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

Abstract

Provided are a crystal form of a thiazole derivative inhibitor, and a preparation method therefor and the use thereof. Particularly provided are a crystal form of a compound as represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing a therapeutically effective amount of the crystal form, and the use thereof as an inhibitor in the treatment of autoimmune diseases.

Description

A crystalline form of a thiazole derivative inhibitor, its preparation method and application Technical Field

[0001] This invention belongs to the field of biomedicine, specifically relating to the crystal form of a thiazole derivative inhibitor, 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 object of this invention is to provide a crystal form of the compound of general formula (I) or its stereoisomers.

[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 2-6 alkynyl group, C 1-6Deuterated 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 1-6 Deuterated 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 6-10 Aryl, 5-10 heteroaryl, the amino, C1-6 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; w is 0, 1, 2, 3, 4, 5 or 6;

[0018] j can be 0, 1, 2, 3, 4 or 5; u can be 0, 1, 2, 3, 4 or 5.

[0019] 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...

[0020] 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...

[0021] 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 1-3The haloalkyl group is preferably methyl, ethyl, methoxy, F, -CHF2, -CH2F, -CF3, -CH2CHF2, -CHF2CH3, -CH2CF3, -CH2OCH3, -CH2OCF3 or OCF3.

[0022] In some embodiments of the present invention, 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.

[0023] 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.

[0024] In some embodiments of the present invention, the compound is shown below:

[0025] In some embodiments of the present invention, the crystal form is 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.

[0026] In some embodiments of the present invention, the crystal form 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 crystal form A;

[0027] The X-ray powder diffraction pattern of crystal form A shows a diffraction peak at 2θ of 6.0 ± 0.2°; or at 9.3 ± 0.2°; or at 10.6 ± 0.2°; or at 14.5 ± 0.2°; or at 16.3 ± 0.2°; or at 17.8 ± 0.2°; or at 19.3 ± 0.2°. The diffraction peak is present at 20.0±0.2°; or at 21.6±0.2°; or at 23.1±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.

[0028] 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 crystal form B;

[0029] The X-ray powder diffraction pattern of crystal form B shows a diffraction peak at 2θ of 5.5 ± 0.2°; or at 5.9 ± 0.2°; or at 11.1 ± 0.2°; or at 18.5 ± 0.2°; or at 19.4 ± 0.2°; or at 22.4 ± 0.2°; or at 23.0 ± 0.2°. The diffraction peak is present at 24.0±0.2°; or at 25.9±0.2°; or at 26.7±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.

[0030] 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 crystal form C;

[0031] The X-ray powder diffraction pattern of crystal form C shows a diffraction peak at 2θ of 5.9 ± 0.2°; or at 9.1 ± 0.2°; or at 12.9 ± 0.2°; or at 14.4 ± 0.2°; or at 16.3 ± 0.2°; or at 18.9 ± 0.2°; or at 19.6 ± 0.2°. The diffraction peak is present at 20.8±0.2°; or at 23.3±0.2°; or at 29.0±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.

[0032] 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 crystal form D;

[0033] The X-ray powder diffraction pattern of crystal form D shows a diffraction peak at 2θ of 6.8 ± 0.2°; or at 9.1 ± 0.2°; or at 11.8 ± 0.2°; or at 13.3 ± 0.2°; or at 15.0 ± 0.2°; or at 17.0 ± 0.2°; or at 18.2 ± 0.2°. The diffraction peak is present at 19.2±0.2°; or at 21.9±0.2°; or at 26.9±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.

[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 crystal form E;

[0035] The X-ray powder diffraction pattern of crystal form E shows a diffraction peak at 2θ of 9.2 ± 0.2°; or at 12.1 ± 0.2°; or at 13.5 ± 0.2°; or at 14.0 ± 0.2°; or at 15.2 ± 0.2°; or at 17.1 ± 0.2°; or at 18.6 ± 0.2°. The diffraction peak is present at 19.5±0.2°; or at 22.2±0.2°; or at 26.1±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.

[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 crystal form F;

[0037] The X-ray powder diffraction pattern of crystal form F shows a diffraction peak at 2θ = 7.0 ± 0.2°; or at 9.2 ± 0.2°; or at 12.2 ± 0.2°; or at 13.5 ± 0.2°; or at 14.1 ± 0.2°; or at 15.3 ± 0.2°; or at 17.0 ± 0.2°. The diffraction peak is present at 18.7±0.2°; or at 19.6±0.2°; or at 22.2±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.

