°;

[0160] 7.3±0.2°, 10.5±0.2°, 12.2±0.2°, 15.6±0.2°, 16.7±0.2°, 17.1±0.2°, 19.9±0.2°, 20.2±0.2°;

[0161] 6.8±0.2°, 7.3±0.2°, 10.5±0.2°, 12.2±0.2°, 15.6±0.2°, 16.7±0.2°, 19.9±0.2°, 20.2±0.2°;

[0162] 6.8±0.2°, 7.3±0.2°, 10.5±0.2°, 12.2±0.2°, 15.6±0.2°, 16.7±0.2°, 17.1±0.2°, 19.9±0.2°, 20.2±0.2°;

[0163] Most preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form A is basically as shown in Figure 16; the TGA-DSC pattern is shown in Figure 17;

[0164] The X-ray powder diffraction pattern of the hydrochloride crystal form B includes at least one or more diffraction peaks located at 2θ of 8.6±0.2°, 10.4±0.2°, 16.1±0.2°, and 19.7±0.2°, preferably two, more preferably three; and even more preferably, it may also include at least one of 5.0±0.2°, 7.3±0.2°, 10.0±0.2°, 14.2±0.2°, 18.0±0.2°, and 22.3±0.2°, preferably two, three, four, five, or six.

[0165] More preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form B includes one or more diffraction points located at 2θ of 5.0±0.2°, 7.3±0.2°, 8.6±0.2°, 10.0±0.2°, 10.4±0.2°, 14.2±0.2°, 16.1±0.2°, 18.0±0.2°, 19.7±0.2°, and 22.3±0.2°. Peaks; preferably, including any 4, 5, 6, 7, 8 or 10 diffraction peaks; more preferably, it may also include at least one of 2θ being 17.1±0.2°, 18.8±0.2°, 21.6±0.2°, 23.4±0.2°, 24.7±0.2°, 26.5±0.2°, preferably including 2, 3, 4, 5 or 6 of them;

[0166] For example, the X-ray powder diffraction pattern of hydrochloride crystal form B shows diffraction peaks at the following positions with a 2θ value:

[0167] 10.4±0.2°, 16.1±0.2°, 19.7±0.2°, 22.3±0.2°, 23.4±0.2°, 26.5±0.2°;

[0168] 8.6±0.2°, 10.4±0.2°, 14.2±0.2°, 16.1±0.2°, 18.0±0.2°, 19.7±0.2°, 22.3±0.2°;

[0169] 7.3±0.2°, 8.6±0.2°, 10.4±0.2°, 16.1±0.2°, 18.0±0.2°, 19.7±0.2°, 22.3±0.2°;

[0170] 5.0±0.2°, 8.6±0.2°, 10.4±0.2°, 16.1±0.2°, 18.0±0.2°, 19.7±0.2°, 22.3±0.2°;

[0171] 8.6±0.2°, 10.0±0.2°, 10.4±0.2°, 14.2±0.2°, 16.1±0.2°, 18.0±0.2°, 19.7±0.2°, 22.3±0.2°;

[0172] 5.0±0.2°, 7.3±0.2°, 8.6±0.2°, 10.4±0.2°, 16.1±0.2°, 18.0±0.2°, 19.7±0.2°, 22.3±0.2°;

[0173] 5.0±0.2°, 8.6±0.2°, 10.4±0.2°, 14.2±0.2°, 16.1±0.2°, 18.0±0.2°, 19.7±0.2°, 22.3±0.2°;

[0174] 8.6±0.2°, 10.4±0.2°, 14.2±0.2°, 16.1±0.2°, 18.0±0.2°, 19.7±0.2°, 22.3±0.2°, 26.5±0.2°;

[0175] Most preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form B is basically as shown in Figure 18; the TGA-DSC pattern is shown in Figure 19.

[0176] The X-ray powder diffraction pattern of the hydrochloride crystal form C includes at least one or more diffraction peaks located at 2θ of 5.4±0.2°, 6.9±0.2°, 9.4±0.2°, and 10.4±0.2°, preferably two, more preferably three; and even more preferably, it may also include at least one of 11.1±0.2°, 12.6±0.2°, 14.3±0.2°, 16.0±0.2°, and 19.7±0.2°, preferably two, three, four, or five.

[0177] For example, the X-ray powder diffraction pattern of hydrochloride crystal form C shows diffraction peaks at the following positions with a 2θ value:

[0178] 5.4±0.2°, 6.9±0.2°, 9.4±0.2°, 10.4±0.2°, 11.1±0.2°, 16.0±0.2°, 19.7±0.2°;

[0179] 5.4±0.2°, 6.9±0.2°, 9.4±0.2°, 10.4±0.2°, 11.1±0.2°, 12.6±0.2°, 16.0±0.2°;

[0180] 5.4±0.2°, 6.9±0.2°, 9.4±0.2°, 10.4±0.2°, 11.1±0.2°, 12.6±0.2°, 16.0±0.2°, 19.7±0.2°;

[0181] The X-ray powder diffraction pattern of the hydrobromide crystal form A includes at least one or more diffraction peaks located at 2θ of 6.5±0.2°, 7.0±0.2°, 16.3±0.2°, and 20.1±0.2°, preferably two, more preferably three; even more preferably, it may also include at least one of 11.3±0.2°, 12.0±0.2°, 15.2±0.2°, 21.0±0.2°, 21.5±0.2°, and 30.3±0.2°, preferably two, three, four, five, or six of these peaks.

[0182] More preferably, the X-ray powder diffraction pattern of the hydrobromide crystal form A includes one or more diffraction points located at 2θ of 6.5±0.2°, 7.0±0.2°, 11.3±0.2°, 12.0±0.2°, 15.2±0.2°, 16.3±0.2°, 20.1±0.2°, 21.0±0.2°, 21.5±0.2°, and 30.3±0.2°. Diffraction peaks; preferably, including any 4, 5, 6, 7, 8 or 10 diffraction peaks; more preferably, it may also include at least one of 2θ being 18.0±0.2°, 22.5±0.2°, 22.9±0.2°, 23.3±0.2°, 24.1±0.2°, 26.1±0.2°, preferably including 2, 3, 4, 5 or 6 of them;

[0183] For example, the X-ray powder diffraction pattern of hydrobromide crystal form A shows diffraction peaks at the following positions with a 2θ value:

[0184] 6.5±0.2°, 7.0±0.2°, 11.3±0.2°, 12.0±0.2°, 16.3±0.2°, 20.1±0.2°, 21.0±0.2°;

[0185] 11.3±0.2°, 12.0±0.2°, 15.2±0.2°, 16.3±0.2°, 20.1±0.2°, 21.0±0.2°, 30.3±0.2°;

[0186] 11.3±0.2°, 12.0±0.2°, 16.3±0.2°, 20.1±0.2°, 21.0±0.2°, 21.5±0.2°, 30.3±0.2°;

[0187] 11.3±0.2°, 12.0±0.2°, 15.2±0.2°, 16.3±0.2°, 18.0±0.2°, 20.1±0.2°, 30.3±0.2°;

[0188] 6.5±0.2°, 7.0±0.2°, 11.3±0.2°, 12.0±0.2°, 15.2±0.2°, 16.3±0.2°, 20.1±0.2°, 21.0±0.2°;

[0189] 11.3±0.2°, 12.0±0.2°, 15.2±0.2°, 16.3±0.2°, 20.1±0.2°, 21.0±0.2°, 21.5±0.2°, 30.3±0.2°;

[0190] Most preferably, the X-ray powder diffraction pattern of the hydrobromide crystal form A is basically as shown in Figure 21; the TGA-DSC pattern is shown in Figure 22.

[0191] The X-ray powder diffraction pattern of the hydrobromide crystal form B includes at least one or more diffraction peaks located at 2θ of 7.4±0.2°, 9.9±0.2°, 10.4±0.2°, and 17.1±0.2°, preferably two, more preferably three; even more preferably, it may also include at least one of 6.3±0.2°, 12.7±0.2°, 19.1±0.2°, 20.6±0.2°, 22.3±0.2°, and 24.3±0.2°, preferably two, three, four, five, or six of these peaks;

[0192] More preferably, the X-ray powder diffraction pattern of the hydrobromide crystal form B includes one or more diffraction peaks located at 2θ of 6.3±0.2°, 7.4±0.2°, 9.9±0.2°, 10.4±0.2°, 12.7±0.2°, 17.1±0.2°, 19.1±0.2°, 20.6±0.2°, 22.3±0.2°, and 24.3±0.2°; preferably, it includes 4, 5, 6, 7, 8, or 10 diffraction peaks; more preferably, it may also include at least one at 2θ of 16.8±0.2°, 17.5±0.2°, 18.5±0.2°, and 20.9±0.2°, preferably 2, 3, or 4 such peaks;

[0193] For example, the X-ray powder diffraction pattern of hydrobromide crystal form B shows diffraction peaks at the following positions with a 2θ value:

[0194] 7.4±0.2°, 9.9±0.2°, 10.4±0.2°, 12.7±0.2°, 17.1±0.2°, 19.1±0.2°, 24.3±0.2°;

[0195] 6.3±0.2°, 7.4±0.2°, 9.9±0.2°, 10.4±0.2°, 12.7±0.2°, 17.1±0.2°, 24.3±0.2°;

[0196] 7.4±0.2°, 9.9±0.2°, 10.4±0.2°, 12.7±0.2°, 17.1±0.2°, 19.1±0.2°, 20.6±0.2°, 24.3±0.2°;

[0197] Most preferably, the X-ray powder diffraction pattern of the hydrobromide crystal form B is basically as shown in Figure 23; the DSC pattern is shown in Figure 24.

[0198] The X-ray powder diffraction pattern of the hydrobromide crystal form C includes at least one or more diffraction peaks located at 2θ of 8.8±0.2°, 10.4±0.2°, 16.1±0.2°, 19.7±0.2°, and 23.6±0.2°, preferably including two of them, more preferably including three, four, or five; even more preferably, it may also include at least one of 7.4±0.2°, 9.9±0.2°, 12.9±0.2°, 16.7±0.2°, 20.7±0.2°, and 22.3±0.2°, preferably including two, three, four, five, or six of them;

[0199] More preferably, the X-ray powder diffraction pattern of the hydrobromide crystal form C includes one or more locations located at 2θ of 8.8±0.2°, 9.9±0.2°, 10.4±0.2°, 12.9±0.2°, 16.1±0.2°, 16.7±0.2°, 19.7±0.2°, 20.7±0.2°, 22.3±0.2°, and 23.6±0.2°. Diffraction peaks; preferably, including any 4, 5, 6, 7, 8 or 10 diffraction peaks; more preferably, it may also include at least one of 2θ being 7.4±0.2°, 14.2±0.2°, 20.2±0.2°, 24.6±0.2°, 26.6±0.2°, 29.5±0.2°, preferably including 2, 3, 4, 5 or 6 of them;

[0200] For example, the X-ray powder diffraction pattern of hydrobromide crystal form C shows diffraction peaks at the following positions with a 2θ value:

[0201] 10.4±0.2°, 12.9±0.2°, 16.1±0.2°, 16.7±0.2°, 19.7±0.2°, 22.3±0.2°, 23.6±0.2°;

[0202] 8.8±0.2°, 10.4±0.2°, 12.9±0.2°, 16.1±0.2°, 19.7±0.2°, 22.3±0.2°, 23.6±0.2°;

[0203] 9.9±0.2°, 10.4±0.2°, 12.9±0.2°, 16.1±0.2°, 19.7±0.2°, 22.3±0.2°, 23.6±0.2°;

[0204] 7.4±0.2°, 10.4±0.2°, 12.9±0.2°, 16.1±0.2°, 19.7±0.2°, 22.3±0.2°, 23.6±0.2°;

[0205] 10.4±0.2°, 12.9±0.2°, 16.1±0.2°, 16.7±0.2°, 19.7±0.2°, 20.7±0.2°, 22.3±0.2°, 23.6±0.2°;

[0206] 8.8±0.2°, 10.4±0.2°, 12.9±0.2°, 16.1±0.2°, 19.7±0.2°, 20.7±0.2°, 22.3±0.2°, 23.6±0.2°;

[0207] 9.9±0.2°, 10.4±0.2°, 12.9±0.2°, 16.1±0.2°, 19.7±0.2°, 20.7±0.2°, 22.3±0.2°, 23.6±0.2°;

[0208] Most preferably, the X-ray powder diffraction pattern of the hydrobromide crystal form C is basically as shown in Figure 25; the TGA-DSC pattern is shown in Figure 26.

[0209] The X-ray powder diffraction pattern of the hydrobromide crystal form D includes at least one or more diffraction peaks located at 2θ of 10.5±0.2°, 12.4±0.2°, 16.9±0.2°, 19.1±0.2°, and 20.8±0.2°, preferably including two of them, more preferably including three, four, or five; even more preferably, it may also include at least one of 9.8±0.2°, 15.3±0.2°, 17.6±0.2°, 20.0±0.2°, 22.6±0.2°, and 24.6±0.2°, preferably including two, three, four, five, or six of them;

[0210] More preferably, the X-ray powder diffraction pattern of the hydrobromide crystal form D includes one or more of the following 2θ values: 10.5±0.2°, 12.4±0.2°, 15.3±0.2°, 16.9±0.2°, 17.6±0.2°, 19.1±0.2°, 20.0±0.2°, 20.8±0.2°, 22.6±0.2°, and 24.6±0.2°. The diffraction peaks are located at 4, 5, 6, 7, 8, or 10 locations; more preferably, the diffraction peaks are located at at least one of the following 2θ values: 9.8±0.2°, 12.9±0.2°, 14.9±0.2°, 22.1±0.2°, 25.8±0.2°, or 26.4±0.2°, preferably 2, 3, 4, 5, or 6 locations.

[0211] For example, the X-ray powder diffraction pattern of hydrobromide crystal form D shows diffraction peaks at the following positions with a 2θ value:

[0212] 10.5±0.2°, 12.4±0.2°, 15.3±0.2°, 16.9±0.2°, 19.1±0.2°, 20.0±0.2°, 20.8±0.2°;

[0213] 10.5±0.2°, 12.4±0.2°, 15.3±0.2°, 16.9±0.2°, 19.1±0.2°, 20.8±0.2°, 22.6±0.2°;

[0214] 10.5±0.2°, 12.4±0.2°, 15.3±0.2°, 16.9±0.2°, 19.1±0.2°, 20.0±0.2°, 20.8±0.2°, 22.6±0.2°;

[0215] 10.5±0.2°, 12.4±0.2°, 15.3±0.2°, 16.9±0.2°, 17.6±0.2°, 19.1±0.2°, 20.8±0.2°, 22.6±0.2°;

[0216] 10.5±0.2°, 12.4±0.2°, 15.3±0.2°, 16.9±0.2°, 17.6±0.2°, 19.1±0.2°, 20.0±0.2°, 20.8±0.2°, 22.6±0.2°;

[0217] Most preferably, the X-ray powder diffraction pattern of the hydrobromide crystal form D is basically as shown in Figure 27; the TGA-DSC pattern is shown in Figure 28;

[0218] The X-ray powder diffraction pattern of the benzoate crystal form A includes at least one or more diffraction peaks located at 2θ of 8.7±0.2°, 16.6±0.2°, 17.5±0.2°, and 19.5±0.2°, preferably two, more preferably three; and even more preferably, it may also include at least one of 5.1±0.2°, 9.0±0.2°, 13.1±0.2°, 20.9±0.2°, 21.5±0.2°, and 24.6±0.2°, preferably two, three, four, five, or six.

[0219] More preferably, the X-ray powder diffraction pattern of the benzoate crystal form A includes one or more diffraction peaks located at 2θ of 5.1±0.2°, 8.7±0.2°, 9.0±0.2°, 13.1±0.2°, 16.6±0.2°, 17.5±0.2°, 19.5±0.2°, 20.9±0.2°, 21.5±0.2°, and 24.6±0.2°; preferably, it includes 4, 5, 6, 7, 8, or 10 diffraction peaks; more preferably, it may also include at least one at 2θ of 10.1±0.2°, 14.2±0.2°, 20.2±0.2°, 22.0±0.2°, and 24.3±0.2°, preferably 2, 3, 4, or 5 such peaks;

[0220] Most preferably, the X-ray powder diffraction pattern of the benzoate crystal form A is basically as shown in Figure 29; the TGA-DSC pattern is shown in Figure 30.

[0221] The X-ray powder diffraction pattern of the benzoate crystal form B includes at least one or more diffraction peaks located at 2θ of 6.6±0.2°, 7.0±0.2°, 7.5±0.2°, and 17.0±0.2°, preferably two, more preferably three; and even more preferably, it may also include at least one of 10.0±0.2°, 10.5±0.2°, 13.5±0.2°, 15.4±0.2°, 18.2±0.2°, and 19.7±0.2°, preferably two, three, four, five, or six.

[0222] More preferably, the X-ray powder diffraction pattern of the benzoate crystal form B includes one or more diffraction peaks located at 2θ of 6.6±0.2°, 7.0±0.2°, 7.5±0.2°, 10.0±0.2°, 10.5±0.2°, 13.5±0.2°, 15.4±0.2°, 17.0±0.2°, 18.2±0.2°, and 19.7±0.2°; preferably, it includes 4, 5, 6, 7, 8, or 10 diffraction peaks; more preferably, it may also include at least one at 2θ of 20.5±0.2°, 21.7±0.2°, 23.6±0.2°, 28.9±0.2°, and 31.8±0.2°, preferably 2, 3, 4, or 5 such peaks;

[0223] Most preferably, the X-ray powder diffraction pattern of the benzoate crystal form B is basically as shown in Figure 31; the TGA-DSC pattern is shown in Figure 32.

[0224] The X-ray powder diffraction pattern of the fumarate crystal form A includes at least one or more diffraction peaks located at 2θ of 5.2±0.2°, 8.9±0.2°, 11.3±0.2°, and 18.4±0.2°, preferably two, more preferably three; and even more preferably, it may also include at least one of 7.0±0.2°, 13.2±0.2°, 13.7±0.2°, 15.6±0.2°, 22.4±0.2°, and 23.2±0.2°, preferably two, three, four, five, or six.

[0225] In certain embodiments of the present invention, the acid salt of the compound or its stereoisomer or its crystal form is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxopiridine-1-yl)-2-((R)-2-methylmorpholino)ethyl)thiazo-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-(ethyl-d5)-1H-pyrazole-5-carboxamide hydrochloride crystal form A;

[0226] The X-ray powder diffraction pattern of the hydrochloride crystal form A shows a diffraction peak at 2θ of 5.3 ± 0.2°; or at 7.4 ± 0.2°; or at 11.8 ± 0.2°; or at 12.9 ± 0.2°; or at 16.7 ± 0.2°; or at 17.5 ± 0.2°; or at 19.1 ± 0.2°. The diffraction peaks are present; or diffraction peaks are present at 21.7±0.2°; or diffraction peaks are present at 22.4±0.2°; or diffraction peaks are present at 23.7±0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks are included; more preferably, any 6, 7, 8, 9, or 10 of the above diffraction peaks are included.

[0227] The X-ray powder diffraction pattern of the hydrochloride crystal form A includes at least one or more diffraction peaks located at 2θ of 5.3±0.2°, 7.4±0.2°, 11.8±0.2°, and 16.7±0.2°, preferably two, more preferably three or four; even more preferably, it may also include at least one of 2θ of 12.9±0.2°, 17.5±0.2°, 19.1±0.2°, 21.7±0.2°, 22.4±0.2°, and 23.7±0.2°, preferably two, three, four, five, or six.

[0228] More preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form A includes one or more diffraction peaks located at 5.3±0.2°, 7.4±0.2°, 11.8±0.2°, 12.9±0.2°, 16.7±0.2°, 17.5±0.2°, 19.1±0.2°, 21.7±0.2°, 22.4±0.2°, and 23.7±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 8, or 10 locations.

[0229] More preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form A may also include one or more diffraction peaks selected from 9.1±0.2°, 15.8±0.2°, 19.4±0.2°, 19.7±0.2°, 23.0±0.2°, and 26.5±0.2°; preferably, it includes at least 2-3, 4-5, or 5-6 peaks; more preferably, it includes any 2, 3, 4, 5, or 6 peaks.

[0230] For example, the X-ray powder diffraction pattern of the hydrochloride crystal form A has diffraction peaks at the following positions with a 2θ value:

[0231] 5.3±0.2°、7.4±0.2°、11.8±0.2°、16.7±0.2°、12.9±0.2°、17.5±0.2°、19.1±0.2°；

[0232] 5.3±0.2°、7.4±0.2°、11.8±0.2°、16.7±0.2°、21.7±0.2°、22.4±0.2°、23.7±0.2°；

[0233] 5.3±0.2°、7.4±0.2°、9.1±0.2°、11.8±0.2°、15.8±0.2°、16.7±0.2°、19.4±0.2°；

[0234] 5.3±0.2°、7.4±0.2°、11.8±0.2°、16.7±0.2°、19.7±0.2°、23.0±0.2°、26.5±0.2°；

[0235] 12.9±0.2°、17.5±0.2°、15.8±0.2°、16.7±0.2°、19.1±0.2°、19.4±0.2°、21.7±0.2°；

[0236] 12.9±0.2°、17.5±0.2°、19.1±0.2°、19.7±0.2°、21.7±0.2°、23.0±0.2°、26.5±0.2°；

[0237] 5.3±0.2°、7.4±0.2°、11.8±0.2°、12.9±0.2°、16.7±0.2°、17.5±0.2°、19.1±0.2°、21.7±0.2°；

[0238] 5.3±0.2°、7.4±0.2°、11.8±0.2°、16.7±0.2°、19.1±0.2°、21.7±0.2°、22.4±0.2°、23.7±0.2°；

[0239] 5.3±0.2°、7.4±0.2°、11.8±0.2°、16.7±0.2°、17.5±0.2°、19.1±0.2°、21.7±0.2°、22.4±0.2°；

[0240] 5.3±0.2°、7.4±0.2°、9.1±0.2°、11.8±0.2°、12.9±0.2°、15.8±0.2°、16.7±0.2°、17.5±0.2°；

[0241] 5.3±0.2°, 7.4±0.2°, 11.8±0.2°, 16.7±0.2°, 22.4±0.2°, 23.0±0.2°, 23.7±0.2°, 26.5±0.2°;

[0242] 5.3±0.2°, 7.4±0.2°, 9.1±0.2°, 11.8±0.2°, 12.9±0.2°, 16.7±0.2°, 23.7±0.2°, 26.5±0.2°;

[0243] 5.3±0.2°, 7.4±0.2°, 11.8±0.2°, 12.9±0.2°, 16.7±0.2°, 17.5±0.2°, 19.1±0.2°, 21.7±0.2°, 22.4±0.2°;

[0244] 5.3±0.2°, 7.4±0.2°, 11.8±0.2°, 16.7±0.2°, 17.5±0.2°, 19.1±0.2°, 21.7±0.2°, 22.4±0.2°, 23.7±0.2°;

[0245] Most preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form A is basically as shown in Figure 40; the DSC pattern is shown in Figure 41.

[0246] Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxopiridine-1-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-(ethyl-d5)-1H-pyrazole-5-carboxamide hydrochloride crystal form B;

[0247] The X-ray powder diffraction pattern of the hydrochloride crystal form B shows a diffraction peak at 2θ of 9.1 ± 0.2°; or at 13.7 ± 0.2°; or at 15.3 ± 0.2°; or at 17.8 ± 0.2°; or at 18.6 ± 0.2°; or at 18.9 ± 0.2°; or at 20.4 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 20.8±0.2°; or has diffraction peaks at 22.8±0.2°; or has diffraction peaks at 23.3±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them;

[0248] The X-ray powder diffraction pattern of the hydrochloride crystal form B includes at least one or more diffraction peaks located at 2θ of 9.1±0.2°, 13.7±0.2°, 17.8±0.2°, and 20.8±0.2°, preferably two of these peaks, more preferably three or four; even more preferably, it may also include at least one of 2θ of 15.3±0.2°, 18.6±0.2°, 18.9±0.2°, 20.4±0.2°, 22.8±0.2°, and 23.3±0.2°, preferably two, three, four, five, or six of these peaks.

[0249] More preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form B includes one or more diffraction peaks located at 9.1±0.2°, 13.7±0.2°, 15.3±0.2°, 17.8±0.2°, 18.6±0.2°, 18.9±0.2°, 20.4±0.2°, 20.8±0.2°, 22.8±0.2°, and 23.3±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 8, or 10 of these locations.

[0250] More preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form B may also include one or more diffraction peaks selected from 8.4±0.2°, 16.9±0.2°, 18.2±0.2°, 25.9±0.2°, 27.3±0.2°, and 30.8±0.2°; preferably, it includes at least 2-3, 4-5, or 5-6 peaks; more preferably, it includes any 2, 3, 4, 5, or 6 peaks.

[0251] For example, the X-ray powder diffraction pattern of the hydrochloride crystal form B shows diffraction peaks at the following positions with a 2θ value:

[0252] 9.1±0.2°, 13.7±0.2°, 17.8±0.2°, 15.3±0.2°, 18.6±0.2°, 18.9±0.2°, 20.8±0.2°;

[0253] 9.1±0.2°, 13.7±0.2°, 17.8±0.2°, 20.4±0.2°, 20.8±0.2°, 22.8±0.2°, 23.3±0.2°;

[0254] 8.4±0.2°, 9.1±0.2°, 13.7±0.2°, 16.9±0.2°, 17.8±0.2°, 18.2±0.2°, 20.8±0.2°;

[0255] 9.1±0.2°、13.7±0.2°、17.8±0.2°、20.8±0.2°、25.9±0.2°、27.3±0.2°、30.8±0.2°；

[0256] 9.1±0.2°、13.7±0.2°、17.8±0.2°、20.8±0.2°、15.3±0.2°、18.6±0.2°、18.9±0.2°、20.4±0.2°；

[0257] 9.1±0.2°、13.7±0.2°、17.8±0.2°、20.8±0.2°、18.9±0.2°、20.4±0.2°、22.8±0.2°、23.3±0.2°；

[0258] 9.1±0.2°、13.7±0.2°、17.8±0.2°、20.8±0.2°、8.4±0.2°、16.9±0.2°、18.2±0.2°、25.9±0.2°；

[0259] 9.1±0.2°、13.7±0.2°、17.8±0.2°、20.8±0.2°、18.2±0.2°、25.9±0.2°、27.3±0.2°、30.8±0.2°；

[0260] 8.4±0.2°、9.1±0.2°、13.7±0.2°、15.3±0.2°、16.9±0.2°、17.8±0.2°、18.6±0.2°、20.8±0.2°；

[0261] 8.4±0.2°、9.1±0.2°、13.7±0.2°、17.8±0.2°、20.8±0.2°、15.3±0.2°、23.3±0.2°、30.8±0.2°；

[0262] 9.1±0.2°、13.7±0.2°、17.8±0.2°、20.8±0.2°、22.8±0.2°、23.3±0.2°、27.3±0.2°、30.8±0.2°；

[0263] 9.1±0.2°、13.7±0.2°、17.8±0.2°、20.8±0.2°、15.3±0.2°、18.6±0.2°、18.9±0.2°、20.4±0.2°、22.8±0.2°；

[0264] 9.1±0.2°, 13.7±0.2°, 17.8±0.2°, 20.8±0.2°, 18.6±0.2°, 18.9±0.2°, 20.4±0.2°, 22.8±0.2°, 23.3±0.2°;

[0265] 9.1±0.2°, 13.7±0.2°, 17.8±0.2°, 20.8±0.2°, 8.4±0.2°, 16.9±0.2°, 18.2±0.2°, 25.9±0.2°, 27.3±0.2°;

[0266] 9.1±0.2°, 13.7±0.2°, 17.8±0.2°, 20.8±0.2°, 16.9±0.2°, 18.2±0.2°, 25.9±0.2°, 27.3±0.2°, 30.8±0.2°;

[0267] Most preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form B is basically as shown in Figure 42; the DSC pattern is shown in Figure 43.

[0268] Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxopiridine-1-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-(ethyl-d5)-1H-pyrazole-5-carboxamide hydrochloride crystal form C;

[0269] The X-ray powder diffraction pattern of the hydrochloride crystal form C shows a diffraction peak at 2θ of 4.3 ± 0.2°; or at 17.2 ± 0.2°; or at 21.5 ± 0.2°; or at 22.0 ± 0.2°; or at 8.6 ± 0.2°; or at 9.8 ± 0.2°; or at 13.5 ± 0.2°. The diffraction peaks are present; or diffraction peaks are present at 16.1±0.2°; or diffraction peaks are present at 18.3±0.2°; or diffraction peaks are present at 26.0±0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks are included; more preferably, any 6, 7, 8, 9, or 10 of the above diffraction peaks are included.

[0270] The X-ray powder diffraction pattern of the hydrochloride crystal form C includes at least one or more diffraction peaks located at 2θ of 4.3±0.2°, 17.2±0.2°, 21.5±0.2°, and 22.0±0.2°, preferably two of these peaks, more preferably three or four; even more preferably, it may also include at least one of 2θ of 8.6±0.2°, 9.8±0.2°, 13.5±0.2°, 16.1±0.2°, 18.3±0.2°, and 26.0±0.2°, preferably two, three, four, five, or six of these peaks.

[0271] More preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form C includes one or more diffraction peaks located at 4.3±0.2°, 8.6±0.2°, 9.8±0.2°, 13.5±0.2°, 16.1±0.2°, 17.2±0.2°, 18.3±0.2°, 21.5±0.2°, 22.0±0.2°, and 26.0±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 8, or 10 locations.

[0272] More preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form C may further include one or more diffraction peaks selected from 9.5±0.2°, 11.3±0.2°, 12.9±0.2°, 17.9±0.2°, 18.6±0.2°, 19.1±0.2°, 20.1±0.2°, and 23.9±0.2°; preferably, it includes at least 2-3, 4-5, 5-6, or 7-8 peaks; more preferably, it includes any 2, 3, 4, 5, 6, 7, or 8 peaks.

[0273] For example, the X-ray powder diffraction pattern of the hydrochloride crystal form C shows diffraction peaks at the following positions with a 2θ value:

[0274] 4.3±0.2°, 8.6±0.2°, 9.8±0.2°, 13.5±0.2°, 17.2±0.2°, 21.5±0.2°, 22.0±0.2°;

[0275] 4.3±0.2°, 16.1±0.2°, 17.2±0.2°, 18.3±0.2°, 21.5±0.2°, 22.0±0.2°, 26.0±0.2°;

[0276] 4.3±0.2°, 9.5±0.2°, 11.3±0.2°, 12.9±0.2°, 17.2±0.2°, 21.5±0.2°, 22.0±0.2°;

[0277] 4.3±0.2°、12.9±0.2°、17.2±0.2°、17.9±0.2°、18.6±0.2°、21.5±0.2°、22.0±0.2°；

[0278] 4.3±0.2°、17.2±0.2°、19.1±0.2°、20.1±0.2°、21.5±0.2°、22.0±0.2°、23.9±0.2°；

[0279] 4.3±0.2°、8.6±0.2°、9.8±0.2°、13.5±0.2°、16.1±0.2°、17.2±0.2°、21.5±0.2°、22.0±0.2°；

[0280] 4.3±0.2°、13.5±0.2°、16.1±0.2°、17.2±0.2°、18.3±0.2°、21.5±0.2°、22.0±0.2°、26.0±0.2°；

[0281] 4.3±0.2°、9.5±0.2°、11.3±0.2°、12.9±0.2°、17.9±0.2°、17.2±0.2°、21.5±0.2°、22.0±0.2°；

[0282] 4.3±0.2°、17.2±0.2°、18.6±0.2°、19.1±0.2°、20.1±0.2°、21.5±0.2°、22.0±0.2°、23.9±0.2°；

[0283] 4.3±0.2°、8.6±0.2°、9.8±0.2°、9.5±0.2°、11.3±0.2°、17.2±0.2°、21.5±0.2°、22.0±0.2°；

[0284] 4.3±0.2°、17.2±0.2°、18.3±0.2°、20.1±0.2°、21.5±0.2°、22.0±0.2°、23.9±0.2°、26.0±0.2°；

[0285] 4.3±0.2°、8.6±0.2°、9.5±0.2°、17.2±0.2°、21.5±0.2°、22.0±0.2°、23.9±0.2°、26.0±0.2°；

[0286] 4.3±0.2°, 8.6±0.2°, 9.8±0.2°, 13.5±0.2°, 16.1±0.2°, 17.2±0.2°, 18.3±0.2°, 21.5±0.2°, 22.0±0.2°;

[0287] 4.3±0.2°, 9.8±0.2°, 13.5±0.2°, 16.1±0.2°, 17.2±0.2°, 18.3±0.2°, 21.5±0.2°, 22.0±0.2°, 26.0±0.2°;

[0288] 4.3±0.2°, 9.5±0.2°, 11.3±0.2°, 12.9±0.2°, 17.2±0.2°, 17.9±0.2°, 18.6±0.2°, 21.5±0.2°, 22.0±0.2°;

[0289] 4.3±0.2°, 17.2±0.2°, 17.9±0.2°, 18.6±0.2°, 19.1±0.2°, 20.1±0.2°, 21.5±0.2°, 22.0±0.2°, 23.9±0.2°;

[0290] Most preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form C is basically as shown in Figure 44; the DSC pattern is shown in Figure 45.

[0291] Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxopiridine-1-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-(ethyl-d5)-1H-pyrazole-5-carboxamide hydrochloride crystal form D;

[0292] The X-ray powder diffraction pattern of the hydrochloride crystal form D shows a diffraction peak at 2θ of 8.7 ± 0.2°; or at 10.7 ± 0.2°; or at 11.3 ± 0.2°; or at 13.8 ± 0.2°; or at 14.2 ± 0.2°; or at 18.3 ± 0.2°; or at 18.7 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 19.2±0.2°; or has diffraction peaks at 19.5±0.2°; or has diffraction peaks at 28.2±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them;

[0293] The X-ray powder diffraction pattern of the hydrochloride crystal form D includes at least one or more diffraction peaks located at 2θ of 8.7±0.2°, 13.8±0.2°, 14.2±0.2°, and 18.3±0.2°, preferably two of these peaks, more preferably three or four; even more preferably, it may also include at least one of 2θ of 10.7±0.2°, 11.3±0.2°, 18.7±0.2°, 19.2±0.2°, 19.5±0.2°, and 28.2±0.2°, preferably two, three, four, five, or six of these peaks.

[0294] More preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form D includes one or more diffraction peaks located at 8.7±0.2°, 10.7±0.2°, 11.3±0.2°, 13.8±0.2°, 14.2±0.2°, 18.3±0.2°, 18.7±0.2°, 19.2±0.2°, 19.5±0.2°, and 28.2±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 8, or 10 of these locations.

[0295] More preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form D may also include one or more diffraction peaks selected from 9.6±0.2°, 12.7±0.2°, 14.4±0.2°, 15.5±0.2°, 17.1±0.2°, and 17.7±0.2°; preferably, it includes at least any 2-3, 4-5, or 5-6 peaks; more preferably, it includes any 2, 3, 4, 5, or 6 peaks.

[0296] For example, the X-ray powder diffraction pattern of the hydrochloride crystal form D shows diffraction peaks at the following positions with a 2θ value:

[0297] 8.7±0.2°, 13.8±0.2°, 14.2±0.2°, 18.3±0.2°, 10.7±0.2°, 11.3±0.2°, 18.7±0.2°;

[0298] 8.7±0.2°, 13.8±0.2°, 14.2±0.2°, 18.3±0.2°, 19.2±0.2°, 19.5±0.2°, 28.2±0.2°;

[0299] 8.7±0.2°, 13.8±0.2°, 14.2±0.2°, 18.3±0.2°, 9.6±0.2°, 12.7±0.2°, 14.4±0.2°;

[0300] 8.7±0.2°、13.8±0.2°、14.2±0.2°、18.3±0.2°、15.5±0.2°、17.1±0.2°、17.7±0.2°；

[0301] 8.7±0.2°、13.8±0.2°、14.2±0.2°、18.3±0.2°、10.7±0.2°、11.3±0.2°、18.7±0.2°、19.2±0.2°；

[0302] 8.7±0.2°、13.8±0.2°、14.2±0.2°、18.3±0.2°、18.7±0.2°、19.2±0.2°、19.5±0.2°、28.2±0.2°；

[0303] 8.7±0.2°、13.8±0.2°、14.2±0.2°、18.3±0.2°、9.6±0.2°、12.7±0.2°、14.4±0.2°、15.5±0.2°；

[0304] 8.7±0.2°、13.8±0.2°、14.2±0.2°、18.3±0.2°、14.4±0.2°、15.5±0.2°、17.1±0.2°、17.7±0.2°；

[0305] 8.7±0.2°、13.8±0.2°、14.2±0.2°、18.3±0.2°、10.7±0.2°、11.3±0.2°、9.6±0.2°、12.7±0.2°；

[0306] 8.7±0.2°、13.8±0.2°、14.2±0.2°、18.3±0.2°、19.5±0.2°、28.2±0.2°、17.1±0.2°、17.7±0.2°；

[0307] 8.7±0.2°、13.8±0.2°、14.2±0.2°、18.3±0.2°、10.7±0.2°、28.2±0.2°、9.6±0.2°、17.7±0.2°；

[0308] 8.7±0.2°、13.8±0.2°、14.2±0.2°、18.3±0.2°、10.7±0.2°、11.3±0.2°、18.7±0.2°、19.2±0.2°、19.5±0.2°；

[0309] 8.7±0.2°, 13.8±0.2°, 14.2±0.2°, 18.3±0.2°, 11.3±0.2°, 18.7±0.2°, 19.2±0.2°, 19.5±0.2°, 28.2±0.2°;

[0310] 8.7±0.2°, 13.8±0.2°, 14.2±0.2°, 18.3±0.2°, 9.6±0.2°, 12.7±0.2°, 14.4±0.2°, 15.5±0.2°, 17.1±0.2°;

[0311] 8.7±0.2°, 13.8±0.2°, 14.2±0.2°, 18.3±0.2°, 12.7±0.2°, 14.4±0.2°, 15.5±0.2°, 17.1±0.2°, 17.7±0.2°;

[0312] Most preferably, the TGA-DSC spectrum of the hydrochloride crystal form D is shown in Figure 46;

[0313] Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxopiridine-1-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-(ethyl-d5)-1H-pyrazole-5-carboxamide hydrochloride crystal form E;

[0314] The X-ray powder diffraction pattern of the hydrochloride crystal form E shows a diffraction peak at 2θ of 9.6 ± 0.2°; or at 13.7 ± 0.2°; or at 15.2 ± 0.2°; or at 16.3 ± 0.2°; or at 16.8 ± 0.2°; or at 17.7 ± 0.2°; or at 19.2 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 20.0±0.2°; or has diffraction peaks at 24.1±0.2°; or has diffraction peaks at 28.5±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them;

[0315] The X-ray powder diffraction pattern of the hydrochloride crystal form E includes at least one or more diffraction peaks located at 2θ of 9.6±0.2°, 16.8±0.2°, 17.7±0.2°, and 19.2±0.2°, preferably two, more preferably three or four; even more preferably, it may also include at least one at 2θ of 13.7±0.2°, 15.2±0.2°, 16.3±0.2°, 20.0±0.2°, 24.1±0.2°, and 28.5±0.2°, preferably two, three, four, five, or six.

[0316] More preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form E includes one or more diffraction peaks located at 9.6±0.2°, 13.7±0.2°, 15.2±0.2°, 16.3±0.2°, 16.8±0.2°, 17.7±0.2°, 19.2±0.2°, 20.0±0.2°, 24.1±0.2°, and 28.5±0.2°; preferably, it includes diffraction peaks at any of the selected 4, 5, 6, 8, or 10 locations.

[0317] More preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form E may also include one or more diffraction peaks selected from 4.4±0.2°, 6.9±0.2°, 7.2±0.2°, 20.6±0.2°, 29.0±0.2°, and 31.7±0.2°; preferably, it includes at least 2-3, 4-5, or 5-6 peaks; more preferably, it includes any 2, 3, 4, 5, or 6 peaks.