[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 crystal form G;

[0039] The X-ray powder diffraction pattern of the crystal form G shows a diffraction peak at 2θ of 9.1 ± 0.2°; or at 12.2 ± 0.2°; or at 13.5 ± 0.2°; or at 15.1 ± 0.2°; or at 16.9 ± 0.2°; or at 18.5 ± 0.2°; or at 19.5 ± 0.2°. The diffraction peak is present at 22.0±0.2°; or at 22.6±0.2°; or at 26.1±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.

[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 crystal form H;

[0041] The X-ray powder diffraction pattern of crystal form H shows a diffraction peak at 2θ of 6.9 ± 0.2°; or at 9.0 ± 0.2°; or at 12.0 ± 0.2°; or at 13.3 ± 0.2°; or at 13.9 ± 0.2°; or at 15.0 ± 0.2°; or at 16.7 ± 0.2°. The diffraction peak is present at 18.5±0.2°; or at 19.4±0.2°; or at 21.8±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 crystal form I;

[0043] The X-ray powder diffraction pattern of crystal form I shows a diffraction peak at 2θ = 7.1 ± 0.2°; or at 9.3 ± 0.2°; or at 12.4 ± 0.2°; or at 13.8 ± 0.2°; or at 14.3 ± 0.2°; or at 15.5 ± 0.2°; or at 17.2 ± 0.2°. The diffraction peak is present at 19.1±0.2°; or at 20.0±0.2°; or at 22.5±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.

[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 crystal form J;

[0045] The X-ray powder diffraction pattern of crystal form J shows a diffraction peak at 2θ of 7.0 ± 0.2°; or at 9.1 ± 0.2°; or at 12.2 ± 0.2°; or at 13.6 ± 0.2°; or at 15.3 ± 0.2°; or at 17.0 ± 0.2°; or at 17.7 ± 0.2°. The diffraction peak is present at 18.8±0.2°; or at 19.7±0.2°; or at 22.2±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.

[0046] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystal form A includes at least one or more diffraction peaks located at 2θ of 9.3±0.2°, 16.3±0.2°, 19.3±0.2°, and 21.6±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 6.0±0.2°, 10.6±0.2°, 14.5±0.2°, 17.8±0.2°, 20.0±0.2°, and 23.1±0.2°, preferably including two, three, four, five, or six such peaks;

[0047] More preferably, the X-ray powder diffraction pattern of crystal form A includes one or more diffraction peaks located at 6.0±0.2°, 9.3±0.2°, 10.6±0.2°, 14.5±0.2°, 16.3±0.2°, 17.8±0.2°, 19.3±0.2°, 20.0±0.2°, 21.6±0.2°, and 23.1±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 8, or 10 of these locations.

[0048] More preferably, the X-ray powder diffraction pattern of crystal form A may also include one or more diffraction peaks with 2θ values ​​of 12.0±0.2°, 13.4±0.2°, 17.1±0.2°, 20.4±0.2°, and 25.9±0.2°; preferably, it includes at least 2-3 peaks, or 4-5 peaks; more preferably, it includes any 2, 3, 4, or 5 peaks.

[0049] For example, the X-ray powder diffraction pattern of crystal form A has diffraction peaks at the following positions with a 2θ value:

[0050] 6.0±0.2°, 9.3±0.2°, 10.6±0.2°, 16.3±0.2°, 19.3±0.2°, 21.6±0.2°, 23.1±0.2°;

[0051] 9.3±0.2°, 10.6±0.2°, 16.3±0.2°, 19.3±0.2°, 20.0±0.2°, 21.6±0.2°, 23.1±0.2°;

[0052] 6.0±0.2°, 9.3±0.2°, 10.6±0.2°, 16.3±0.2°, 19.3±0.2°, 20.0±0.2°, 21.6±0.2°;

[0053] 6.0±0.2°, 9.3±0.2°, 10.6±0.2°, 16.3±0.2°, 19.3±0.2°, 20.0±0.2°, 21.6±0.2°, 23.1±0.2°;

[0054] 6.0±0.2°, 9.3±0.2°, 10.6±0.2°, 16.3±0.2°, 17.8±0.2°, 19.3±0.2°, 21.6±0.2°, 23.1±0.2°;