[0318] For example, the X-ray powder diffraction pattern of the hydrochloride crystal form E shows diffraction peaks at the following positions with a 2θ value:

[0319] 9.6±0.2°, 16.8±0.2°, 17.7±0.2°, 19.2±0.2°, 13.7±0.2°, 15.2±0.2°, 16.3±0.2°;

[0320] 9.6±0.2°, 16.8±0.2°, 17.7±0.2°, 19.2±0.2°, 20.0±0.2°, 24.1±0.2°, 28.5±0.2°;

[0321] 9.6±0.2°, 16.8±0.2°, 17.7±0.2°, 19.2±0.2°, 4.4±0.2°, 6.9±0.2°, 7.2±0.2°;

[0322] 9.6±0.2°、16.8±0.2°、17.7±0.2°、19.2±0.2°、20.6±0.2°、29.0±0.2°、31.7±0.2°；

[0323] 9.6±0.2°、16.8±0.2°、17.7±0.2°、19.2±0.2°、13.7±0.2°、15.2±0.2°、16.3±0.2°、20.0±0.2°；

[0324] 9.6±0.2°、16.8±0.2°、17.7±0.2°、19.2±0.2°、16.3±0.2°、20.0±0.2°、24.1±0.2°、28.5±0.2°；

[0325] 9.6±0.2°、16.8±0.2°、17.7±0.2°、19.2±0.2°、4.4±0.2°、6.9±0.2°、7.2±0.2°、20.6±0.2°；

[0326] 9.6±0.2°、16.8±0.2°、17.7±0.2°、19.2±0.2°、7.2±0.2°、20.6±0.2°、29.0±0.2°、31.7±0.2°；

[0327] 9.6±0.2°、16.8±0.2°、17.7±0.2°、19.2±0.2°、13.7±0.2°、15.2±0.2°、4.4±0.2°、6.9±0.2°；

[0328] 9.6±0.2°、16.8±0.2°、17.7±0.2°、19.2±0.2°、24.1±0.2°、28.5±0.2°、29.0±0.2°、31.7±0.2°；

[0329] 9.6±0.2°、16.8±0.2°、17.7±0.2°、19.2±0.2°、13.7±0.2°、28.5±0.2°、4.4±0.2°、31.7±0.2°；

[0330] 9.6±0.2°、16.8±0.2°、17.7±0.2°、19.2±0.2°、13.7±0.2°、15.2±0.2°、16.3±0.2°、20.0±0.2°、24.1±0.2°；

[0331] 9.6±0.2°, 16.8±0.2°, 17.7±0.2°, 19.2±0.2°, 15.2±0.2°, 16.3±0.2°, 20.0±0.2°, 24.1±0.2°, 28.5±0.2°;

[0332] 9.6±0.2°, 16.8±0.2°, 17.7±0.2°, 19.2±0.2°, 4.4±0.2°, 6.9±0.2°, 7.2±0.2°, 20.6±0.2°, 29.0±0.2°;

[0333] 9.6±0.2°, 16.8±0.2°, 17.7±0.2°, 19.2±0.2°, 6.9±0.2°, 7.2±0.2°, 20.6±0.2°, 29.0±0.2°, 31.7±0.2°;

[0334] Most preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form E is basically as shown in Figure 47;

[0335] Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxopiridine-1-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-(ethyl-d5)-1H-pyrazole-5-carboxamide sulfate crystal form A;

[0336] The X-ray powder diffraction pattern of the sulfate crystal form A shows a diffraction peak at 2θ of 9.5 ± 0.2°; or at 10.7 ± 0.2°; or at 18.3 ± 0.2°; or at 19.5 ± 0.2°; or at 15.9 ± 0.2°; or at 21.7 ± 0.2°; or at 22.8 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 23.1±0.2°; or has diffraction peaks at 25.4±0.2°; or has diffraction peaks at 25.7±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them;

[0337] The X-ray powder diffraction pattern of the sulfate crystal form A includes at least one or more diffraction peaks located at 2θ of 9.5±0.2°, 10.7±0.2°, 18.3±0.2°, and 19.5±0.2°, preferably two, more preferably three or four; even more preferably, it may also include at least one of 2θ of 15.9±0.2°, 21.7±0.2°, 22.8±0.2°, 23.1±0.2°, 25.4±0.2°, and 25.7±0.2°, preferably two, three, four, five, or six.

[0338] More preferably, the X-ray powder diffraction pattern of the sulfate crystal form A includes one or more diffraction peaks located at 9.5±0.2°, 10.7±0.2°, 15.9±0.2°, 18.3±0.2°, 19.5±0.2°, 21.7±0.2°, 22.8±0.2°, 23.1±0.2°, 25.4±0.2°, and 25.7±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 8, or 10 of these locations.

[0339] More preferably, the X-ray powder diffraction pattern of the sulfate crystal form A may also include one or more diffraction peaks selected from 12.7±0.2°, 14.9±0.2°, 18.9±0.2°, 21.1±0.2°, 23.8±0.2°, and 24.6±0.2°; preferably, it includes at least 2-3, 4-5, or 5-6 peaks; more preferably, it includes any 2, 3, 4, 5, or 6 peaks.

[0340] For example, the X-ray powder diffraction pattern of the sulfate crystal form A has diffraction peaks at the following positions with a 2θ value:

[0341] 9.5±0.2°, 10.7±0.2°, 15.9±0.2°, 18.3±0.2°, 19.5±0.2°, 21.7±0.2°, 22.8±0.2°;

[0342] 9.5±0.2°, 10.7±0.2°, 18.3±0.2°, 19.5±0.2°, 23.1±0.2°, 25.4±0.2°, 25.7±0.2°;

[0343] 9.5±0.2°, 10.7±0.2°, 12.7±0.2°, 14.9±0.2°, 18.3±0.2°, 18.9±0.2°, 19.5±0.2°;

[0344] 9.5±0.2°、10.7±0.2°、18.3±0.2°、19.5±0.2°、21.1±0.2°、23.8±0.2°、24.6±0.2°；

[0345] 9.5±0.2°、10.7±0.2°、15.9±0.2°、18.3±0.2°、19.5±0.2°、21.7±0.2°、22.8±0.2°、23.1±0.2°；

[0346] 9.5±0.2°、10.7±0.2°、18.3±0.2°、19.5±0.2°、22.8±0.2°、23.1±0.2°、25.4±0.2°、25.7±0.2°；

[0347] 9.5±0.2°、10.7±0.2°、12.7±0.2°、14.9±0.2°、18.3±0.2°、18.9±0.2°、19.5±0.2°、21.1±0.2°；

[0348] 9.5±0.2°、10.7±0.2°、18.3±0.2°、18.9±0.2°、19.5±0.2°、21.1±0.2°、23.8±0.2°、24.6±0.2°；

[0349] 9.5±0.2°、10.7±0.2°、12.7±0.2°、14.9±0.2°、15.9±0.2°、18.3±0.2°、19.5±0.2°、21.7±0.2°；

[0350] 9.5±0.2°、10.7±0.2°、18.3±0.2°、19.5±0.2°、23.8±0.2°、24.6±0.2°、25.4±0.2°、25.7±0.2°；

[0351] 9.5±0.2°、10.7±0.2°、12.7±0.2°、15.9±0.2°、18.3±0.2°、19.5±0.2°、24.6±0.2°、25.7±0.2°；

[0352] 9.5±0.2°、10.7±0.2°、15.9±0.2°、18.3±0.2°、19.5±0.2°、21.7±0.2°、22.8±0.2°、23.1±0.2°、25.4±0.2°；

[0353] 9.5±0.2°, 10.7±0.2°, 18.3±0.2°, 19.5±0.2°, 21.7±0.2°, 22.8±0.2°, 23.1±0.2°, 25.4±0.2°, 25.7±0.2°;

[0354] 9.5±0.2°, 10.7±0.2°, 12.7±0.2°, 14.9±0.2°, 18.3±0.2°, 18.9±0.2°, 19.5±0.2°, 21.1±0.2°, 23.8±0.2°;

[0355] 9.5±0.2°, 10.7±0.2°, 14.9±0.2°, 18.3±0.2°, 18.9±0.2°, 19.5±0.2°, 21.1±0.2°, 23.8±0.2°, 24.6±0.2°;

[0356] Most preferably, the X-ray powder diffraction pattern of the sulfate crystal form A is basically as shown in Figure 48; the TGA-DSC pattern is shown in Figure 49;

[0357] Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxopiridine-1-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-(ethyl-d5)-1H-pyrazole-5-carboxamide sulfate crystal form B;

[0358] The X-ray powder diffraction pattern of the sulfate crystal form A shows a diffraction peak at 2θ of 9.6 ± 0.2°; or at 9.9 ± 0.2°; or at 16.1 ± 0.2°; or at 17.7 ± 0.2°; or at 5.4 ± 0.2°; or at 10.8 ± 0.2°; or at 18.3 ± 0.2°. The diffraction peaks are present; or diffraction peaks are present at 19.7±0.2°; or diffraction peaks are present at 21.2±0.2°; or diffraction peaks are present at 23.2±0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks are included; more preferably, any 6, 7, 8, 9, or 10 of the above diffraction peaks are included.

[0359] The X-ray powder diffraction pattern of the sulfate crystal form B includes at least one or more diffraction peaks located at 2θ of 9.6±0.2°, 9.9±0.2°, 16.1±0.2°, and 17.7±0.2°, preferably two of these peaks, more preferably three or four; even more preferably, it may also include at least one of 2θ of 5.4±0.2°, 10.8±0.2°, 18.3±0.2°, 19.7±0.2°, 21.2±0.2°, and 23.2±0.2°, preferably two, three, four, five, or six of these peaks.

[0360] More preferably, the X-ray powder diffraction pattern of the sulfate crystal form B includes one or more diffraction peaks located at 5.4±0.2°, 9.6±0.2°, 9.9±0.2°, 10.8±0.2°, 16.1±0.2°, 17.7±0.2°, 18.3±0.2°, 19.7±0.2°, 21.2±0.2°, and 23.2±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 8, or 10 of these locations.

[0361] More preferably, the X-ray powder diffraction pattern of the sulfate crystal form B may also include one or more diffraction peaks selected from 12.7±0.2°, 15.0±0.2°, 20.1±0.2°, 21.8±0.2°, 24.7±0.2°, and 25.5±0.2°; preferably, it includes at least 2-3, 4-5, or 5-6 peaks; more preferably, it includes any 2, 3, 4, 5, or 6 peaks.

[0362] For example, the X-ray powder diffraction pattern of the sulfate crystal form B shows diffraction peaks at the following positions with a 2θ value:

[0363] 9.6±0.2°, 9.9±0.2°, 16.1±0.2°, 17.7±0.2°, 5.4±0.2°, 10.8±0.2°, 18.3±0.2°;

[0364] 9.6±0.2°, 9.9±0.2°, 16.1±0.2°, 17.7±0.2°, 19.7±0.2°, 21.2±0.2°, 23.2±0.2°;

[0365] 9.6±0.2°, 9.9±0.2°, 16.1±0.2°, 17.7±0.2°, 12.7±0.2°, 15.0±0.2°, 20.1±0.2°;

[0366] 9.6±0.2°、9.9±0.2°、16.1±0.2°、17.7±0.2°、21.8±0.2°、24.7±0.2°、25.5±0.2°；

[0367] 9.6±0.2°、9.9±0.2°、16.1±0.2°、17.7±0.2°、5.4±0.2°、10.8±0.2°、18.3±0.2°、19.7±0.2°；

[0368] 9.6±0.2°、9.9±0.2°、16.1±0.2°、17.7±0.2°、18.3±0.2°、19.7±0.2°、21.2±0.2°、23.2±0.2°；

[0369] 9.6±0.2°、9.9±0.2°、16.1±0.2°、17.7±0.2°、12.7±0.2°、15.0±0.2°、20.1±0.2°、21.8±0.2°；

[0370] 9.6±0.2°、9.9±0.2°、16.1±0.2°、17.7±0.2°、20.1±0.2°、21.8±0.2°、24.7±0.2°、25.5±0.2°；

[0371] 9.6±0.2°、9.9±0.2°、16.1±0.2°、17.7±0.2°、5.4±0.2°、10.8±0.2°、12.7±0.2°、15.0±0.2°；

[0372] 9.6±0.2°、9.9±0.2°、16.1±0.2°、17.7±0.2°、21.2±0.2°、23.2±0.2°、12.7±0.2°、15.0±0.2°；

[0373] 9.6±0.2°、9.9±0.2°、16.1±0.2°、17.7±0.2°、5.4±0.2°、23.2±0.2°、12.7±0.2°、25.5±0.2°；

[0374] 9.6±0.2°、9.9±0.2°、16.1±0.2°、17.7±0.2°、5.4±0.2°、10.8±0.2°、18.3±0.2°、19.7±0.2°、21.2±0.2°；

[0375] 9.6±0.2°, 9.9±0.2°, 16.1±0.2°, 17.7±0.2°, 10.8±0.2°, 18.3±0.2°, 19.7±0.2°, 21.2±0.2°, 23.2±0.2°;

[0376] 9.6±0.2°, 9.9±0.2°, 16.1±0.2°, 17.7±0.2°, 12.7±0.2°, 15.0±0.2°, 20.1±0.2°, 21.8±0.2°, 24.7±0.2°;

[0377] 9.6±0.2°, 9.9±0.2°, 16.1±0.2°, 17.7±0.2°, 15.0±0.2°, 20.1±0.2°, 21.8±0.2°, 24.7±0.2°, 25.5±0.2°;

[0378] Most preferably, the X-ray powder diffraction pattern of the sulfate crystal form B is basically as shown in Figure 50;

[0379] Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxopiridine-1-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-(ethyl-d5)-1H-pyrazole-5-carboxamide maleate crystal form A;

[0380] The X-ray powder diffraction pattern of the maleate crystal form A shows a diffraction peak at 2θ of 9.6 ± 0.2°; or at 10.0 ± 0.2°; or at 11.1 ± 0.2°; or at 15.8 ± 0.2°; or at 17.9 ± 0.2°; or at 18.4 ± 0.2°; or at 18.7 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 19.0±0.2°; or has diffraction peaks at 19.2±0.2°; or has diffraction peaks at 20.0±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them;

[0381] The X-ray powder diffraction pattern of the maleate crystal form A includes at least one or more diffraction peaks located at 2θ of 9.6±0.2°, 15.8±0.2°, 18.4±0.2°, and 18.7±0.2°, preferably two, more preferably three or four; even more preferably, it may also include at least one of 2θ of 10.0±0.2°, 11.1±0.2°, 17.9±0.2°, 19.0±0.2°, 19.2±0.2°, and 20.0±0.2°, preferably two, three, four, five, or six.

[0382] More preferably, the X-ray powder diffraction pattern of the maleate crystal form A includes one or more diffraction peaks located at 9.6±0.2°, 10.0±0.2°, 11.1±0.2°, 15.8±0.2°, 17.9±0.2°, 18.4±0.2°, 18.7±0.2°, 19.0±0.2°, 19.2±0.2°, and 20.0±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 8, or 10 locations.

[0383] More preferably, the X-ray powder diffraction pattern of the maleate crystal form A may also include one or more diffraction peaks selected from 10.3±0.2°, 10.7±0.2°, 14.5±0.2°, 17.6±0.2°, 19.7±0.2°, and 21.5±0.2°; preferably, it includes at least 2-3, 4-5, or 5-6 peaks; more preferably, it includes any 2, 3, 4, 5, or 6 peaks.

[0384] For example, the X-ray powder diffraction pattern of the maleate crystal form A has diffraction peaks at the following positions with a 2θ value:

[0385] 9.6±0.2°, 15.8±0.2°, 18.4±0.2°, 18.7±0.2°, 10.0±0.2°, 11.1±0.2°, 17.9±0.2°;

[0386] 9.6±0.2°, 15.8±0.2°, 18.4±0.2°, 18.7±0.2°, 19.0±0.2°, 19.2±0.2°, 20.0±0.2°;

[0387] 9.6±0.2°, 15.8±0.2°, 18.4±0.2°, 18.7±0.2°, 10.3±0.2°, 10.7±0.2°, 14.5±0.2°;

[0388] 9.6±0.2°、15.8±0.2°、18.4±0.2°、18.7±0.2°、17.6±0.2°、19.7±0.2°、21.5±0.2°；

[0389] 9.6±0.2°、15.8±0.2°、18.4±0.2°、18.7±0.2°、10.0±0.2°、11.1±0.2°、17.9±0.2°、19.0±0.2°；

[0390] 9.6±0.2°、15.8±0.2°、18.4±0.2°、18.7±0.2°、17.9±0.2°、19.0±0.2°、19.2±0.2°、20.0±0.2°；

[0391] 9.6±0.2°、15.8±0.2°、18.4±0.2°、18.7±0.2°、10.3±0.2°、10.7±0.2°、14.5±0.2°、17.6±0.2°；

[0392] 9.6±0.2°、15.8±0.2°、18.4±0.2°、18.7±0.2°、14.5±0.2°、17.6±0.2°、19.7±0.2°、21.5±0.2°；

[0393] 9.6±0.2°、15.8±0.2°、18.4±0.2°、18.7±0.2°、10.0±0.2°、11.1±0.2°、10.3±0.2°、10.7±0.2°；

[0394] 9.6±0.2°、15.8±0.2°、18.4±0.2°、18.7±0.2°、19.2±0.2°、20.0±0.2°、19.7±0.2°、21.5±0.2°；

[0395] 9.6±0.2°、15.8±0.2°、18.4±0.2°、18.7±0.2°、10.0±0.2°、20.0±0.2°、10.3±0.2°、21.5±0.2°；

[0396] 9.6±0.2°、15.8±0.2°、18.4±0.2°、18.7±0.2°、10.0±0.2°、11.1±0.2°、17.9±0.2°、19.0±0.2°、19.2±0.2°；

[0397] 9.6±0.2°, 15.8±0.2°, 18.4±0.2°, 18.7±0.2°, 11.1±0.2°, 17.9±0.2°, 19.0±0.2°, 19.2±0.2°, 20.0±0.2°;

[0398] 9.6±0.2°, 15.8±0.2°, 18.4±0.2°, 18.7±0.2°, 10.3±0.2°, 10.7±0.2°, 14.5±0.2°, 17.6±0.2°, 19.7±0.2°;

[0399] 9.6±0.2°, 15.8±0.2°, 18.4±0.2°, 18.7±0.2°, 10.7±0.2°, 14.5±0.2°, 17.6±0.2°, 19.7±0.2°, 21.5±0.2°;

[0400] Most preferably, the X-ray powder diffraction pattern of the maleate crystal form A is basically as shown in Figure 51;

[0401] Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxopiridine-1-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-(ethyl-d5)-1H-pyrazole-5-carboxamide benzenesulfonate crystal form A;

[0402] The X-ray powder diffraction pattern of the benzenesulfonate crystal form A shows a diffraction peak at 2θ of 6.6 ± 0.2°; or at 7.1 ± 0.2°; or at 7.6 ± 0.2°; or at 8.0 ± 0.2°; or at 10.0 ± 0.2°; or at 10.3 ± 0.2°; or at 11.6 ± 0.2°. The diffraction peaks are present; or diffraction peaks are present at 17.2±0.2°; or diffraction peaks are present at 20.8±0.2°; or diffraction peaks are present at 21.0±0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks are included; more preferably, any 6, 7, 8, 9, or 10 of the above diffraction peaks are included.

[0403] The X-ray powder diffraction pattern of the benzenesulfonate crystal form A includes at least one or more diffraction peaks located at 2θ of 6.6±0.2°, 8.0±0.2°, 10.0±0.2°, and 17.2±0.2°, preferably two, more preferably three or four; even more preferably, it may also include at least one of 2θ of 7.1±0.2°, 7.6±0.2°, 10.3±0.2°, 11.6±0.2°, 20.8±0.2°, and 21.0±0.2°, preferably two, three, four, five, or six.

[0404] More preferably, the X-ray powder diffraction pattern of the benzenesulfonate crystal form A includes one or more diffraction peaks located at 6.6±0.2°, 7.1±0.2°, 7.6±0.2°, 8.0±0.2°, 10.0±0.2°, 10.3±0.2°, 11.6±0.2°, 17.2±0.2°, 20.8±0.2°, and 21.0±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 8, or 10 of these locations.

[0405] For example, the X-ray powder diffraction pattern of the benzenesulfonate crystal form A has diffraction peaks at the following positions with a 2θ value:

[0406] 6.6±0.2°, 8.0±0.2°, 7.1±0.2°, 7.6±0.2°, 10.0±0.2°, 10.3±0.2°, 17.2±0.2°;

[0407] 6.6±0.2°, 8.0±0.2°, 10.0±0.2°, 11.6±0.2°, 17.2±0.2°, 20.8±0.2°, 21.0±0.2°;

[0408] 6.6±0.2°, 7.1±0.2°, 7.6±0.2°, 8.0±0.2°, 10.0±0.2°, 10.3±0.2°, 11.6±0.2°, 17.2±0.2°;

[0409] 6.6±0.2°, 8.0±0.2°, 10.0±0.2°, 17.2±0.2°, 10.3±0.2°, 11.6±0.2°, 20.8±0.2°, 21.0±0.2°;

[0410] 6.6±0.2°, 7.1±0.2°, 7.6±0.2°, 8.0±0.2°, 10.0±0.2°, 10.3±0.2°, 11.6±0.2°, 17.2±0.2°, 20.8±0.2°;

[0411] 6.6±0.2°, 7.6±0.2°, 8.0±0.2°, 10.0±0.2°, 10.3±0.2°, 11.6±0.2°, 17.2±0.2°, 20.8±0.2°, 21.0±0.2°;

[0412] Most preferably, the X-ray powder diffraction pattern of the benzenesulfonate crystal form A is basically as shown in Figure 52; the TGA-DSC pattern is shown in Figure 53;

[0413] Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxopiridine-1-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-(ethyl-d5)-1H-pyrazole-5-carboxamide phosphate crystal form A;

[0414] The X-ray powder diffraction pattern of the phosphate crystal form A shows a diffraction peak at 2θ of 4.6 ± 0.2°; or at 8.5 ± 0.2°; or at 13.8 ± 0.2°; or at 18.6 ± 0.2°; or at 9.7 ± 0.2°; or at 10.6 ± 0.2°; or at 12.4 ± 0.2°. The diffraction peaks are present; or diffraction peaks are present at 16.1±0.2°; or diffraction peaks are present at 17.8±0.2°; or diffraction peaks are present at 21.6±0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks are included; more preferably, any 6, 7, 8, 9, or 10 of the above diffraction peaks are included.

[0415] The X-ray powder diffraction pattern of the phosphate crystal form A includes at least one or more diffraction peaks located at 2θ of 4.6±0.2°, 8.5±0.2°, 13.8±0.2°, and 18.6±0.2°, preferably two of these peaks, more preferably three or four; even more preferably, it may also include at least one of 2θ of 9.7±0.2°, 10.6±0.2°, 12.4±0.2°, 16.1±0.2°, 17.8±0.2°, and 21.6±0.2°, preferably two, three, four, five, or six of these peaks.

[0416] More preferably, the X-ray powder diffraction pattern of the phosphate crystal form A includes one or more diffraction peaks located at 4.6±0.2°, 8.5±0.2°, 9.7±0.2°, 10.6±0.2°, 12.4±0.2°, 13.8±0.2°, 16.1±0.2°, 17.8±0.2°, 18.6±0.2°, and 21.6±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 8, or 10 of these locations.

[0417] For example, the X-ray powder diffraction pattern of the phosphate crystal form A has diffraction peaks at the following positions with a 2θ value:

[0418] 4.6±0.2°, 8.5±0.2°, 9.7±0.2°, 10.6±0.2°, 12.4±0.2°, 13.8±0.2°, 18.6±0.2°;

[0419] 4.6±0.2°, 8.5±0.2°, 13.8±0.2°, 16.1±0.2°, 17.8±0.2°, 18.6±0.2°, 21.6±0.2°;

[0420] 4.6±0.2°, 8.5±0.2°, 9.7±0.2°, 10.6±0.2°, 12.4±0.2°, 13.8±0.2°, 16.1±0.2°, 18.6±0.2°;

[0421] 4.6±0.2°, 8.5±0.2°, 12.4±0.2°, 13.8±0.2°, 16.1±0.2°, 17.8±0.2°, 18.6±0.2°, 21.6±0.2°;

[0422] 4.6±0.2°, 8.5±0.2°, 13.8±0.2°, 9.7±0.2°, 10.6±0.2°, 12.4±0.2°, 16.1±0.2°, 17.8±0.2°, 18.6±0.2°;

[0423] 4.6±0.2°, 8.5±0.2°, 10.6±0.2°, 12.4±0.2°, 13.8±0.2°, 16.1±0.2°, 17.8±0.2°, 18.6±0.2°, 21.6±0.2°;

[0424] Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxopiridine-1-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-(ethyl-d5)-1H-pyrazole-5-carboxamide phosphate crystal form B;

[0425] The X-ray powder diffraction pattern of the phosphate crystal form B shows a diffraction peak at 2θ of 9.6 ± 0.2°; or at 10.7 ± 0.2°; or at 11.3 ± 0.2°; or at 13.4 ± 0.2°; or at 18.7 ± 0.2°; or at 19.0 ± 0.2°; or at 19.6 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 20.9±0.2°; or has diffraction peaks at 21.5±0.2°; or has diffraction peaks at 22.9±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them;

[0426] The X-ray powder diffraction pattern of the phosphate crystal form B includes at least one or more diffraction peaks located at 2θ of 9.6±0.2°, 11.3±0.2°, 19.0±0.2°, and 21.5±0.2°, preferably two of these peaks, more preferably three or four; even more preferably, it may also include at least one of 2θ of 10.7±0.2°, 13.4±0.2°, 18.7±0.2°, 19.6±0.2°, 20.9±0.2°, and 22.9±0.2°, preferably two, three, four, five, or six of these peaks.

[0427] More preferably, the X-ray powder diffraction pattern of the phosphate crystal form B includes one or more diffraction peaks located at 9.6±0.2°, 10.7±0.2°, 11.3±0.2°, 13.4±0.2°, 18.7±0.2°, 19.0±0.2°, 19.6±0.2°, 20.9±0.2°, 21.5±0.2°, and 22.9±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 8, or 10 locations.

[0428] More preferably, the X-ray powder diffraction pattern of the phosphate crystal form B may also include one or more diffraction peaks selected from 12.5±0.2°, 18.0±0.2°, 20.1±0.2°, 22.5±0.2°, 23.7±0.2°, and 26.5±0.2°; preferably, it includes at least 2-3, 4-5, or 5-6 peaks; more preferably, it includes any 2, 3, 4, 5, or 6 peaks.

[0429] For example, the X-ray powder diffraction pattern of the phosphate crystal form B shows diffraction peaks at the following positions with a 2θ value:

[0430] 9.6±0.2°, 11.3±0.2°, 19.0±0.2°, 21.5±0.2°, 10.7±0.2°, 13.4±0.2°, 18.7±0.2°;

[0431] 9.6±0.2°, 11.3±0.2°, 19.0±0.2°, 21.5±0.2°, 19.6±0.2°, 20.9±0.2°, 22.9±0.2°;

[0432] 9.6±0.2°, 11.3±0.2°, 19.0±0.2°, 21.5±0.2°, 12.5±0.2°, 18.0±0.2°, 20.1±0.2°;

[0433] 9.6±0.2°, 11.3±0.2°, 19.0±0.2°, 21.5±0.2°, 22.5±0.2°, 23.7±0.2°, 26.5±0.2°;

[0434] 9.6±0.2°, 11.3±0.2°, 19.0±0.2°, 21.5±0.2°, 10.7±0.2°, 13.4±0.2°, 18.7±0.2°, 19.6±0.2°;

[0435] 9.6±0.2°, 11.3±0.2°, 19.0±0.2°, 21.5±0.2°, 18.7±0.2°, 19.6±0.2°, 20.9±0.2°, 22.9±0.2°;

[0436] 9.6±0.2°, 11.3±0.2°, 19.0±0.2°, 21.5±0.2°, 12.5±0.2°, 18.0±0.2°, 20.1±0.2°, 22.5±0.2°;

[0437] 9.6±0.2°, 11.3±0.2°, 19.0±0.2°, 21.5±0.2°, 20.1±0.2°, 22.5±0.2°, 23.7±0.2°, 26.5±0.2°;

[0438] 9.6±0.2°, 11.3±0.2°, 19.0±0.2°, 21.5±0.2°, 10.7±0.2°, 13.4±0.2°, 12.5±0.2°, 18.0±0.2°;

[0439] 9.6±0.2°, 11.3±0.2°, 19.0±0.2°, 21.5±0.2°, 20.9±0.2°, 22.9±0.2°, 23.7±0.2°, 26.5±0.2°;

[0440] 9.6±0.2°, 11.3±0.2°, 19.0±0.2°, 21.5±0.2°, 10.7±0.2°, 22.9±0.2°, 12.5±0.2°, 26.5±0.2°;

[0441] 9.6±0.2°, 11.3±0.2°, 19.0±0.2°, 21.5±0.2°, 10.7±0.2°, 13.4±0.2°, 18.7±0.2°, 19.6±0.2°, 20.9±0.2°;

[0442] 9.6±0.2°, 11.3±0.2°, 19.0±0.2°, 21.5±0.2°, 13.4±0.2°, 18.7±0.2°, 19.6±0.2°, 20.9±0.2°, 22.9±0.2°;

[0443] 9.6±0.2°, 11.3±0.2°, 19.0±0.2°, 21.5±0.2°, 12.5±0.2°, 18.0±0.2°, 20.1±0.2°, 22.5±0.2°, 23.7±0.2°;

[0444] 9.6±0.2°, 11.3±0.2°, 19.0±0.2°, 21.5±0.2°, 18.0±0.2°, 20.1±0.2°, 22.5±0.2°, 23.7±0.2°, 26.5±0.2°;

[0445] Most preferably, the X-ray powder diffraction pattern of the phosphate crystal form B is basically as shown in Figure 54; the TGA-DSC pattern is shown in Figure 55.

[0446] In certain embodiments of the present invention, the p-toluenesulfonate crystal forms A, B, C, D, E, F, and G of the N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide are described. The 2θ error of the top ten diffraction peaks with the highest relative intensities in the X-ray powder diffraction patterns of type H, hydrochloride crystal form A, hydrobromide crystal form B, hydrobromide crystal form C, hydrobromide crystal form D, benzoate crystal form A, benzoate crystal form B, and fumarate crystal form A, respectively, relative to the positions of the diffraction peaks in Figures 1, 3, 6, 9, 10, 12, 13, 14, 16, 18, 21, 23, 25, 27, 29, and 31, is ±0.2° to ±0.5°; preferably ±0.2° to ±0.3°, and most preferably ±0.2°.

[0447] In certain embodiments of the present invention, the N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxopiridine-1-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-(ethyl-d5)-1H-pyrazole-5-carboxamide hydrochloride crystal form A, hydrochloride crystal form B, hydrochloride crystal form C, and salt The positions of the top ten diffraction peaks with the highest relative intensities in the X-ray powder diffraction patterns of salt crystal form E, sulfate crystal form A, sulfate crystal form B, maleate crystal form A, benzenesulfonate crystal form A, and phosphate crystal form B have a 2θ error of ±0.2° to ±0.5° with respect to the diffraction peaks at the corresponding positions in Figures 40, 42, 44, 47, 48, 50, 51, 52, and 54, respectively; preferably ±0.2° to ±0.3°, and most preferably ±0.2°.

[0448] The present invention also provides a method for preparing an acidic salt of the compound or its stereoisomer as described above, or its crystal form, comprising the following steps:

[0449] Method 1:

[0450] 1) Weigh an appropriate amount of free base and dissolve or disperse it in solvent I;

[0451] 2) Weigh an appropriate amount of the counterion acid, dissolve it in an organic solvent, water, or add it directly to the solid counterion acid; the amount of counterion acid is preferably 1-3 times the equivalent, more preferably 1.1 or 2.1 equivalents;

[0452] 3) Combine the two solutions mentioned above, and optionally add seed crystals and stir to precipitate, or add solvent II dropwise and then stir to precipitate; preferably, the amount of seed crystals added is 0.05%-10%, more preferably 0.1%-6%, and even more preferably 2%-5%;

[0453] 4) Centrifugation and vacuum drying yield the target product;

[0454] Method 2: 1) Weigh an appropriate amount of a certain salt crystal form, dissolve or disperse it with solvent III, and stir or cool to allow crystals to precipitate;

[0455] 2) Centrifugation and vacuum drying yield the target product;

[0456] Method 3: 1) Weigh an appropriate amount of a certain salt crystal form and dissolve it in solvent IV;

[0457] 2) Volatilization and solidification yield the target product;

[0458] in:

[0459] Solvent I is selected from one or more of methanol, acetone, ethyl acetate, isopropyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone, 3-pentanone or N-methylpyrrolidone, and water; preferably tert-butanol, acetone, ethyl acetate, 2-butanone, and 2-methyltetrahydrofuran.

[0460] The organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol, or N,N-dimethylformamide; preferably methanol, ethanol, acetone, or acetonitrile; the above-mentioned benign solvents and organic solutions must be miscible when used.

[0461] Solvent II is selected from one or more of heptane, cyclohexane, n-hexane, n-pentane, water, ethyl acetate, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, isopropyl acetate, methyl isobutyl ketone, tert-butanol, toluene, or isopropyl ether; preferably one or more of water, heptane, methyl tert-butyl ether, or isopropyl ether.

[0462] Solvent III is selected from one or more of ethyl acetate, acetone, isopropyl acetate, methyl isobutyl ketone, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclohexane, water, and dichloromethane;

[0463] The solvent IV is selected from one or more of methanol, ethanol, isopropanol, ethyl acetate, acetonitrile, acetone, 2-butanone, tetrahydrofuran, and water;

[0464] 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, 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-toluenesulfonic acid, or L-malic acid; preferably hydrochloric acid, hydrobromic acid, or p-toluenesulfonic acid; more preferably p-toluenesulfonic acid.

[0465] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the above-described compound or its stereoisomer acid salt or crystal form thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0466] The present invention also provides the use of the acid salt of the compound or its stereoisomer as described above or its crystal form or the pharmaceutical composition as described above in a medicament for treating and / or preventing IL-17-related diseases, particularly in a medicament for treating and / or preventing IL-17A-related diseases.

[0467] The present invention also provides the use of the above-described compound or its stereoisomer acid salt or its crystal form or the above-described pharmaceutical composition in a medicament for treating and / or preventing autoimmune diseases; preferably, the autoimmune diseases are selected from psoriasis, plaque psoriasis, punctate psoriasis, retrograde psoriasis, pustular psoriasis, erythrodermic psoriasis, psoriatic arthritis, ankylosing spondylitis, hidradenitis suppurativa, rheumatoid arthritis, palmoplantar psoriasis, spondyloarthritis and non-infectious uveitis.

[0468] The present invention also provides a method for treating and / or preventing autoimmune diseases, comprising administering to a desired subject an acidic salt of the compound or its stereoisomer or its crystal form, or a pharmaceutical composition as described above, preferably, the autoimmune disease being selected from psoriasis, plaque psoriasis, punctate psoriasis, retrograde psoriasis, pustular psoriasis, erythrodermic psoriasis, psoriatic arthritis, ankylosing spondylitis, hidradenitis suppurativa, rheumatoid arthritis, palmoplantar psoriasis, spondyloarthritis, and non-infectious uveitis.

[0469] Detailed description of the invention

[0470] "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.

[0471] "Medicinal salts" refer to the salts of the compounds of this invention, which are safe and effective when used in mammals and have the appropriate biological activity.

[0472] The term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group, which may optionally be substituted with one or more substituents. In certain embodiments, alkyl refers to a group having a carbon density of 1 to 20 (C). 1-20 ), 1 to 15 (C 1-15 ), 1 to 12 (C 1-12 ), 1 to 10 (C 1-10 ), 1 to 8 (C 1- 8) 1 to 6 (C) 1-6 ) or 1 to 3 (C 1-3 A straight-chain saturated hydrocarbon group with 3 to 20 carbon atoms, or a group with 3 to 20 carbon atoms. 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 A branched saturated hydrocarbon group with 1 carbon atom. The straight-chain C group used here... 1-6 Alkyl and branched C 3-6 Alkyl groups are also called "lower alkyl groups". For example, C 1-6 Alkyl groups refer to linear saturated monovalent hydrocarbon groups having 1 to 6 carbon atoms or branched saturated monovalent hydrocarbon groups having 3 to 6 carbon atoms. In one embodiment, the C... 1-6The alkyl group contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) 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 various branched isomers thereof. In one embodiment, the alkyl group is an optionally substituted alkyl group as described elsewhere herein.

[0473] The term "alkylene" refers to an alkyl group in which one hydrogen atom is further substituted, wherein "alkyl" is defined as described above. Non-limiting examples of "alkylene" include methylene (-CH2-), ethylene (-(CH2)2-), propylene (-(CH2)3-), or butylene (-(CH2)4-). In one embodiment, the alkylene is an optionally substituted alkyl group as described elsewhere herein.

[0474] The term "alkenyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond, which can be located at any position within the alkenyl group, and the alkenyl group may optionally be substituted by one or more substituents. In a particular embodiment, the alkenyl group has a carbon content of 2 to 20 (C₂O₃). 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ) or 2 to 4 (C 2-4 A straight-chain unsaturated hydrocarbon group with 3 to 20 carbon atoms, or a hydrocarbon group with 3 to 20 carbon atoms. 3-20 ), 3 to 15 (C3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3- 8) or 3 to 6 (C) 3-6 A branched unsaturated hydrocarbon group with 16 carbon atoms. Unless otherwise specified, the term "alkenyl" as used herein includes both straight-chain and branched alkenyl groups. For example, C 2-6 Alkenyl refers to a straight-chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. In one embodiment, the C 2-6 Alkenyl groups contain 2 to 6 (e.g., 2, 3, 4, 5, or 6) carbon atoms. Non-limiting examples of alkenyl groups include: Those skilled in the art will understand that the term "alkenyl" may also include groups having "cis" and "trans" configurations, or alternatively, "E" and "Z" configurations. In one embodiment, the alkenyl is an optionally substituted alkenyl as described elsewhere herein.

[0475] The term "alkynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon triple bond, which can be located at any position within the alkynyl group. The alkynyl group may optionally be substituted by one or more substituents. In a particular embodiment, the alkynyl group has a carbon content of 2 to 20 (C₂O₃). 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ) or 2 to 4 (C 2-4 A straight-chain unsaturated hydrocarbon group with 3 to 20 carbon atoms, or a hydrocarbon group with 3 to 20 carbon atoms. 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 A branched unsaturated hydrocarbon group with 12 carbon atoms. Unless otherwise specified, the term "alkynyl" as used herein includes both straight-chain and branched alkynyl groups. For example, C 2-6 Alkyne refers to a straight-chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. In one embodiment, the C 2-6 The alkynyl group contains 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples of the alkynyl group include: In one embodiment, the alkynyl group is an optionally substituted alkynyl group as described elsewhere herein.

[0476] The term "cycloalkyl" refers to a monocyclic or polycyclic (two or more) cyclic group of a saturated or partially unsaturated aliphatic hydrocarbon, which may optionally be substituted with one or more substituents. In certain embodiments, the cycloalkyl ring comprises 3 to 20 (C 3-20 ), 3 to 12 (C 3-12 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms; in one embodiment, the cycloalkyl ring comprises 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 It has 10 carbon atoms; it may contain one or more double bonds, but does not have a fully conjugated π-electron system. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, or cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic alkyl, fused cycloalkyl, and bridged cycloalkyl groups in one embodiment. In one embodiment, the cycloalkyl group is an optionally substituted cycloalkyl group or an optionally fused cycloalkyl group with a heterocyclic group, aryl group, or heteroaryl group as described elsewhere herein, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc.