[0055] 6.0±0.2°, 9.3±0.2°, 10.6±0.2°, 14.5±0.2°, 16.3±0.2°, 19.3±0.2°, 21.6±0.2°, 23.1±0.2°;

[0056] 6.0±0.2°, 9.3±0.2°, 10.6±0.2°, 16.3±0.2°, 17.8±0.2°, 19.3±0.2°, 21.6±0.2°, 23.1±0.2°;

[0057] 6.0±0.2°, 9.3±0.2°, 10.6±0.2°, 16.3±0.2°, 17.8±0.2°, 19.3±0.2°, 20.0±0.2°, 21.6±0.2°, 23.1±0.2°;

[0058] 6.0±0.2°, 9.3±0.2°, 10.6±0.2°, 14.5±0.2°, 16.3±0.2°, 17.8±0.2°, 19.3±0.2°, 21.6±0.2°, 23.1±0.2°;

[0059] 6.0±0.2°, 9.3±0.2°, 10.6±0.2°, 14.5±0.2°, 16.3±0.2°, 19.3±0.2°, 20.0±0.2°, 21.6±0.2°, 23.1±0.2°;

[0060] Most preferably, the X-ray powder diffraction pattern of crystal form A is basically as shown in Figure 1; the TGA-DSC pattern is shown in Figure 2;

[0061] The X-ray powder diffraction pattern of crystal form B includes at least one or more diffraction peaks located at 2θ of 5.5±0.2°, 11.1±0.2°, 18.5±0.2°, and 19.4±0.2°, preferably two, more preferably three; and even more preferably, it may also include at least one of 2θ of 5.9±0.2°, 22.4±0.2°, 23.0±0.2°, 24.0±0.2°, 25.9±0.2°, and 26.7±0.2°, preferably two, three, four, or five.

[0062] 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 5.5±0.2°, 5.9±0.2°, 11.1±0.2°, 18.5±0.2°, 19.4±0.2°, 22.4±0.2°, 23.0±0.2°, 24.0±0.2°, 25.9±0.2°, and 26.7±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 7, 8, or 10 locations.

[0063] For example, the X-ray powder diffraction pattern of crystal form B shows diffraction peaks at the following positions with a 2θ value:

[0064] 5.5±0.2°, 5.9±0.2°, 11.1±0.2°, 18.5±0.2°, 19.4±0.2°, 24.0±0.2°, 25.9±0.2°;

[0065] 5.5±0.2°, 5.9±0.2°, 18.5±0.2°, 19.4±0.2°, 22.4±0.2°, 25.9±0.2°, 26.7±0.2°;

[0066] 5.5±0.2°, 5.9±0.2°, 18.5±0.2°, 19.4±0.2°, 24.0±0.2°, 25.9±0.2°, 26.7±0.2°;

[0067] 5.5±0.2°, 5.9±0.2°, 11.1±0.2°, 18.5±0.2°, 19.4±0.2°, 22.4±0.2°, 24.0±0.2°, 25.9±0.2°;

[0068] Most preferably, the X-ray powder diffraction pattern of crystal form B is basically as shown in Figure 3;

[0069] The X-ray powder diffraction pattern of crystal form C includes at least one or more diffraction peaks located at 2θ of 5.9±0.2°, 9.1±0.2°, 18.9±0.2°, and 19.6±0.2°, preferably two, more preferably three; and even more preferably, it may also include at least one of 2θ of 12.9±0.2°, 14.4±0.2°, 16.3±0.2°, 20.8±0.2°, 23.3±0.2°, and 29.0±0.2°, preferably two, three, four, five, or six.

[0070] More preferably, the X-ray powder diffraction pattern of crystal form C includes one or more diffraction peaks located at 2θ of 5.9±0.2°, 9.1±0.2°, 12.9±0.2°, 14.4±0.2°, 16.3±0.2°, 18.9±0.2°, 19.6±0.2°, 20.8±0.2°, 23.3±0.2°, and 29.0±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 11.9±0.2°, 14.7±0.2°, 17.0±0.2°, 17.7±0.2°, 22.4±0.2°, and 25.4±0.2°, preferably 2, 3, 4, 5, or 6 peaks.