[0477] The term "spirocycloalkyl" refers to an aliphatic hydrocarbon polycyclic group that shares a single carbon atom (called a spiro atom) between its monocyclic rings. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. In certain embodiments, the spirocycloalkyl group comprises 5 to 20 carbon atoms. 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 (e.g., 7, 8, 9, 10) carbon atoms. Spirocycloalkyl groups are classified as monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between rings, with one embodiment being monospirocycloalkyl and bispirocycloalkyl. In one embodiment, it is a 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocycloalkyl. In one embodiment, the spirocycloalkyl group is an optionally substituted spirocycloalkyl group described elsewhere herein. Non-limiting examples of spirocycloalkyl groups include:

[0478] The term "fused-cycle alkyl" refers to a fully carbon polycyclic group in which each ring in a system shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron system. In a particular embodiment, the fused-cycle alkyl comprises 5 to 20 (C 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10(e.g., 7, 8, 9, 10) carbon atoms. Depending on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused-ring alkyl groups. In one embodiment, they are bicyclic or tricyclic, and in another embodiment, they are 3-membered / 5-membered, 4-membered / 5-membered, 5-membered / 5-membered, or 5-membered / 6-membered bicyclic alkyl groups. In one embodiment, the fused-ring alkyl group is an optionally substituted fused-ring alkyl group described elsewhere herein or an fused-ring alkyl group optionally fused with a heterocyclic group, aryl group, or heteroaryl group. Non-limiting examples of fused-ring alkyl groups include:

[0479] The term "bridged cycloalkyl" refers to a fully carbon polycyclic group in which any two rings share two non-directly bonded carbon atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. In certain embodiments, the bridged cycloalkyl group comprises 5 to 20 (C...) 5- 20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 (e.g., 7, 8, 9, 10) carbon atoms. Depending on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged alkyl groups, preferably bicyclic or tricyclic. In one embodiment, the bridged alkyl group is an optionally substituted bridged alkyl group described elsewhere herein. Non-limiting examples of bridged alkyl groups include:

[0480] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, wherein the nitrogen, phosphorus, or sulfur atom may optionally be oxidized, the nitrogen atom may optionally be quaternized, the ring carbon atom may optionally be substituted with oxygen, excluding the -OO- or -OS- ring moiety, and the remaining ring atoms are carbon, which may contain one or more double bonds but does not have a fully conjugated π-electron system. In a particular embodiment, the heterocyclic group comprises 3 to 20, 3 to 12, 3 to 8, or 3 to 6 ring atoms, wherein 1 to 4 are heteroatoms; in one embodiment, the heterocyclic group comprises 3 to 6, 4 to 6, 3 to 8, 3 to 10, 6 to 10, or 7 to 11 ring atoms; in one embodiment, the heterocyclic group comprises 3 to 8 (e.g., 3, 4, 5, 6, 7, 8) ring atoms. Non-limiting examples of monocyclic heterocyclic groups include tetrahydropyrrole, azahexacyclic butyl, oxacyclobutyl, oxacyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrole, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and pyranyl. Polycyclic heterocyclic groups include spiroheterocyclic, fused heterocyclic, and bridged heterocyclic groups. In one embodiment, the heterocyclic group is optionally substituted as described elsewhere herein, or is a heterocyclic group further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring.

[0481] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group in which one or more ring atoms share a single atom (called a spiro atom), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. In certain embodiments, the spiroheterocyclic group comprises 5 to 20 or 6 to 14 ring atoms; in one embodiment, it comprises 7 to 11 (e.g., 7, 8, 9, 10, 11) ring atoms; spiroheterocyclic groups are classified as monospirocyclic, bispirocyclic, or multispirocyclic groups according to the number of spiro atoms shared between the rings; monospirocyclic and bispirocyclic groups are preferred; in one embodiment, the spiroheterocyclic group is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocyclic group; in one embodiment, the spiroheterocyclic group is an optionally substituted spiroheterocyclic group described elsewhere herein; non-limiting examples of spiroheterocyclic groups include:

[0482] The term "fused heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in a system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, and the remaining ring atoms are carbon. In a particular embodiment, the fused heterocyclic group comprises 5 to 20 or 6 to 14 ring atoms, and in one embodiment comprises 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups depending on the number of constituent rings; bicyclic or tricyclic is preferred; in one embodiment, it is a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group; in one embodiment, the fused heterocyclic group is optionally substituted as described elsewhere herein, or a fused heterocyclic group that can be fused with cycloalkyl, heterocyclic, aryl, or heteroaryl groups; non-limiting examples of fused heterocyclic groups include:

[0483] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two non-directly bonded atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, and the remaining ring atoms are carbon. In certain embodiments, the bridged heterocyclic group comprises 5 to 20 or 6 to 14 ring atoms; in one embodiment, it comprises 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic group; preferably bicyclic, tricyclic, or tetracyclic; in one embodiment, it is bicyclic or tricyclic; in one embodiment, the bridged heterocyclic group is an optionally substituted bridged heterocyclic group described elsewhere herein; non-limiting examples of bridged heterocyclic groups include:

[0484] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group containing at least one conjugated π-electron system, which may optionally be substituted by one or more substituents. In certain embodiments, the aryl group comprises 6 to 20, 6 to 14, or 6 to 10 ring atoms; in one embodiment, the aryl group may further refer to a bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring is an aromatic ring, and the other rings may be saturated, partially unsaturated carbon rings, or rings containing one or more heteroatoms independently selected from O, S, and N; in one embodiment, the aryl group is selected from benzo5-10-membered heteroaryl, benzo3-10-membered cycloalkyl, or benzo3-10-membered heterocyclic groups. In one embodiment, the aryl group is selected from benzo5-6-membered heteroaryl, benzo3-6-membered cycloalkyl, or benzo3-6-membered heterocyclic groups, wherein the heterocyclic group is a heterocyclic group containing 1 to 3 nitrogen, oxygen, or sulfur atoms. Non-limiting examples include phenyl, naphthyl, fluorenyl, chamomilecycloyl, anthraceneyl, phenanthryl, pyrene, biphenyl, terphenyl, dihydronaphthyl, indene, tetrahydronaphthyl (naphthyl),

[0485] The term "arylene" refers to a divalent aryl group formed by further substitution of one hydrogen atom of an aryl group, wherein the arylene group may be optionally substituted or unsubstituted, as defined above for aryl groups.

[0486] The term "heteroaryl" refers to an optionally substituted monocyclic, polycyclic group or ring system comprising at least one aromatic ring having one or more heteroatoms independently selected from O, S, and N. In certain embodiments, the heteroaryl comprises 5 to 20, 5 to 15, or 5 to 10 ring atoms, of which 1 to 4 are heteroatoms; in one embodiment, the heteroaryl comprises 5 or 6 ring atoms; in certain embodiments, the heteroaryl may further refer to a bicyclic, tricyclic, or tetracyclic ring, wherein at least one ring is an aromatic ring having one or more heteroatoms independently selected from O, S, and N, and the other rings may be saturated, partially unsaturated carbocyclic rings, or rings comprising one or more heteroatoms independently selected from O, S, and N. In one embodiment, the heteroaryl group is selected from heteroaryl-6-10 aryl, heteroaryl-3-10 cycloalkyl, or heteroaryl-3-10 heterocyclic group; in a further embodiment, the heteroaryl group is selected from 5- or 6-membered heteroaryl-6-10 aryl, 5- or 6-membered heteroaryl-3-6 cycloalkyl, or 5- or 6-membered heteroaryl-3-6 heterocyclic group, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms. Non-limiting examples include: furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrroloyl, thiadiazolyl, thiazolyl, thiophene, tetrazolyl, triazinyl, triazolyl, benzofuranyl, benzimidazolyl, benziisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiaphenyl, benzobenzenethio, benzothiaphenyl, benzotriazolyl, imidazopyridyl, imidazothiazolyl Indazinyl, indolyl, inzolyl, isobenzofuranyl, isobenzothiophenyl, isoindolyl, isoquinolinyl, naphridinyl, oxazolopyridyl, phthalazinyl, pteridinyl, purine, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxolinyl, quinazolinyl, thiadiazopyrimidinyl, thienenopyridyl, acridineyl, benzoindolyl, carbazole, biphenylfuranyl, phenanthrololinyl, phenanthidyl, phenpyrazinyl, phenazinyl, phenthiazinyl, phenoxazinyl, xanthonyl,

[0487] The term "heteroaryl" refers to a divalent heteroaryl group formed by further substitution of one hydrogen atom of a cycloalkyl group, wherein the heteroaryl group may be optionally substituted or unsubstituted, as defined above.

[0488] The term "heteroalkyl" refers to a stable straight-chain or branched, or cyclic, hydrocarbon group, or a combination thereof, consisting of the indicated number of carbon atoms and one or more (one to three in one embodiment) heteroatoms selected from O, N, Si, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom may optionally be quaternized. In one embodiment, the heteroatoms O, N, and S may be placed at any internal position within the heteroalkyl group. In one embodiment, the heteroatom Si may be placed at any position within the heteroalkyl group (e.g., internal or terminal positions), including positions where the alkyl group is attached to the remainder of the molecule. Non-limiting examples include: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. At most two heteroatoms can be consecutive, for example, -CH2-NH-O-CH3 and -CH2-O-Si(CH3)3. In certain embodiments, the heteroalkyl group is an optionally substituted heteroalkyl group described elsewhere herein.

[0489] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), wherein the definition of alkyl or cycloalkyl is as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, or cyclohexyloxy. In one embodiment, the alkoxy group is an optionally substituted alkoxy group as described elsewhere herein.

[0490] The term "alkylacyl" refers to -C(O)-alkyl, where the definition of alkyl is as described above.

[0491] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein the definition of alkyl is as described above. Non-limiting examples of said haloalkyl groups include: trifluoromethyl, -CH2CF3,

[0492] The term “haloalkoxy” refers to an alkoxy group that has been substituted with one or more halogens, where the definition of an alkoxy group is as described above.

[0493] The term "hydroxyalkyl" refers to an alkyl group that has been substituted with a hydroxyl group, where the definition of alkyl is as described above.

[0494] The term "aminocarbonyl" refers to NH2-C(O)-.

[0495] The term "hydrogen" includes protons ( 1 H), deuterium ( 2 H), tritium (3 H) and / or mixtures thereof. In certain embodiments, one or more hydrogen-occupied sites in the compound may be enriched with deuterium and / or tritium. Such isotopically enriched analogs can be prepared from suitable isotopically labeled starting materials available from commercial sources or by known literature procedures.

[0496] The alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, arylene, heteroaryl, heteroarylene, heteroalkyl, alkoxy, alkylthio, hydroxyalkyl, alkenylcarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylamino, and alkylacyl groups may be substituted or unsubstituted. In one embodiment, the substituent is selected from one or more of the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, alkylacyl, halogen, mercapto, hydroxyl, nitro, cyano, azide, oxime, phosphate ester, oxo, thio, carboxyl, carboxylic acid ester, cycloalkyl, heterocyclic, aryl, heteroaryl, heterocycloalkoxy, cycloalkylthio, or heterocycloalkylthio.

[0497] Linking substituents are described in various parts of this invention. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it should be understood that "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

[0498] "Substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, provided that the valence state of the particular atom is normal and the substituted compound is stable in one embodiment and in another. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents can be arbitrary on a chemically feasible basis. It goes without saying that 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).

[0499] Unless otherwise stated, the indefinite articles “a” and “an” and the definite article “the” in this specification and claims include both plural and singular forms.

[0500] "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.

[0501] "Stereoisomers" encompass all enantiomers / non-corresponding isomers / stereoisomers of the present invention, as well as enantiomers / non-corresponding isomers / stereoisomers enriched in this invention.

[0502] "Stereoisopure" refers to a composition containing one stereoisomer of a compound but substantially lacking another stereoisomer of that compound. For example, a stereoisopure composition of a compound having one chiral center will substantially lack the opposing enantiomer of that compound. A stereoisopure composition of a compound having two chiral centers will substantially lack other diastereomers of that compound. A typical stereoisomeric pure compound comprises, by mass, more than about 80% of one stereoisomer of the compound and less than about 20% of another stereoisomer of the compound; more than about 90% of one stereoisomer of the compound and less than about 10% of another stereoisomer of the compound; more than about 95% of one stereoisomer of the compound and less than about 5% of another stereoisomer of the compound; more than about 97% of one stereoisomer of the compound and less than about 3% of another stereoisomer of the compound; or more than about 99% of one stereoisomer of the compound and less than about 1% of another stereoisomer of the compound.

[0503] "Stereoisomeric enrichment" refers to a composition containing a stereoisomer of a compound at a mass content greater than about 55%, about 60%, about 70%, or about 80%.

[0504] "Enantiomerically pure" refers to a stereoisomerically pure composition of a compound having a single chiral center. Similarly, the term "enantiomerically enriched" refers to a stereoisomerically enriched composition of a compound having a single chiral center.

[0505] "Optical activity" and "enantiomeric activity" refer to a molecular combination having an enantiomer excess of not less than about 50%, not less than about 70%, not less than about 80%, not less than about 90%, not less than about 91%, not less than about 92%, not less than about 93%, not less than about 94%, not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%. In a particular embodiment, the compound comprises about 95% or more of the desired enantiomer or diastereomer by weight of the racemic compound and about 5% or less of the subpreferred enantiomer or diastereomer.

[0506] In describing optically active compounds, the prefixes R and S are used to indicate the absolute configuration of the molecule relative to its chiral center. (+) and (-) are used to indicate the optical rotation of the compound, i.e., the direction of the plane of polarized light rotated by the optically active compound. The prefix (-) indicates that the compound is levorotatory, i.e., the compound rotates the plane of polarized light to the left or counterclockwise. The prefix (+) indicates that the compound is dextrorotatory, i.e., the compound rotates the plane of polarized light to the right or clockwise. However, the signs (+) and (-) for optical rotation are independent of the absolute configuration R and S of the molecule. Attached Figure Description

[0507] Figure 1 shows the X-ray powder diffraction pattern of p-toluenesulfonate crystal form A of the compound in Example 7.

[0508] Figure 2 is a TGA-DSC diagram of p-toluenesulfonate crystal form A of the compound in Example 7.

[0509] Figure 3 shows the X-ray powder diffraction pattern of p-toluenesulfonate crystal form B of the compound in Example 7.

[0510] Figure 4 is a DSC diagram of p-toluenesulfonate crystal form B of the compound in Example 7.

[0511] Figure 5 shows the TGA spectrum of p-toluenesulfonate crystal form B of the compound in Example 7.

[0512] Figure 6 shows the X-ray powder diffraction pattern of p-toluenesulfonate crystal form C of compound 7.

[0513] Figure 7 shows the DSC spectrum of toluenesulfonate crystal form C of the compound from Example 7.

[0514] Figure 8 shows the TGA spectrum of toluenesulfonate crystal form C of the compound from Example 7.

[0515] Figure 9 shows the X-ray powder diffraction pattern of p-toluenesulfonate crystal form D of the compound in Example 7.

[0516] Figure 10 shows the X-ray powder diffraction pattern of p-toluenesulfonate crystal form E of the compound in Example 7.

[0517] Figure 11 shows the TGA-DSC spectrum of p-toluenesulfonate crystal form E of the compound in Example 7.

[0518] Figure 12 shows the X-ray powder diffraction pattern of p-toluenesulfonate crystal form F of compound 7.

[0519] Figure 13 shows the X-ray powder diffraction pattern of p-toluenesulfonate crystal form G of compound 7 in Example 7.

[0520] Figure 14 shows the X-ray powder diffraction pattern of p-toluenesulfonate crystal form H of compound 7 in Example 7.

[0521] Figure 15 shows the TGA-DSC spectrum of p-toluenesulfonate H of the compound in Example 7.

[0522] Figure 16 shows the X-ray powder diffraction pattern of the hydrochloride crystal form A of the compound in Example 7.

[0523] Figure 17 shows the TGA-DSC spectrum of the hydrochloride crystal form A of the compound in Example 7.

[0524] Figure 18 shows the X-ray powder diffraction pattern of the hydrochloride crystal form B of the compound in Example 7.

[0525] Figure 19 shows the TGA-DSC spectrum of the hydrochloride crystal form B of the compound in Example 7.

[0526] Figure 20 shows the TGA-DSC spectrum of the hydrochloride crystal form C of the compound in Example 7.

[0527] Figure 21 shows the X-ray powder diffraction pattern of the hydrobromide crystal form A of the compound in Example 7.

[0528] Figure 22 shows the TGA-DSC spectrum of the hydrobromide crystal form A of the compound in Example 7.

[0529] Figure 23 shows the X-ray powder diffraction pattern of the hydrobromide crystal form B of the compound in Example 7.

[0530] Figure 24 shows the DSC spectrum of the hydrobromide crystal form B of the compound in Example 7.

[0531] Figure 25 shows the X-ray powder diffraction pattern of the hydrobromide crystal form C of the compound in Example 7.

[0532] Figure 26 shows the TGA-DSC spectrum of the hydrobromide crystal form C of the compound in Example 7.

[0533] Figure 27 shows the X-ray powder diffraction pattern of the hydrobromide crystal form D of the compound in Example 7.

[0534] Figure 28 shows the TGA-DSC spectrum of the hydrobromide crystal form D of the compound in Example 7.

[0535] Figure 29 shows the X-ray powder diffraction pattern of benzoate crystal form A of the compound in Example 7.

[0536] Figure 30 shows the TGA-DSC spectrum of benzoate crystal form A of the compound in Example 7.

[0537] Figure 31 shows the X-ray powder diffraction pattern of benzoate crystal form B of the compound in Example 7.

[0538] Figure 32 shows the TGA-DSC spectrum of benzoate form B of the compound in Example 7.

[0539] Figure 33 shows the TGA-DSC spectrum of fumarate crystal form A of the compound in Example 7.

[0540] Figure 34 shows the TGA-DSC spectrum of fumarate crystal form B of the compound in Example 7.

[0541] Figure 35 shows the TGA-DSC spectrum of the fumarate crystal form C of the compound in Example 7.

[0542] Figure 36 shows the TGA-DSC spectrum of maleate crystal form A of the compound in Example 7.

[0543] Figure 37 shows the TGA-DSC spectrum of the methanesulfonate crystal form B of the compound in Example 7.

[0544] Figure 38 shows the TGA-DSC spectrum of the methanesulfonate crystal form A of the compound in Example 7.

[0545] Figure 39 shows the TGA-DSC spectrum of phosphate crystal form A of the compound in Example 7.

[0546] Figure 40 shows the X-ray powder diffraction pattern of the hydrochloride crystal form A of the compound in Example 3.

[0547] Figure 41 shows the DSC spectrum of the hydrochloride crystal form A of the compound in Example 3.

[0548] Figure 42 shows the X-ray powder diffraction pattern of the hydrochloride crystal form B of the compound in Example 3.

[0549] Figure 43 shows the TGA-DSC spectrum of the hydrochloride crystal form B of the compound in Example 3.

[0550] Figure 44 shows the X-ray powder diffraction pattern of the hydrochloride crystal form C of the compound in Example 3.

[0551] Figure 45 shows the DSC spectrum of the hydrochloride crystal form C of the compound in Example 3.

[0552] Figure 46 shows the TGA-DSC spectrum of the hydrochloride crystal form D of the compound in Example 3.

[0553] Figure 47 shows the X-ray powder diffraction pattern of the hydrochloride crystal form E of the compound in Example 3.

[0554] Figure 48 shows the X-ray powder diffraction pattern of sulfate crystal form A of the compound in Example 3.

[0555] Figure 49 shows the TGA-DSC spectrum of sulfate crystal form A of the compound in Example 3.

[0556] Figure 50 shows the X-ray powder diffraction pattern of sulfate crystal form B of the compound in Example 3.

[0557] Figure 51 shows the X-ray powder diffraction pattern of maleate crystal form A of the compound in Example 3.

[0558] Figure 52 shows the X-ray powder diffraction pattern of benzenesulfonate crystal form A of the compound in Example 3.

[0559] Figure 53 shows the TGA-DSC spectrum of benzenesulfonate crystal form A of the compound in Example 3.

[0560] Figure 54 shows the X-ray powder diffraction pattern of phosphate crystal form B of the compound in Example 3.

[0561] Figure 55 shows the TGA-DSC spectrum of phosphate crystal form B of the compound in Example 3. Detailed Implementation

[0562] 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.

[0563] I. Preparation of Compounds

[0564] Example

[0565] 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.

[0566] LC-M determination was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC determination was performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18 150×4.6mm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C). 18 (150×4.6mm chromatographic column).

[0567] 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 separating and purifying products using TLC is 0.4mm to 0.5mm. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0568] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0569] 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.

[0570] Preparation of Intermediate 1

[0571] Step 1: Preparation of tert-butyl (5-(2-methoxyacetyl)thiazolyl-2-yl)carbamate

[0572] 10.3 g (51.43 mmol) of tert-butylthiazole-2-carbamate was dissolved in 200 mL of dry tetrahydrofuran. The reaction mixture was protected with dry nitrogen and cooled to -78 °C. A solution of n-butyllithium (127.5 mmol, 51 mL, 2.5 M n-hexane) was slowly added dropwise. After the addition was complete, the reaction mixture was stirred at -78 °C for 30 minutes. N,2-Dimethoxy-N-methylacetamide (19.17 g, 144.01 mmol) was added, and the reaction mixture was stirred at -78 °C for 2 hours. The reaction was quenched with saturated ammonium chloride solution in the reaction flask, resulting in the precipitation of a white solid. The precipitate was collected by filtration under reduced pressure and dried under reduced pressure to give the title compound (5.8 g, 41%). MS m / z (ESI): 273.1 [M+H] + .

[0573] Step 2: Preparation of tert-butyl(5-(1-((3-amino-2,2-difluoropropyl)amino)-2-methoxyethyl)thiazolyl-2-yl)carbamate

[0574] tert-Butyl(5-(2-methoxyacetyl)thiazolyl-2-yl)carbamate (5 g, 18.36 mmol) and 2,2-difluoropropane-1,3-diamine dihydrochloride (6.72 g, 36.72 mmol) were dissolved in a mixed solvent of DMA (15 mL) and methanol (8 mL). Triethylamine (8.36 g, 82.62 mmol) was added, and the reaction mixture was heated to 75 °C and stirred for 12 hours. After cooling to room temperature, acetic acid (6.61 g, 110.16 mmol) and sodium cyanoborohydride (6.92 g, 110.16 mmol) were added, and the mixture was heated to 40 °C and stirred for 6 hours. The reaction solution was diluted with ethyl acetate and washed successively with saturated sodium carbonate aqueous solution and saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the title compound (3.6 g, 54%). MS m / z(ESI): 367.2 [M+H] + .

[0575] Step 3: Preparation of tert-butyl(5-(1-(5,5-difluoro-2-carbonyltetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)thiazolyl-2-yl)carbamate

[0576] 0.56 g (1.47 mmol) of tert-butyl(5-(1-((3-amino-2,2-difluoropropyl)amino)-2-methoxyethyl)thiazolyl-2-yl)carbamate was dissolved in tetrahydrofuran (6 mL), and N,N'-carbonyldiimidazole (477 mg (2.94 mmol)) was added. The reaction mixture was stirred at 30 °C for 1 hour, and a white solid precipitated. The precipitate was filtered, and the filter cake was washed with a small amount of ethyl acetate. The filter cake was collected and dried under reduced pressure to give the title compound (340 mg, 57%). MS m / z (ESI): 393.1 [M+H] + .

[0577] Preparation of intermediate 2

[0578] Step 1: Preparation of tert-butyl (5-(1-hydroxy-2-methoxyethyl)thiazolyl-2-yl)carbamate

[0579] At room temperature, tert-butyl(5-(2-methoxyacetyl)thiazolyl-2-yl)carbamate (2 g, 7.34 mmol) was dissolved in methanol (35 mL), and sodium borohydride (278 mg, 7.34 mmol) was added. The mixture was stirred at room temperature for 1 hour, concentrated under reduced pressure, and the residue was subjected to column chromatography to give the title compound (1.81 g, 90%). MS m / z (ESI): 275.1 [M+H] +.

[0580] Step 2: Preparation of 1-(2-((tert-butoxycarbonyl)amino)thiazolyl)-2-methoxyethyl 4-methylbenzenesulfonate

[0581] At 0 °C, tert-butyl(5-(1-hydroxy-2-methoxyethyl)thiazolyl-2-yl)carbamate (650 mg, 2.37 mmol) was dissolved in dichloromethane (15 mL), and p-toluenesulfonyl chloride (903 mg, 4.74 mmol), 4-dimethylaminopyridine (27 mg, 218.71 μmol), and DIPEA (612 mg, 1.46 mmol) were added. The mixture was then stirred at room temperature for 6 hours. The reaction solution was diluted with dichloromethane, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. After filtration, the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography to obtain 960 mg of the title compound, which was used directly in the next step. MS m / z (ESI): 429.1 [M+H] +.

[0582] Step 3: Preparation of tert-butyl(5-(1-(5,5-difluoro-2-carbonylpiperidin-1-yl)-2-methoxyethyl)thiazolyl-2-yl)carbamate

[0583] At room temperature, 5,5-difluoropiperidin-2-one (378 mg, 2.8 mmol) was dissolved in tetrahydrofuran (10 mL), and sodium hydride (224 mg, 5.6 mmol, 60 wt%) was added. The mixture was stirred at room temperature for 1 hour, and then 1-(2-((tert-butoxycarbonyl)amino)thiazolyl-5-yl)-2-methoxyethyl 4-methylbenzenesulfonate (600 mg, 1.4 mmol) was added. The mixture was heated to 60 °C and stirred for 12 hours. After cooling to room temperature, the reaction was quenched with saturated ammonium chloride solution, and the reaction solution was diluted with ethyl acetate. The mixture was washed with saturated sodium chloride solution and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was subjected to column chromatography to give the title compound (190 mg, 34.7%). MS m / z (ESI): 392.1 [M+H] + .

[0584] Preparation of intermediate 3

[0585] Step 1: Preparation of N-methoxy-N-methyl-2-morpholinoacetamide

[0586] At room temperature, 2-chloro-N-methoxy-N-methylacetamide (10.0 g, 72.6 mmol) and morpholine (8.2 g, 94.3 mmol) were dissolved in acetonitrile (100 mL), and potassium carbonate (20.0 g, 147 mmol) was added. The mixture was stirred at room temperature for 10 hours, filtered, and the organic solvent was concentrated under reduced pressure. The title compound (11.1 g, 82%) was obtained by column chromatography. MS m / z (ES) + ):189.1[M+H] + .

[0587] Step 2: Preparation of tert-butyl(5-(2-morpholinoacetyl)thiazolyl-2-yl)carbamate

[0588] At room temperature, tert-butylthiazolyl-2-ylcarbamate (11.7 g, 58.5 mmol) was dissolved in tetrahydrofuran (150 mL). The solution was cooled to -78 °C, and n-butyllithium (58.5 mL, 146.3 mmol) was added dropwise. After the addition was complete, the mixture was stirred at -78 °C for 1 hour. Then, a solution of N-methoxy-N-methyl-2-morpholinoacetamide (11.0 g, 58.5 mmol) dissolved in tetrahydrofuran (20 mL) was added dropwise. After the addition was complete, the mixture was stirred at -78 °C for 1 hour. A saturated ammonium chloride solution was added, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the organic solvent was concentrated under reduced pressure, and the solution was separated by column chromatography to give the title compound (7.7 g, 40%). MS m / z (ES) + ):328.1[M+H] + .

[0589] Step 3: Preparation of tert-butyl (5-(1-hydroxy-2-morpholinoethyl)thiazolyl-2-yl)carbamate

[0590] At room temperature, tert-butyl(5-(2-morpholinoacetyl)thiazolyl-2-yl)carbamate (7.7 g, 23.5 mmol) was dissolved in tetrahydrofuran / methanol solution (50 mL), cooled to 0 °C, and sodium borohydride (1.7 g, 47.0 mmol) was added in portions. The mixture was stirred at 0 °C for 1 hour, the organic solvent was concentrated under reduced pressure, water was added, and the mixture was extracted three times with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. Column chromatography was used to separate the title compound (6.2 g, 81%). MS m / z (ES + ):330.1[M+H] + .

[0591] Preparation of intermediate 4

[0592] Step 1: Preparation of 1-(1-(2-aminothiazol-5-yl)-2-hydroxyethyl)-5,5-difluoropiperidin-2-one

[0593] 30.0 g (76.7 mmol) of tert-butyl(5-(1-(5,5-difluoro-2-oxopiperidin-1-yl)-2-methoxyethyl)thiazolyl-2-yl)carbamate was dissolved in 1 L of dichloromethane and cooled to -78 °C. Boron tribromide (153.5 mL, 307 mmol, 2 M dichloromethane solution) was slowly added dropwise. After the addition was complete, the mixture was gradually brought to room temperature and stirred for 2 hours. LC-MS showed that the starting material reacted completely. The reaction system was cooled to 0 °C, and the reaction was quenched by slowly adding 50 mL of methanol. The organic solvent was concentrated under reduced pressure to obtain the crude product of the title compound, which was used directly in the next reaction. MS m / z (ESI): 278.1 [M+H] + .

[0594] Step 2: Preparation of tert-butyl(5-(1-(5,5-difluoro-2-oxopiridin-1-yl)-2-hydroxyethyl)thiazolyl-2-yl)carbamate

[0595] The crude product of 1-(1-(2-aminothiazol-5-yl)-2-hydroxyethyl)-5,5-difluoropiperidin-2-one was dissolved in methanol (800 mL), and N,N-diisopropylethylamine (49.7 g, 383.5 mmol) and di-tert-butyl dicarbonate (100.0 g, 460.2 mmol) were added sequentially. The mixture was heated to 60 °C and stirred for 5 hours. The reaction system was cooled to 0 °C, and ammonia water (20 mL) was slowly added dropwise. The organic solvent was concentrated under reduced pressure. The crude product was dissolved in ethyl acetate, washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated. The residue was purified by column chromatography to give the title compound (23.7 g, overall yield of 82%). MS m / z (ESI): 378.1 [M+H] + .

[0596] Step 3: Preparation of tert-butyl(5-(1-(5,5-difluoro-2-oxopiperidin-1-yl)-2-oxoethyl)thiazolyl-2-yl)carbamate

[0597] 6.4 g (17.0 mmol) of tert-butyl(5-(1-(5,5-difluoro-2-oxopiperidin-1-yl)-2-hydroxyethyl)thiazolyl-2-yl)carbamate was dissolved in a mixture of dichloromethane and dimethyl sulfoxide (120 mL / 30 mL). The solution was cooled to 0 °C, and triethylamine (6.9 g, 68.0 mmol) was added. Pyridine sulfur trioxide (10.8 g, 68.0 mmol) was added in portions, and the mixture was stirred at 0 °C for 1 hour. The reaction was quenched with water, and the mixture was extracted with ethyl acetate. The organic phase was washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated. The crude product was purified by column chromatography to give the title compound (5.5 g, 86%). MS m / z (ESI): 376.1 [M+H] + .

[0598] Preparation of Example 1

[0599] Step 1: Preparation of tert-butyl carbamate of nitrogen-[5-[1-[(3-amino-2,2-difluoro-propyl)amino]-2-morpholino-ethyl]thiazolyl-2-yl]carbamate

[0600] To a solution of nitrogen-[5-(1-hydroxy-2-morpholino-ethyl)thiazolyl-2-yl]carbamate tert-butyl ester (2 g, 6.07 mmol) in dichloromethane (20 mL), methanesulfonic anhydride (1.59 g, 9.11 mmol), DIPEA (2.35 g, 18.21 mmol, 3.17 mL) and 4-dimethylaminopyridine (148.34 mg, 1.21 mmol) were added. The mixture was stirred at room temperature for 12 h, washed with saturated sodium chloride solution, and the aqueous phase was extracted three times with dichloromethane. The organic phases were combined, and anhydrous sulfur was removed. The sodium chloride solution was dried, concentrated under reduced pressure, and the residue was dissolved in acetonitrile (20 mL). 2,2-Difluoropropane-1,3-diamine hydrochloride (668 mg, 3.65 mmol, 2 mL) and DIPEA (2.35 g, 18.21 mmol, 3.17 mL) were added sequentially. The mixture was heated to 60 °C and stirred for 12 h. The solvent was removed by concentration under reduced pressure. The residue was dispersed in ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain the title compound (1.1 g, 43%). MS m / z (ESI): 422.2 [M+H] + .

[0601] Step 2: Preparation of nitrogen-[5-[1-(5,5-difluoro-2-carbonyl-hexahydropyrimidin-1-yl)-2-morpholino-ethyl]thiazolyl-2-yl]tert-butyl carbamate

[0602] CDI (1.06 g, 6.52 mmol) was added to a tetrahydrofuran (50 mL) solution of nitrogen-[5-[1-[(3-amino-2,2-difluoro-propyl)amino]-2-morpholino-ethyl]thiazo-2-yl]carbamate tert-butyl ester (1.1 g, 2.61 mmol), and the mixture was stirred at room temperature for 2 h. The reaction was quenched with 5 M sodium hydroxide aqueous solution (10 mL), washed with saturated sodium chloride solution, extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain the title compound (400 mg, 34%). MS m / z (ESI): 448.2 [M+H] + .

[0603] Step 3: Preparation of nitrogen-[(1S)-2-[[5-[1-(5,5-difluoro-2-carbonyl-hexahydropyrimidin-1-yl)-2-morpholino-ethyl]thiazolyl-2-yl]amino]-1-(4-methylcyclohexyl)-2-carbonyl-ethyl]tert-butyl carbamate

[0604] To a methanol (2 mL) solution of tert-butyl carbamate (400 mg, 893.86 μmol), 4 M dioxane (10 mL) was added, and the mixture was stirred at room temperature for 8 h. The solvent was removed under reduced pressure, and tert-butyl carbamate (241.67 mg, 8 mL) of nitrogen-[(1S)-2-amino-1-(4-methylcyclohexyl)-2-carbonyl-ethyl]carbamate (241.67 mg, 8 mL) was added to the residue. 93.86 μmol), DIPEA (115.52 mg, 893.86 μmol, 155.69 μL), DMF (10 mL), HATU (337.22 mg, 893.86 μmol), stirred at room temperature for 12 h, added ammonium chloride aqueous solution (25 mL), washed with saturated sodium chloride solution, extracted three times with ethyl acetate, combined the organic phases, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain the title compound (350 mg, 65%). MS m / z (ESI): 601.3 [M+H] + .

[0605] Step 4: Preparation of nitrogen-[(1S)-2-[[5-[1-(5,5-difluoro-2-carbonyl-hexahydropyrimidin-1-yl)-2-morpholino-ethyl]thiazolyl-2-yl]amino]-1-(4-methylcyclohexyl)-2-carbonyl-ethyl]-1-fluoro-cyclopropylformamide

[0606] To a methanol (2 mL) solution of tert-butyl carbamate (350 mg, 582.63 μmol), 4 M dioxane (10 mL) was added. The mixture was stirred at room temperature for 1 h, and the solvent was removed under reduced pressure. The residue was dissolved in DMF (10 mL). 1-Fluoro-cyclopropanecarboxylic acid (91 mg, 874 μmol), DIPEA (377 mg, 2.9 mmol, 508 μL) and HATU (330 mg, 874 μmol) were added sequentially, and the mixture was stirred at room temperature for 2 h. An aqueous solution of ammonium chloride (25 mL) was added, and the mixture was washed with saturated sodium chloride solution. The mixture was extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was chirally resolved to give the title compound (100 mg, 29%).

[0607] 1 H NMR(400MHz,DMSO-d6)δ12.17(s,1H),8.33(d,J=8.1Hz,1H),7.35(s,1H),6.87 (s,1H),5.71(t,J=7.8Hz,1H),4.39(t,J=8.3Hz,1H),3.66-3.43(m,7H),2.83( dd,J=12.6,9.1Hz,1H),2.73(dd,J=12.7,7.1Hz,1H),2.47-2.38(m,3H),1.79( d,J=9.6Hz,2H),1.67(t,J=9.0Hz,2H),1.50-1.07(m,8H),1.03-0.76(m,7H); MS m / z (ESI): 587.2 [M+H] + .

[0608] Preparation of Example 2

[0609] Step 1: Preparation of tert-butyl(5-(1-(5,5-difluoro-2-oxopiperidin-1-yl)-2-morpholinoethyl)thiazolyl-2-yl)carbamate

[0610] 500 mg (1.3 mmol) of tert-butyl(5-(1-(5,5-difluoro-2-oxopiperidin-1-yl)-2-oxoethyl)thiazolyl-2-yl)carbamate was dissolved in 20 mL of 1,2-dichloroethane. Morpholine (340 mg, 3.9 mmol) was added, followed by 2 drops of acetic acid. The mixture was stirred at room temperature for 2 hours, then sodium triacetoxyborohydride (826 mg, 3.9 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated. The crude product was purified by column chromatography to give the title compound (492 mg, 85%). MS m / z (ESI): 447.2 [M+H] + .

[0611] Step 2: Preparation of 1-(1-(2-aminothiazolyl-5-yl)-2-morpholinoethyl)-5,5-difluoropiperidin-2-one

[0612] 492 mg, 1.1 mmol of tert-butyl(5-(1-(5,5-difluoro-2-oxopiperidin-1-yl)-2-morpholinoethyl)thiazolyl-2-)carbamate was dissolved in 3 mL of dichloromethane, and 6 mL of 4 M dioxane hydrochloride solution was added. The mixture was stirred at 45 °C for 8 hours. The solvent was removed by concentration under reduced pressure to obtain the crude title compound, which was used directly in the next reaction. MS m / z (ESI): 347.1 [M+H] + .

[0613] Step 3: Preparation of tert-butyl((1S)-2-((5-(1-(5,5-difluoro-2-oxoperidin-1-yl)-2-morpholinoethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate

[0614] (S)-2-((tert-butoxycarbonyl)amino)-2-((trans)-4-methylcyclohexyl)acetic acid (597 mg, 2.2 mmol) and crude 1-(1-(2-aminothiazol-5-yl)-2-morpholinoethyl)-5,5-difluoropiperidin-2-one were dissolved in N,N-dimethylformamide (6 mL), followed by the addition of triethylamine (333.3 mg, 3.3 mmol) and benzotriazol-1-yl-oxytripyrrolidinephosphine hexafluorophosphate (1.2 g, 2.2 mmol). The mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate, washed with saturated brine, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated. The residue was separated by column chromatography to give the title compound (528 mg, 80% overall yield). MS m / z (ESI): 600.3 [M+H] + .

[0615] Step 4: Preparation of (2S)-2-amino-N-(5-(1-(5,5-difluoro-2-oxoperidin-1-yl)-2-morpholinoethyl)thiazolyl)-2-((1r,4S)-4-methylcyclohexyl)acetamide

[0616] 528 mg (0.88 mmol) of tert-butyl((1S)-2-((5-(1-(5,5-difluoro-2-oxopiperidin-1-yl)-2-morpholinoethyl)thiazolyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate was dissolved in 3 mL of dichloromethane, and 3 mL of 4 M dioxane hydrochloride solution was added. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed by concentration under reduced pressure to obtain the crude title compound, which was used directly in the next reaction. MS m / z (ESI): 500.1 [M+H] + .

[0617] Step 5: Preparation of N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxopiridin-1-yl)-2-morpholinoethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-(ethyl-d5)-1H-pyrazole-5-carboxamide

[0618] 1-(ethyl-d5)-1H-pyrazole-5-carboxylic acid (256 mg, 1.76 mmol) and crude (2S)-2-amino-N-(5-(1-(5,5-difluoro-2-oxopiperidin-1-yl)-2-morpholinoethyl)thiazolyl)-2-((1r,4S)-4-methylcyclohexyl)acetamide were dissolved in N,N-dimethylformamide (6 mL), followed by the addition of triethylamine (253 mg, 2.5 mmol) and benzotriazol-1-yl-oxytripyrrolylphosphonate hexafluorophosphate (885 mg, 1.7 mmol). The mixture was stirred at room temperature for 1 hour. The solution was diluted with ethyl acetate, washed with saturated sodium chloride solution, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was subjected to column chromatography and chiral resolution to give the title compound (107 mg, overall yield of 19%).