[0071] For example, the X-ray powder diffraction pattern of crystal form C shows diffraction peaks at the following positions with a 2θ value:

[0072] 5.9±0.2°, 9.1±0.2°, 16.3±0.2°, 18.9±0.2°, 19.6±0.2°, 20.8±0.2°, 23.3±0.2°;

[0073] 5.9±0.2°, 9.1±0.2°, 16.3±0.2°, 18.9±0.2°, 19.6±0.2°, 23.3±0.2°, 29.0±0.2°;

[0074] 5.9±0.2°, 9.1±0.2°, 14.4±0.2°, 16.3±0.2°, 18.9±0.2°, 19.6±0.2°, 23.3±0.2°;

[0075] 5.9±0.2°, 9.1±0.2°, 14.4±0.2°, 16.3±0.2°, 18.9±0.2°, 19.6±0.2°, 20.8±0.2°, 23.3±0.2°

[0076] 5.9±0.2°, 9.1±0.2°, 14.4±0.2°, 16.3±0.2°, 18.9±0.2°, 19.6±0.2°, 23.3±0.2°, 29.0±0.2°;

[0077] 5.9±0.2°, 9.1±0.2°, 14.4±0.2°, 16.3±0.2°, 18.9±0.2°, 19.6±0.2°, 20.8±0.2°, 23.3±0.2°, 29.0±0.2°;

[0078] 5.9±0.2°, 9.1±0.2°, 12.9±0.2°, 14.4±0.2°, 16.3±0.2°, 18.9±0.2°, 19.6±0.2°, 20.8±0.2°, 23.3±0.2°;

[0079] Most preferably, the X-ray powder diffraction pattern of crystal form C is basically as shown in Figure 4; the TGA-DSC pattern is shown in Figure 5;

[0080] The X-ray powder diffraction pattern of the crystal form D includes at least one or more diffraction peaks located at 2θ of 13.3±0.2°, 15.0±0.2°, 18.2±0.2°, and 21.9±0.2°, preferably two, more preferably three; and even more preferably, it may also include at least one of 2θ of 6.8±0.2°, 9.1±0.2°, 11.8±0.2°, 17.0±0.2°, 19.2±0.2°, and 26.9±0.2°, preferably two, three, four, five, or six.

[0081] More preferably, the X-ray powder diffraction pattern of the crystal form D includes one or more diffraction peaks located at 2θ of 6.8±0.2°, 9.1±0.2°, 11.8±0.2°, 13.3±0.2°, 15.0±0.2°, 17.0±0.2°, 18.2±0.2°, 19.2±0.2°, 21.9±0.2°, and 26.9±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 13.7±0.2°, 22.9±0.2°, 24.8±0.2°, 25.6±0.2°, 25.9±0.2°, and 27.7±0.2°, preferably 2, 3, 4, 5, or 6 peaks.

[0082] For example, the X-ray powder diffraction pattern of crystal form D shows diffraction peaks at the following positions with a 2θ value:

[0083] 9.1±0.2°, 13.3±0.2°, 15.0±0.2°, 17.0±0.2°, 18.2±0.2°, 19.2±0.2°, 21.9±0.2°;

[0084] 13.3±0.2°, 15.0±0.2°, 17.0±0.2°, 18.2±0.2°, 19.2±0.2°, 21.9±0.2°, 26.9±0.2°;

[0085] 6.8±0.2°, 13.3±0.2°, 15.0±0.2°, 17.0±0.2°, 18.2±0.2°, 19.2±0.2°, 21.9±0.2°;

[0086] 9.1±0.2°, 11.8±0.2°, 13.3±0.2°, 15.0±0.2°, 17.0±0.2°, 18.2±0.2°, 19.2±0.2°, 21.9±0.2°;

[0087] 9.1±0.2°, 13.3±0.2°, 15.0±0.2°, 17.0±0.2°, 18.2±0.2°, 19.2±0.2°, 21.9±0.2°, 26.9±0.2°;

[0088] 6.8±0.2°, 9.1±0.2°, 13.3±0.2°, 15.0±0.2°, 17.0±0.2°, 18.2±0.2°, 19.2±0.2°, 21.9±0.2°;

[0089] Most preferably, the X-ray powder diffraction pattern of the crystal form D is basically as shown in Figure 6; the TGA-DSC pattern is shown in Figure 7;

[0090] The X-ray powder diffraction pattern of the crystal form E includes at least one or more diffraction peaks located at 2θ of 9.2±0.2°, 13.5±0.2°, 15.2±0.2°, and 18.6±0.2°, preferably two, more preferably three; and even more preferably, it may also include at least one of 2θ of 12.1±0.2°, 14.0±0.2°, 17.1±0.2°, 19.5±0.2°, 22.2±0.2°, and 26.1±0.2°, preferably two, three, four, five, or six.

[0091] More preferably, the X-ray powder diffraction pattern of crystal form E includes one or more diffraction peaks located at 2θ of 9.2±0.2°, 12.1±0.2°, 13.5±0.2°, 14.0±0.2°, 15.2±0.2°, 17.1±0.2°, 18.6±0.2°, 19.5±0.2°, 22.2±0.2°, and 26.1±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 7.0±0.2°, 18.0±0.2°, 22.9±0.2°, 24.4±0.2°, 25.4±0.2°, and 27.3±0.2°, preferably 2, 3, 4, 5, or 6 peaks.

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

[0093] 9.2±0.2°, 13.5±0.2°, 14.0±0.2°, 15.2±0.2°, 17.1±0.2°, 18.6±0.2°, 19.5±0.2°;

[0094] 9.2±0.2°, 13.5±0.2°, 15.2±0.2°, 17.1±0.2°, 18.6±0.2°, 19.5±0.2°, 22.2±0.2°;

[0095] 9.2±0.2°, 12.1±0.2°, 13.5±0.2°, 15.2±0.2°, 17.1±0.2°, 18.6±0.2°, 19.5±0.2°;

[0096] 7.0±0.2°, 9.2±0.2°, 13.5±0.2°, 14.0±0.2°, 15.2±0.2°, 17.1±0.2°, 18.6±0.2°, 19.5±0.2°;

[0097] 9.2±0.2°, 12.1±0.2°, 13.5±0.2°, 14.0±0.2°, 15.2±0.2°, 17.1±0.2°, 18.6±0.2°, 19.5±0.2°;

[0098] 9.2±0.2°, 12.1±0.2°, 13.5±0.2°, 15.2±0.2°, 17.1±0.2°, 18.6±0.2°, 19.5±0.2°, 22.2±0.2°;

[0099] 9.2±0.2°, 13.5±0.2°, 14.0±0.2°, 15.2±0.2°, 17.1±0.2°, 18.6±0.2°, 19.5±0.2°, 22.2±0.2°;

[0100] 9.2±0.2°, 12.1±0.2°, 13.5±0.2°, 14.0±0.2°, 15.2±0.2°, 17.1±0.2°, 18.6±0.2°, 19.5±0.2°, 22.2±0.2°;

[0101] Most preferably, the X-ray powder diffraction pattern of the crystal form E is basically as shown in Figure 8;

[0102] The X-ray powder diffraction pattern of the crystal form F includes at least one or more diffraction peaks located at 2θ of 9.2±0.2°, 13.5±0.2°, 15.3±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 7.0±0.2°, 12.2±0.2°, 14.1±0.2°, 17.0±0.2°, 18.7±0.2°, and 19.6±0.2°, preferably two, three, four, five, or six.

[0103] More preferably, the X-ray powder diffraction pattern of the crystal form F includes one or more diffraction peaks located at 2θ of 7.0±0.2°, 9.2±0.2°, 12.2±0.2°, 13.5±0.2°, 14.1±0.2°, 15.3±0.2°, 17.0±0.2°, 18.7±0.2°, 19.6±0.2°, and 22.2±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 17.9±0.2°, 22.8±0.2°, 25.6±0.2°, 26.0±0.2°, 26.3±0.2°, and 27.4±0.2°, preferably 2, 3, 4, 5, or 6 peaks.

[0104] For example, the X-ray powder diffraction pattern of crystal form F shows diffraction peaks at the following positions with a 2θ value:

[0105] 9.2±0.2°, 13.5±0.2°, 15.3±0.2°, 17.0±0.2°, 18.7±0.2°, 19.6±0.2°, 22.2±0.2;

[0106] 7.0±0.2°, 9.2±0.2°, 13.5±0.2°, 15.3±0.2°, 17.0±0.2°, 19.6±0.2°, 22.2±0.2;

[0107] 9.2±0.2°, 13.5±0.2°, 14.1±0.2°, 15.3±0.2°, 17.0±0.2°, 19.6±0.2°, 22.2±0.2;

[0108] 9.2±0.2°, 13.5±0.2°, 14.1±0.2°, 15.3±0.2°, 17.0±0.2°, 18.7±0.2°, 19.6±0.2°, 22.2±0.2;