[0619] 1 H NMR (400MHz, DMSO-d6) δ12.27(s,1H),8.57(d,J=8.0Hz,1H),7.48(d,J=2.0Hz,1 H),7.40(s,1H),7.00(d,J=2.0Hz,1H),5.89(t,J=8.0Hz,1H),4.46(t,J=8.2Hz,1 H),3.71-3.38(m,5H),3.29-3.26(m,1H),2.93-2.83(m,1H),2.76-2.65(m,1H), 2.47-2.36(m,4H),2.33-2.23(m,3H),1.89-1.73(m,2H),1.72-1.63(m,2H),1.52 -1.41(m,1H),1.39-0.94(m,4H),0.92-0.78(m,5H); MS m / z(ESI):627.3[M+H] + .

[0620] Preparation of Example 3

[0621] Step 1: Preparation of tert-butyl(5-(1-(5,5-difluoro-2-oxopiridin-1-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)carbamate

[0622] tert-Butyl(5-(1-(5,5-difluoro-2-oxopiperidin-1-yl)-2-oxoethyl)thiazolyl-2-yl)carbamate (500 mg, 1.3 mmol) was dissolved in 1,2-dichloroethane (20 mL), and (R)-2-methylmorpholine (395 mg, 3.9 mmol) was added. Two drops of acetic acid were added dropwise, and the mixture was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (826 mg, 3.9 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated. The crude product was purified by column chromatography to give the title compound (495 mg, 81%). MS m / z (ESI): 461.2 [M+H] + .

[0623] Step 2: Preparation of 1-(1-(2-aminothiazolyl-5-yl)-2-((R)-2-methylmorpholino)ethyl)-5,5-difluoropiperidin-2-one

[0624] 495 mg, 1.1 mmol of tert-butyl(5-(1-(5,5-difluoro-2-oxopiperidin-1-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)carbamate was dissolved in 3 mL of dichloromethane, and 6 mL of 4 M dioxane hydrochloride solution was added. The mixture was stirred at 45 °C for 8 hours. The solvent was removed by concentration under reduced pressure to obtain the crude title compound, which was used directly in the next reaction. MS m / z (ESI): 361.1 [M+H] + .

[0625] Step 3: Preparation of tert-butyl((1S)-2-((5-(1-(5,5-difluoro-2-oxopiridin-1-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate

[0626] (S)-2-((tert-butoxycarbonyl)amino)-2-((trans)-4-methylcyclohexyl)acetic acid (597 mg, 2.2 mmol) and 1-(1-(2-aminothiazol-5-yl)-2-((R)-2-methylmorpholino)ethyl)-5,5-difluoropiperidin-2-one (385 mg, 1.1 mmol) were dissolved in N,N-dimethylformamide (6 mL), followed by the addition of triethylamine (333.3 mg, 3.3 mmol) and benzotriazol-1-yl-oxytripyrrolidinephosphine hexafluorophosphate (1.2 g, 2.2 mmol). The mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate, washed with saturated brine, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated. The residue was separated by column chromatography to give the title compound (520 mg, overall yield of 77%). MS m / z (ESI): 614.3 [M+H] + .

[0627] Step 4: Preparation of (2S)-2-amino-N-(5-(1-(5,5-difluoro-2-oxopiperidin-1-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl)-2-((1r,4S)-4-methylcyclohexyl)acetamide

[0628] 520 mg (0.85 mmol) of tert-butyl((1S)-2-((5-(1-(5,5-difluoro-2-oxopiperidin-1-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate was dissolved in 3 mL of dichloromethane, and 3 mL of 4 M dioxane hydrochloride solution was added. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed by concentration under reduced pressure to obtain the crude title compound, which was directly used in the next reaction. MS m / z (ESI): 514.1 [M+H] + .

[0629] Step 5: Preparation of N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxopiridin-1-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-(ethyl-d5)-1H-pyrazole-5-carboxamide

[0630] 1-(ethyl-d5)-1H-pyrazole-5-carboxylic acid (247 mg, 1.7 mmol) and crude (2S)-2-amino-N-(5-(1-(5,5-difluoro-2-oxopiridin-1-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl)-2-((1r,4S)-4-methylcyclohexyl)acetamide were dissolved in N,N-dimethylformamide (6 mL), followed by the addition of triethylamine (253 mg, 2.5 mmol) and benzotriazol-1-yl-oxytripyrrolidinylphosphine hexafluorophosphate (885 mg, 1.7 mmol). The mixture was stirred at room temperature for 1 hour. The solution was diluted with ethyl acetate, washed with saturated sodium chloride solution, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography and chiral resolution to give the title compound (94 mg, overall yield of 17%).

[0631] 1 H NMR (400MHz, DMSO-d) 6 )δ12.30(s,1H),8.60(d,J=7.6Hz,1H),7.48(d,J=2.0Hz,1H),7.43-7.38(m,1H),7.05-6.99(m,1H),5.89(t,J =8.0Hz,1H),4.46(t,J=8.2Hz,1H),3.78-3.71(m,1H),3.67-3.58(m,1H),3.50-3.40(m,3H),2.92-2.84(m,1H ),2.78(d,J=10.8Hz,1H),2.74-2.67(m,2H),2.56-2.51(m,1H),2.36-2.24(m,2H),2.20-2.11(m,1H),1.87-1 .74(m,3H),1.72-1.64(m,2H),1.50-1.42(m,1H),1.33-1.14(m,2H),1.09-0.97(m,4H),0.93-0.78(m,6H);MS m / z(ESI):641.3[M+H] + .

[0632] Preparation of Example 4

[0633] Step 1: Preparation of tert-butyl(S)-2-((((trifluoromethyl)sulfonyl)oxo)methyl)morpholine-4-carboxylic acid ester

[0634] 75 g (345.21 mmol) of tert-butyl(2S)-2-(hydroxymethyl)morpholine-4-carboxylic acid ester and pyridine (41 g, 517.81 mmol) were dissolved in 600 mL of dichloromethane. The mixture was cooled to -25 °C, and a solution of 150 mL of dichloromethane containing 116.88 g (414.25 mmol) of trifluoromethanesulfonic anhydride was added dropwise. The mixture was stirred at -25 °C for 1 hour, and the reaction was quenched with 1 N hydrochloric acid solution. The dichloromethane layer was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was used directly for the next reaction. MS m / z (ESI): 350.1 [M+H] + .

[0635] Step 2: Preparation of tert-butyl(S)-2-(fluoromethyl)morpholine-4-carboxylic acid ester

[0636] The crude tert-butyl(S)-2-((((trifluoromethyl)sulfonyl)oxo)methyl)morpholine-4-carboxylic acid ester was dissolved in tetrahydrofuran (300 mL). Under nitrogen protection, a 1 M tetrabutylammonium fluoride solution in tetrahydrofuran (520 mL) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 1 hour. The solvent was removed by concentration under reduced pressure, and the residue was separated by column chromatography to give the title compound (69.3 g, overall yield of 91%). MS m / z (ESI): 220.1 [M+H] + .

[0637] Step 3: Preparation of (S)-2-(fluoromethyl)morpholine

[0638] At 0 °C, tert-butyl(S)-2-(fluoromethyl)morpholine-4-carboxylic acid ester (69.3 g, 316 mmol) was dissolved in 200 mL of 4 M dioxane hydrochloride solution. The solution was transferred to room temperature and stirred for 1 hour. The solvent was removed by concentration under reduced pressure. The residue was slurryed with ethyl acetate, filtered, and the filter residue was collected and dried under reduced pressure to give the title compound (44.8 g, 91%). MS m / z (ESI): 120.1 [M+H] + .

[0639] Step 4: Preparation of tert-butyl(5-(1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-hydroxyethyl)thiazolyl-2-yl)carbamate

[0640] Under ice bath cooling, tert-butyl(5-(1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)thiazolyl-2-yl)carbamate (30 g, 76.45 mmol) was dissolved in dichloromethane (1 L). A solution of boron tribromide in dichloromethane (2 M, 300 mL) was slowly added dropwise with stirring. The reaction mixture was transferred to room temperature and stirred for 24 hours. After cooling to -78 °C, the reaction was quenched by adding methanol (500 mL). The organic solvent was removed by vacuum concentration. Methanol (500 mL), DIPEA (98.80 g, 764.49 mmol, 133.16 mL), and di-tert-butyl dicarbonate (38.68 g, 382.24 mmol) were added sequentially to the residue. The reaction mixture was heated and stirred at 60 °C for 6 hours. The reaction mixture was cooled to room temperature and poured into ice water (3 L), precipitating a white solid. The filter cake was collected, dried under reduced pressure, and the title compound (22.5 g, 78%) was given as a white solid. MS m / z (ESI): 379.1 [M+H] + .

[0641] Step 5: Preparation of tert-butyl(5-(1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-oxoethyl)thiazolyl-2-yl)carbamate

[0642] At 3°C, tert-butyl(5-(1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-hydroxyethyl)thiazolyl-2-yl)carbamate (7 g, 18.50 mmol) was dispersed in a mixed solvent of dimethyl sulfoxide (40 mL) and ethyl acetate (40 mL). Triethylamine (7.49 g, 74.00 mmol, 10.32 mL) and pyridine sulfur trioxide (11.78 g, 74.00 mmol) were added sequentially with stirring, and the mixture was stirred at 3°C ​​for 30 minutes. The reaction solution was diluted with ethyl acetate (200 mL), washed sequentially with 10% citric acid solution and saturated brine, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the organic solvent, yielding the crude title compound (5.6 g). This crude compound was used directly in the next reaction without further purification. MS m / z (ESI): 377.1 [M+H] + .

[0643] Step 6: Preparation of tert-butyl(5-(1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((S)-2-(fluoromethyl)morpholino)ethyl)thiazolyl-2-yl)carbamate

[0644] tert-Butyl(5-(1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-oxoethyl)thiazo-2-yl)carbamate (500 mg, 1.33 mmol), 3-(S)-3-methylmorpholine (620 mg, 3.99 mmol), and DIPEA (504 mg, 3.9 mmol) were dissolved in DCE (20 mL) and reacted at 30 °C with stirring for 2 hours. Acetic acid (1 mL) was added, and the reaction was continued at 30 °C with stirring for 12 hours. Sodium triacetoxyborohydride (1.4 g, 6.65 mmol) was added, and the reaction was stirred at room temperature for 1 hour. The solvent was removed by concentration under reduced pressure, and the residue was dissolved in ethyl acetate. The residue was washed successively with saturated sodium carbonate aqueous solution and saturated brine to separate the organic phase. The residue was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the title compound (364 mg, 57%). MS m / z(ESI): 480.2[M+H]+.

[0645] Step 7: Preparation of 1-((R)-1-(2-aminothiazolyl-5-yl)-2-((S)-2-(fluoromethyl)morpholino)ethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one

[0646] 364 mg (0.76 mmol) of tert-butyl(5-(1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((S)-2-(fluoromethyl)morpholino)ethyl)thiazolyl-2-yl)carbamate was dissolved in methanol (2 mL), and 10 mL of 4 M dioxane hydrochloride solution was added. The reaction mixture was stirred at 50 °C for 4 hours. The solvent was removed by concentration under reduced pressure, and the residue was chirally resolved to give the title compound (130 mg, 45%). MS m / z (ESI): 380.2 [M+H]+.

[0647] Step 8: Preparation of tert-butyl((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((S)-2-(fluoromethyl)morpholino)ethyl)thiazolyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate

[0648] (S)-2-((tert-butoxycarbonyl)amino)-2-((trans)-4-methylcyclohexyl)acetic acid (184 mg, 0.68 mmol) was dissolved in DMF (10 mL), followed by the addition of HATU (259 mg, 0.68 mmol) and DIPEA (220 mg, 1.7 mmol). The mixture was stirred at room temperature for 10 minutes, and then 1-((R)-1-(2-aminothiazolyl-5-yl)-2-((S)-2-(fluoromethyl)morpholino)ethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one (130 mg, 0.34 mmol) was added. The reaction mixture was stirred at 40 °C for 1 hour. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by column chromatography to obtain the title compound (194 mg, 90%). MS m / z (ESI): 633.3 [M+H] + .

[0649] Step 9: Preparation of (S)-2-amino-N-(5-((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((S)-2-(fluoromethyl)morpholino)ethyl)thiazolyl)-2-((1r,4S)-4-methylcyclohexyl)acetamide

[0650] 194 mg, 0.306 mmol of tert-butyl((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((S)-3-methylmorpholino)ethyl)thiazolyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate (2 mL) was dissolved in dichloromethane, and 10 mL of 4M dioxane hydrochloride solution was added. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed by concentration under reduced pressure to obtain the crude title compound, which was directly used in the next reaction. MS m / z (ESI): 533.3 [M+H] + .

[0651] Step 10: Preparation of N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((S)-2-(fluoromethyl)morpholino)ethyl)thiazolyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide

[0652] 1-Fluorocyclopropanecarboxylic acid (64 mg, 0.612 mmol) was dissolved in DMF (10 mL), followed by the addition of HATU (233 mg, 0.612 mmol) and DIPEATM (237 mg, 1.836 mmol). The reaction mixture was stirred at room temperature for 5 minutes. Crude (S)-2-amino-N-(5-((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((S)-2-(fluoromethyl)morpholino)ethyl)thiazolyl)-2-((1r,4S)-4-methylcyclohexyl)acetamide was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by column chromatography to give the title compound (150 mg, 80% overall yield from both steps).

[0653] 1 H NMR (400MHz, DMSO-d6) δ12.17(s,1H),8.32(d,J=8.0Hz,1H),7.36(d,J=1.2Hz,1H),6.87(d,J=3.0Hz,1H),5.72(t,J=8.0 Hz,1H),4.40(dd,J=47.5,4.4Hz,2H),4.38(d,J=8.0Hz,1H),3.85-3.78(m,1H),3.70-3.44(m,5H),3.42-3.38(m,1H),2.9 1-2.82(m,2H),2.80-2.65(m,2H),2.22(td,J=11.2,3.2Hz,1H),1.98(t,J=10.2Hz,1H),1.86-1.72(m,2H),1.71-1.58(m, MS m / z(ESI):619.3[M+H] + .

[0654] Preparation of Example 5

[0655] Step 1: Preparation of tert-butyl(5-(1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((2R,5R)-2,5-dimethylmorpholino)ethyl)thiazolyl-2-yl)carbamate

[0656] Tert-butyl(5-(1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-oxoethyl)thiazo-2-yl)carbamate (0.8 g, 2.13 mmol) and (2R,5R)-2,5-dimethylmorpholine (0.97 g, 6.40 mmol) were dissolved in 1,2-dichloroethane (15 mL), and triethylamine (1.1 g, 10.90 mmol) was added. The reaction mixture was heated to 30 °C and stirred for 3 hours. Acetic acid (0.9 g, 15 mmol) and sodium triacetoxyborohydride (2.3 g, 10.85 mmol) were added, and the reaction was continued at 30 °C for 2 hours. The reaction mixture was concentrated, diluted with ethyl acetate, washed successively with saturated sodium carbonate aqueous solution and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by column chromatography to give the title compound (0.95 g, 94%). MS m / z (ESI): 476.2 [M+H] + .

[0657] Step 2: Preparation of 1-(1-(2-aminothiazolyl-5-yl)-2-((2R,5R)-2,5-dimethylmorpholino)ethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one

[0658] 0.95 g (2.0 mmol) of tert-butyl(5-(1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((2R,5R)-2,5-dimethylmorpholino)ethyl)thiazolyl-2-yl)carbamate was dissolved in methanol (5 mL), and 15 mL of 4M dioxane hydrochloride solution was added. The reaction mixture was stirred at 45 °C for 3 hours. The solvent was removed by concentration under reduced pressure to obtain the crude title compound, which was directly used in the next reaction. MS m / z (ESI): 376.2 [M+H] + .

[0659] Step 3: Preparation of tert-butyl((1S)-2-((5-(1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((2R,5R)-2,5-dimethylmorpholino)ethyl)thiazolyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate

[0660] (S)-2-((tert-butoxycarbonyl)amino)-2-((trans)-4-methylcyclohexyl)acetic acid (1.1 g, 4.0 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of HATU (1.52 g, 4.0 mmol) and N,N-diisopropylethylamine (2.6 g, 20.0 mmol). The reaction mixture was stirred at room temperature for 30 minutes, and then 1-(1-(2-aminothiazolyl-5-yl)-2-((2R,5R)-2,5-dimethylmorpholino)ethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one was added. The reaction mixture was stirred at 40 °C for 1 hour. The solution was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by column chromatography to give the title compound (600 mg, overall yield of 48%). MS m / z (ESI): 629.3 [M+H] + .

[0661] Step 4: Preparation of (2S)-2-amino-N-(5-(1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((2R,5R)-2,5-dimethylmorpholino)ethyl)thiazolyl)-2-((1r,4S)-4-methylcyclohexyl)acetamide

[0662] 600 mg (0.96 mmol) of tert-butyl((1S)-2-((5-(1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((2R,5R)-2,5-dimethylmorpholino)ethyl)thiazolyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate was dissolved in 15 mL of 4 M dioxane hydrochloride solution. The mixture was stirred at 30 °C for 30 min. The solvent was removed by concentration under reduced pressure to obtain the title compound. The crude product was used directly in the next step. MS m / z (ESI): 529.3 [M+H] + .

[0663] Step 5: Preparation of N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((2R,5R)-2,5-dimethylmorpholino)ethyl)thiazolyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide

[0664] 1-Fluorocyclopropane-1-carboxylic acid (200 mg, 1.92 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of HATU (738 mg, 1.92 mmol) and N,N-diisopropylethylamine (621 mg, 4.8 mmol). The reaction mixture was stirred at room temperature for 25 minutes. Crude (2S)-2-amino-N-(5-(1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((2R,5R)-2,5-dimethylmorpholino)ethyl)thiazolyl)-2-((1r,4S)-4-methylcyclohexyl)acetamide was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by column chromatography and chiral resolution to give the title compound (105 mg, overall yield of 18% in both steps).

[0665] 1 H NMR (400MHz, DMSO-d6) δ12.19(s,1H),8.36(d,J=8.1Hz,1H),7.37(d,J=1.1Hz,1H),6.8 7(d,J=3.3Hz,1H),5.67(t,J=8.1Hz,1H),4.38(t,J=8.4Hz,1H),3.63-3.40(m,6H),3.3 8-3.30(m,1H),2.90-2.85(m,1H),2.81-2.67(m,2H),2.59-2.50(m,1H),2.24(t,J=10. 7Hz,1H),1.81-1.64(m,5H),1.44-1.12(m,6H),1.05-0.98(m,7H),0.92-0.79(m,5H).MS m / z(ESI):615.3[M+H] + .

[0666] Preparation of Example 6

[0667] Step 1: Preparation of tert-butyl(5-(1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)thiazolyl-2-yl)carbamate

[0668] Tert-butyl(5-(1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-oxoethyl)thiazolyl-2-yl)carbamate (5 g, 13.28 mmol) and 4,4-difluoropiperidine (4.83 g, 39.85 mmol) were dissolved in DCE (80 mL). The reaction mixture was heated to 30 °C and stirred for 3 hours. After cooling to room temperature, acetic acid (6.6 mL) and sodium triacetylborohydride (4.67 g, 22.05 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate and washed successively with saturated sodium carbonate aqueous solution and saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography to give the title compound (3.6 g, 56%). MS m / z (ESI): 482.2 [M+H] + .

[0669] Step 2: Preparation of 1-(1-(2-aminothiazolyl-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)-5,5-difluorotetrahydropyrimidine-2(1H)-one

[0670] 120 mg (0.25 mmol) of tert-butyl(5-(1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)thiazolyl-2-yl)carbamate was dissolved in methanol (1 mL), and 3 mL of 4 M dioxane hydrochloride solution was added. The reaction mixture was stirred at room temperature for 8 hours. The solvent was removed by concentration under reduced pressure to obtain the crude title compound (113 mg), which was used directly in the next step. MS m / z (ESI): 382.2 [M+H] + .

[0671] Step 3: Preparation of tert-butyl((1S)-2-((5-(1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)thiazolyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate

[0672] (S)-2-((tert-butoxycarbonyl)amino)-2-((trans)-4-methylcyclohexyl)acetic acid (115 mg, 0.42 mmol) was dissolved in DMF (3 mL), followed by the addition of HATU (160 mg, 0.42 mmol) and DIPEA (274 mg, 2.12 mmol). The reaction mixture was stirred at room temperature for 10 minutes. Crude 1-(1-(2-aminothiazol-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one was added, and the reaction mixture was stirred at room temperature for another hour. The mixture was diluted with ethyl acetate, washed with saturated brine, and the organic phase was separated. The solution was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the title compound (116 mg, overall yield of 73%). MS m / z (ESI): 635.2 [M+H] + .

[0673] Step 4: Preparation of (2S)-2-amino-N-(5-(1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)thiazolyl)-2-((1r,4S)-4-methylcyclohexyl)acetamide

[0674] 116 mg (0.18 mmol) of tert-butyl((1S)-2-((5-(1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)thiazolyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate was dissolved in methanol (2 mL), and 5 mL of 4M dioxane hydrochloride solution was added. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed by concentration under reduced pressure to obtain the crude title compound (110 mg), which was used directly in the next step. MS m / z (ESI): 535.2 [M+H] + .

[0675] Step 5: Preparation of N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)thiazolyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide

[0676] 1-Fluorocyclopropane-1-carboxylic acid (37 mg, 0.36 mmol) was dissolved in DMF (2 mL), and HATU (137 mg, 0.36 mmol) and DIPEA (146 mg, 1.13 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 5 minutes, and (2S)-2-amino-N-(5-(1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)thiazolyl)-2-((1r,4S)-4-methylcyclohexyl)acetamide (110 mg, 0.18 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed with saturated brine, the organic phase was separated, dried with anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography and then resolved by chiral HPLC to obtain the title compound (22 mg, overall yield of 20%).

[0677] 1 H NMR (400MHz, DMSO-d6) δ12.19(s,1H),8.36(d,J=8.2Hz,1H),7.35(d,J=1.2Hz,1H),6.89(d,J=3.0Hz ,1H),5.70(t,J=8.0Hz,1H),4.38(t,J=8.4Hz,1H),3.65-3.44(m,3H),3.43-3.39(m,1H),2.95-2.86 (m,1H),2.85-2.75(m,1H),2.72-2.54(m,4H),2.05-1.86(m,4H),1.85-1.73(m,2H),1.70-1.60(m,2 H),1.46-1.37(m,1H),1.36-1.22(m,3H),1.20-1.07(m,3H),1.02-0.86(m,2H),0.86-0.75(m,4H); m / z(ESI):621.3[M+H] + .

[0678] Preparation of Example 7

[0679] Step 1: Preparation of tert-butyl(5-(1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)carbamate

[0680] Tert-butyl(5-(1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-oxoethyl)thiazo-2-yl)carbamate (1 g, 2.66 mmol) and (R)-2-methylmorpholine (0.81 g, 7.97 mmol) were dissolved in 1,2-dichloroethane (15 mL) and acetic acid (1.5 mL). The reaction mixture was heated to 30 °C and stirred for 3 hours. After cooling to room temperature, sodium triacetylborohydride (0.93 g, 4.38 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was removed by concentration under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with saturated sodium carbonate solution and saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography to give the title compound (0.89 g, 72%). MS m / z (ESI): 462.2 [M+H] + .

[0681] Step 2: Preparation of 1-((R)-1-(2-aminothiazolyl-5-yl)-2-((R)-2-methylmorpholino)ethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one

[0682] 890 mg (1.93 mmol) of tert-butyl(5-(1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)carbamate was dissolved in methanol (1 mL), and 10 mL of 4M dioxane chloride solution was added. The reaction mixture was stirred at room temperature for 8 hours. After removing the solvent by concentration under reduced pressure, the solid was dissolved in methanol, and the pH was adjusted to 7-8 by adding triethylamine. The crude product was then concentrated under reduced pressure and chirally separated (using a Daicel chemically bonded chiral column, model: ChiralPak). AD-H, specifications: 50mm*250mm, 10μm, mobile phase: n-hexane:ethanol:methanol:diethylamine = 60:20:20:0.1, detection wavelength: 214nm, column temperature: 25℃, isocratic elution for 20min, title compound was the first peak, elution time was 11.56min) to obtain the title compound (260mg, 37%).

[0683] 1H NMR(400MHz,MeOD-d6)δ6.85(d,J=1.3Hz,1H),5.71(dd,J=10.0,6.0Hz,1H),3.81(ddd,J =11.3,3.4,1.6Hz,1H),3.69-3.59(m,1H),3.63-3.53(m,2H),3.57-3.40(m,2H),3.43-3 .32(m,1H),2.96(dt,J=11.1,2.0Hz,1H),2.85(dd,J=12.9,10.0Hz,1H),2.76-2.61(m,2 H), 2.30 (td, J=11.4, 3.3Hz, 1H), 1.80 (dd, J=11.1, 9.8Hz, 1H), 1.11 (d, J=6.3Hz, 3H); MS m / z(ESI):362.1[M+H] + .

[0684] Step 3: Preparation of tert-butyl((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate

[0685] (S)-2-((tert-butoxycarbonyl)amino)-2-((trans)-4-methylcyclohexyl)acetic acid (114 mg, 0.42 mmol) was dissolved in DMF (3 mL), followed by the addition of HATU (160 mg, 0.42 mmol) and DIPEA (274 mg, 2.12 mmol). The mixture was stirred at room temperature for 10 minutes, and then 1-((R)-1-(2-aminothiazolyl-5-yl)-2-((R)-2-methylmorpholino)ethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one (138 mg, 0.38 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate, washed with saturated brine, and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the title compound (160 mg, 68%). MS m / z (ESI): 615.3 [M+H] + .

[0686] Step 4: Preparation of (S)-2-amino-N-(5-((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl)-2-((1r,4S)-4-methylcyclohexyl)acetamide

[0687] 160 mg (0.26 mmol) of tert-butyl((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate was dissolved in 1.5 mL of methanol, and 5 mL of 4 M dioxane hydrochloride solution was added. The reaction mixture was stirred at room temperature for 1 hour, and the solvent was removed by concentration under reduced pressure to obtain the crude product of the title compound. MS m / z (ESI): 515.2 [M+H] + .

[0688] Step 5: Preparation of N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide

[0689] 1-Fluorocyclopropane-1-carboxylic acid (38 mg, 0.36 mmol) was dissolved in DMF (5 mL), followed by the addition of HATU (137 mg, 0.36 mmol) and DIPEA (146 mg, 1.13 mmol). The reaction mixture was stirred at room temperature for 5 minutes. The crude (S)-2-amino-N-(5-((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl)-2-((1r,4S)-4-methylcyclohexyl)acetamide from the previous step was added, and the reaction was continued at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography, followed by reversed-phase HPLC to obtain the title compound (28 mg, overall yield of 18%).

[0690] 1H NMR (400MHz, DMSO-d6) δ12.03(s,1H),8.35(d,J=8.0Hz,1H),7.35(d,J=1.2Hz,1H),6.89(d,J=3.0H z,1H),5.71(t,J=7.8Hz,1H),4.38(t,J=8.4Hz,1H),3.80-3.67(m,1H),3.63-3.36(m,6H),2.90-2.7 5(m,2H),2.75-2.62(m,2H),2.15(td,J=11.2,3.2Hz,1H),1.85-1.73(m,3H),1.72-1.61(m,2H),1. 43(d,J=12.8Hz,1H),1.37-1.22(m,3H),1.21-1.10(m,3H),1.09-0.95(m,4H),0.99-0.78(m,5H);MS m / z(ESI):601.3[M+H] + .

[0691] Preparation of Example 8

[0692] Step 1: Preparation of tert-butyl(5-(1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((S)-3-methylmorpholino)ethyl)thiazolyl-2-yl)carbamate

[0693] Tert-butyl(5-(1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-oxoethyl)thiazo-2-yl)carbamate (6.10 g, 16.21 mmol) and 3-(S)-3-methylmorpholine (4.92 g, 48.62 mmol) were dissolved in ethanol (60 mL), and the mixture was heated to 50 °C and stirred for 2 hours. Acetic acid (2.92 g, 48.62 mmol) and sodium cyanoborohydride (5.09 g, 81.04 mmol) were added, and the mixture was stirred at 50 °C for 6 hours. The solvent was removed by vacuum concentration, and the residue was dissolved in ethyl acetate. The residue was washed successively with saturated sodium carbonate aqueous solution and saturated brine to separate the organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under vacuum. The residue was separated by column chromatography to give the title compound (4.8 g, 64%). MS m / z (ESI): 462.2 [M+H]+.

[0694] Step 2: Preparation of 1-((R)-1-(2-aminothiazolyl-5-yl)-2-((S)-3-methylmorpholino)ethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one

[0695] 4.8 g (10.4 mmol) of tert-butyl(5-(1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((S)-3-methylmorpholino)ethyl)thiazolyl-2-yl)carbamate was dissolved in methanol (10 mL), and 30 mL of 4 M dioxane hydrochloride solution was added. The reaction mixture was stirred at 50 °C for 4 hours. The solvent was removed by concentration under reduced pressure, and the residue was chirally resolved to give the title compound (1.71 g, 45%). MS m / z (ESI): 362.2 [M+H]+.

[0696] Step 3: Preparation of tert-butyl((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((S)-3-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate

[0697] (S)-2-((tert-butoxycarbonyl)amino)-2-((trans)-4-methylcyclohexyl)acetic acid (1.54 g, 5.68 mmol) was dissolved in DMF (20 mL), followed by the addition of HATU (2.16 g, 5.68 mmol) and DIPEA (1.83 g, 14.19 mmol). The mixture was stirred at room temperature for 10 minutes, and then 1-((R)-1-(2-aminothiazolyl-5-yl)-2-((S)-3-methylmorpholino)ethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one (1.71 g, 4.73 mmol) was added. The reaction mixture was stirred at 40 °C for 1 hour. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by column chromatography to obtain the title compound (2.61 g, 90%). MS m / z (ESI): 615.3 [M+H] + .

[0698] Step 4: Preparation of (S)-2-amino-N-(5-((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((S)-3-methylmorpholino)ethyl)thiazolyl)-2-((1r,4S)-4-methylcyclohexyl)acetamide

[0699] 2.61 g (4.25 mmol) of tert-butyl((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((S)-3-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate was dissolved in 10 mL of dichloromethane, and 30 mL of 4 M dioxane hydrochloride solution was added. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed by concentration under reduced pressure to obtain the crude title compound, which was used directly in the next reaction. MS m / z (ESI): 515.3 [M+H] + .

[0700] Step 5: Preparation of N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((S)-3-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide

[0701] 1-Fluorocyclopropanecarboxylic acid (492 mg, 4.72 mmol) was dissolved in DMF (20 mL), followed by the addition of HATU (1.79 g, 4.72 mmol) and DIPEA (1.52 g, 11.79 mmol). The reaction mixture was stirred at room temperature for 5 minutes. Crude (S)-2-amino-N-(5-((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((S)-3-methylmorpholino)ethyl)thiazolyl)-2-((1r,4S)-4-methylcyclohexyl)acetamide was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by column chromatography to give the title compound (2.11 g, overall yield of 83%).

[0702] 1H NMR (400MHz, DMSO-d6) δ12.20(s,1H),8.37(d,J=8.1Hz,1H),7.39(d,J=1.1Hz,1H),6.8 8(d,J=3.1Hz,1H),5.71(dd,J=10.2,5.8Hz,1H),4.37(t,J=8.4Hz,1H),3.70-3.36(m,8H ),3.22-3.07(m,2H),2.87-2.79(m,1H),2.48-2.36(m,1H),2.25-2.18(m,1H),1.85-1.7 2(m,2H),1.70-1.61(m,2H),1.47-1.06(m,7H),1.01-0.92(m,4H),0.89-0.77(m,5H); MS m / z(ESI):601.3[M+H] + .

[0703] Preparation of Example 9

[0704] The preparation method of Example 9 is the same as that of Example 3.

[0705] 1 H NMR (400MHz, DMSO-d6) δ12.25(s,1H),8.58(d,J=7.8Hz,1H),7.48(d,J=2.0Hz,1H),7.35(s,1H),7.01(d,J=2.0 Hz,1H),5.85(t,J=7.8Hz,1H),4.52-4.31(m,3H),3.70-3.56(m,1H),3.54-3.38(m,1H),2.84-2.72(m,1H),2.72 -2.63(m,1H),2.55-2.52(m,1H),2.44-2.36(m,3H),2.33-2.20(m,2H),1.88-1.74(m,2H),1.73-1.62(m,2H),1. 55-1.42(m,5H),1.41-1.29(m,3H),1.29-1.22(m,4H),1.22-1.12(m,1H),1.10-1.01(m,1H),0.99-0.70(m,6H).

[0706] Biological testing evaluation

[0707] 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.

[0708] Test Example 1: Determination of the competitive binding activity of the compound of the present invention with the human IL-17 receptor to its ligand.

[0709] 1. Experimental objective: To quantitatively detect the blocking effect of the compound on the binding of human IL-17RA to IL-17A protein by competitive ELISA under in vitro conditions.

[0710] 2. Experimental instruments and reagents:

[0711] 2.1 Instruments:

[0712] 2.2 Reagents:

[0713] 3. Experimental Methods: 0.0625 μg / mL IL-17A was added to each well at 100 μL and incubated overnight at 4°C in a 96-well plate. After washing the plate four times with 300 μL of PBST per well, 300 μL of ELISA Blocker blocking buffer was added to each well, and the plate was blocked at 24°C for 2 h. The plate was washed again under the same conditions. 80 μL of PBS solution containing 1% BSA and 10 μL of 10× test compound solution were added to each well, mixed, and incubated at room temperature for 1 h. Then, 10 μL of IL-17RA solution was added to bring the final concentration to 5 nM, mixed, and incubated at 24°C for 1 h. DMSO solution of the appropriate concentration and volume without the compound was added to the positive control wells, and 1% BSA solution without IL-17RA was added to the negative control wells. After washing the plate four times, 100 μL of anti-Fc-tagged HRP-conjugated antibody was added, and the plate was incubated at 37°C for 1 h. After washing the plate four times, add 100 μL of TMB substrate to each well and incubate at 37°C in the dark. After color development, add 100 μL of stop solution to each well to terminate the reaction, and measure the absorbance at 450 nm and 570 nm using a microplate reader.

[0714] 4. Experimental data processing methods:

[0715] 1) Inhibition rate (%): The inhibition rate is obtained by calculating the original data (OD450-OD570) according to the following formula.

[0716] Inhibition rate % = [(average value of positive control wells – value of sample wells) / (average value of positive control wells – average value of negative control wells)] × 100, where the positive control wells are the wells without the compound and the negative control wells are the wells without IL-17RA protein solution.

[0717] 2) Curve Fitting: Using the log(inhibitor) vs. response -- Variable slope (four parameters) function in GraphPad Prism 8, a fitting equation analysis was performed on the compound concentration and its corresponding inhibition rate. The fitted curve was then used to derive the IC50 of the compound. 50 value.

[0718] The fitted calculation equation is Y = Bottom + (Top - Bottom) / (1 + 10^(LogIC)). 50 -X)*HillSlope))

[0719] 5. Experimental Results and Conclusions:

[0720] Table 1

[0721] 6. Conclusion: The compounds of this invention exhibit excellent competitive binding to human IL-17 receptor ligands.

[0722] Test Example 2: Determination of the inhibitory effect of the compound of the present invention on Groα secretion by HT-29 cells.

[0723] Experimental objective: The purpose of this test case is to measure the inhibitory effect of the compound on Groα secretion in HT-29 cells in order to evaluate the inhibitory effect of the compound on the IL-17A pathway.

[0724] Experimental instruments and reagents:

[0725] instrument:

[0726] Reagents:

[0727] Experimental Methods: A cell suspension of 50,000 cells / ml was prepared. 200 μl of the cell suspension was added to each well of a 96-well plate (10,000 cells / well), and the cells were incubated overnight. In 96-well V-plates, the 5 mM compound was serially diluted 3-fold with DMSO; the compound was also diluted 100-fold with complete culture medium in each well. IL-17A protein (R&D, #BT7955-025 / CF) had a stock concentration of 100 μg / ml and was diluted 333.33-fold with complete culture medium. The compound and IL-17A were mixed at a 1:1 volume ratio and incubated at 37°C for 30 minutes. 50 μl of the compound and IL-17A mixture was added to each well, bringing the final IL-17A protein concentration to 30 ng / ml. The cells were incubated at 37°C in a 5% CO2 cell culture incubator for 48 hours. The concentration of Groα in the supernatant was determined using the Human Groα Valukin ELISA kit (Biotechne, #VAL139), and the absorbance at 450 nm was measured using a microplate reader (PE, EnVision2105). Data were analyzed using GraphPad Prism 8.3.0.

[0728] Experimental data processing method: GraphPad Prism 8.3.0 was used to analyze the data.

[0729] Inhibition rate % = [(Average value of positive control wells – Value of sample wells) / (Average value of positive control wells – Average value of negative control wells)] × 100%, where the sample wells are wells with cells added with compounds at different concentration gradients, the positive control wells are wells with cells added with IL-17A, and the negative control wells are wells with culture medium added with IL-17A.

[0730] Curve fitting: Based on the inhibition rate (%) at each concentration, use log(inhibitor) vs. response--Variable slope (four parameters) in GraphPad Prism 6.0 to perform curve fitting to obtain the IC 50 value, and the calculation equation is Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC 50 -X) * HillSlope)).

[0731] Experimental results and conclusions:

[0732] Table 2

[0733] Conclusion: The compounds of the present invention show excellent inhibitory effects on the secretion of Groα by HT-29 cells.

[0734] Test Example 3, Pharmacokinetic determination of Wistar rats

[0735] 1. Experimental purpose: Using Wistar rats as test animals, study the pharmacokinetic behavior of the compounds of the present invention in rats (plasma) after oral administration at a dose of 30 mg / kg.

[0736] 2. Experimental protocol

[0737] 2.1 Test drug: Prepared by the present invention's embodiment.

[0738] 2.2 Test animals: 3 Wistar rats in each group, female, Beijing Vital River Laboratory Animal Technology Co., Ltd., animal production license number (SCXK (Beijing) 2021 - 0011).

[0739] 2.3 Drug preparation: Oral administration drug preparation: 30% PEG400 + 70% (10% Solutol) water

[0740] Solutol HS15 was melted in a water bath at 50-60℃. 50 mL of the melt was added to 450 mL of ultrapure water, and the mixture was stirred and sonicated to obtain 500 mL of a 10% Solutol HS15 solution. The compound was weighed and added to 30% PEG solution according to the total volume ratio of the drug to be administered. The solution was shaken well, sonicated until clear, and then 70% (10% Solutol) water was added to obtain a colorless, clear solution with a concentration of 3.0 mg / mL.

[0741] 2.4 Dosing regimen: Three female Wistar rats were used in each group. After fasting overnight, the rats were administered the drug PO at a dose of 30 mg / kg and a volume of 10 mL / kg.

[0742] 2.5 Sample collection: After oral administration to rats, 0.2 mL of blood was collected from the jugular vein at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours, placed in EDTA-K2 tubes, centrifuged at 6000 rpm for 6 min at 4℃ to separate plasma, and stored at -80℃.

[0743] 2.6 Sample preparation:

[0744] 1) Add 250uL of acetonitrile to 50uL of plasma sample to precipitate, mix and centrifuge at 4000rpm at 4℃ for 20 minutes.

[0745] 2) Take the supernatant solution after treatment and perform LC / MS / MS analysis to determine the concentration of the analyte. LC / MS / MS analysis instrument: AB Sciex API-4000 Qtrap-Shimadzu Controller-CBM20A.

[0746] 2.7 Liquid Chromatography Analysis:

[0747] ●Column: Waters Xbridge C18 3.5um 2.1*50mm

[0748] ●Mobile phase: Solution A is a 0.1% formic acid aqueous solution, and Solution B is a 0.1% formic acid acetonitrile solution.

[0749] ● Flow rate: 0.6 mL / min

[0750] ●Eluting time: 0-3.5 minutes, eluent as follows:

[0751] 3. Experimental Results and Analysis: The pharmacokinetic results of the rat pharmacokinetic experiment are shown in Table 3 below, which contains pharmacokinetic parameters.

[0752] Table 3

[0753] 4. Experimental conclusion: As can be seen from the pharmacokinetic experimental results of rats in the table, the embodiments of the present invention exhibit excellent absorption and metabolism properties, significantly improving the exposure amount AUC and blood drug concentration.

[0754] Test Example 4, Pharmacokinetics Determination of Beagle Dogs

[0755] 1. Experimental purpose: Using beagle dogs as test animals, study the pharmacokinetic behavior of the compound of the present invention in beagle dogs (plasma) after oral administration at a dose of 3 mg / kg.

[0756] 2. Experimental scheme

[0757] 2.1 Test drug: The embodiments of the present invention, self-made.

[0758] 2.2 Test animals: 3 beagle dogs in each group, male, Animal Production License Number of Guangxi Grand forest Scientific Primate Company., Ltd. (SCXK (Gui) 2021-0004).

[0759] 2.3 Drug preparation: Oral administration drug preparation: 30% PEG400 + 70% (10% Solutol) water

[0760] After melting Solutol HS15 in a water bath at 50-60 °C, take 50 mL and add it to 450 mL of ultrapure water. After stirring and ultrasonic treatment, a 500 mL 10% Solutol HS15 solution is obtained. Weigh the compound, first add 30% PEG solution according to the total administration volume ratio, shake well, and ultrasonic dissolve until clear. Then add 70% (10% Solutol) water to obtain a colorless and clear solution with a concentration of 0.6 mg / mL.

[0761] 2.4 Administration scheme: 3 beagle dogs in each group, male; after fasting overnight, they are respectively given PO at a dose of 3 mg / kg and an administration volume of 5 mL / kg.

[0762] 2.5 Sample collection: After oral administration to beagle dogs, blood is collected from the anterior limb vein or other appropriate veins at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours. Each sample is collected about 1 mL, anticoagulated with K2-EDTA, and placed on ice after collection. The blood samples are placed on ice and centrifuged to separate plasma within 1 hour (centrifugation conditions: 2200 g, 10 minutes, 2-8 °C). Plasma samples are stored in a -80 °C refrigerator before analysis, and the remaining plasma samples after analysis are continued to be stored in a -80 °C refrigerator.

[0763] 2.6 Sample treatment:

[0764] 1) Add 40uL of plasma sample to 400uL of methanol for precipitation, mix and centrifuge at 4000rpm for 10 minutes.

[0765] 2) Take the supernatant solution after treatment and perform LC / MS / MS analysis to determine the concentration of the analyte. LC / MS / MS instrument: AB Sciex LC-MS / MS-29 (TQ6500+).

[0766] 2.7 Liquid Chromatography Analysis:

[0767] ●Column: ACQUITY UPLC HSS T3 1.8um 2.1*50mm

[0768] ●Mobile phase: Solution A is a 0.1% formic acid aqueous solution, and Solution B is a 0.1% formic acid acetonitrile solution.

[0769] ● Flow rate: 0.6 mL / min

[0770] ●Eluting time: 0-1.4 minutes, eluent as follows:

[0771] 2.7. Experimental Results and Conclusions: The embodiments of the present invention exhibit excellent absorption and metabolic properties, with excellent exposure levels and half-lives. The half-lives of the embodiments of the present invention are above 5 hours, and some embodiments even have half-lives above 6 hours.

[0772] Test Example 5: Pharmacodynamic Experiment of the Compound in a 5% Imiquimod-induced Wistar Rat Psoriasis Model

[0773] 1. Experimental Objective: To evaluate the efficacy of the compound in a 5% imiquimod-induced Wistar rat model of psoriasis.

[0774] 2. Experimental Design

[0775] 2.1 Test reagents: In this embodiment of the invention, they were prepared in-house.

[0776] 2.2 Experimental animals: Five female Wistar rats, 6-7 weeks old, were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. They were fed standard laboratory food and had free access to food and water.

[0777] 2.3 Reagents: 5% imiquimod cream (Sichuan Mingxin Pharmaceutical Co., Ltd.), dexamethasone (Shanghai Titan Pharmaceutical), anti-IL-17 Amouse mAb (BioXcell), Veet hair removal cream (mild type), polyethylene glycol 400 (Sinopharm Chemical Reagent). HS15 (Sigma-Aldrich), PBS pH 7.4 (1X, Gibco)

[0778] 2.4 Administration: The administration volume is 10 mL / kg; the dosage for the test compound group is 5-100 mg / kg (e.g., 7.5, 15, 30, 50, 100).

[0779] 2.5 Experimental Design Note: *30% PEG400 + 70% (10% Solutol) water; **0.5% CMC-Na / 1% Tween 80; ***PBS

[0780] 2.6 Experimental Procedure and Endpoint Sample Collection

[0781] 1. After the animals have adapted for 2-3 days, shave the skin modeling area on the back of the rats and apply an appropriate amount of hair removal cream to remove the hair (3cm*3cm, apply hair removal cream and wash it off with clean water within 5-10 minutes).

[0782] 2. Two to five days after hair removal (depending on the condition of the skin on the back after hair removal), select animals that have been completely hair removed and are undamaged, and include them in the group according to their weight on that day;

[0783] 3. From day 1 to day 6 of the experiment, animals were weighed daily and administered the drug according to the protocol (QD / BID, administration volume 10 mL / kg). The skin of the back model area was scored using the PASI (Psoriasis Area and Severity Index) once a day. The scoring criteria are shown in Table 4. The total PASI score each day is the sum of erythema, scaling, and thickness. One hour after administration, 75 mg of 5% imiquimod was applied to the skin of the back model area.

[0784] Table 4. PASI Scoring Criteria

[0785] 4. On the 7th day of the experiment, the animals were weighed, and the skin of the model area on the back was scored and photographed by PASI. The test compound group was administered the drug sequentially, and plasma was collected at 0.5, 1, 2, 4, 6, 8 and 24 hours after administration. Blood was collected by jugular vein puncture (alternating blood collection, about 120 μL each time).

[0786] 5. Add the collected blood to a centrifuge tube containing EDTA-K2, manually invert 3-4 times, place on ice, and centrifuge at 8000 rpm for 5 minutes. Transfer the centrifuged plasma to a new labeled centrifuge tube, measure ~50 μL of pkJ, and then freeze the plasma sample with dry ice and store at -80°C.

[0787] 6. Eight hours after blood was collected from the animals in the test compound group, the animals were euthanized, and a piece of skin from the lesion on the back was taken, weighed, cut into pieces, and placed in a new grinding tube for testing the skin / plasma concentration ratio.

[0788] 2.7 Key indicators: body weight and PASI score of back skin from D1 to D7, and a photo taken at the end.

[0789] 2.8 Experimental Results and Conclusions: The embodiments of the present invention can effectively improve the symptoms of psoriasis in the 5% imiquimod-induced Wistar rat psoriasis model, significantly improve the PASI score of the back skin, and achieve a 40-50% therapeutic effect on D7 in the antibody group. Some embodiments of the present invention can achieve the same technical effect as the antibody group when taken orally.

[0790] III. Research on Salts and Their Crystal Forms

[0791] 1.1 Experimental Apparatus

[0792] 1.1.1 Some parameters of physicochemical detection instruments

[0793] 1.2 Instruments and Liquid Chromatography Analysis Conditions

[0794] 1.2.1 Instruments and Equipment

[0795] 1.2.2 Chromatographic conditions

[0796] 1.2.3 Chromatographic conditions

[0797] 1.2.4 Chromatographic conditions

[0798] 1. Preparation of different amorphous salts of the compound in Example 7

[0799] 1.1 Amorphous preparation of p-toluenesulfonate

[0800] A. Weigh 400 mg of the free base from Example 7, dissolve it in 2 mL of acetone, add 364 μL of 2 M p-toluenesulfonic acid ethanol solution and 10 mL of isopropyl ether, stir overnight at room temperature, filter, and dry the solid under vacuum at 40 °C to obtain a solid product. X-ray powder diffraction analysis showed that it was an amorphous p-toluenesulfonate.

[0801] B. Weigh 10 mg of the free base from Example 7, add or dissolve it in 0.15 mL of the solvent in Table 5, add 9.7 μL of 2M p-toluenesulfonic acid ethanol solution and 0.9 mL of isopropyl ether, stir overnight at room temperature, filter, and dry the solid under vacuum at 40 °C to obtain a solid product. X-ray powder diffraction analysis showed that it was an amorphous p-toluenesulfonate.

[0802] Table 5

[0803] The results of p-toluenesulfonate ion detection showed that the p-toluenesulfonate ion content was 24.6%.

[0804] 1.2 Preparation of amorphous methanesulfonate

[0805] A. Weigh 10 mg of the free base from Example 7, add 0.15 mL of 2-methyltetrahydrofuran and 9.7 μL of 2M methanesulfonic acid ethanol solution, stir to dissolve, add 0.5 mL of isopropyl ether, stir at room temperature to precipitate, centrifuge, and dry the solid under vacuum at 40 °C to obtain a solid product, which was identified as an amorphous methanesulfonate by X-ray powder diffraction.

[0806] B. Weigh 10 mg of the free base from Example 7, add 0.15 mL of the solvent from Table 6 and 9.7 μL of 2M methanesulfonic acid ethanol solution, stir to dissolve, add 0.5 mL of isopropyl ether, stir at room temperature to precipitate, centrifuge, and dry the solid under vacuum at 40 °C to obtain a solid product, which was identified as an amorphous methanesulfonate by X-ray powder diffraction.

[0807] Table 6

[0808] The methanesulfonate ion detection results showed that the methanesulfonate ion content was 16.6%.

[0809] 1.3 Preparation of amorphous phosphate

[0810] A. Weigh 10 mg of the free base from Example 7, add 0.15 mL of acetone and 9.7 μL of 2 M phosphate ethanol solution, stir to dissolve, add 0.5 mL of isopropyl ether, stir at room temperature to precipitate, centrifuge, and dry the solid under vacuum at 40 °C to obtain a solid product, which was detected by X-ray powder diffraction as an amorphous phosphate.

[0811] B. Weigh 10 mg of the free base from Example 7, add 0.15 mL of the solvent from Table 7 and 9.7 μL of 2M phosphate ethanol solution, stir to dissolve, add 0.5 mL of isopropyl ether, stir at room temperature to precipitate, centrifuge, and dry the solid under vacuum at 40 °C to obtain a solid product, which was identified as an amorphous phosphate by X-ray powder diffraction.

[0812] Table 7

[0813] The phosphate ion detection results showed that the phosphate ion content was 10.7%.

[0814] 1.4 Preparation of amorphous maleate

[0815] A. Weigh 10 mg of the free base from Example 7, add 0.15 mL of ethyl acetate and 9.7 μL of 2 M maleic acid ethanol solution, stir to dissolve, add 0.5 mL of isopropyl ether, stir at room temperature to precipitate, centrifuge, and dry the solid under vacuum at 40 °C to obtain a solid product, which was identified as an amorphous maleate salt by X-ray powder diffraction.

[0816] B. Weigh 10 mg of the free base from Example 7, add 0.15 mL of the solvent from Table 8 and 9.7 μL of 2M maleic acid ethanol solution, stir to dissolve, add 0.5 mL of isopropyl ether, stir at room temperature to precipitate, centrifuge, and dry the solid under vacuum at 40 °C to obtain a solid product, which was identified as an amorphous maleate salt by X-ray powder diffraction.

[0817] Table 8

[0818] The results of maleate ion detection showed that the maleate ion content was 12.7%.

[0819] 1.5 Preparation of amorphous hydrochloride

[0820] A. Weigh 10 mg of the free base from Example 7, dissolve it in 0.15 mL of acetone, add 9.1 μL of 2 M hydrochloric acid ethanol solution and 0.5 mL of isopropyl ether, stir at 5 °C to precipitate, centrifuge, and dry the solid under vacuum at 40 °C to obtain the solid product.

[0821] X-ray powder diffraction analysis revealed that it was an amorphous hydrochloride salt.

[0822] B. Weigh 10 mg of the free base from Example 7, dissolve it in 0.15 mL of the solvent in Table 9, add 9.1 μL of 2M hydrochloric acid ethanol solution and 0.5 mL of isopropyl ether, stir at 5 °C to precipitate, centrifuge, and dry the solid under vacuum at 40 °C to obtain a solid product, which is identified as an amorphous hydrochloride salt by X-ray powder diffraction.

[0823] Table 9

[0824] The hydrochloric acid ion test results showed that the chloride ion content was 6.1%.

[0825] 1.6 Preparation of amorphous sulfate

[0826] A. Weigh 10 mg of the free base from Example 7, dissolve it in 0.15 mL of acetone, add 9.1 μL of 2 M sulfuric acid ethanol solution and 0.5 mL of isopropyl ether, stir at 5 °C to precipitate, centrifuge, and dry the solid under vacuum at 40 °C to obtain the solid product.

[0827] X-ray powder diffraction analysis revealed it to be an amorphous sulfate.

[0828] B. Weigh 10 mg of the free base from Example 7, dissolve it in 0.15 mL of Table 10 solvent, add 9.1 μL of 2M sulfuric acid ethanol solution and 0.5 mL of isopropyl ether, stir at 5 °C to precipitate, centrifuge, and dry the solid under vacuum at 40 °C to obtain a solid product, which was identified as an amorphous sulfate by X-ray powder diffraction.

[0829] Table 10

[0830] The sulfate ion detection results showed that the sulfate ion content was 10.7%.

[0831] 1.7 Preparation of amorphous malate: 10 mg of the free base from Example 7 was weighed and dissolved in 0.15 mL of ethyl acetate. 9.1 μL of 2M malic acid ethanol solution and 0.5 mL of isopropyl ether were added. The mixture was stirred at 5 °C to precipitate, centrifuged, and the solid was dried under vacuum at 40 °C to obtain a solid product. X-ray powder diffraction analysis confirmed that the product was amorphous malate. The malate ion content was 13.7%.

[0832] 1.8 Preparation of amorphous tartrate: 10 mg of the free base from Example 7 was weighed and dissolved in 0.15 mL of acetone. 9.1 μL of 2M tartaric acid ethanol solution and 0.5 mL of isopropyl ether were added. The mixture was stirred at 5 °C to precipitate, centrifuged, and the solid was dried under vacuum at 40 °C to obtain a solid product. X-ray powder diffraction analysis confirmed that the product was amorphous tartrate. The tartrate ion content was 18.1%.

[0833] 2. Preparation of different acid salt crystal forms of the compound in Example 7

[0834] 2.1 Preparation of p-Toluenesulfonate crystal form A

[0835] A. Weigh 10.40 mg of the free base from Example 7 and 3.96 mg of p-toluenesulfonic acid, add 100 μL of tert-butanol, dissolve, stir at room temperature, and precipitate overnight. The obtained solid XRPD was detected as p-toluenesulfonate crystal form A.

[0836] B. Weigh 1004.28 mg of the free base from Example 7 and 380.52 mg of p-toluenesulfonic acid, add 6.66 mL of acetone, stir at room temperature until dissolved, and let it precipitate overnight. The obtained solid XRPD was detected as p-toluenesulfonate crystal form A.

[0837] C. Take 5 mg of the amorphous p-toluenesulfonate obtained in 1.1, add 0.15 mL of methyl isobutyl ketone, stir at 40 °C to dissolve, stir at 5 °C to crystallize, centrifuge, and dry the solid under vacuum at 40 °C. The obtained solid XRPD test shows that it is p-toluenesulfonate crystal form A.

[0838] D. 100 mg of the amorphous p-toluenesulfonate obtained in 1.1 was dissolved in the solvent in Table 11 at 40°C, stirred at 5°C to crystallize, centrifuged, and the solid was vacuum dried at 40°C. The obtained solid was XRPD detected as p-toluenesulfonate crystal form A.

[0839] Table 11

[0840] E. Add 5 mg of the amorphous p-toluenesulfonate obtained in 1.1 to 0.5 mL of the solvent in Table 12, stir overnight at room temperature, centrifuge, and dry the solid under vacuum at 40 °C for 3 h. The obtained solid was XRPD detected as p-toluenesulfonate crystal form A.

[0841] Table 12

[0842] The X-ray powder diffraction of p-toluenesulfonate crystal form A is shown in Figure 1, and the positions of its characteristic peaks are shown in Table 13. The TGA-DSC pattern of p-toluenesulfonate crystal form A is shown in Figure 2. The DSC pattern shows an endothermic peak at 174.87℃, and the TGA pattern shows a weight loss of 7.23% from 30℃ to 155℃. Ion detection results show that the p-toluenesulfonate ion content is 24.5%.

[0843] Table 13

[0844] 2.2 Preparation of p-Toluenesulfonate crystal form B:

[0845] Weigh 50.22 mg of the free base from Example 7 and 19.42 mg of p-toluenesulfonic acid, add 500 μL of tert-butanol, stir at room temperature to dissolve, and let it precipitate overnight. The obtained solid XRPD was detected to be p-toluenesulfonate crystal form B.

[0846] The XRPD pattern of p-toluenesulfonate crystal form B is shown in Figure 3, the positions of its characteristic peaks are shown in Table 14, its DSC pattern is shown in Figure 4, and its TGA pattern is shown in Figure 5.

[0847] Table 14

[0848] 2.3 Preparation of p-Toluenesulfonate crystal form C

[0849] The solid obtained by heating the p-toluenesulfonate crystal form A obtained in step 2.1 to 150°C was identified by XRPD as p-toluenesulfonate crystal form C.

[0850] The XRPD pattern of p-toluenesulfonate crystal form C is shown in Figure 6, the positions of its characteristic peaks are shown in Table 15, its DSC pattern is shown in Figure 7, and its TGA pattern is shown in Figure 8.

[0851] Table 15

[0852] 2.4 Preparation of p-Toluenesulfonate crystal form D

[0853] Weigh 4.538 g of the free base from Example 7 and 1.788 g of p-toluenesulfonic acid monohydrate, add 4.6 mL of methanol, stir at room temperature until dissolved, add 40 mL of methyl tert-butyl ether dropwise at 0 °C, and allow to precipitate overnight. After filtration, dry under vacuum at 50 °C for 24 h. The obtained solid XRPD analysis showed it to be p-toluenesulfonate crystal form D. The XRPD diagram of p-toluenesulfonate crystal form D is shown in Figure 9, and its characteristic peaks are shown in Table 16.

[0854] Table 16

[0855] 2.5 Preparation of p-Toluenesulfonate crystal form E

[0856] A. Weigh 5.043 g of the free base from Example 7, add 10 mL of acetonitrile to dissolve and clarify to form a mother liquor. Separately weigh 1.900 g of p-toluenesulfonic acid monohydrate, add 10 mL of water to dissolve and clarify, add to the mother liquor at 0°C, stir overnight to precipitate, and the obtained solid XRPD test shows that it is p-toluenesulfonate crystal form E.

[0857] B. Add 50 mg of p-toluenesulfonate crystal form A obtained in 2.1 to 0.4 mL of water, stir at room temperature, filter, and dry the solid under vacuum at 40 °C. The obtained solid was XRPD detected as p-toluenesulfonate crystal form E.

[0858] C. Weigh 30 mg of the free base from Example 7, add 0.18 mL of 10% water / acetone (v / v) and 27.5 μL of 2M p-toluenesulfonic acid aqueous solution, stir to dissolve, add 1.2 mL of the solvent in Table 17 and p-toluenesulfonate E seed crystals, stir at room temperature to crystallize, centrifuge, and dry the solid under vacuum at 40 °C. The obtained solid XRPD test showed that it was p-toluenesulfonate crystal form E.

[0859] Table 17

[0860] The XRPD spectrum of p-toluenesulfonate crystal form E is shown in Figure 10, and its characteristic peak positions are shown in Table 18. The TGA-DSC spectrum of p-toluenesulfonate crystal form E is shown in Figure 11. The DSC spectrum shows that the endothermic peaks are at 124.14℃ and 178.28℃, and the TGA spectrum shows a weight loss of 3.54% from 30℃ to 110℃. Ion detection results show that the p-toluenesulfonate ion content is 22.9%.

[0861] Table 18

[0862] 2.6 Preparation of p-toluenesulfonate crystal form F: Weigh 29.48 mg of p-toluenesulfonate crystal form B obtained in 2.2, add 100 μL of ethanol, slurry at room temperature for 7 days, filter, and vacuum dry the solid at 50℃ for 24 h. The obtained solid was identified as p-toluenesulfonate crystal form F by XRPD analysis. The XRPD diagram of p-toluenesulfonate crystal form F is shown in Figure 12, and its characteristic peak positions are shown in Table 19.

[0863] Table 19

[0864] 2.7 Preparation of p-Toluenesulfonate crystal form G

[0865] Weigh 30.22 mg of p-toluenesulfonate crystal form E prepared in step 2.5, add 100 μL of methanol, slurry at room temperature for 7 days, filter, and dry the solid under vacuum at 50 °C for 24 h. The XRPD analysis of the obtained solid shows that it is p-toluenesulfonate crystal form G. The XRPD diagram of p-toluenesulfonate crystal form G is shown in Figure 13, and the positions of its characteristic peaks are shown in Table 20.

[0866] Table 20

[0867] 1.8 Preparation of p-Toluenesulfonate crystal form H

[0868] A. Weigh 31.54 mg of p-toluenesulfonate crystal form E prepared in step 2.5, add 100 μL of ethanol, slurry at room temperature for 7 days, filter, and vacuum dry the solid at 50℃ for 24 h. The obtained solid XRPD test showed that it was p-toluenesulfonate crystal form H.

[0869] B. Dissolve 5 mg of p-toluenesulfonate crystal form E prepared in 2.5 in the solvent in Table 21 at room temperature or 40°C, and allow it to slowly evaporate and solidify at room temperature. The resulting solid XRPD test showed that it was p-toluenesulfonate crystal form H.

[0870] Table 21

[0871] The XRPD pattern of p-toluenesulfonate crystal form H is shown in Figure 14, and the positions of its characteristic peaks are shown in Table 22. The TGA-DSC pattern of p-toluenesulfonate crystal form H is shown in Figure 15. The DSC spectrum shows that the endothermic peaks are at 98.15℃ and 180.15℃, and the TGA spectrum shows that the weight loss is 5.35% from 30℃ to 110℃.

[0872] Table 22

[0873] 2.9 Preparation of hydrochloride crystal form A

[0874] A. Weigh 10 mg of the free base from Example 7, add 100 μL of purified water, add 1 M hydrochloric acid in methanol solution at a molar ratio of 1:1.2, stir at 50 °C, and after dissolution, precipitate out. The obtained solid XRPD was detected as hydrochloride crystal form A.

[0875] B. Dissolve 400 mg of the free base from Example 7 in 2 mL of acetone, add 364 μL of 2 M hydrochloric acid ethanol solution and 10 mL of isopropyl ether, stir at room temperature to crystallize, filter, and dry the solid under vacuum at 40 °C. The obtained solid XRPD test showed that it was hydrochloride crystal form A.

[0876] C. 30 mg of the free base from Example 7 was added to 27.3 μL of 2M hydrochloric acid ethanol solution and 0.45 mL of cyclohexane. The mixture was stirred overnight at 5 °C, centrifuged, and the solid was dried under vacuum at 40 °C. The obtained solid was XRPD tested and found to be hydrochloride crystal form A.

[0877] D. Dissolve 5 mg of hydrochloride crystal form B prepared in 2.10 in the solvent in Table 23 at room temperature or 40°C, and allow it to evaporate and solidify at room temperature. The resulting solid XRPD test showed that it was hydrochloride crystal form A.

[0878] Table 23

[0879] The XRPD spectrum of hydrochloride crystal form A is shown in Figure 16, and its characteristic peak positions are shown in Table 24. The TGA-DSC spectrum of hydrochloride crystal form A is shown in Figure 17. The DSC spectrum shows that the endothermic peaks are at 125.48℃ and 192.63℃, and the TGA spectrum shows a weight loss of 4.35% from 30℃ to 110℃. Ion detection results show that the chloride ion content is 5.2%.

[0880] Table 24

[0881] 2.10 Preparation of hydrochloride crystal form B

[0882] A. Weigh 1502.77 mg of the free base from Example 7, add 5 mL of purified water, and add 1 mL of 3M hydrochloric acid in methanol solution at a molar ratio of 1:1.2. After dissolving, the solid XRPD obtained is identified as hydrochloride crystal form B.

[0883] B. 150 mg of the free base from Example 7 was added to 2.25 mL of 50% water / methanol (v / v) and 136.4 μL of 2M hydrochloric acid ethanol solution. The solution was stirred at 50 °C to dissolve completely, stirred at 5 °C to crystallize, filtered, and the solid was dried under vacuum at 40 °C. The obtained solid XRPD test showed that it was hydrochloride crystal form B.

[0884] C. Dissolve 5 mg of the amorphous hydrochloride prepared in 1.5 in the solvent in Table 25 at room temperature or 40°C, and allow it to evaporate and solidify at room temperature. The resulting solid XRPD test showed that it was hydrochloride crystal form B.

[0885] Table 25

[0886] The XRPD spectrum of hydrochloride crystal form B is shown in Figure 18, and its characteristic peak positions are shown in Table 26. The TGA-DSC spectrum of hydrochloride crystal form B is shown in Figure 19. The DSC spectrum shows that the endothermic peaks are at 54.16℃ and 197.97℃, and the TGA spectrum shows a weight loss of 4.63% from 30℃ to 110℃. Ion detection results show that the chloride ion content is 2.9%.

[0887] Table 26

[0888] 2.11 Preparation of hydrochloride crystal form C

[0889] A. Take 5 mg of hydrochloride crystal form B prepared in 2.10, add 0.5 mL of dichloromethane, stir overnight at 5 °C, centrifuge, and dry the solid under vacuum. The obtained solid XRPD test shows that it is hydrochloride crystal form C.

[0890] B. Dissolve 5 mg of the hydrochloride crystal form A obtained in 2.9 in 0.25 mL of 10% water / isopropanol (v / v), and allow it to evaporate and solidify at room temperature. The resulting solid XRPD test showed that it was hydrochloride crystal form C.

[0891] The characteristic peak positions of the XRPD spectrum of hydrochloride crystal form C are shown in Table 27. The TGA-DSC spectrum of hydrochloride crystal form C is shown in Figure 20. The DSC spectrum shows that the endothermic peak has a peak value of 183.60℃, and the TGA spectrum shows that the weight loss is 6.82% from 32℃ to 175℃.

[0892] Table 27

[0893] 2.12 Preparation of hydrobromide crystal form A

[0894] A. Weigh 10 mg of the free base from Example 7, add 100 μL of purified water, add 2.26 μL of hydrobromic acid solution at a molar ratio of 1:1.2, react at room temperature, and after dissolution, precipitate. The obtained solid XRPD was detected to be hydrobromide crystal form A.

[0895] B. 10 mg of the free base from Example 7 was added to 0.15 mL of acetone and 9.1 μL of 2 M hydrobromic acid ethanol solution, stirred until dissolved, 0.5 mL of isopropyl ether was added, stirred at 5 °C to crystallize, centrifuged, and the solid was dried under vacuum at 40 °C. The obtained solid was XRPD tested and found to be hydrobromide crystal form A.

[0896] C. Dissolve 200 mg of the free base from Example 7 in 3.0 mL of 2-methyltetrahydrofuran, add 182 μL of 2M hydrobromic acid ethanol solution and hydrobromide crystal form A seed crystals, stir at room temperature to precipitate crystals, filter, and dry the solid under vacuum at 40 °C. The obtained solid XRPD test showed that it was hydrobromide crystal form A.

[0897] D. Dissolve 10 mg of the free base from Example 7 in 0.15 mL of the solvent in Table 28, add 9.1 μL of 2M hydrobromic acid ethanol solution and 0.5 mL of isopropyl ether, stir at 5 °C to crystallize, centrifuge, and dry the solid under vacuum at 40 °C. The obtained solid XRPD test showed that it was hydrobromide crystal form A.

[0898] Table 28

[0899] The XRPD spectrum of hydrobromide crystal form A is shown in Figure 21, and its characteristic peak positions are shown in Table 29. The TGA-DSC spectrum of hydrobromide crystal form A is shown in Figure 22. The DSC spectrum shows endothermic peaks at 106.81℃ and 205.65℃, while the TGA spectrum shows a weight loss of 4.16% from 31℃ to 87℃. Ion detection results show a bromide ion content of 12.7%.

[0900] Table 29

[0901] 2.13 Preparation of hydrobromide crystal form B

[0902] Weigh 300 mg of free base, add 3 mL of 2-methyl-tetrahydrofuran or isopropyl acetate, dissolve and clarify at room temperature, add 67.8 μL of hydrobromic acid (concentration of about 8.6 M), and a solid gradually precipitates out. It cannot be stirred. After stirring for 2 hours, the suspension is good. Filter, and the obtained solid is identified as hydrobromide crystal form B.

[0903] The XRPD pattern of hydrobromide crystal form B is shown in Figure 23, the positions of its characteristic peaks are shown in Table 30, and its DSC spectrum is shown in Figure 24.

[0904] Table 30

[0905] 2.14 Preparation of hydrobromide crystal form C

[0906] 150 mg of the free base from Example 7 was added to 2.25 mL of 50% water / methanol (v / v) and 136.4 μL of 2M hydrobromic acid ethanol solution. The solution was stirred at 50 °C to dissolve completely, stirred at 5 °C to crystallize, filtered, and the solid was dried under vacuum at 40 °C. The obtained solid was XRPD tested and found to be hydrobromide crystal form C.

[0907] The XRPD spectrum of hydrobromide crystal form C is shown in Figure 25, and its characteristic peak positions are shown in Table 31. The TGA-DSC spectrum of hydrobromide crystal form C is shown in Figure 26. The DSC spectrum shows endothermic peaks at 112.83℃, 198.17℃, and 204.17℃, while the TGA spectrum shows a weight loss of 4.54% between 30℃ and 110℃. Ion detection results show a bromide ion content of 8.2%.

[0908] Table 31

[0909] 2.15 Preparation of hydrobromide crystal form D

[0910] A. 10 mg of the free base from Example 7 was added to 0.15 mL of 2-methyltetrahydrofuran and 17.5 μL of 2M hydrobromic acid ethanol solution. The mixture was stirred until dissolved, and 0.5 mL of isopropyl ether was added. The mixture was stirred at 5 °C to crystallize. After centrifugation, the solid was dried under vacuum at 40 °C. The XRPD analysis of the obtained solid showed that it was hydrobromide crystal form D.

[0911] B. 10 mg of the free base from Example 7 was added to 0.15 mL of cyclohexane and 9.1 μL of 2 M hydrobromic acid ethanol solution, stirred overnight at room temperature, centrifuged, and the solid was dried under vacuum at 40 °C. The XRPD analysis of the obtained solid showed that it was hydrobromide crystal form D.

[0912] The XRPD spectrum of hydrobromide crystal form D is shown in Figure 27, and its characteristic peak positions are shown in Table 32. The TGA-DSC spectrum of hydrobromide crystal form D is shown in Figure 28. The DSC spectrum shows endothermic peaks at 58.65℃ and 141.49℃, while the TGA spectrum shows a weight loss of 4.36% from 33℃ to 89℃. Ion detection results show a bromide ion content of 21.0%.

[0913] Table 32

[0914] 2.16 Preparation of Benzoate Crystal Form A

[0915] 10 mg of the free base from Example 7 was added to 0.15 mL of cyclohexane and 9.1 μL of 2M benzoic acid ethanol solution. The mixture was stirred at room temperature, centrifuged, and the solid was dried under vacuum at 40 °C. XRPD analysis revealed that the solid was benzoate crystal form A. The XRPD spectrum of benzoate crystal form A is shown in Figure 29, and its characteristic peak positions are shown in Table 33. The TGA-DSC of benzoate crystal form A is shown in Figure 30. The DSC spectrum shows endothermic peaks at 115.15 °C and 154.48 °C, and the TGA spectrum shows a weight loss of 12.90% from 30 °C to 180 °C. NMR results showed an API:benzoic acid ratio of approximately 1:0.5.

[0916] Table 33

[0917] 2.17 Preparation of Benzoate Crystal Form B

[0918] 30 mg of the free base from Example 7 was dissolved in 0.3 mL of ethyl acetate, and 27.3 μL of 2M benzoic acid ethanol solution and 0.9 mL of isopropyl ether were added. The mixture was stirred at 40 °C to induce crystallization, then cooled to 5 °C and stirred overnight. After centrifugation, the solid was dried under vacuum at 40 °C. XRPD analysis revealed that the solid was benzoate crystal form B. The XRPD spectrum of benzoate crystal form B is shown in Figure 31, and its characteristic peak positions are shown in Table 34. The TGA-DSC spectrum of benzoate crystal form B is shown in Figure 32. The DSC spectrum shows an endothermic peak at 152.99 °C, and the TGA spectrum shows a weight loss of 0.84% ​​from 30 °C to 110 °C. Ion detection results showed that the benzoate ion content was 16.7%.

[0919] Table 34

[0920] 2.18 Preparation of fumarate crystal form A

[0921] A. 30 mg of the free base from Example 7 was dissolved in 0.45 mL of acetone, and 6.3 mg of fumaric acid solid was added. The mixture was stirred at room temperature to crystallize, centrifuged, and the solid was dried under vacuum at 40 °C. XRPD analysis showed that the solid obtained was fumarate crystal form A.

[0922] B. Dissolve 10 mg of the free base from Example 7 in 0.15 mL of acetone, add 2.1 mg of fumaric acid solid and 0.5 mL of isopropyl ether, stir at room temperature to crystallize, centrifuge, and dry the solid under vacuum at 40 °C. The obtained solid was XRPD tested and found to be fumarate crystal form A.

[0923] The characteristic peak positions of the XRPD spectrum of fumarate crystal form A are shown in Table 35. The TGA-DSC spectrum of fumarate crystal form A is shown in Figure 33. The DSC spectrum shows an endothermic peak at 118.17℃, and the TGA spectrum shows a weight loss of 4.61% from 30℃ to 110℃. Ionic results show that the fumarate ion content is 17.1%.

[0924] Table 35

[0925] 2.19 Preparation of Fumarate Crystal Form B

[0926] 30 mg of the free base from Example 7 was dissolved in 0.45 mL of acetonitrile, and 6.3 mg of solid fumarate was added. The mixture was suspended overnight at room temperature, centrifuged, and the solid was vacuum-dried at 40 °C overnight. XRPD analysis revealed that the solid was fumarate crystal form B. The characteristic peak positions of the XRPD spectrum of fumarate crystal form B are shown in Table 36. The TGA-DSC spectrum of fumarate crystal form B is shown in Figure 34. The DSC spectrum shows that the endothermic peaks are at 60.15 °C and 115.64 °C, and the TGA spectrum shows a weight loss of 2.60% from 30 °C to 110 °C. Ion detection results showed that the fumarate ion content was 15.0%.

[0927] Table 36

[0928] 2.20 Preparation of fumarate crystal form C

[0929] A. 10 mg of the free base from Example 7 was added to 0.15 mL of 2-methyltetrahydrofuran and 4.2 mg of fumaric acid solid. The mixture was stirred until dissolved, and 0.5 mL of isopropyl ether was added. The mixture was stirred at room temperature to crystallize, centrifuged, and the solid was dried under vacuum at 40 °C. XRPD analysis showed that the solid obtained was fumarate crystal form C.

[0930] B. Add 30 mg of the free base from Example 7 to 0.45 mL of 2-methyltetrahydrofuran, 12 mg of fumaric acid solid, and fumarate crystal form C seed crystals. Stir at room temperature to crystallize, centrifuge, and vacuum dry the solid at 40 °C. The obtained solid was XRPD detected as fumarate crystal form C.

[0931] The characteristic peak positions of the XRPD spectrum of fumarate crystal form C are shown in Table 37. The TGA-DSC spectrum of fumarate crystal form C is shown in Figure 35. The DSC spectrum shows an endothermic peak at 91.79℃, and the TGA spectrum shows a weight loss of 1.20% from 33℃ to 71℃ and a weight loss of 6.32% from 77℃ to 146℃. Ion detection results show that the fumarate ion content is 11.7%.

[0932] Table 37

[0933] 2.21 Preparation of maleate crystal form A

[0934] 8 mg of the free base from Example 7 was dissolved in 0.16 mL of 7% water / ethanol (v / v), and 10.5 μL of 2M maleic acid ethanol solution was added. The mixture was stirred at room temperature to induce crystallization, and then centrifuged. The resulting solid XRPD was detected to be maleate crystal form A.

[0935] The characteristic peak positions of the XRPD spectrum of maleate crystal form A are shown in Table 38. The TGA-DSC spectrum of maleate crystal form A is shown in Figure 36. The DSC spectrum shows an endothermic peak at 116.24℃, and the TGA spectrum shows a weight loss of 1.91% from 30℃ to 100℃. Ion detection results show that the maleate ion content is 16.9%.

[0936] Table 38

[0937] 2.22 Preparation of Methanesulfonate Crystal Form B

[0938] 10 mg of the free base from Example 7 was added to 0.15 mL of acetonitrile and 18.2 μL of 2M methanesulfonic acid ethanol solution. The mixture was stirred until dissolved, and then 0.5 mL of isopropyl ether was added. Crystallization was carried out at room temperature, followed by centrifugation. The solid was dried under vacuum at 40 °C. XRPD analysis revealed that the solid was methanesulfonate crystal form B. The characteristic peak positions of the XRPD spectrum of methanesulfonate crystal form B are shown in Table 39. The TGA-DSC spectrum of methanesulfonate crystal form B is shown in Figure 37. The DSC spectrum shows an endothermic peak at 123.73 °C, and the TGA spectrum shows a weight loss of 3.61% from 30 °C to 98 °C.

[0939] Table 39

[0940] 2.23 Preparation of Methanesulfonate Crystal Form A

[0941] 10 mg of the free base from Example 7 was added to 0.15 mL of acetonitrile and 9.1 μL of 2M methanesulfonic acid ethanol solution, stirred until dissolved, and then 0.5 mL of isopropyl ether was added. Crystallization was carried out at room temperature with stirring, centrifugation was performed, and the solid was dried under vacuum at 40 °C. XRPD analysis revealed that the obtained solid was methanesulfonate crystal form A. The TGA-DSC spectrum of methanesulfonate crystal form A is shown in Figure 38. The DSC spectrum shows endothermic peaks at 75.46 °C and 149.30 °C, and the TGA spectrum shows a weight loss of 4.40% from 31 °C to 114 °C.

[0942] 2.24 Preparation of Phosphate Crystal Form A

[0943] 10 mg of the free base from Example 7 was added to 0.15 mL of ethyl acetate and 9.1 μL of 2M phosphate ethanol solution. The mixture was stirred until dissolved, and then 0.5 mL of isopropyl ether was added. The mixture was stirred at room temperature to induce crystallization. After centrifugation, the solid was dried under vacuum at 40 °C. XRPD analysis revealed that the solid was phosphate crystal form A. The TGA-DSC spectrum of phosphate crystal form A is shown in Figure 39. The DSC spectrum shows endothermic peaks at 62.64 °C and 157.47 °C, while the TGA spectrum shows a weight loss of 2.99% from 32 °C to 104 °C.

[0944] 3. Preparation of different amorphous salts of the compound in Example 3

[0945] 3.1 Amorphous preparation of hydrochloride

[0946] Weigh 301 mg of the free base from Example 3, add 3 mL of acetone to dissolve and clarify, add 51 μL of concentrated hydrochloric acid (reaction molar ratio 1:1.2) to react and clarify, dry in a forced-air oven at 60 °C overnight to obtain a solid, which was identified as 287 mg of amorphous hydrochloride by X-ray powder diffraction.