[0109] 7.0±0.2°, 9.2±0.2°, 113.5±0.2°, 14.1±0.2°, 15.3±0.2°, 17.0±0.2°, 19.6±0.2°, 22.2±0.2;

[0110] 9.2±0.2°, 12.2±0.2°, 13.5±0.2°, 14.1±0.2°, 15.3±0.2°, 17.0±0.2°, 19.6±0.2°, 22.2±0.2;

[0111] 7.0±0.2°, 9.2±0.2°, 13.5±0.2°, 14.1±0.2°, 15.3±0.2°, 17.0±0.2°, 18.7±0.2°, 19.6±0.2°, 22.2±0.2;

[0112] 9.2±0.2°, 12.2±0.2°, 13.5±0.2°, 14.1±0.2°, 15.3±0.2°, 17.0±0.2°, 18.7±0.2°, 19.6±0.2°, 22.2±0.2°;

[0113] Most preferably, the X-ray powder diffraction pattern of the crystal form F is basically as shown in Figure 9; the DSC pattern is shown in Figure 10.

[0114] The X-ray powder diffraction pattern of the crystal form G includes at least one or more diffraction peaks located at 2θ of 15.1±0.2°, 16.9±0.2°, 18.5±0.2°, and 19.5±0.2°, preferably two, more preferably three; and even more preferably, it may also include at least one of 2θ of 9.1±0.2°, 12.2±0.2°, 13.5±0.2°, 22.0±0.2°, 22.6±0.2°, and 26.1±0.2°, preferably two, three, four, five, or six.

[0115] More preferably, the X-ray powder diffraction pattern of the crystal form G includes one or more diffraction points located at 2θ of 9.1±0.2°, 12.2±0.2°, 13.5±0.2°, 15.1±0.2°, 16.9±0.2°, 18.5±0.2°, 19.5±0.2°, 22.0±0.2°, 22.6±0.2°, and 26.1±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 25.1±0.2°, 25.5±0.2°, 25.7±0.2°, 27.1±0.2°, 33.0±0.2° and 37.1±0.2°, preferably including 2, 3, 4, 5 or 6 of them;

[0116] For example, the X-ray powder diffraction pattern of crystal form G shows diffraction peaks at the following positions with a 2θ value:

[0117] 9.1±0.2°, 12.2±0.2°, 15.1±0.2°, 16.9±0.2°, 18.5±0.2°, 19.5±0.2°, 22.0±0.2°;

[0118] 15.1±0.2°, 16.9±0.2°, 18.5±0.2°, 19.5±0.2°, 22.0±0.2°, 22.6±0.2°, 26.1±0.2°;

[0119] 9.1±0.2°, 12.2±0.2°, 13.5±0.2°, 15.1±0.2°, 16.9±0.2°, 18.5±0.2°, 19.5±0.2°;

[0120] 9.1±0.2°, 12.2±0.2°, 13.5±0.2°, 15.1±0.2°, 16.9±0.2°, 18.5±0.2°, 19.5±0.2°, 22.0±0.2°;

[0121] 9.1±0.2°, 12.2±0.2°, 15.1±0.2°, 16.9±0.2°, 18.5±0.2°, 19.5±0.2°, 22.0±0.2°, 26.1±0.2°;

[0122] 9.1±0.2°, 12.2±0.2°, 13.5±0.2°, 15.1±0.2°, 16.9±0.2°, 18.5±0.2°, 19.5±0.2°, 22.0±0.2°, 22.6±0.2°;

[0123] 9.1±0.2°, 12.2±0.2°, 15.1±0.2°, 16.9±0.2°, 18.5±0.2°, 19.5±0.2°, 22.0±0.2°, 22.6±0.2°, 26.1±0.2°;

[0124] Most preferably, the X-ray powder diffraction pattern of the crystal form G is basically as shown in Figure 11;

[0125] The X-ray powder diffraction pattern of the crystal form H includes at least one or more diffraction peaks located at 2θ of 12.0±0.2°, 15.0±0.2°, 18.7±0.2°, and 19.4±0.2°, preferably two, more preferably three; and even more preferably, it may also include at least one of 6.9±0.2°, 9.0±0.2°, 13.3±0.2°, 13.9±0.2°, 16.7±0.2°, and 21.8±0.2°, preferably two, three, four, five, or six of these peaks.