[0947] 3.2 Preparation of amorphous sulfate

[0948] Weigh 10 mg of the free base from Example 3, add 100 μL of ethyl acetate and 18.7 μL of sulfuric acid methanol solution (1 mol / L), clarify, evaporate to dryness, add another 100 μL of ethyl acetate, clarify, add 400 μL of methyl tert-butyl ether, stir at room temperature for 7 days, centrifuge, remove the supernatant, dry the obtained solid under vacuum at 40 °C for 16 hours, and X-ray powder diffraction analysis shows that it is an amorphous sulfate.

[0949] 3.3 Preparation of amorphous phosphate

[0950] Weigh 300 mg of the free base from Example 3, add 3 mL of ethyl acetate and 38.4 μL of concentrated phosphoric acid, precipitate a solid, slurry at room temperature for 16 hours, filter, and vacuum dry the solid at 40 °C for 16 hours. X-ray powder diffraction analysis showed that it was 278 mg of amorphous phosphate.

[0951] 3.4 Preparation of amorphous maleic acid:

[0952] Weigh 20 mg of the free base from Example 3 and 4.35 mg of maleic acid, add 200 μL of methanol, stir and clarify, add 400 μL of isopropyl ether, precipitate solid, suspend and slurry for 7 days, centrifuge, and vacuum dry the solid at 40°C for 16 h. X-ray powder diffraction analysis shows that it is an amorphous maleate salt.

[0953] 4. Preparation of different acid salt crystal forms of the compound in Example 3

[0954] 4.1 Preparation of hydrochloride crystal form A

[0955] Weigh 10 mg of amorphous hydrochloride, add 100 μL of isopropanol or tert-butanol, and stir magnetically at 50 °C for 48 hours. Centrifuge, and dry the resulting solid with N2. XRPD analysis shows that it is hydrochloride crystal form A.

[0956] The X-ray powder diffraction pattern of hydrochloride crystal form A is shown in Figure 40, and the positions of its characteristic peaks are shown in Table 40. The DSC pattern of hydrochloride crystal form A is shown in Figure 41.

[0957] Table 40

[0958] 4.2 Preparation of hydrochloride crystal form B

[0959] Weigh 23326.67 mg of the free base from Example 3, add 230 mL of 10% acetonitrile aqueous solution, add 3.91 mL of concentrated hydrochloric acid at 80°C, and after 30 min, the solid gradually increases. Pulp at 50°C for 72 h, filter, and dry in a forced-air environment at 60°C for 4 h to obtain 22776.12 g of solid, which was identified by XRPD as hydrochloride crystal form B.

[0960] The X-ray powder diffraction pattern of hydrochloride crystal form B is shown in Figure 42, and the positions of its characteristic peaks are shown in Table 41. The TGA-DSC pattern of hydrochloride crystal form B is shown in Figure 43.

[0961] Table 41

[0962] 4.3 Preparation of hydrochloride crystal form C

[0963] Weigh 20 mg of the free base from Example 3, add 200 μL of 10% ethanol aqueous solution or 10% acetone aqueous solution, add 45.6 μL of hydrochloric acid aqueous solution (1 mol / L), and place at 50 °C with magnetic stirring for 48 hours. Centrifuge, and dry the resulting solid under vacuum at 40 °C for 16 hours. XRPD analysis shows that it is hydrochloride crystal form C.

[0964] The X-ray powder diffraction pattern of hydrochloride crystal form C is shown in Figure 44, and the positions of its characteristic peaks are shown in Table 42. The TGA-DSC pattern of hydrochloride crystal form C is shown in Figure 45.

[0965] Table 42

[0966] 4.4 Preparation of hydrochloride crystal form D

[0967] Weigh 20 mg of the free base from Example 3, add 200 μL of 5% methanol aqueous solution, add 45.6 μL of hydrochloric acid aqueous solution (1 mol / L), and place at 50 °C with magnetic stirring for 48 hours. Centrifuge, and dry the resulting solid under vacuum at 40 °C for 16 hours. XRPD analysis shows that it is hydrochloride crystal form D.

[0968] The characteristic peak positions of hydrochloride crystal form D are shown in Table 43. The TGA-DSC spectrum of hydrochloride crystal form D is shown in Figure 46.

[0969] Table 43

[0970] 4.5 Preparation of hydrochloride crystal form E

[0971] Weigh 100 mg of the free base from Example 3, add 1 mL of 10% ethanol aqueous solution, add 17 μL of concentrated hydrochloric acid at 80°C, cool to room temperature and slurry for 16 hours, filter, and vacuum dry the solid at 40°C for 16 hours. XRPD analysis showed that it was hydrochloride crystal form E.

[0972] The X-ray powder diffraction of hydrochloride crystal form E is shown in Figure 47, and the positions of its characteristic peaks are shown in Table 44.

[0973] Table 44

[0974] 4.6 Preparation of Sulfate Crystal Form A: 200 mg of the free base from Example 3 was weighed, and 1 mL of acetone and 374 μL of sulfuric acid aqueous solution (1 mol / L) were added. After stirring for 30 minutes, 2 mL of water was added, and a white solid precipitated. Another 4 mL of water was added, and the mixture was stirred for 16 hours. The mixture was then filtered, and the resulting solid was dried under vacuum at 40 °C for 16 hours. XRPD analysis confirmed it to be sulfate crystal form A. The X-ray powder diffraction pattern of sulfate crystal form A is shown in Figure 48, and its characteristic peak positions are shown in Table 45. The TGA-DSC pattern of sulfate crystal form A is shown in Figure 49.

[0975] Table 45

[0976] 4.7 Preparation of sulfate crystal form B: Weigh an appropriate amount of sulfate crystal form A, and carry out the hygroscopicity test according to the following procedure. After the experiment, the solid obtained by XRPD detection is sulfate crystal form B.

[0977] The X-ray powder diffraction of sulfate crystal form B is shown in Figure 50, and the positions of its characteristic peaks are shown in Table 46.

[0978] Table 46

[0979] 4.8 Preparation of maleate crystal form A: 200 mg of the free base from Example 3 was weighed, and 2 mL of acetone and 53.03 mg of maleic acid were added to obtain a clear solution. 8 mL of isopropyl ether was added to the solution, and the mixture was stirred overnight. After filtration, the resulting solid was dried under vacuum at 40 °C for 16 hours. XRPD analysis confirmed that it was maleate crystal form A. The X-ray powder diffraction pattern of maleate crystal form A is shown in Figure 51, and the positions of its characteristic peaks are shown in Table 47.

[0980] Table 47

[0981] 4.9 Preparation of benzenesulfonate crystal form A: Weigh 10 mg of the free base from Example 3, add 100 μL of 88% acetone, dissolve and clarify at room temperature, add 18.7 μL of 1M benzenesulfonic acid aqueous solution, clarify, and evaporate to dryness at room temperature. Add 100 μL of ethyl acetate to the evaporated sample, suspend and slurry at room temperature for 3 days, centrifuge, remove the supernatant, and dry the resulting solid under vacuum at 40 °C for 16 hours. XRPD analysis confirms it as benzenesulfonate crystal form A. The X-ray powder diffraction pattern of benzenesulfonate crystal form A is shown in Figure 52, and its characteristic peak positions are shown in Table 48. The TGA-DSC pattern of benzenesulfonate crystal form A is shown in Figure 53.

[0982] Table 48

[0983] 4.10 Preparation of Phosphate Crystal Form A: Weigh 100 mg of the free base from Example 3, add 100 μL of methanol, stir until clear, add 12.8 μL of concentrated phosphoric acid, let it clarify, slowly add 400 μL of methyl tert-butyl ether, precipitate turbidity, stir for 48 hours, and observe that it is crystallized by PLM. Filter, and dry the obtained solid under vacuum at 40 °C for 4 hours. XRPD detection shows that it is phosphate crystal form A. The characteristic peak positions of phosphate crystal form A are shown in Table 49.

[0984] Table 49

[0985] 4.11 Preparation of Phosphate Crystal Form B: 101.45 mg of the free base from Example 3 was weighed, added to 100 μL of ethanol, stirred until clear, then 12.8 μL of concentrated phosphoric acid was added, and the mixture was clarified. 400 μL of water was slowly added, resulting in precipitation of turbidity. After stirring for 48 hours, PLM observation showed crystals. The solid was filtered, and dried under vacuum at 40 °C for 4 hours. XRPD analysis confirmed it to be phosphate crystal form B. The X-ray powder diffraction pattern of phosphate crystal form B is shown in Figure 54, and its characteristic peak positions are shown in Table 50. The TGA-DSC pattern of phosphate crystal form B is shown in Figure 55.

[0986] Table 50

[0987] 5. Example 7: Determination of the hygroscopicity of the acid salt crystal form of the compound.

[0988] 5.1 Experimental Objective: To investigate the hygroscopicity of different salts of compounds under different relative humidity conditions, and to provide a basis for the screening and storage of compound salts.

[0989] 5.2 Experimental Procedure:

[0990] Dynamic moisture adsorption: The detection was performed using SMSDVS Advantage at 25℃, with humidity changes of 50%-95%-0%-95%-50% in 10% increments (5% in the final step). The judgment criteria were Tmax 360min and dm / dt not exceeding 0.002%.

[0991] 5.3 Experimental Results:

[0992] 1) DVS testing showed that p-toluenesulfonate crystal form A had a moisture absorption weight gain of about 3.2% under normal storage conditions (i.e., 25°C, 60% RH); under accelerated experimental conditions (i.e., 70% RH), the moisture absorption weight gain was about 3.7%; under extreme conditions (90% RH), the moisture absorption weight gain was about 5.1%; after DVS testing, the crystal form was retested and no change was observed.

[0993] 2) DVS testing showed that p-toluenesulfonate crystal form C gained 1.883% weight by hygroscopic absorption under RH 80% conditions, indicating slight hygroscopicity. After two cycles of hygroscopic absorption and desorption under 0-95% relative humidity conditions, the XRPD spectrum of p-toluenesulfonate crystal form C did not change, meaning the crystal form did not change.

[0994] 3) DVS testing showed that p-toluenesulfonate crystal form E had a moisture absorption weight gain of approximately 2.0% under normal storage conditions (i.e., 25°C, 60% RH); under accelerated testing conditions (i.e., 70% RH), the moisture absorption weight gain was approximately 2.2%; under extreme conditions (90% RH), the moisture absorption weight gain was approximately 2.4%; after DVS testing, the crystal form was retested and no change was observed.

[0995] 4) DVS testing showed that under normal storage conditions (i.e., 25°C, 60% RH), the hydrochloride crystal form A had a moisture absorption weight gain of about 1.5%; under accelerated experimental conditions (i.e., 70% RH), the moisture absorption weight gain was about 1.9%; under extreme conditions (90% RH), the moisture absorption weight gain was about 4.1%; after DVS testing, the crystal form was retested and no change was observed.

[0996] 5) DVS testing showed that under normal storage conditions (i.e., 25°C, 60% RH), the hydrochloride crystal form B had a moisture absorption weight gain of about 0.4%; under accelerated experimental conditions (i.e., 70% RH), the moisture absorption weight gain was about 0.5%; under extreme conditions (90% RH), the moisture absorption weight gain was about 0.8%; after DVS testing, the crystal form was retested and no change was observed.

[0997] 6) DVS testing showed that hydrobromide crystal form A had a moisture absorption weight gain of about 0.6% under normal storage conditions (i.e., 25℃, 60%RH); under accelerated experimental conditions (i.e., 70%RH), the moisture absorption weight gain was about 0.6%; under extreme conditions (90%RH), the moisture absorption weight gain was about 0.9%; after DVS testing, the crystal form was retested and remained unchanged.

[0998] 7) DVS testing showed that under normal storage conditions (i.e., 25℃, 60%RH), the weight gain of hydrobromide crystal form C was about 0.5% due to moisture absorption; under accelerated experimental conditions (i.e., 70%RH), the weight gain was about 0.6% due to moisture absorption; under extreme conditions (90%RH), the weight gain was about 1.0% due to moisture absorption; after DVS testing, the crystal form was retested and remained unchanged.

[0999] 8) DVS testing showed that benzoate crystal form B had a moisture absorption weight gain of about 0.4% under normal storage conditions (i.e., 25℃, 60%RH); under accelerated testing conditions (i.e., 70%RH), the moisture absorption weight gain was about 0.5%; under extreme conditions (90%RH), the moisture absorption weight gain was about 0.8%; after DVS testing, the crystal form was retested and no change was observed.

[1000] 6. Study on the stability of the acid salt crystal form of the compound in Example 7

[1001] 6.1 Influencing Factors

[1002] Hydrochloride crystal form A, hydrochloride crystal form B, hydrobromide crystal form A, hydrobromide crystal form C, p-toluenesulfonate C, and p-toluenesulfonate E were laid out in an open container to investigate their stability under high temperature (40℃ and 60℃), high humidity (RH 75% and RH 92.5%), and light (4500 lux) conditions. The sampling period was 30 days (chromatographic conditions 1.2.3).

[1003] Table 51

[1004] Conclusion: The influencing factor experiment showed that hydrochloride crystal form B, hydrobromide crystal form A, hydrobromide crystal form C, p-toluenesulfonate crystal form C, and p-toluenesulfonate crystal form E exhibited good physical and chemical stability for 30 days under the influencing factors of high temperature (40℃, 60℃), high humidity (75%RH, 92.5%RH), and light exposure. Hydrochloride crystal form A showed good physical stability for 30 days under high temperature (40℃, 60℃) conditions, but its chemical purity decreased. Under high humidity (75%RH, 92.5%RH) and light exposure conditions, it also exhibited good physical and chemical stability for 30 days.

[1005] 6.2 Long-term accelerated experiment

[1006] The stability of hydrochloride crystal form A, hydrochloride crystal form B, hydrobromide crystal form A, hydrobromide crystal form C, p-toluenesulfonate C, and p-toluenesulfonate E was investigated under conditions of 25℃ / 60%RH and 40℃ / 75%RH (chromatographic conditions 1.2.3).

[1007] Table 52

[1008] Conclusion: Long-term accelerated experiments showed that hydrobromide crystal form A, hydrobromide crystal form C, hydrochloride crystal form A, hydrochloride crystal form B, and p-toluenesulfonate crystal form C were physically and chemically stable for 2 months under conditions of 25℃ / 60%RH and 40℃ / 75%RH. p-Toluenesulfonate crystal form E was physically and chemically stable for 1 month under conditions of 25℃ / 60%RH and 40℃ / 75%RH.

[1009] 7. Example 3: Solid stability experiment of acid salt crystal form

[1010] 7.1 Experimental Objective: To investigate the physicochemical stability of hydrochloride crystal form B under high temperature (60℃), high humidity (room temperature / 92.5% RH) and high temperature and high humidity (50℃ / 75% RH) conditions, so as to provide a basis for the development and storage of compound salts.

[1011] 7.2 Experimental Procedure: Approximately 1 mg of hydrochloride crystal form B was weighed into 2 mL glass bottles and placed under the following conditions for 7 and 14 days: 60℃ (GW, closed), 50℃ / 75%RH (WS, open), and room temperature / 92.5%RH (GS, open). Samples were taken at different time points and analyzed by HPLC. The content was determined by external standard method, and the changes in salt-related substances were calculated by peak area normalization method (chromatographic conditions are shown in 1.2.4).

[1012] 8. Example 3 Hygroscopicity test of acid salt crystal form

[1013] 8.1 Experimental Objective: To investigate the hygroscopicity of the acid salt crystal form of the compound under different relative humidity conditions, so as to provide a basis for the screening and storage of compound salts.

[1014] 8.2 Experimental Procedure: The acid salt crystal form was placed in saturated water vapor at different relative humidities to allow the compound to reach dynamic equilibrium with the water vapor. The percentage of the compound's weight gain due to moisture absorption after equilibrium was calculated. The measurement was performed using SMS Intrinsic at 25℃ with humidity changes of 0%-95%-0%-95%-0% in 10% increments (5% for the final step). The judgment criteria were Tmax 180 min and dm / dt not exceeding 0.02%.

[1015] 8.3 Experimental Results: Hydrochloride crystal form B did not show any increase in weight due to moisture absorption under RH 80% conditions. After two cycles of moisture absorption and desorption under 0-95% relative humidity conditions, the XRPD spectrum of hydrochloride crystal form B did not change, indicating that the crystal form did not change.

[1016] 9. Rats pharmacokinetic study of different acid salt crystal forms of the compound in Example 7

[1017] 9.1 Experimental Objective: Using SD rats as test animals, this study investigates the pharmacokinetic behavior of compound A hydrochloride, C p-toluenesulfonate, and E p-toluenesulfonate in rats after a single oral administration (in plasma), and compares the changes in exposure levels.

[1018] 9.2 Experimental protocol: Hydrochloride crystal form A was suspended in 0.5% HPMC K4M solvent and administered by gavage to rats. Three parallel rats were used, and the dosage was 100 mg / kg.

[1019] p-Toluenesulfonate crystal form C was suspended in 0.5% HPMC K4M solvent and administered by gavage to rats. Three parallel rats were administered the drug at a dose of 100 mg / kg.

[1020] p-Toluenesulfonate crystal form E was suspended in 0.5% HPMC K4M solvent and administered by gavage to rats. Three parallel rats were administered the drug at a dose of 100 mg / kg.

[1021] 9.3 Experimental Results:

[1022] 9.4 Experimental Conclusion: As can be seen from the above data, the acid salt crystal form of the present invention has a good exposure level.

Claims

1. An acid salt of a compound of general formula (I) or its stereoisomer, or its crystal form. in: Ring B is selected from C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; Ring E is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl; M2 is selected from CH2 or NH; R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2- 6-acetylinyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; R 2-1-1 Each group is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, oxo, thio, =CF2, =CHF, =NOC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Heteroalkyl, C 1-6 Deuterated heteroalkyl, C 1-6 Halogenated heteroalkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Heteroalkyl, C 1-6 Deuterated heteroalkyl, C 1-6 Halogenated heteroalkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, oxo, thio, =CF2, =CHF, =NOC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Heteroalkyl, C 1-6 Deuterated heteroalkyl, C 1-6 Halogenated heteroalkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; R 4-1-1 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2- 6-olefin, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1- 6-hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups; R5 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1- 6-Deuterated Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1- 6-Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; x is 0, 1, 2, 3, 4 or 5; w is 0, 1, 2, 3, 4, 5, or 6; j can be 0, 1, 2, 3, 4 or 5; u can be 0, 1, 2, 3, 4 or 5; The acid is an inorganic acid or an organic acid, wherein the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, or phosphoric acid; and the organic acid is selected from 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphtholic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxyxamic acid, adipic 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, diphenyl Formicotartaric 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-toluenesulfonic acid, or L-malic acid, preferably hydrochloric acid, hydrobromic acid, or p-toluenesulfonic acid; more preferably p-toluenesulfonic acid.

2. The acid salt of the compound or its stereoisomer according to claim 1, or its crystal form, characterized in that, Ring B is selected from C 3-6 Cycloalkyl, phenyl, or 5-6-membered heteroaryl; or ring B is absent; preferably, ring B is selected from... Ring E is a 5-9 membered heterocyclic group, more preferably a 5-6 membered heterocyclic group; preferably, ring E is selected from... R 2-1-1 Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1- 3-hydroxyalkyl, C 1-3 Heteroalkyl, C 1-3 Halogenated heteroalkyl groups, preferably methyl, ethyl, methoxy, F, -CHF2, -CH2F, -CF3, -CH2CHF2, -CHF2CH3, -CH2CF3, -CH2OCH3, -CH2OCF3 or OCF3; R 4-1-1 Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy group; preferably methyl or F; R1 is independently selected from hydrogen, deuterium, halogens, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy group; preferably methyl or F.

3. The acid salt of the compound or its stereoisomer according to claim 1 or 2, or its crystal form, characterized in that, The compound is shown below:

4. The acid salt of the compound or its stereoisomer according to any one of claims 1 to 3, or its crystal form, characterized in that, The number of acids in the acid salt 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, and even more preferably 1.

5. The acid salt of the compound or its stereoisomer according to any one of claims 1 to 4, or its crystal form, characterized in that, The acid salt is a hydrate or anhydrous form; 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. The crystal form is either a hydrate crystal form or an anhydrous crystal form; when the 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, and more preferably 2.

6. The acid salt of the compound or its stereoisomer according to any one of claims 1 to 5, or its crystal form, characterized in that, It is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide p-toluenesulfonate crystal form A; The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form A shows a diffraction peak at 2θ of 4.3 ± 0.2°; or at 5.8 ± 0.2°; or at 6.8 ± 0.2°; or at 8.1 ± 0.2°; or at 11.6 ± 0.2°; or at 12.3 ± 0.2°; or at 16.4 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 17.3±0.2°; or has diffraction peaks at 18.1±0.2°; or has diffraction peaks at 20.5±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them; Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide p-toluenesulfonate crystal form B; The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form B shows a diffraction peak at 2θ of 4.2 ± 0.2°; or at 6.1 ± 0.2°; or at 7.1 ± 0.2°; or at 8.4 ± 0.2°; or at 15.7 ± 0.2°; or at 16.6 ± 0.2°; or at 18.5 ± 0.2°; or at 19.1°. The diffraction peak is present at ±0.2°; or at 19.8±0.2°; or at 22.4±0.2°; or at 22.6±0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-11 of the above diffraction peaks are included; more preferably, any 6, 7, 8, 9, 10, or 11 of the above diffraction peaks are included. Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide p-toluenesulfonate crystal form C; The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form C has a diffraction peak at 2θ of 4.8 ± 0.2°; or at 7.3 ± 0.2°; or at 9.5 ± 0.2°; or at 14.3 ± 0.2°; or at 15.3 ± 0.2°; or at 16.2 ± 0.2°; or at 17.4 ± 0.2°; or at 22.2 ± 0.2°; or at 22.7 ± 0.2°; preferably, it includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-9 of the above diffraction peaks; more preferably, it includes any 6, 7, 8, or 9 of them; Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide p-toluenesulfonate crystal form D; The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form D shows a diffraction peak at 2θ of 7.1 ± 0.2°; or at 12.3 ± 0.2°; or at 14.6 ± 0.2°; or at 15.2 ± 0.2°; or at 17.2 ± 0.2°; or at 17.7 ± 0.2°; or at 19.7 ± 0.2°. It has a diffraction peak; or a diffraction peak at 20.8±0.2°; or a diffraction peak at 20.9±0.2°; or a diffraction peak at 22.4±0.2°; preferably, it includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably, it includes any 6, 7, 8, 9, or 10 of them; Alternatively, it is N-((S)-2-((5-((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide p-toluenesulfonate crystal form E; The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form E shows a diffraction peak at 2θ of 10.5 ± 0.2°; or at 11.0 ± 0.2°; or at 15.3 ± 0.2°; or at 17.5 ± 0.2°; or at 18.7 ± 0.2°; or at 20.3 ± 0.2°; or at 21.1 ± 0.2°. The diffraction peak is present at: 22.0 ± 0.2°; or at 24.2 ± 0.2°; or at 30.8 ± 0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks are included; more preferably, any 6, 7, 8, 9, or 10 of the above diffraction peaks are included. Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide p-toluenesulfonate crystal form F; The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form F shows a diffraction peak at 2θ of 4.8 ± 0.2°; or at 7.4 ± 0.2°; or at 7.6 ± 0.2°; or at 10.8 ± 0.2°; or at 12.4 ± 0.2°; or at 14.1 ± 0.2°; or at 14.6 ± 0.2°; or at 17. The diffraction peak is present at 5±0.2°; or at 19.7±0.2°; or at 20.8±0.2°; or at 22.2±0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-11 of the above diffraction peaks are included; more preferably, any 6, 7, 8, 9, 10, or 11 of the above diffraction peaks are included. Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide p-toluenesulfonate crystal form G; The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form G shows a diffraction peak at 2θ of 6.9 ± 0.2°; or at 7.0 ± 0.2°; or at 10.8 ± 0.2°; or at 14.7 ± 0.2°; or at 17.8 ± 0.2°; or at 19.3 ± 0.2°; or at 19.7 ± 0.2°. It has diffraction peaks; or diffraction peaks at 20.9±0.2°; or diffraction peaks at 28.0±0.2°; or diffraction peaks at 32.1±0.2°; preferably, it includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably, it includes any 6, 7, 8, 9, or 10 of them; Alternatively, it is N-((S)-2-((5-((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide p-toluenesulfonate crystal form H; The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form H shows a diffraction peak at 2θ of 6.8 ± 0.2°; or at 10.5 ± 0.2°; or at 11.6 ± 0.2°; or at 12.1 ± 0.2°; or at 14.4 ± 0.2°; or at 15.0 ± 0.2°; or at 17.1 ± 0.2°. It has diffraction peaks; or diffraction peaks at 19.5±0.2°; or diffraction peaks at 20.6±0.2°; or diffraction peaks at 22.2±0.2°; preferably, it includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably, it includes any 6, 7, 8, 9, or 10 of them; Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide hydrochloride crystal form A; The X-ray powder diffraction pattern of the hydrochloride crystal form A shows a diffraction peak at 2θ of 6.8 ± 0.2°; or at 7.3 ± 0.2°; or at 10.5 ± 0.2°; or at 12.2 ± 0.2°; or at 15.6 ± 0.2°; or at 16.3 ± 0.2°; or at 16.7 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 17.1±0.2°; or has diffraction peaks at 19.9±0.2°; or has diffraction peaks at 20.2±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them; Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide hydrochloride crystal form B; The X-ray powder diffraction pattern of the hydrochloride crystal form B shows a diffraction peak at 2θ of 5.0 ± 0.2°; or at 7.3 ± 0.2°; or at 8.6 ± 0.2°; or at 10.0 ± 0.2°; or at 10.4 ± 0.2°; or at 14.2 ± 0.2°; or at 16.1 ± 0.2°. The diffraction peaks are present; or diffraction peaks are present at 18.0±0.2°; or diffraction peaks are present at 19.7±0.2°; or diffraction peaks are present at 22.3±0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks are included; more preferably, any 6, 7, 8, 9, or 10 of the above diffraction peaks are included. Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide hydrochloride crystal form C; The X-ray powder diffraction pattern of the hydrochloride crystal form C has a diffraction peak at 2θ of 5.4±0.2°; or at 6.9±0.2°; or at 9.4±0.2°; or at 10.4±0.2°; or at 11.1±0.2°; or at 12.6±0.2°; or at 14.3±0.2°; or at 16.0±0.2°; or at 19.7±0.2°; preferably, it includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-9 of the above diffraction peaks; more preferably, it includes any 6, 7, 8, or 9 of them; Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide hydrobromide crystal form A; The X-ray powder diffraction pattern of the hydrobromide crystal form A exhibits a diffraction peak at 2θ of 6.5 ± 0.2°; or at 7.0 ± 0.2°; or at 11.3 ± 0.2°; or at 12.0 ± 0.2°; or at 15.2 ± 0.2°; or at 16.3 ± 0.2°; or at 20.1 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 21.0±0.2°; or has diffraction peaks at 21.5±0.2°; or has diffraction peaks at 30.3±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them; Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide hydrobromide crystal form B; The X-ray powder diffraction pattern of the hydrobromide crystal form B shows a diffraction peak at 2θ of 6.3 ± 0.2°; or at 7.4 ± 0.2°; or at 9.9 ± 0.2°; or at 10.4 ± 0.2°; or at 12.7 ± 0.2°; or at 17.1 ± 0.2°; or at 19.1 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 20.6±0.2°; or has diffraction peaks at 22.3±0.2°; or has diffraction peaks at 24.3±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them; Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide hydrobromide crystal form C; The X-ray powder diffraction pattern of the hydrobromide crystal form C exhibits diffraction peaks at 2θ of 8.8 ± 0.2°; or at 9.9 ± 0.2°; or at 10.4 ± 0.2°; or at 12.9 ± 0.2°; or at 16.1 ± 0.2°; or at 16.7 ± 0.2°; or at 19.7 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 20.7±0.2°; or has diffraction peaks at 22.3±0.2°; or has diffraction peaks at 23.6±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them; Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide hydrobromide crystal form D; The X-ray powder diffraction pattern of the hydrobromide crystal form D shows a diffraction peak at 2θ of 10.5 ± 0.2°; or at 12.4 ± 0.2°; or at 15.3 ± 0.2°; or at 16.9 ± 0.2°; or at 17.6 ± 0.2°; or at 19.1 ± 0.2°; or at 20.0 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 20.8±0.2°; or has diffraction peaks at 22.6±0.2°; or has diffraction peaks at 24.6±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them; Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide benzoate crystal form A; The X-ray powder diffraction pattern of the benzoate crystal form A exhibits a diffraction peak at 2θ of 5.1 ± 0.2°; or at 8.7 ± 0.2°; or at 9.0 ± 0.2°; or at 13.1 ± 0.2°; or at 16.6 ± 0.2°; or at 17.5 ± 0.2°; or at 19.5 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 20.9±0.2°; or has diffraction peaks at 21.5±0.2°; or has diffraction peaks at 24.6±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them; Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide benzoate crystal form B; The X-ray powder diffraction pattern of the benzoate crystal form B exhibits a diffraction peak at 2θ of 6.6 ± 0.2°; or at 7.0 ± 0.2°; or at 7.5 ± 0.2°; or at 10.0 ± 0.2°; or at 10.5 ± 0.2°; or at 13.5 ± 0.2°; or at 15.4 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 17.0±0.2°; or has diffraction peaks at 18.2±0.2°; or has diffraction peaks at 19.7±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them; Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide fumarate crystal form A; The X-ray powder diffraction pattern of the fumarate crystal form A exhibits a diffraction peak at 2θ of 5.2 ± 0.2°; or at 7.0 ± 0.2°; or at 8.9 ± 0.2°; or at 11.3 ± 0.2°; or at 13.2 ± 0.2°; or at 13.7 ± 0.2°; or at 15.6 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 18.4±0.2°; or has diffraction peaks at 22.4±0.2°; or has diffraction peaks at 23.2±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them; Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide fumarate crystal form B; The X-ray powder diffraction pattern of the fumarate crystal form B has a diffraction peak at 2θ of 5.2 ± 0.2°; or at 6.8 ± 0.2°; or at 7.5 ± 0.2°; or at 9.3 ± 0.2°; or at 11.1 ± 0.2°; or at 15.0 ± 0.2°; or at 15.6 ± 0.2°; or at 16.4 ± 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. Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide fumarate crystal form C; The X-ray powder diffraction pattern of the fumarate crystal form C exhibits diffraction peaks at 2θ of 5.2 ± 0.2°; or at 7.5 ± 0.2°; or at 8.6 ± 0.2°; or at 10.5 ± 0.2°; or at 13.3 ± 0.2°; or at 14.0 ± 0.2°; or at 15.8 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 18.4±0.2°; or has diffraction peaks at 20.2±0.2°; or has diffraction peaks at 23.2±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them; Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide maleate crystal form A; The X-ray powder diffraction pattern of the maleate crystal form A shows a diffraction peak at 2θ of 5.9 ± 0.2°; or at 6.8 ± 0.2°; or at 7.5 ± 0.2°; or at 8.4 ± 0.2°; or at 12.7 ± 0.2°; or at 14.6 ± 0.2°; or at 15.6 ± 0.2°; or at 17.8 ± 0.2°. The diffraction peak is present at ±0.2°; or at 20.0±0.2°; or at 20.6±0.2°; or at 22.1±0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-11 of the above diffraction peaks are included; more preferably, any 6, 7, 8, 9, 10, or 11 of the above diffraction peaks are included. Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide methanesulfonate crystal form B; The X-ray powder diffraction pattern of the methanesulfonate crystal form B has a diffraction peak at 2θ of 5.8±0.2°; or at 7.1±0.2°; or at 12.5±0.2°; or at 13.5±0.2°; or at 16.7±0.2°; or at 18.9±0.2°; or at 20.7±0.2°; or at 23.7±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.

7. The acid salt of the compound or its stereoisomer according to claim 6, or its crystal form, characterized in that, The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form A includes at least one or more diffraction peaks located at 2θ of 5.8±0.2°, 6.8±0.2°, 8.1±0.2°, and 20.5±0.2°, preferably two, more preferably three or four; even more preferably, it may also include at least one of 2θ of 4.3±0.2°, 11.6±0.2°, 12.3±0.2°, 16.4±0.2°, 18.1±0.2°, and 17.3±0.2°, preferably two, three, four, five, or six. More preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form A includes one or more diffraction peaks located at 4.3±0.2°, 5.8±0.2°, 6.8±0.2°, 8.1±0.2°, 11.6±0.2°, 12.3±0.2°, 16.4±0.2°, 17.3±0.2°, 18.1±0.2°, and 20.5±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 8, or 10 locations. More preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form A may also include one or more diffraction peaks with 2θ values ​​of 15.3±0.2°, 15.7±0.2°, 19.2±0.2°, 22.2±0.2°, 23.4±0.2°, and 27.0±0.2°; preferably, it includes at least 2-3, 4-5, or 5-6 peaks; more preferably, it includes any 2, 3, 4, 5, or 6 peaks. For example, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form A has diffraction peaks at the following positions with a 2θ value: 5.8±0.2°、6.8±0.2°、8.1±0.2°、11.6±0.2°、17.3±0.2°、18.1±0.2°、20.5±0.2°； 4.3±0.2°、5.8±0.2°、6.8±0.2°、8.1±0.2°、11.6±0.2°、17.3±0.2°、18.1±0.2°、20.5±0.2°； 5.8±0.2°、6.8±0.2°、8.1±0.2°、11.6±0.2°、15.7±0.2°、17.3±0.2°、18.1±0.2°、20.5±0.2°； 5.8±0.2°、6.8±0.2°、8.1±0.2°、11.6±0.2°、17.3±0.2°、18.1±0.2°、19.2±0.2°、20.5±0.2°； 5.8±0.2°、6.8±0.2°、8.1±0.2°、11.6±0.2°、17.3±0.2°、18.1±0.2°、20.5±0.2°、23.4±0.2°； 5.8±0.2°、6.8±0.2°、8.1±0.2°、11.6±0.2°、17.3±0.2°、18.1±0.2°、20.5±0.2°、27.0±0.2°； 4.3±0.2°、5.8±0.2°、6.8±0.2°、8.1±0.2°、11.6±0.2°、15.7±0.2°、17.3±0.2°、18.1±0.2°、20.5±0.2°； 4.3±0.2°、5.8±0.2°、6.8±0.2°、8.1±0.2°、11.6±0.2°、15.7±0.2°、17.3±0.2°、18.1±0.2°、20.5±0.2°、23.4±0.2°； 4.3±0.2°、5.8±0.2°、6.8±0.2°、8.1±0.2°、11.6±0.2°、15.7±0.2°、17.3±0.2°、18.1±0.2°、20.5±0.2°、23.4±0.2°、27.0±0.2°； Most preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form A is basically as shown in Figure 1; the TGA-DSC pattern is shown in Figure 2; The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form B includes at least one or more diffraction peaks located at 2θ of 4.2±0.2°, 6.1±0.2°, 7.1±0.2°, 15.7±0.2°, 22.4±0.2°, and 22.6±0.2°, preferably two, more preferably three; and even more preferably, it may also include at least one of 2θ of 8.4±0.2°, 16.6±0.2°, 18.5±0.2°, 19.1±0.2°, and 19.8±0.2°, preferably two, three, four, or five. More preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form B includes one or more diffraction peaks located at 2θ of 4.2±0.2°, 6.1±0.2°, 7.1±0.2°, 8.4±0.2°, 15.7±0.2°, 16.6±0.2°, 18.5±0.2°, 19.1±0.2°, 19.8±0.2°, 22.4±0.2°, and 22.6±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 7, 8, 10, or 11 locations. For example, the X-ray powder diffraction pattern of p-toluenesulfonate crystal form B shows diffraction peaks at the following positions with a 2θ value: 4.2±0.2°、6.1±0.2°、7.1±0.2°、15.7±0.2°、22.4±0.2°、22.6±0.2°； 4.2±0.2°、6.1±0.2°、7.1±0.2°、8.4±0.2°、15.7±0.2°、22.4±0.2°、22.6±0.2°； 4.2±0.2°、6.1±0.2°、7.1±0.2°、8.4±0.2°、15.7±0.2°、16.6±0.2°、22.4±0.2°、22.6±0.2°； Most preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form B is basically as shown in Figure 3; the DSC pattern is shown in Figure 4; and the TGA pattern is shown in Figure 5. The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form C includes at least one or more diffraction peaks located at 2θ of 4.8±0.2°, 7.3±0.2°, 9.5±0.2°, and 22.2±0.2°, preferably two, more preferably three; and even more preferably, it may also include at least one of 2θ of 14.3±0.2°, 15.3±0.2°, 16.2±0.2°, 17.4±0.2°, and 22.7±0.2°, preferably two, three, four, or five. For example, the X-ray powder diffraction pattern of p-toluenesulfonate crystal form C shows diffraction peaks at the following positions with a 2θ value: 4.8±0.2°, 7.3±0.2°, 9.5±0.2°, 22.2±0.2°, 14.3±0.2°, 17.4±0.2° and 22.7±0.2°; 4.8±0.2°, 7.3±0.2°, 9.5±0.2°, 22.2±0.2°, 14.3±0.2°, 16.2±0.2°, 17.4±0.2° and 22.7±0.2°; 4.8±0.2°, 7.3±0.2°, 9.5±0.2°, 22.2±0.2°, 14.3±0.2°, 15.3±0.2°, 17.4±0.2° and 22.7±0.2°; Most preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form C is shown in Figure 6; the DSC pattern is shown in Figure 7; and the TGA pattern is shown in Figure 8. The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form D includes at least one or more diffraction peaks located at 2θ of 7.1±0.2°, 14.6±0.2°, 20.8±0.2°, and 20.9±0.2°, preferably two, more preferably three; and even more preferably, it may also include at least one of 2θ of 12.3±0.2°, 15.2±0.2°, 17.2±0.2°, 17.7±0.2°, 19.7±0.2°, and 22.4±0.2°, preferably two, three, four, five, or six. More preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form D includes one or more of the following 2θ values: 7.1±0.2°, 14.6±0.2°, 12.3±0.2°, 15.2±0.2°, 17.2±0.2°, 17.7±0.2°, 19.7±0.2°, 20.8±0.2°, 20.9±0.2°, and 22.4±0.2°. The diffraction peaks are located at 4, 5, 6, 7, 8, or 10 locations; more preferably, the diffraction peaks are located at at least one of the following 2θ values: 10.7±0.2°, 13.0±0.2°, 22.8±0.2°, 23.1±0.2°, 24.3±0.2°, or 28.0±0.2°, and more preferably at 2, 3, 4, 5, or 6 locations. For example, the X-ray powder diffraction pattern of p-toluenesulfonate crystal form D shows diffraction peaks at the following positions with a 2θ value: 7.1±0.2°、12.3±0.2°、14.6±0.2°、19.7±0.2°、20.8±0.2°、20.9±0.2°、22.4±0.2°； 7.1±0.2°、12.3±0.2°、14.6±0.2°、15.2±0.2°、19.7±0.2°、20.9±0.2°、22.4±0.2°； 7.1±0.2°、12.3±0.2°、14.6±0.2°、15.2±0.2°、19.7±0.2°、20.8±0.2°、20.9±0.2°、22.4±0.2°； 7.1±0.2°、10.7±0.2°、12.3±0.2°、14.6±0.2°、19.7±0.2°、20.8±0.2°、20.9±0.2°、22.4±0.2°； Most preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form D is basically as shown in Figure 9; The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form E includes at least one or more diffraction peaks located at 2θ of 11.0±0.2°, 18.7±0.2°, 21.1±0.2°, and 22.0±0.2°, preferably two, more preferably three; and even more preferably, it may also include at least one of 2θ of 10.5±0.2°, 15.3±0.2°, 17.5±0.2°, 20.3±0.2°, 24.2±0.2°, and 30.8±0.2°, preferably two, three, four, five, or six. More preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form E includes one or more of the following 2θ values: 10.5±0.2°, 11.0±0.2°, 15.3±0.2°, 17.5±0.2°, 18.7±0.2°, 20.3±0.2°, 21.1±0.2°, 22.0±0.2°, 24.2±0.2°, and 30.8±0.2°. The diffraction peaks are located at 4, 5, 6, 7, 8, or 10 locations; more preferably, the diffraction peaks are located at at least one of the following 2θ values: 10.6±0.2°, 12.7±0.2°, 13.2±0.2°, 15.0±0.2°, 18.1±0.2°, and 25.7±0.2°, preferably 2, 3, 4, 5, or 6 locations. For example, the X-ray powder diffraction pattern of p-toluenesulfonate crystal form E shows diffraction peaks at the following positions with a 2θ value: 10.5±0.2°、11.0±0.2°、18.7±0.2°、20.3±0.2°、21.1±0.2°、22.0±0.2°、24.2±0.2°； 11.0±0.2°、15.3±0.2°、17.5±0.2°、18.7±0.2°、20.3±0.2°、21.1±0.2°、22.0±0.2°； 10.5±0.2°、11.0±0.2°、18.7±0.2°、20.3±0.2°、21.1±0.2°、22.0±0.2°、30.8±0.2°； 10.5±0.2°、11.0±0.2°、17.5±0.2°、18.7±0.2°、20.3±0.2°、21.1±0.2°、22.0±0.2°； 11.0±0.2°、15.3±0.2°、18.7±0.2°、20.3±0.2°、21.1±0.2°、22.0±0.2°、30.8±0.2°； 10.5±0.2°、11.0±0.2°、18.1±0.2°、18.7±0.2°、21.1±0.2°、22.0±0.2°、30.8±0.2°； 10.5±0.2°、11.0±0.2°、15.0±0.2°、18.7±0.2°、21.1±0.2°、22.0±0.2°、30.8±0.2°； 10.5±0.2°、11.0±0.2°、15.3±0.2°、17.5±0.2°、18.7±0.2°、20.3±0.2°、21.1±0.2°、30.8±0.2°； 10.5±0.2°、11.0±0.2°、18.7±0.2°、20.3±0.2°、21.1±0.2°、22.0±0.2°、24.2±0.2°、30.8±0.2°； 10.5±0.2°、11.0±0.2°、18.1±0.2°、18.7±0.2°、20.3±0.2°、21.1±0.2°、22.0±0.2°、24.2±0.2°； 10.5±0.2°、11.0±0.2°、18.1±0.2°、18.7±0.2°、21.1±0.2°、22.0±0.2°、24.2±0.2°、30.8±0.2°； Most preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form E is basically as shown in Figure 10; the TGA-DSC pattern is shown in Figure 11. The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form F includes at least one or more diffraction peaks located at 2θ of 14.8±0.2°, 14.1±0.2°, 14.6±0.2°, and 20.8±0.2°, preferably two, more preferably three; and even more preferably, it may also include at least one of 2θ of 7.4±0.2°, 7.6±0.2°, 10.8±0.2°, 12.4±0.2°, 17.5±0.2°, 19.7±0.2°, and 22.2±0.2°, preferably two, three, four, five, six, or seven. More preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form F includes one or more diffraction peaks located at 2θ of 7.4±0.2°, 7.6±0.2°, 10.8±0.2°, 12.4±0.2°, 14.8±0.2°, 14.1±0.2°, 14.6±0.2°, 17.5±0.2°, 19.7±0.2°, 20.8±0.2°, and 22.2±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 7, 8, or 10 locations. For example, the X-ray powder diffraction pattern of p-toluenesulfonate crystal form F shows diffraction peaks at the following positions with a 2θ value: 7.4±0.2°, 14.8±0.2°, 14.1±0.2°, 14.6±0.2°, 17.5±0.2°, 20.8±0.2° and 22.2±0.2°; 12.4±0.2°, 14.8±0.2°, 14.1±0.2°, 14.6±0.2°, 17.5±0.2°, 20.8±0.2° and 22.2±0.2°; 7.4±0.2°, 12.4±0.2°, 14.8±0.2°, 14.1±0.2°, 14.6±0.2°, 17.5±0.2°, 20.8±0.2° and 22.2±0.2°; Most preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form F is basically as shown in Figure 12; The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form G includes at least one or more diffraction peaks located at 2θ of 7.0±0.2°, 10.8±0.2°, 14.7±0.2°, and 20.9±0.2°, preferably two, more preferably three; and even more preferably, it may also include at least one of 2θ of 6.9±0.2°, 17.8±0.2°, 19.3±0.2°, 19.7±0.2°, 28.0±0.2°, and 32.1±0.2°, preferably two, three, four, five, or six. More preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form G includes one or more diffraction peaks located at 2θ of 6.9±0.2°, 7.0±0.2°, 10.8±0.2°, 14.7±0.2°, 17.8±0.2°, 19.3±0.2°, 19.7±0.2°, 20.9±0.2°, 28.0±0.2°, and 32.1±0.2°; preferably, it includes 4, 5, 6, 7, 8, or 10 diffraction peaks; more preferably, it may also include at least one at 2θ of 11.8±0.2°, 15.3±0.2°, 22.5±0.2°, 24.4±0.2°, and 26.8±0.2°, preferably 2, 3, 4, or 5 such peaks; For example, the X-ray powder diffraction pattern of p-toluenesulfonate crystal form G shows diffraction peaks at the following positions with a 2θ value: 7.0±0.2°, 10.8±0.2°, 14.7±0.2°, 17.8±0.2°, 19.3±0.2°, 19.7±0.2° and 20.9±0.2°; 7.0±0.2°, 10.8±0.2°, 14.7±0.2°, 17.8±0.2°, 19.3±0.2°, 19.7±0.2° and 32.1±0.2°; 7.0±0.2°, 10.8±0.2°, 14.7±0.2°, 17.8±0.2°, 19.3±0.2°, 19.7±0.2°, 20.9±0.2° and 32.1±0.2°; Most preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form G is basically as shown in Figure 13; The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form H includes at least one or more diffraction peaks located at 2θ of 10.5±0.2°, 12.1±0.2°, 14.4±0.2°, and 20.6±0.2°, preferably two, more preferably three; and even more preferably, it may also include at least one of 6.8±0.2°, 11.6±0.2°, 15.0±0.2°, 17.1±0.2°, 19.5±0.2°, and 22.2±0.2°, preferably two, three, four, five, or six. More preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form H includes one or more of the following 2θ values: 6.8±0.2°, 10.5±0.2°, 11.6±0.2°, 12.1±0.2°, 14.4±0.2°, 15.0±0.2°, 17.1±0.2°, 19.5±0.2°, 20.6±0.2°, and 22.2±0.2°. The diffraction peaks are located at 4, 5, 6, 7, 8, or 10 locations; more preferably, the diffraction peaks are located at at least one of the following 2θ values: 10.0±0.2°, 12.8±0.2°, 17.6±0.2°, 22.6±0.2°, 24.1±0.2°, or 24.7±0.2°, preferably 2, 3, 4, 5, or 6 locations. For example, the X-ray powder diffraction pattern of p-toluenesulfonate crystal form H shows diffraction peaks at the following positions with a 2θ value: 6.8±0.2°、11.6±0.2°、14.4±0.2°、15.0±0.2°、17.1±0.2°、20.6±0.2°、22.2±0.2°； 6.8±0.2°、12.8±0.2°、14.4±0.2°、15.0±0.2°、17.1±0.2°、20.6±0.2°、22.2±0.2°； 6.8±0.2°、11.6±0.2°、14.4±0.2°、15.0±0.2°、17.6±0.2°、20.6±0.2°、22.2±0.2°； 6.8±0.2°、11.6±0.2°、14.4±0.2°、15.0±0.2°、17.1±0.2°、17.6±0.2°、20.6±0.2°、22.2±0.2°； 6.8±0.2°、11.6±0.2°、12.8±0.2°、14.4±0.2°、15.0±0.2°、17.1±0.2°、20.6±0.2°、22.2±0.2°； Most preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form H is basically as shown in Figure 14; the TGA-DSC pattern is shown in Figure 15. The X-ray powder diffraction pattern of the hydrochloride crystal form A includes at least one or more diffraction peaks located at 2θ of 7.3±0.2°, 10.5±0.2°, 16.7±0.2°, and 19.9±0.2°, preferably two, more preferably three; and even more preferably, it may also include at least one of 6.8±0.2°, 12.2±0.2°, 15.6±0.2°, 16.3±0.2°, 17.1±0.2°, and 20.2±0.2°, preferably two, three, four, five, or six. More preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form A includes one or more diffraction peaks located at 2θ of 6.8±0.2°, 7.3±0.2°, 10.5±0.2°, 12.2±0.2°, 15.6±0.2°, 16.3±0.2°, 16.7±0.2°, 17.1±0.2°, 19.9±0.2°, and 20.2±0.2°; preferably, it includes 4, 5, 6, 7, 8, or 10 diffraction peaks; more preferably, it may also include at least one at 2θ of 8.1±0.2°, 8.8±0.2°, 10.0±0.2°, 18.0±0.2°, 22.3±0.2°, and 24.7±0.2°, preferably 2, 3, 4, 5, or 6 peaks. For example, the X-ray powder diffraction pattern of hydrochloride crystal form A shows diffraction peaks at the following positions with a 2θ value: 6.8±0.2°、7.3±0.2°、10.5±0.2°、16.7±0.2°、17.1±0.2°、19.9±0.2°、20.2±0.2°； 7.3±0.2°、10.5±0.2°、12.2±0.2°、15.6±0.2°、16.7±0.2°、19.9±0.2°、20.2±0.2°； 7.3±0.2°、10.5±0.2°、12.2±0.2°、16.7±0.2°、17.1±0.2°、19.9±0.2°、20.2±0.2°； 7.3±0.2°、10.5±0.2°、12.2±0.2°、15.6±0.2°、16.7±0.2°、17.1±0.2°、19.9±0.2°、20.2±0.2°； 7.3±0.2°、10.5±0.2°、12.2±0.2°、15.6±0.2°、16.7±0.2°、19.9±0.2°、20.2±0.2°； 6.8±0.2°、7.3±0.2°、10.5±0.2°、12.2±0.2°、16.7±0.2°、19.9±0.2°、20.2±0.2°； 7.3±0.2°、10.0±0.2°、10.5±0.2°、12.2±0.2°、16.7±0.2°、19.9±0.2°、20.2±0.2°； 6.8±0.2°、7.3±0.2°、10.0±0.2°、10.5±0.2°、12.2±0.2°、16.7±0.2°、19.9±0.2°、20.2±0.2°； 7.3±0.2°、10.5±0.2°、12.2±0.2°、15.6±0.2°、16.7±0.2°、17.1±0.2°、19.9±0.2°、20.2±0.2°； 6.8±0.2°、7.3±0.2°、10.5±0.2°、12.2±0.2°、15.6±0.2°、16.7±0.2°、19.9±0.2°、20.2±0.2°； 6.8±0.2°、7.3±0.2°、10.5±0.2°、12.2±0.2°、15.6±0.2°、16.7±0.2°、17.1±0.2°、19.9±0.2°、20.2±0.2°； Most preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form A is basically as shown in Figure 16; the TGA-DSC pattern is shown in Figure 17; The X-ray powder diffraction pattern of the hydrochloride crystal form B includes at least one or more diffraction peaks located at 2θ of 8.6±0.2°, 10.4±0.2°, 16.1±0.2°, and 19.7±0.2°, preferably two, more preferably three; and even more preferably, it may also include at least one of 5.0±0.2°, 7.3±0.2°, 10.0±0.2°, 14.2±0.2°, 18.0±0.2°, and 22.3±0.2°, preferably two, three, four, five, or six. More preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form B includes one or more diffraction points located at 2θ of 5.0±0.2°, 7.3±0.2°, 8.6±0.2°, 10.0±0.2°, 10.4±0.2°, 14.2±0.2°, 16.1±0.2°, 18.0±0.2°, 19.7±0.2°, and 22.3±0.2°. Peaks; preferably, including any 4, 5, 6, 7, 8 or 10 diffraction peaks; more preferably, it may also include at least one of 2θ being 17.1±0.2°, 18.8±0.2°, 21.6±0.2°, 23.4±0.2°, 24.7±0.2°, 26.5±0.2°, preferably including 2, 3, 4, 5 or 6 of them; For example, the X-ray powder diffraction pattern of hydrochloride crystal form B shows diffraction peaks at the following positions with a 2θ value: 10.4±0.2°、16.1±0.2°、19.7±0.2°、22.3±0.2°、23.4±0.2°、26.5±0.2°； 8.6±0.2°、10.4±0.2°、14.2±0.2°、16.1±0.2°、18.0±0.2°、19.7±0.2°、22.3±0.2°； 7.3±0.2°、8.6±0.2°、10.4±0.2°、16.1±0.2°、18.0±0.2°、19.7±0.2°、22.3±0.2°； 5.0±0.2°、8.6±0.2°、10.4±0.2°、16.1±0.2°、18.0±0.2°、19.7±0.2°、22.3±0.2°； 8.6±0.2°、10.0±0.2°、10.4±0.2°、14.2±0.2°、16.1±0.2°、18.0±0.2°、19.7±0.2°、22.3±0.2°； 5.0±0.2°、7.3±0.2°、8.6±0.2°、10.4±0.2°、16.1±0.2°、18.0±0.2°、19.7±0.2°、22.3±0.2°； 5.0±0.2°、8.6±0.2°、10.4±0.2°、14.2±0.2°、16.1±0.2°、18.0±0.2°、19.7±0.2°、22.3±0.2°； 8.6±0.2°、10.4±0.2°、14.2±0.2°、16.1±0.2°、18.0±0.2°、19.7±0.2°、22.3±0.2°、26.5±0.2°； Most preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form B is basically as shown in Figure 18; the TGA-DSC pattern is shown in Figure 19; The X-ray powder diffraction pattern of the hydrochloride crystal form C includes at least one or more diffraction peaks located at 2θ of 5.4±0.2°, 6.9±0.2°, 9.4±0.2°, and 10.4±0.2°, preferably two, more preferably three; and even more preferably, it may also include at least one of 11.1±0.2°, 12.6±0.2°, 14.3±0.2°, 16.0±0.2°, and 19.7±0.2°, preferably two, three, four, or five. For example, the X-ray powder diffraction pattern of hydrochloride crystal form C shows diffraction peaks at the following positions with a 2θ value: 5.4±0.2°、6.9±0.2°、9.4±0.2°、10.4±0.2°、11.1±0.2°、16.0±0.2°、19.7±0.2°； 5.4±0.2°、6.9±0.2°、9.4±0.2°、10.4±0.2°、11.1±0.2°、12.6±0.2°、16.0±0.2°； 5.4±0.2°、6.9±0.2°、9.4±0.2°、10.4±0.2°、11.1±0.2°、12.6±0.2°、16.0±0.2°、19.7±0.2°； The X-ray powder diffraction pattern of the hydrobromide crystal form A includes at least one or more diffraction peaks located at 2θ of 6.5±0.2°, 7.0±0.2°, 16.3±0.2°, and 20.1±0.2°, preferably two, more preferably three; even more preferably, it may also include at least one of 11.3±0.2°, 12.0±0.2°, 15.2±0.2°, 21.0±0.2°, 21.5±0.2°, and 30.3±0.2°, preferably two, three, four, five, or six of these peaks. More preferably, the X-ray powder diffraction pattern of the hydrobromide crystal form A includes one or more diffraction points located at 2θ of 6.5±0.2°, 7.0±0.2°, 11.3±0.2°, 12.0±0.2°, 15.2±0.2°, 16.3±0.2°, 20.1±0.2°, 21.0±0.2°, 21.5±0.2°, and 30.3±0.2°. Diffraction peaks; preferably, including any 4, 5, 6, 7, 8 or 10 diffraction peaks; more preferably, it may also include at least one of 2θ being 18.0±0.2°, 22.5±0.2°, 22.9±0.2°, 23.3±0.2°, 24.1±0.2°, 26.1±0.2°, preferably including 2, 3, 4, 5 or 6 of them; For example, the X-ray powder diffraction pattern of hydrobromide crystal form A shows diffraction peaks at the following positions with a 2θ value: 6.5±0.2°、7.0±0.2°、11.3±0.2°、12.0±0.2°、16.3±0.2°、20.1±0.2°、21.0±0.2°； 11.3±0.2°、12.0±0.2°、15.2±0.2°、16.3±0.2°、20.1±0.2°、21.0±0.2°、30.3±0.2°； 11.3±0.2°、12.0±0.2°、16.3±0.2°、20.1±0.2°、21.0±0.2°、21.5±0.2°、30.3±0.2°； 11.3±0.2°、12.0±0.2°、15.2±0.2°、16.3±0.2°、18.0±0.2°、20.1±0.2°、30.3±0.2°； 6.5±0.2°、7.0±0.2°、11.3±0.2°、12.0±0.2°、15.2±0.2°、16.3±0.2°、20.1±0.2°、21.0±0.2°； 11.3±0.2°、12.0±0.2°、15.2±0.2°、16.3±0.2°、20.1±0.2°、21.0±0.2°、21.5±0.2°、30.3±0.2°； Most preferably, the X-ray powder diffraction pattern of the hydrobromide crystal form A is basically as shown in Figure 21; the TGA-DSC pattern is shown in Figure 22. The X-ray powder diffraction pattern of the hydrobromide crystal form B includes at least one or more diffraction peaks located at 2θ of 7.4±0.2°, 9.9±0.2°, 10.4±0.2°, and 17.1±0.2°, preferably two, more preferably three; even more preferably, it may also include at least one of 6.3±0.2°, 12.7±0.2°, 19.1±0.2°, 20.6±0.2°, 22.3±0.2°, and 24.3±0.2°, preferably two, three, four, five, or six of these peaks; More preferably, the X-ray powder diffraction pattern of the hydrobromide crystal form B includes one or more diffraction peaks located at 2θ of 6.3±0.2°, 7.4±0.2°, 9.9±0.2°, 10.4±0.2°, 12.7±0.2°, 17.1±0.2°, 19.1±0.2°, 20.6±0.2°, 22.3±0.2°, and 24.3±0.2°; preferably, it includes 4, 5, 6, 7, 8, or 10 diffraction peaks; more preferably, it may also include at least one at 2θ of 16.8±0.2°, 17.5±0.2°, 18.5±0.2°, and 20.9±0.2°, preferably 2, 3, or 4 such peaks; For example, the X-ray powder diffraction pattern of hydrobromide crystal form B shows diffraction peaks at the following positions with a 2θ value: 7.4±0.2°、9.9±0.2°、10.4±0.2°、12.7±0.2°、17.1±0.2°、19.1±0.2°、24.3±0.2°； 6.3±0.2°、7.4±0.2°、9.9±0.2°、10.4±0.2°、12.7±0.2°、17.1±0.2°、24.3±0.2°； 7.4±0.2°、9.9±0.2°、10.4±0.2°、12.7±0.2°、17.1±0.2°、19.1±0.2°、20.6±0.2°、24.3±0.2°； Most preferably, the X-ray powder diffraction pattern of the hydrobromide crystal form B is basically as shown in Figure 23; the DSC pattern is shown in Figure 24. The X-ray powder diffraction pattern of the hydrobromide crystal form C includes at least one or more diffraction peaks located at 2θ of 8.8±0.2°, 10.4±0.2°, 16.1±0.2°, 19.7±0.2°, and 23.6±0.2°, preferably including two of them, more preferably including three, four, or five; even more preferably, it may also include at least one of 7.4±0.2°, 9.9±0.2°, 12.9±0.2°, 16.7±0.2°, 20.7±0.2°, and 22.3±0.2°, preferably including two, three, four, five, or six of them; More preferably, the X-ray powder diffraction pattern of the hydrobromide crystal form C includes one or more locations located at 2θ of 8.8±0.2°, 9.9±0.2°, 10.4±0.2°, 12.9±0.2°, 16.1±0.2°, 16.7±0.2°, 19.7±0.2°, 20.7±0.2°, 22.3±0.2°, and 23.6±0.2°. Diffraction peaks; preferably, including any 4, 5, 6, 7, 8 or 10 diffraction peaks; more preferably, it may also include at least one of 2θ being 7.4±0.2°, 14.2±0.2°, 20.2±0.2°, 24.6±0.2°, 26.6±0.2°, 29.5±0.2°, preferably including 2, 3, 4, 5 or 6 of them; For example, the X-ray powder diffraction pattern of hydrobromide crystal form C shows diffraction peaks at the following positions with a 2θ value: 10.4±0.2°、12.9±0.2°、16.1±0.2°、16.7±0.2°、19.7±0.2°、22.3±0.2°、23.6±0.2°； 8.8±0.2°、10.4±0.2°、12.9±0.2°、16.1±0.2°、19.7±0.2°、22.3±0.2°、23.6±0.2°； 9.9±0.2°、10.4±0.2°、12.9±0.2°、16.1±0.2°、19.7±0.2°、22.3±0.2°、23.6±0.2°； 7.4±0.2°、10.4±0.2°、12.9±0.2°、16.1±0.2°、19.7±0.2°、22.3±0.2°、23.6±0.2°； 10.4±0.2°、12.9±0.2°、16.1±0.2°、16.7±0.2°、19.7±0.2°、20.7±0.2°、22.3±0.2°、23.6±0.2°； 8.8±0.2°、10.4±0.2°、12.9±0.2°、16.1±0.2°、19.7±0.2°、20.7±0.2°、22.3±0.2°、23.6±0.2°； 9.9±0.2°、10.4±0.2°、12.9±0.2°、16.1±0.2°、19.7±0.2°、20.7±0.2°、22.3±0.2°、23.6±0.2°； Most preferably, the X-ray powder diffraction pattern of the hydrobromide crystal form C is basically as shown in Figure 25; the TGA-DSC pattern is shown in Figure 26. The X-ray powder diffraction pattern of the hydrobromide crystal form D includes at least one or more diffraction peaks located at 2θ of 10.5±0.2°, 12.4±0.2°, 16.9±0.2°, 19.1±0.2°, and 20.8±0.2°, preferably including two of them, more preferably including three, four, or five; even more preferably, it may also include at least one of 9.8±0.2°, 15.3±0.2°, 17.6±0.2°, 20.0±0.2°, 22.6±0.2°, and 24.6±0.2°, preferably including two, three, four, five, or six of them; More preferably, the X-ray powder diffraction pattern of the hydrobromide crystal form D includes one or more of the following 2θ values: 10.5±0.2°, 12.4±0.2°, 15.3±0.2°, 16.9±0.2°, 17.6±0.2°, 19.1±0.2°, 20.0±0.2°, 20.8±0.2°, 22.6±0.2°, and 24.6±0.2°. The diffraction peaks are located at 4, 5, 6, 7, 8, or 10 locations; more preferably, the diffraction peaks are located at at least one of the following 2θ values: 9.8±0.2°, 12.9±0.2°, 14.9±0.2°, 22.1±0.2°, 25.8±0.2°, or 26.4±0.2°, preferably 2, 3, 4, 5, or 6 locations. For example, the X-ray powder diffraction pattern of hydrobromide crystal form D shows diffraction peaks at the following positions with a 2θ value: 10.5±0.2°、12.4±0.2°、15.3±0.2°、16.9±0.2°、19.1±0.2°、20.0±0.2°、20.8±0.2°； 10.5±0.2°、12.4±0.2°、15.3±0.2°、16.9±0.2°、19.1±0.2°、20.8±0.2°、22.6±0.2°； 10.5±0.2°、12.4±0.2°、15.3±0.2°、16.9±0.2°、19.1±0.2°、20.0±0.2°、20.8±0.2°、22.6±0.2°； 10.5±0.2°、12.4±0.2°、15.3±0.2°、16.9±0.2°、17.6±0.2°、19.1±0.2°、20.8±0.2°、22.6±0.2°； 10.5±0.2°、12.4±0.2°、15.3±0.2°、16.9±0.2°、17.6±0.2°、19.1±0.2°、20.0±0.2°、20.8±0.2°、22.6±0.2°； Most preferably, the X-ray powder diffraction pattern of the hydrobromide crystal form D is basically as shown in Figure 27; the TGA-DSC pattern is shown in Figure 28; The X-ray powder diffraction pattern of the benzoate crystal form A includes at least one or more diffraction peaks located at 2θ of 8.7±0.2°, 16.6±0.2°, 17.5±0.2°, and 19.5±0.2°, preferably two, more preferably three; and even more preferably, it may also include at least one of 5.1±0.2°, 9.0±0.2°, 13.1±0.2°, 20.9±0.2°, 21.5±0.2°, and 24.6±0.2°, preferably two, three, four, five, or six. More preferably, the X-ray powder diffraction pattern of the benzoate crystal form A includes one or more diffraction peaks located at 2θ of 5.1±0.2°, 8.7±0.2°, 9.0±0.2°, 13.1±0.2°, 16.6±0.2°, 17.5±0.2°, 19.5±0.2°, 20.9±0.2°, 21.5±0.2°, and 24.6±0.2°; preferably, it includes 4, 5, 6, 7, 8, or 10 diffraction peaks; more preferably, it may also include at least one at 2θ of 10.1±0.2°, 14.2±0.2°, 20.2±0.2°, 22.0±0.2°, and 24.3±0.2°, preferably 2, 3, 4, or 5 such peaks; Most preferably, the X-ray powder diffraction pattern of the benzoate crystal form A is basically as shown in Figure 29; the TGA-DSC pattern is shown in Figure 30. The X-ray powder diffraction pattern of the benzoate crystal form B includes at least one or more diffraction peaks located at 2θ of 6.6±0.2°, 7.0±0.2°, 7.5±0.2°, and 17.0±0.2°, preferably two, more preferably three; and even more preferably, it may also include at least one of 10.0±0.2°, 10.5±0.2°, 13.5±0.2°, 15.4±0.2°, 18.2±0.2°, and 19.7±0.2°, preferably two, three, four, five, or six. More preferably, the X-ray powder diffraction pattern of the benzoate crystal form B includes one or more diffraction peaks located at 2θ of 6.6±0.2°, 7.0±0.2°, 7.5±0.2°, 10.0±0.2°, 10.5±0.2°, 13.5±0.2°, 15.4±0.2°, 17.0±0.2°, 18.2±0.2°, and 19.7±0.2°; preferably, it includes 4, 5, 6, 7, 8, or 10 diffraction peaks; more preferably, it may also include at least one at 2θ of 20.5±0.2°, 21.7±0.2°, 23.6±0.2°, 28.9±0.2°, and 31.8±0.2°, preferably 2, 3, 4, or 5 such peaks; Most preferably, the X-ray powder diffraction pattern of the benzoate crystal form B is basically as shown in Figure 31; the TGA-DSC pattern is shown in Figure 32. The X-ray powder diffraction pattern of the fumarate crystal form A includes at least one or more diffraction peaks located at 2θ of 5.2±0.2°, 8.9±0.2°, 11.3±0.2°, and 18.4±0.2°, preferably two, more preferably three; and even more preferably, it may also include at least one of 7.0±0.2°, 13.2±0.2°, 13.7±0.2°, 15.6±0.2°, 22.4±0.2°, and 23.2±0.2°, preferably two, three, four, five, or six.

8. The acid salt of the compound or its stereoisomer according to any one of claims 1 to 5, or its crystal form, characterized in that, It is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxopiridin-1-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-(ethyl-d5)-1H-pyrazole-5-carboxamide hydrochloride crystal form A; The X-ray powder diffraction pattern of the hydrochloride crystal form A shows a diffraction peak at 2θ of 5.3 ± 0.2°; or at 7.4 ± 0.2°; or at 11.8 ± 0.2°; or at 12.9 ± 0.2°; or at 16.7 ± 0.2°; or at 17.5 ± 0.2°; or at 19.1 ± 0.2°. The diffraction peaks are present; or diffraction peaks are present at 21.7±0.2°; or diffraction peaks are present at 22.4±0.2°; or diffraction peaks are present at 23.7±0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks are included; more preferably, any 6, 7, 8, 9, or 10 of the above diffraction peaks are included. The X-ray powder diffraction pattern of the hydrochloride crystal form A includes at least one or more diffraction peaks located at 2θ of 5.3±0.2°, 7.4±0.2°, 11.8±0.2°, and 16.7±0.2°, preferably two, more preferably three or four; even more preferably, it may also include at least one of 2θ of 12.9±0.2°, 17.5±0.2°, 19.1±0.2°, 21.7±0.2°, 22.4±0.2°, and 23.7±0.2°, preferably two, three, four, five, or six. More preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form A includes one or more diffraction peaks located at 5.3±0.2°, 7.4±0.2°, 11.8±0.2°, 12.9±0.2°, 16.7±0.2°, 17.5±0.2°, 19.1±0.2°, 21.7±0.2°, 22.4±0.2°, and 23.7±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 8, or 10 locations. More preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form A may also include one or more diffraction peaks selected from 9.1±0.2°, 15.8±0.2°, 19.4±0.2°, 19.7±0.2°, 23.0±0.2°, and 26.5±0.2°; preferably, it includes at least 2-3, 4-5, or 5-6 peaks; more preferably, it includes any 2, 3, 4, 5, or 6 peaks. For example, the X-ray powder diffraction pattern of the hydrochloride crystal form A has diffraction peaks at the following positions with a 2θ value: 5.3±0.2°、7.4±0.2°、11.8±0.2°、16.7±0.2°、12.9±0.2°、17.5±0.2°、19.1±0.2°； 5.3±0.2°、7.4±0.2°、11.8±0.2°、16.7±0.2°、21.7±0.2°、22.4±0.2°、23.7±0.2°； 5.3±0.2°、7.4±0.2°、9.1±0.2°、11.8±0.2°、15.8±0.2°、16.7±0.2°、19.4±0.2°； 5.3±0.2°、7.4±0.2°、11.8±0.2°、16.7±0.2°、19.7±0.2°、23.0±0.2°、26.5±0.2°； 12.9±0.2°、17.5±0.2°、15.8±0.2°、16.7±0.2°、19.1±0.2°、19.4±0.2°、21.7±0.2°； 12.9±0.2°、17.5±0.2°、19.1±0.2°、19.7±0.2°、21.7±0.2°、23.0±0.2°、26.5±0.2°； 5.3±0.2°、7.4±0.2°、11.8±0.2°、12.9±0.2°、16.7±0.2°、17.5±0.2°、19.1±0.2°、21.7±0.2°； 5.3±0.2°、7.4±0.2°、11.8±0.2°、16.7±0.2°、19.1±0.2°、21.7±0.2°、22.4±0.2°、23.7±0.2°； 5.3±0.2°、7.4±0.2°、11.8±0.2°、16.7±0.2°、17.5±0.2°、19.1±0.2°、21.7±0.2°、22.4±0.2°； 5.3±0.2°、7.4±0.2°、9.1±0.2°、11.8±0.2°、12.9±0.2°、15.8±0.2°、16.7±0.2°、17.5±0.2°； 5.3±0.2°、7.4±0.2°、11.8±0.2°、16.7±0.2°、22.4±0.2°、23.0±0.2°、23.7±0.2°、26.5±0.2°； 5.3±0.2°、7.4±0.2°、9.1±0.2°、11.8±0.2°、12.9±0.2°、16.7±0.2°、23.7±0.2°、26.5±0.2°； 5.3±0.2°、7.4±0.2°、11.8±0.2°、12.9±0.2°、16.7±0.2°、17.5±0.2°、19.1±0.2°、21.7±0.2°、22.4±0.2°； 5.3±0.2°、7.4±0.2°、11.8±0.2°、16.7±0.2°、17.5±0.2°、19.1±0.2°、21.7±0.2°、22.4±0.2°、23.7±0.2°； Most preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form A is basically as shown in Figure 40; the DSC pattern is shown in Figure 41. Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxopiridine-1-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-(ethyl-d5)-1H-pyrazole-5-carboxamide hydrochloride crystal form B; The X-ray powder diffraction pattern of the hydrochloride crystal form B shows a diffraction peak at 2θ of 9.1 ± 0.2°; or at 13.7 ± 0.2°; or at 15.3 ± 0.2°; or at 17.8 ± 0.2°; or at 18.6 ± 0.2°; or at 18.9 ± 0.2°; or at 20.4 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 20.8±0.2°; or has diffraction peaks at 22.8±0.2°; or has diffraction peaks at 23.3±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them; The X-ray powder diffraction pattern of the hydrochloride crystal form B includes at least one or more diffraction peaks located at 2θ of 9.1±0.2°, 13.7±0.2°, 17.8±0.2°, and 20.8±0.2°, preferably two of these peaks, more preferably three or four; even more preferably, it may also include at least one of 2θ of 15.3±0.2°, 18.6±0.2°, 18.9±0.2°, 20.4±0.2°, 22.8±0.2°, and 23.3±0.2°, preferably two, three, four, five, or six of these peaks. More preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form B includes one or more diffraction peaks located at 9.1±0.2°, 13.7±0.2°, 15.3±0.2°, 17.8±0.2°, 18.6±0.2°, 18.9±0.2°, 20.4±0.2°, 20.8±0.2°, 22.8±0.2°, and 23.3±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 8, or 10 of these locations. More preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form B may also include one or more diffraction peaks selected from 8.4±0.2°, 16.9±0.2°, 18.2±0.2°, 25.9±0.2°, 27.3±0.2°, and 30.8±0.2°; preferably, it includes at least 2-3, 4-5, or 5-6 peaks; more preferably, it includes any 2, 3, 4, 5, or 6 peaks. For example, the X-ray powder diffraction pattern of the hydrochloride crystal form B has diffraction peaks at the following positions with a 2θ value: 9.1±0.2°、13.7±0.2°、17.8±0.2°、15.3±0.2°、18.6±0.2°、18.9±0.2°、20.8±0.2°； 9.1±0.2°、13.7±0.2°、17.8±0.2°、20.4±0.2°、20.8±0.2°、22.8±0.2°、23.3±0.2°； 8.4±0.2°、9.1±0.2°、13.7±0.2°、16.9±0.2°、17.8±0.2°、18.2±0.2°、20.8±0.2°； 9.1±0.2°、13.7±0.2°、17.8±0.2°、20.8±0.2°、25.9±0.2°、27.3±0.2°、30.8±0.2°； 9.1±0.2°、13.7±0.2°、17.8±0.2°、20.8±0.2°、15.3±0.2°、18.6±0.2°、18.9±0.2°、20.4±0.2°； 9.1±0.2°、13.7±0.2°、17.8±0.2°、20.8±0.2°、18.9±0.2°、20.4±0.2°、22.8±0.2°、23.3±0.2°； 9.1±0.2°、13.7±0.2°、17.8±0.2°、20.8±0.2°、8.4±0.2°、16.9±0.2°、18.2±0.2°、25.9±0.2°； 9.1±0.2°、13.7±0.2°、17.8±0.2°、20.8±0.2°、18.2±0.2°、25.9±0.2°、27.3±0.2°、30.8±0.2°； 8.4±0.2°、9.1±0.2°、13.7±0.2°、15.3±0.2°、16.9±0.2°、17.8±0.2°、18.6±0.2°、20.8±0.2°； 8.4±0.2°、9.1±0.2°、13.7±0.2°、17.8±0.2°、20.8±0.2°、15.3±0.2°、23.3±0.2°、30.8±0.2°； 9.1±0.2°、13.7±0.2°、17.8±0.2°、20.8±0.2°、22.8±0.2°、23.3±0.2°、27.3±0.2°、30.8±0.2°； 9.1±0.2°、13.7±0.2°、17.8±0.2°、20.8±0.2°、15.3±0.2°、18.6±0.2°、18.9±0.2°、20.4±0.2°、22.8±0.2°； 9.1±0.2°、13.7±0.2°、17.8±0.2°、20.8±0.2°、18.6±0.2°、18.9±0.2°、20.4±0.2°、22.8±0.2°、23.3±0.2°； 9.1±0.2°、13.7±0.2°、17.8±0.2°、20.8±0.2°、8.4±0.2°、16.9±0.2°、18.2±0.2°、25.9±0.2°、27.3±0.2°； 9.1±0.2°、13.7±0.2°、17.8±0.2°、20.8±0.2°、16.9±0.2°、18.2±0.2°、25.9±0.2°、27.3±0.2°、30.8±0.2°； Most preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form B is basically as shown in Figure 42; the DSC pattern is shown in Figure 43. Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxopiridine-1-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-(ethyl-d5)-1H-pyrazole-5-carboxamide hydrochloride crystal form C; The X-ray powder diffraction pattern of the hydrochloride crystal form C shows a diffraction peak at 2θ of 4.3 ± 0.2°; or at 17.2 ± 0.2°; or at 21.5 ± 0.2°; or at 22.0 ± 0.2°; or at 8.6 ± 0.2°; or at 9.8 ± 0.2°; or at 13.5 ± 0.2°. The diffraction peaks are present; or diffraction peaks are present at 16.1±0.2°; or diffraction peaks are present at 18.3±0.2°; or diffraction peaks are present at 26.0±0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks are included; more preferably, any 6, 7, 8, 9, or 10 of the above diffraction peaks are included. The X-ray powder diffraction pattern of the hydrochloride crystal form C includes at least one or more diffraction peaks located at 2θ of 4.3±0.2°, 17.2±0.2°, 21.5±0.2°, and 22.0±0.2°, preferably two of these peaks, more preferably three or four; even more preferably, it may also include at least one of 2θ of 8.6±0.2°, 9.8±0.2°, 13.5±0.2°, 16.1±0.2°, 18.3±0.2°, and 26.0±0.2°, preferably two, three, four, five, or six of these peaks. More preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form C includes one or more diffraction peaks located at 4.3±0.2°, 8.6±0.2°, 9.8±0.2°, 13.5±0.2°, 16.1±0.2°, 17.2±0.2°, 18.3±0.2°, 21.5±0.2°, 22.0±0.2°, and 26.0±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 8, or 10 locations. More preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form C may further include one or more diffraction peaks selected from 9.5±0.2°, 11.3±0.2°, 12.9±0.2°, 17.9±0.2°, 18.6±0.2°, 19.1±0.2°, 20.1±0.2°, and 23.9±0.2°; preferably, it includes at least 2-3, 4-5, 5-6, or 7-8 peaks; more preferably, it includes any 2, 3, 4, 5, 6, 7, or 8 peaks. For example, the X-ray powder diffraction pattern of the hydrochloride crystal form C shows diffraction peaks at the following positions with a 2θ value: 4.3±0.2°、8.6±0.2°、9.8±0.2°、13.5±0.2°、17.2±0.2°、21.5±0.2°、22.0±0.2°； 4.3±0.2°、16.1±0.2°、17.2±0.2°、18.3±0.2°、21.5±0.2°、22.0±0.2°、26.0±0.2°； 4.3±0.2°、9.5±0.2°、11.3±0.2°、12.9±0.2°、17.2±0.2°、21.5±0.2°、22.0±0.2°； 4.3±0.2°、12.9±0.2°、17.2±0.2°、17.9±0.2°、18.6±0.2°、21.5±0.2°、22.0±0.2°； 4.3±0.2°、17.2±0.2°、19.1±0.2°、20.1±0.2°、21.5±0.2°、22.0±0.2°、23.9±0.2°； 4.3±0.2°、8.6±0.2°、9.8±0.2°、13.5±0.2°、16.1±0.2°、17.2±0.2°、21.5±0.2°、22.0±0.2°； 4.3±0.2°、13.5±0.2°、16.1±0.2°、17.2±0.2°、18.3±0.2°、21.5±0.2°、22.0±0.2°、26.0±0.2°； 4.3±0.2°、9.5±0.2°、11.3±0.2°、12.9±0.2°、17.9±0.2°、17.2±0.2°、21.5±0.2°、22.0±0.2°； 4.3±0.2°、17.2±0.2°、18.6±0.2°、19.1±0.2°、20.1±0.2°、21.5±0.2°、22.0±0.2°、23.9±0.2°； 4.3±0.2°、8.6±0.2°、9.8±0.2°、9.5±0.2°、11.3±0.2°、17.2±0.2°、21.5±0.2°、22.0±0.2°； 4.3±0.2°、17.2±0.2°、18.3±0.2°、20.1±0.2°、21.5±0.2°、22.0±0.2°、23.9±0.2°、26.0±0.2°； 4.3±0.2°、8.6±0.2°、9.5±0.2°、17.2±0.2°、21.5±0.2°、22.0±0.2°、23.9±0.2°、26.0±0.2°； 4.3±0.2°、8.6±0.2°、9.8±0.2°、13.5±0.2°、16.1±0.2°、17.2±0.2°、18.3±0.2°、21.5±0.2°、22.0±0.2°； 4.3±0.2°、9.8±0.2°、13.5±0.2°、16.1±0.2°、17.2±0.2°、18.3±0.2°、21.5±0.2°、22.0±0.2°、26.0±0.2°； 4.3±0.2°、9.5±0.2°、11.3±0.2°、12.9±0.2°、17.2±0.2°、17.9±0.2°、18.6±0.2°、21.5±0.2°、22.0±0.2°； 4.3±0.2°、17.2±0.2°、17.9±0.2°、18.6±0.2°、19.1±0.2°、20.1±0.2°、21.5±0.2°、22.0±0.2°、23.9±0.2°； Most preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form C is basically as shown in Figure 44; the DSC pattern is shown in Figure 45. Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxopiridine-1-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-(ethyl-d5)-1H-pyrazole-5-carboxamide hydrochloride crystal form D; The X-ray powder diffraction pattern of the hydrochloride crystal form D shows a diffraction peak at 2θ of 8.7 ± 0.2°; or at 10.7 ± 0.2°; or at 11.3 ± 0.2°; or at 13.8 ± 0.2°; or at 14.2 ± 0.2°; or at 18.3 ± 0.2°; or at 18.7 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 19.2±0.2°; or has diffraction peaks at 19.5±0.2°; or has diffraction peaks at 28.2±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them; The X-ray powder diffraction pattern of the hydrochloride crystal form D includes at least one or more diffraction peaks located at 2θ of 8.7±0.2°, 13.8±0.2°, 14.2±0.2°, and 18.3±0.2°, preferably two of these peaks, more preferably three or four; even more preferably, it may also include at least one of 2θ of 10.7±0.2°, 11.3±0.2°, 18.7±0.2°, 19.2±0.2°, 19.5±0.2°, and 28.2±0.2°, preferably two, three, four, five, or six of these peaks. More preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form D includes one or more diffraction peaks located at 8.7±0.2°, 10.7±0.2°, 11.3±0.2°, 13.8±0.2°, 14.2±0.2°, 18.3±0.2°, 18.7±0.2°, 19.2±0.2°, 19.5±0.2°, and 28.2±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 8, or 10 of these locations. More preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form D may also include one or more diffraction peaks selected from 9.6±0.2°, 12.7±0.2°, 14.4±0.2°, 15.5±0.2°, 17.1±0.2°, and 17.7±0.2°; preferably, it includes at least any 2-3, 4-5, or 5-6 peaks; more preferably, it includes any 2, 3, 4, 5, or 6 peaks. For example, the X-ray powder diffraction pattern of the hydrochloride crystal form D shows diffraction peaks at the following positions with a 2θ value: 8.7±0.2°、13.8±0.2°、14.2±0.2°、18.3±0.2°、10.7±0.2°、11.3±0.2°、18.7±0.2°； 8.7±0.2°、13.8±0.2°、14.2±0.2°、18.3±0.2°、19.2±0.2°、19.5±0.2°、28.2±0.2°； 8.7±0.2°、13.8±0.2°、14.2±0.2°、18.3±0.2°、9.6±0.2°、12.7±0.2°、14.4±0.2°； 8.7±0.2°、13.8±0.2°、14.2±0.2°、18.3±0.2°、15.5±0.2°、17.1±0.2°、17.7±0.2°； 8.7±0.2°、13.8±0.2°、14.2±0.2°、18.3±0.2°、10.7±0.2°、11.3±0.2°、18.7±0.2°、19.2±0.2°； 8.7±0.2°、13.8±0.2°、14.2±0.2°、18.3±0.2°、18.7±0.2°、19.2±0.2°、19.5±0.2°、28.2±0.2°； 8.7±0.2°、13.8±0.2°、14.2±0.2°、18.3±0.2°、9.6±0.2°、12.7±0.2°、14.4±0.2°、15.5±0.2°； 8.7±0.2°、13.8±0.2°、14.2±0.2°、18.3±0.2°、14.4±0.2°、15.5±0.2°、17.1±0.2°、17.7±0.2°； 8.7±0.2°、13.8±0.2°、14.2±0.2°、18.3±0.2°、10.7±0.2°、11.3±0.2°、9.6±0.2°、12.7±0.2°； 8.7±0.2°、13.8±0.2°、14.2±0.2°、18.3±0.2°、19.5±0.2°、28.2±0.2°、17.1±0.2°、17.7±0.2°； 8.7±0.2°、13.8±0.2°、14.2±0.2°、18.3±0.2°、10.7±0.2°、28.2±0.2°、9.6±0.2°、17.7±0.2°； 8.7±0.2°、13.8±0.2°、14.2±0.2°、18.3±0.2°、10.7±0.2°、11.3±0.2°、18.7±0.2°、19.2±0.2°、19.5±0.2°； 8.7±0.2°、13.8±0.2°、14.2±0.2°、18.3±0.2°、11.3±0.2°、18.7±0.2°、19.2±0.2°、19.5±0.2°、28.2±0.2°； 8.7±0.2°、13.8±0.2°、14.2±0.2°、18.3±0.2°、9.6±0.2°、12.7±0.2°、14.4±0.2°、15.5±0.2°、17.1±0.2°； 8.7±0.2°、13.8±0.2°、14.2±0.2°、18.3±0.2°、12.7±0.2°、14.4±0.2°、15.5±0.2°、17.1±0.2°、17.7±0.2°； Most preferably, the TGA-DSC spectrum of the hydrochloride crystal form D is shown in Figure 46; Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxopiridine-1-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-(ethyl-d5)-1H-pyrazole-5-carboxamide hydrochloride crystal form E; The X-ray powder diffraction pattern of the hydrochloride crystal form E shows a diffraction peak at 2θ of 9.6 ± 0.2°; or at 13.7 ± 0.2°; or at 15.2 ± 0.2°; or at 16.3 ± 0.2°; or at 16.8 ± 0.2°; or at 17.7 ± 0.2°; or at 19.2 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 20.0±0.2°; or has diffraction peaks at 24.1±0.2°; or has diffraction peaks at 28.5±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them; The X-ray powder diffraction pattern of the hydrochloride crystal form E includes at least one or more diffraction peaks located at 2θ of 9.6±0.2°, 16.8±0.2°, 17.7±0.2°, and 19.2±0.2°, preferably two, more preferably three or four; even more preferably, it may also include at least one at 2θ of 13.7±0.2°, 15.2±0.2°, 16.3±0.2°, 20.0±0.2°, 24.1±0.2°, and 28.5±0.2°, preferably two, three, four, five, or six. More preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form E includes one or more diffraction peaks located at 9.6±0.2°, 13.7±0.2°, 15.2±0.2°, 16.3±0.2°, 16.8±0.2°, 17.7±0.2°, 19.2±0.2°, 20.0±0.2°, 24.1±0.2°, and 28.5±0.2°; preferably, it includes diffraction peaks at any of the selected 4, 5, 6, 8, or 10 locations. More preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form E may also include one or more diffraction peaks selected from 4.4±0.2°, 6.9±0.2°, 7.2±0.2°, 20.6±0.2°, 29.0±0.2°, and 31.7±0.2°; preferably, it includes at least 2-3, 4-5, or 5-6 peaks; more preferably, it includes any 2, 3, 4, 5, or 6 peaks. For example, the X-ray powder diffraction pattern of the hydrochloride crystal form E has diffraction peaks at the following positions with a 2θ value: 9.6±0.2°、16.8±0.2°、17.7±0.2°、19.2±0.2°、13.7±0.2°、15.2±0.2°、16.3±0.2°； 9.6±0.2°、16.8±0.2°、17.7±0.2°、19.2±0.2°、20.0±0.2°、24.1±0.2°、28.5±0.2°； 9.6±0.2°、16.8±0.2°、17.7±0.2°、19.2±0.2°、4.4±0.2°、6.9±0.2°、7.2±0.2°； 9.6±0.2°、16.8±0.2°、17.7±0.2°、19.2±0.2°、20.6±0.2°、29.0±0.2°、31.7±0.2°； 9.6±0.2°、16.8±0.2°、17.7±0.2°、19.2±0.2°、13.7±0.2°、15.2±0.2°、16.3±0.2°、20.0±0.2°； 9.6±0.2°、16.8±0.2°、17.7±0.2°、19.2±0.2°、16.3±0.2°、20.0±0.2°、24.1±0.2°、28.5±0.2°； 9.6±0.2°、16.8±0.2°、17.7±0.2°、19.2±0.2°、4.4±0.2°、6.9±0.2°、7.2±0.2°、20.6±0.2°； 9.6±0.2°、16.8±0.2°、17.7±0.2°、19.2±0.2°、7.2±0.2°、20.6±0.2°、29.0±0.2°、31.7±0.2°； 9.6±0.2°、16.8±0.2°、17.7±0.2°、19.2±0.2°、13.7±0.2°、15.2±0.2°、4.4±0.2°、6.9±0.2°； 9.6±0.2°、16.8±0.2°、17.7±0.2°、19.2±0.2°、24.1±0.2°、28.5±0.2°、29.0±0.2°、31.7±0.2°； 9.6±0.2°、16.8±0.2°、17.7±0.2°、19.2±0.2°、13.7±0.2°、28.5±0.2°、4.4±0.2°、31.7±0.2°； 9.6±0.2°、16.8±0.2°、17.7±0.2°、19.2±0.2°、13.7±0.2°、15.2±0.2°、16.3±0.2°、20.0±0.2°、24.1±0.2°； 9.6±0.2°、16.8±0.2°、17.7±0.2°、19.2±0.2°、15.2±0.2°、16.3±0.2°、20.0±0.2°、24.1±0.2°、28.5±0.2°； 9.6±0.2°、16.8±0.2°、17.7±0.2°、19.2±0.2°、4.4±0.2°、6.9±0.2°、7.2±0.2°、20.6±0.2°、29.0±0.2°； 9.6±0.2°、16.8±0.2°、17.7±0.2°、19.2±0.2°、6.9±0.2°、7.2±0.2°、20.6±0.2°、29.0±0.2°、31.7±0.2°； Most preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form E is basically as shown in Figure 47; Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxopiridine-1-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-(ethyl-d5)-1H-pyrazole-5-carboxamide sulfate crystal form A; The X-ray powder diffraction pattern of the sulfate crystal form A shows a diffraction peak at 2θ of 9.5 ± 0.2°; or at 10.7 ± 0.2°; or at 18.3 ± 0.2°; or at 19.5 ± 0.2°; or at 15.9 ± 0.2°; or at 21.7 ± 0.2°; or at 22.8 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 23.1±0.2°; or has diffraction peaks at 25.4±0.2°; or has diffraction peaks at 25.7±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them; The X-ray powder diffraction pattern of the sulfate crystal form A includes at least one or more diffraction peaks located at 2θ of 9.5±0.2°, 10.7±0.2°, 18.3±0.2°, and 19.5±0.2°, preferably two, more preferably three or four; even more preferably, it may also include at least one of 2θ of 15.9±0.2°, 21.7±0.2°, 22.8±0.2°, 23.1±0.2°, 25.4±0.2°, and 25.7±0.2°, preferably two, three, four, five, or six. More preferably, the X-ray powder diffraction pattern of the sulfate crystal form A includes one or more diffraction peaks located at 9.5±0.2°, 10.7±0.2°, 15.9±0.2°, 18.3±0.2°, 19.5±0.2°, 21.7±0.2°, 22.8±0.2°, 23.1±0.2°, 25.4±0.2°, and 25.7±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 8, or 10 of these locations. More preferably, the X-ray powder diffraction pattern of the sulfate crystal form A may also include one or more diffraction peaks selected from 12.7±0.2°, 14.9±0.2°, 18.9±0.2°, 21.1±0.2°, 23.8±0.2°, and 24.6±0.2°; preferably, it includes at least 2-3, 4-5, or 5-6 peaks; more preferably, it includes any 2, 3, 4, 5, or 6 peaks. For example, the X-ray powder diffraction pattern of the sulfate crystal form A shows diffraction peaks at the following positions with a 2θ value: 9.5±0.2°、10.7±0.2°、15.9±0.2°、18.3±0.2°、19.5±0.2°、21.7±0.2°、22.8±0.2°； 9.5±0.2°、10.7±0.2°、18.3±0.2°、19.5±0.2°、23.1±0.2°、25.4±0.2°、25.7±0.2°； 9.5±0.2°、10.7±0.2°、12.7±0.2°、14.9±0.2°、18.3±0.2°、18.9±0.2°、19.5±0.2°； 9.5±0.2°、10.7±0.2°、18.3±0.2°、19.5±0.2°、21.1±0.2°、23.8±0.2°、24.6±0.2°； 9.5±0.2°、10.7±0.2°、15.9±0.2°、18.3±0.2°、19.5±0.2°、21.7±0.2°、22.8±0.2°、23.1±0.2°； 9.5±0.2°、10.7±0.2°、18.3±0.2°、19.5±0.2°、22.8±0.2°、23.1±0.2°、25.4±0.2°、25.7±0.2°； 9.5±0.2°、10.7±0.2°、12.7±0.2°、14.9±0.2°、18.3±0.2°、18.9±0.2°、19.5±0.2°、21.1±0.2°； 9.5±0.2°、10.7±0.2°、18.3±0.2°、18.9±0.2°、19.5±0.2°、21.1±0.2°、23.8±0.2°、24.6±0.2°； 9.5±0.2°、10.7±0.2°、12.7±0.2°、14.9±0.2°、15.9±0.2°、18.3±0.2°、19.5±0.2°、21.7±0.2°； 9.5±0.2°、10.7±0.2°、18.3±0.2°、19.5±0.2°、23.8±0.2°、24.6±0.2°、25.4±0.2°、25.7±0.2°； 9.5±0.2°、10.7±0.2°、12.7±0.2°、15.9±0.2°、18.3±0.2°、19.5±0.2°、24.6±0.2°、25.7±0.2°； 9.5±0.2°、10.7±0.2°、15.9±0.2°、18.3±0.2°、19.5±0.2°、21.7±0.2°、22.8±0.2°、23.1±0.2°、25.4±0.2°； 9.5±0.2°、10.7±0.2°、18.3±0.2°、19.5±0.2°、21.7±0.2°、22.8±0.2°、23.1±0.2°、25.4±0.2°、25.7±0.2°； 9.5±0.2°、10.7±0.2°、12.7±0.2°、14.9±0.2°、18.3±0.2°、18.9±0.2°、19.5±0.2°、21.1±0.2°、23.8±0.2°； 9.5±0.2°、10.7±0.2°、14.9±0.2°、18.3±0.2°、18.9±0.2°、19.5±0.2°、21.1±0.2°、23.8±0.2°、24.6±0.2°； Most preferably, the X-ray powder diffraction pattern of the sulfate crystal form A is basically as shown in Figure 48; the TGA-DSC pattern is shown in Figure 49; Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxopiridine-1-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-(ethyl-d5)-1H-pyrazole-5-carboxamide sulfate crystal form B; The X-ray powder diffraction pattern of the sulfate crystal form A shows a diffraction peak at 2θ of 9.6 ± 0.2°; or at 9.9 ± 0.2°; or at 16.1 ± 0.2°; or at 17.7 ± 0.2°; or at 5.4 ± 0.2°; or at 10.8 ± 0.2°; or at 18.3 ± 0.2°. The diffraction peaks are present; or diffraction peaks are present at 19.7±0.2°; or diffraction peaks are present at 21.2±0.2°; or diffraction peaks are present at 23.2±0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks are included; more preferably, any 6, 7, 8, 9, or 10 of the above diffraction peaks are included. The X-ray powder diffraction pattern of the sulfate crystal form B includes at least one or more diffraction peaks located at 2θ of 9.6±0.2°, 9.9±0.2°, 16.1±0.2°, and 17.7±0.2°, preferably two of these peaks, more preferably three or four; even more preferably, it may also include at least one of 2θ of 5.4±0.2°, 10.8±0.2°, 18.3±0.2°, 19.7±0.2°, 21.2±0.2°, and 23.2±0.2°, preferably two, three, four, five, or six of these peaks. More preferably, the X-ray powder diffraction pattern of the sulfate crystal form B includes one or more diffraction peaks located at 5.4±0.2°, 9.6±0.2°, 9.9±0.2°, 10.8±0.2°, 16.1±0.2°, 17.7±0.2°, 18.3±0.2°, 19.7±0.2°, 21.2±0.2°, and 23.2±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 8, or 10 of these locations. More preferably, the X-ray powder diffraction pattern of the sulfate crystal form B may also include one or more diffraction peaks selected from 12.7±0.2°, 15.0±0.2°, 20.1±0.2°, 21.8±0.2°, 24.7±0.2°, and 25.5±0.2°; preferably, it includes at least 2-3, 4-5, or 5-6 peaks; more preferably, it includes any 2, 3, 4, 5, or 6 peaks. For example, the X-ray powder diffraction pattern of the sulfate crystal form B shows diffraction peaks at the following positions with a 2θ value: 9.6±0.2°、9.9±0.2°、16.1±0.2°、17.7±0.2°、5.4±0.2°、10.8±0.2°、18.3±0.2°； 9.6±0.2°、9.9±0.2°、16.1±0.2°、17.7±0.2°、19.7±0.2°、21.2±0.2°、23.2±0.2°； 9.6±0.2°、9.9±0.2°、16.1±0.2°、17.7±0.2°、12.7±0.2°、15.0±0.2°、20.1±0.2°； 9.6±0.2°、9.9±0.2°、16.1±0.2°、17.7±0.2°、21.8±0.2°、24.7±0.2°、25.5±0.2°； 9.6±0.2°、9.9±0.2°、16.1±0.2°、17.7±0.2°、5.4±0.2°、10.8±0.2°、18.3±0.2°、19.7±0.2°； 9.6±0.2°、9.9±0.2°、16.1±0.2°、17.7±0.2°、18.3±0.2°、19.7±0.2°、21.2±0.2°、23.2±0.2°； 9.6±0.2°、9.9±0.2°、16.1±0.2°、17.7±0.2°、12.7±0.2°、15.0±0.2°、20.1±0.2°、21.8±0.2°； 9.6±0.2°、9.9±0.2°、16.1±0.2°、17.7±0.2°、20.1±0.2°、21.8±0.2°、24.7±0.2°、25.5±0.2°； 9.6±0.2°、9.9±0.2°、16.1±0.2°、17.7±0.2°、5.4±0.2°、10.8±0.2°、12.7±0.2°、15.0±0.2°； 9.6±0.2°、9.9±0.2°、16.1±0.2°、17.7±0.2°、21.2±0.2°、23.2±0.2°、12.7±0.2°、15.0±0.2°； 9.6±0.2°、9.9±0.2°、16.1±0.2°、17.7±0.2°、5.4±0.2°、23.2±0.2°、12.7±0.2°、25.5±0.2°； 9.6±0.2°、9.9±0.2°、16.1±0.2°、17.7±0.2°、5.4±0.2°、10.8±0.2°、18.3±0.2°、19.7±0.2°、21.2±0.2°； 9.6±0.2°、9.9±0.2°、16.1±0.2°、17.7±0.2°、10.8±0.2°、18.3±0.2°、19.7±0.2°、21.2±0.2°、23.2±0.2°； 9.6±0.2°、9.9±0.2°、16.1±0.2°、17.7±0.2°、12.7±0.2°、15.0±0.2°、20.1±0.2°、21.8±0.2°、24.7±0.2°； 9.6±0.2°、9.9±0.2°、16.1±0.2°、17.7±0.2°、15.0±0.2°、20.1±0.2°、21.8±0.2°、24.7±0.2°、25.5±0.2°； Most preferably, the X-ray powder diffraction pattern of the sulfate crystal form B is basically as shown in Figure 50; Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxopiridine-1-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-(ethyl-d5)-1H-pyrazole-5-carboxamide maleate crystal form A; The X-ray powder diffraction pattern of the maleate crystal form A shows a diffraction peak at 2θ of 9.6 ± 0.2°; or at 10.0 ± 0.2°; or at 11.1 ± 0.2°; or at 15.8 ± 0.2°; or at 17.9 ± 0.2°; or at 18.4 ± 0.2°; or at 18.7 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 19.0±0.2°; or has diffraction peaks at 19.2±0.2°; or has diffraction peaks at 20.0±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them; The X-ray powder diffraction pattern of the maleate crystal form A includes at least one or more diffraction peaks located at 2θ of 9.6±0.2°, 15.8±0.2°, 18.4±0.2°, and 18.7±0.2°, preferably two, more preferably three or four; even more preferably, it may also include at least one of 2θ of 10.0±0.2°, 11.1±0.2°, 17.9±0.2°, 19.0±0.2°, 19.2±0.2°, and 20.0±0.2°, preferably two, three, four, five, or six. More preferably, the X-ray powder diffraction pattern of the maleate crystal form A includes one or more diffraction peaks located at 9.6±0.2°, 10.0±0.2°, 11.1±0.2°, 15.8±0.2°, 17.9±0.2°, 18.4±0.2°, 18.7±0.2°, 19.0±0.2°, 19.2±0.2°, and 20.0±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 8, or 10 locations. More preferably, the X-ray powder diffraction pattern of the maleate crystal form A may also include one or more diffraction peaks selected from 10.3±0.2°, 10.7±0.2°, 14.5±0.2°, 17.6±0.2°, 19.7±0.2°, and 21.5±0.2°; preferably, it includes at least 2-3, 4-5, or 5-6 peaks; more preferably, it includes any 2, 3, 4, 5, or 6 peaks. For example, the X-ray powder diffraction pattern of the maleate crystal form A has diffraction peaks at the following positions with a 2θ value: 9.6±0.2°、15.8±0.2°、18.4±0.2°、18.7±0.2°、10.0±0.2°、11.1±0.2°、17.9±0.2°； 9.6±0.2°、15.8±0.2°、18.4±0.2°、18.7±0.2°、19.0±0.2°、19.2±0.2°、20.0±0.2°； 9.6±0.2°、15.8±0.2°、18.4±0.2°、18.7±0.2°、10.3±0.2°、10.7±0.2°、14.5±0.2°； 9.6±0.2°、15.8±0.2°、18.4±0.2°、18.7±0.2°、17.6±0.2°、19.7±0.2°、21.5±0.2°； 9.6±0.2°、15.8±0.2°、18.4±0.2°、18.7±0.2°、10.0±0.2°、11.1±0.2°、17.9±0.2°、19.0±0.2°； 9.6±0.2°、15.8±0.2°、18.4±0.2°、18.7±0.2°、17.9±0.2°、19.0±0.2°、19.2±0.2°、20.0±0.2°； 9.6±0.2°、15.8±0.2°、18.4±0.2°、18.7±0.2°、10.3±0.2°、10.7±0.2°、14.5±0.2°、17.6±0.2°； 9.6±0.2°、15.8±0.2°、18.4±0.2°、18.7±0.2°、14.5±0.2°、17.6±0.2°、19.7±0.2°、21.5±0.2°； 9.6±0.2°、15.8±0.2°、18.4±0.2°、18.7±0.2°、10.0±0.2°、11.1±0.2°、10.3±0.2°、10.7±0.2°； 9.6±0.2°、15.8±0.2°、18.4±0.2°、18.7±0.2°、19.2±0.2°、20.0±0.2°、19.7±0.2°、21.5±0.2°； 9.6±0.2°、15.8±0.2°、18.4±0.2°、18.7±0.2°、10.0±0.2°、20.0±0.2°、10.3±0.2°、21.5±0.2°； 9.6±0.2°、15.8±0.2°、18.4±0.2°、18.7±0.2°、10.0±0.2°、11.1±0.2°、17.9±0.2°、19.0±0.2°、19.2±0.2°； 9.6±0.2°、15.8±0.2°、18.4±0.2°、18.7±0.2°、11.1±0.2°、17.9±0.2°、19.0±0.2°、19.2±0.2°、20.0±0.2°； 9.6±0.2°、15.8±0.2°、18.4±0.2°、18.7±0.2°、10.3±0.2°、10.7±0.2°、14.5±0.2°、17.6±0.2°、19.7±0.2°； 9.6±0.2°、15.8±0.2°、18.4±0.2°、18.7±0.2°、10.7±0.2°、14.5±0.2°、17.6±0.2°、19.7±0.2°、21.5±0.2°； Most preferably, the X-ray powder diffraction pattern of the maleate crystal form A is basically as shown in Figure 51; Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxopiridine-1-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-(ethyl-d5)-1H-pyrazole-5-carboxamide benzenesulfonate crystal form A; The X-ray powder diffraction pattern of the benzenesulfonate crystal form A shows a diffraction peak at 2θ of 6.6 ± 0.2°; or at 7.1 ± 0.2°; or at 7.6 ± 0.2°; or at 8.0 ± 0.2°; or at 10.0 ± 0.2°; or at 10.3 ± 0.2°; or at 11.6 ± 0.2°. The diffraction peaks are present; or diffraction peaks are present at 17.2±0.2°; or diffraction peaks are present at 20.8±0.2°; or diffraction peaks are present at 21.0±0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks are included; more preferably, any 6, 7, 8, 9, or 10 of the above diffraction peaks are included. The X-ray powder diffraction pattern of the benzenesulfonate crystal form A includes at least one or more diffraction peaks located at 2θ of 6.6±0.2°, 8.0±0.2°, 10.0±0.2°, and 17.2±0.2°, preferably two, more preferably three or four; even more preferably, it may also include at least one of 2θ of 7.1±0.2°, 7.6±0.2°, 10.3±0.2°, 11.6±0.2°, 20.8±0.2°, and 21.0±0.2°, preferably two, three, four, five, or six. More preferably, the X-ray powder diffraction pattern of the benzenesulfonate crystal form A includes one or more diffraction peaks located at 6.6±0.2°, 7.1±0.2°, 7.6±0.2°, 8.0±0.2°, 10.0±0.2°, 10.3±0.2°, 11.6±0.2°, 17.2±0.2°, 20.8±0.2°, and 21.0±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 8, or 10 of these locations. For example, the X-ray powder diffraction pattern of the benzenesulfonate crystal form A has diffraction peaks at the following positions with a 2θ value: 6.6±0.2°、8.0±0.2°、7.1±0.2°、7.6±0.2°、10.0±0.2°、10.3±0.2°、17.2±0.2°； 6.6±0.2°、8.0±0.2°、10.0±0.2°、11.6±0.2°、17.2±0.2°、20.8±0.2°、21.0±0.2°； 6.6±0.2°、7.1±0.2°、7.6±0.2°、8.0±0.2°、10.0±0.2°、10.3±0.2°、11.6±0.2°、17.2±0.2°； 6.6±0.2°、8.0±0.2°、10.0±0.2°、17.2±0.2°、10.3±0.2°、11.6±0.2°、20.8±0.2°、21.0±0.2°； 6.6±0.2°、7.1±0.2°、7.6±0.2°、8.0±0.2°、10.0±0.2°、10.3±0.2°、11.6±0.2°、17.2±0.2°、20.8±0.2°； 6.6±0.2°、7.6±0.2°、8.0±0.2°、10.0±0.2°、10.3±0.2°、11.6±0.2°、17.2±0.2°、20.8±0.2°、21.0±0.2°； Most preferably, the X-ray powder diffraction pattern of the benzenesulfonate crystal form A is basically as shown in Figure 52; the TGA-DSC pattern is shown in Figure 53; Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxopiridine-1-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-(ethyl-d5)-1H-pyrazole-5-carboxamide phosphate crystal form A; The X-ray powder diffraction pattern of the phosphate crystal form A shows a diffraction peak at 2θ of 4.6 ± 0.2°; or at 8.5 ± 0.2°; or at 13.8 ± 0.2°; or at 18.6 ± 0.2°; or at 9.7 ± 0.2°; or at 10.6 ± 0.2°; or at 12.4 ± 0.2°. The diffraction peaks are present; or diffraction peaks are present at 16.1±0.2°; or diffraction peaks are present at 17.8±0.2°; or diffraction peaks are present at 21.6±0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks are included; more preferably, any 6, 7, 8, 9, or 10 of the above diffraction peaks are included. The X-ray powder diffraction pattern of the phosphate crystal form A includes at least one or more diffraction peaks located at 2θ of 4.6±0.2°, 8.5±0.2°, 13.8±0.2°, and 18.6±0.2°, preferably two of these peaks, more preferably three or four; even more preferably, it may also include at least one of 2θ of 9.7±0.2°, 10.6±0.2°, 12.4±0.2°, 16.1±0.2°, 17.8±0.2°, and 21.6±0.2°, preferably two, three, four, five, or six of these peaks. More preferably, the X-ray powder diffraction pattern of the phosphate crystal form A includes one or more diffraction peaks located at 4.6±0.2°, 8.5±0.2°, 9.7±0.2°, 10.6±0.2°, 12.4±0.2°, 13.8±0.2°, 16.1±0.2°, 17.8±0.2°, 18.6±0.2°, and 21.6±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 8, or 10 of these locations. For example, the X-ray powder diffraction pattern of the phosphate crystal form A has diffraction peaks at the following positions with a 2θ value: 4.6±0.2°、8.5±0.2°、9.7±0.2°、10.6±0.2°、12.4±0.2°、13.8±0.2°、18.6±0.2°； 4.6±0.2°、8.5±0.2°、13.8±0.2°、16.1±0.2°、17.8±0.2°、18.6±0.2°、21.6±0.2°； 4.6±0.2°、8.5±0.2°、9.7±0.2°、10.6±0.2°、12.4±0.2°、13.8±0.2°、16.1±0.2°、18.6±0.2°； 4.6±0.2°、8.5±0.2°、12.4±0.2°、13.8±0.2°、16.1±0.2°、17.8±0.2°、18.6±0.2°、21.6±0.2°； 4.6±0.2°、8.5±0.2°、13.8±0.2°、9.7±0.2°、10.6±0.2°、12.4±0.2°、16.1±0.2°、17.8±0.2°、18.6±0.2°； 4.6±0.2°、8.5±0.2°、10.6±0.2°、12.4±0.2°、13.8±0.2°、16.1±0.2°、17.8±0.2°、18.6±0.2°、21.6±0.2°； Alternatively, it is N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxopiridine-1-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-(ethyl-d5)-1H-pyrazole-5-carboxamide phosphate crystal form B; The X-ray powder diffraction pattern of the phosphate crystal form B shows a diffraction peak at 2θ of 9.6 ± 0.2°; or at 10.7 ± 0.2°; or at 11.3 ± 0.2°; or at 13.4 ± 0.2°; or at 18.7 ± 0.2°; or at 19.0 ± 0.2°; or at 19.6 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 20.9±0.2°; or has diffraction peaks at 21.5±0.2°; or has diffraction peaks at 22.9±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them; The X-ray powder diffraction pattern of the phosphate crystal form B includes at least one or more diffraction peaks located at 2θ of 9.6±0.2°, 11.3±0.2°, 19.0±0.2°, and 21.5±0.2°, preferably two of these peaks, more preferably three or four; even more preferably, it may also include at least one of 2θ of 10.7±0.2°, 13.4±0.2°, 18.7±0.2°, 19.6±0.2°, 20.9±0.2°, and 22.9±0.2°, preferably two, three, four, five, or six of these peaks. More preferably, the X-ray powder diffraction pattern of the phosphate crystal form B includes one or more diffraction peaks located at 9.6±0.2°, 10.7±0.2°, 11.3±0.2°, 13.4±0.2°, 18.7±0.2°, 19.0±0.2°, 19.6±0.2°, 20.9±0.2°, 21.5±0.2°, and 22.9±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 8, or 10 locations. More preferably, the X-ray powder diffraction pattern of the phosphate crystal form B may also include one or more diffraction peaks selected from 12.5±0.2°, 18.0±0.2°, 20.1±0.2°, 22.5±0.2°, 23.7±0.2°, and 26.5±0.2°; preferably, it includes at least 2-3, 4-5, or 5-6 peaks; more preferably, it includes any 2, 3, 4, 5, or 6 peaks. For example, the X-ray powder diffraction pattern of the phosphate crystal form B shows diffraction peaks at the following positions with a 2θ value: 9.6±0.2°、11.3±0.2°、19.0±0.2°、21.5±0.2°、10.7±0.2°、13.4±0.2°、18.7±0.2°； 9.6±0.2°、11.3±0.2°、19.0±0.2°、21.5±0.2°、19.6±0.2°、20.9±0.2°、22.9±0.2°； 9.6±0.2°、11.3±0.2°、19.0±0.2°、21.5±0.2°、12.5±0.2°、18.0±0.2°、20.1±0.2°； 9.6±0.2°、11.3±0.2°、19.0±0.2°、21.5±0.2°、22.5±0.2°、23.7±0.2°、26.5±0.2°； 9.6±0.2°、11.3±0.2°、19.0±0.2°、21.5±0.2°、10.7±0.2°、13.4±0.2°、18.7±0.2°、19.6±0.2°； 9.6±0.2°、11.3±0.2°、19.0±0.2°、21.5±0.2°、18.7±0.2°、19.6±0.2°、20.9±0.2°、22.9±0.2°； 9.6±0.2°、11.3±0.2°、19.0±0.2°、21.5±0.2°、12.5±0.2°、18.0±0.2°、20.1±0.2°、22.5±0.2°； 9.6±0.2°、11.3±0.2°、19.0±0.2°、21.5±0.2°、20.1±0.2°、22.5±0.2°、23.7±0.2°、26.5±0.2°； 9.6±0.2°、11.3±0.2°、19.0±0.2°、21.5±0.2°、10.7±0.2°、13.4±0.2°、12.5±0.2°、18.0±0.2°； 9.6±0.2°、11.3±0.2°、19.0±0.2°、21.5±0.2°、20.9±0.2°、22.9±0.2°、23.7±0.2°、26.5±0.2°； 9.6±0.2°、11.3±0.2°、19.0±0.2°、21.5±0.2°、10.7±0.2°、22.9±0.2°、12.5±0.2°、26.5±0.2°； 9.6±0.2°、11.3±0.2°、19.0±0.2°、21.5±0.2°、10.7±0.2°、13.4±0.2°、18.7±0.2°、19.6±0.2°、20.9±0.2°； 9.6±0.2°、11.3±0.2°、19.0±0.2°、21.5±0.2°、13.4±0.2°、18.7±0.2°、19.6±0.2°、20.9±0.2°、22.9±0.2°； 9.6±0.2°、11.3±0.2°、19.0±0.2°、21.5±0.2°、12.5±0.2°、18.0±0.2°、20.1±0.2°、22.5±0.2°、23.7±0.2°； 9.6±0.2°、11.3±0.2°、19.0±0.2°、21.5±0.2°、18.0±0.2°、20.1±0.2°、22.5±0.2°、23.7±0.2°、26.5±0.2°； Most preferably, the X-ray powder diffraction pattern of the phosphate crystal form B is basically as shown in Figure 54; the TGA-DSC pattern is shown in Figure 55.

9. The acid salt of the compound or its stereoisomer according to any one of claims 6-8, or its crystal form, characterized in that, It is the p-toluenesulfonate crystal form A, p-toluenesulfonate crystal form B, p-toluenesulfonate crystal form C, p-toluenesulfonate crystal form D, p-toluenesulfonate crystal form E, p-toluenesulfonate crystal form F, p-toluenesulfonate crystal form G, p-toluenesulfonate crystal form H, and hydrochloride crystal form of N-((S)-2-((5-((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazo-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide. The 2θ error of the top ten diffraction peaks with the highest relative intensities in the X-ray powder diffraction patterns of type A, hydrochloride type B, hydrobromide type A, hydrobromide type B, hydrobromide type C, hydrobromide type D, benzoate type A, benzoate type B, and fumarate type A, respectively, compared with the corresponding positions in Figures 1, 3, 6, 9, 10, 12, 13, 14, 16, 18, 21, 23, 25, 27, 29, and 31, is ±0.2° to ±0.5°; preferably ±0.2° to ±0.3°, and most preferably ±0.2°. Alternatively, it can be N-((S)-2-((5-(((R)-1-(5,5-difluoro-2-oxopiridine-1-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-(ethyl-d5)-1H-pyrazole-5-carboxamide hydrochloride crystal form A, hydrochloride crystal form B, hydrochloride crystal form C, and hydrochloride crystal form E. The positions of the top ten diffraction peaks with the highest relative intensities in the X-ray powder diffraction patterns of sulfate crystal form A, sulfate crystal form B, maleate crystal form A, benzenesulfonate crystal form A, and phosphate crystal form B have a 2θ error of ±0.2° to ±0.5° with respect to the diffraction peaks at the corresponding positions in Figures 40, 42, 44, 47, 48, 50, 51, 52, and 54, respectively; preferably ±0.2° to ±0.3°, and most preferably ±0.2°.

10. A method for preparing an acid salt of the compound or its stereoisomer as described in any one of claims 1-9, or its crystal form, characterized in that, Includes the following steps: Method 1: 1) Weigh an appropriate amount of free base and dissolve or disperse it in solvent I; 2) Weigh an appropriate amount of the counterion acid, dissolve it in an organic solvent, water, or add it directly to the solid counterion acid; the amount of counterion acid is preferably 1-3 times the equivalent, more preferably 1.1 or 2.1 equivalents; 3) Combine the two solutions mentioned above, and optionally add seed crystals and stir to precipitate, or add solvent II dropwise and then stir to precipitate; preferably, the amount of seed crystals added is 0.05%-10%, more preferably 0.1%-6%, and even more preferably 2%-5%; 4) Centrifugation and vacuum drying yield the target product; Method 2: 1) Weigh an appropriate amount of a certain salt crystal form, dissolve or disperse it with solvent III, and stir or cool to allow crystals to precipitate; 2) Centrifugation and vacuum drying yield the target product; Method 3: 1) Weigh an appropriate amount of a certain salt crystal form and dissolve it in solvent IV; 2) Volatilization and solidification yield the target product; Wherein: Solvent I is selected from one or more of methanol, acetone, ethyl acetate, isopropyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone, 3-pentanone or N-methylpyrrolidone, and water; preferably tert-butanol, acetone, ethyl acetate, 2-butanone, and 2-methyltetrahydrofuran; The organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol, or N,N-dimethylformamide; preferably methanol, ethanol, acetone, or acetonitrile; the above-mentioned benign solvents and organic solutions must be miscible when used. Solvent II is selected from one or more of heptane, cyclohexane, n-hexane, n-pentane, water, ethyl acetate, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, isopropyl acetate, methyl isobutyl ketone, tert-butanol, toluene, or isopropyl ether; preferably one or more of water, heptane, methyl tert-butyl ether, or isopropyl ether. Solvent III is selected from one or more of ethyl acetate, acetone, isopropyl acetate, methyl isobutyl ketone, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclohexane, water, and dichloromethane; The solvent IV is selected from one or more of methanol, ethanol, isopropanol, ethyl acetate, acetonitrile, acetone, 2-butanone, tetrahydrofuran, and water; 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, 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-toluenesulfonic acid, or L-malic acid; preferably hydrochloric acid, hydrobromic acid, or p-toluenesulfonic acid; more preferably p-toluenesulfonic acid.

11. A pharmaceutical composition comprising a therapeutically effective amount of an acid salt of any one of claims 1 to 9 or a stereoisomer thereof or a crystal form thereof, and one or more pharmaceutically acceptable carriers or excipients.

12. The use of the compound or its stereoisomer, an acid salt or crystal form thereof, according to any one of claims 1 to 9, in a medicament for treating and / or preventing IL-17-related diseases, particularly in a medicament for treating and / or preventing IL-17A-related diseases.

13. The use of the compound or its stereoisomer, an acid salt or crystal form thereof, according to any one of claims 1 to 9, in a medicament for treating and / or preventing autoimmune diseases; preferably, the autoimmune disease is selected from psoriasis, plaque psoriasis, punctate psoriasis, retrograde psoriasis, pustular psoriasis, erythrodermic psoriasis, psoriatic arthritis, ankylosing spondylitis, hidradenitis suppurativa, rheumatoid arthritis, palmoplantar psoriasis, spondyloarthritis, and non-infectious uveitis.

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