[0126] More preferably, the X-ray powder diffraction pattern of the crystal form H includes one or more diffraction peaks located at 2θ of 6.9±0.2°, 9.0±0.2°, 12.0±0.2°, 13.3±0.2°, 13.9±0.2°, 15.0±0.2°, 16.7±0.2°, 18.5±0.2°, 19.4±0.2°, and 21.8±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 21.0±0.2°, 24.9±0.2°, 25.3±0.2°, 25.9±0.2°, 26.9±0.2°, and 32.8±0.2°, preferably 2, 3, 4, 5, or 6 peaks.

[0127] For example, the X-ray powder diffraction pattern of crystal form H shows diffraction peaks at the following positions with a 2θ value:

[0128] 6.9±0.2°, 12.0±0.2°, 13.3±0.2°, 13.9±0.2°, 15.0±0.2°, 18.5±0.2°, 19.4±0.2°;

[0129] 12.0±0.2°, 13.3±0.2°, 13.9±0.2°, 15.0±0.2°, 18.5±0.2°, 19.4±0.2°, 21.8±0.2°;

[0130] 12.0±0.2°, 13.3±0.2°, 13.9±0.2°, 15.0±0.2°, 16.7±0.2°, 18.5±0.2°, 19.4±0.2°;

[0131] 6.9±0.2°, 9.0±0.2°, 12.0±0.2°, 13.3±0.2°, 13.9±0.2°, 15.0±0.2°, 18.5±0.2°, 19.4±0.2°;

[0132] 12.0±0.2°, 13.3±0.2°, 13.9±0.2°, 15.0±0.2°, 16.7±0.2°, 18.5±0.2°, 19.4±0.2°, 21.8±0.2°;

[0133] 6.9±0.2°, 12.0±0.2°, 13.3±0.2°, 13.9±0.2°, 15.0±0.2°, 18.5±0.2°, 19.4±0.2°, 21.8±0.2°;

[0134] 6.9±0.2°, 9.0±0.2°, 12.0±0.2°, 13.3±0.2°, 13.9±0.2°, 15.0±0.2°, 18.5±0.2°, 19.4±0.2°, 21.8±0.2°;

[0135] Most preferably, the X-ray powder diffraction pattern of the crystal form H is basically as shown in Figure 12;

[0136] The X-ray powder diffraction pattern of crystal form I includes at least one or more diffraction peaks located at 2θ of 7.1±0.2°, 13.8±0.2°, 14.3±0.2°, and 15.5±0.2°, preferably two, more preferably three; and even more preferably, it may also include at least one of 9.3±0.2°, 12.4±0.2°, 17.2±0.2°, 19.1±0.2°, 20.0±0.2°, and 22.5±0.2°, preferably two, three, four, five, or six.

[0137] More preferably, the X-ray powder diffraction pattern of crystal form I includes one or more diffraction peaks located at 2θ of 7.1±0.2°, 9.3±0.2°, 12.4±0.2°, 13.8±0.2°, 14.3±0.2°, 15.5±0.2°, 17.2±0.2°, 19.1±0.2°, 20.0±0.2°, and 22.5±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 21.6±0.2°, 21.8±0.2°, 25.8±0.2°, 26.1±0.2°, 26.8±0.2°, and 33.9±0.2°, preferably 2, 3, 4, 5, or 6 such peaks;

[0138] For example, the X-ray powder diffraction pattern of crystal form I shows diffraction peaks at the following positions with a 2θ value:

[0139] 7.1±0.2°, 9.3±0.2°, 13.8±0.2°, 14.3±0.2°, 15.5±0.2°, 19.1±0.2°, 20.0±0.2°;

[0140] 7.1±0.2°, 9.3±0.2°, 13.8±0.2°, 14.3±0.2°, 15.5±0.2°, 26.1±0.2°, 26.8±0.2°;

[0141] 7.1±0.2°, 9.3±0.2°, 12.4±0.2°, 13.8±0.2°, 14.3±0.2°, 15.5±0.2°, 22.5±0.2°;

[0142] 7.1±0.2°, 9.3±0.2°, 13.8±0.2°, 14.3±0.2°, 15.5±0.2°, 19.1±0.2°, 22.5±0.2°;

[0143] 7.1±0.2°, 9.3±0.2°, 13.8±0.2°, 14.3±0.2°, 15.5±0.2°, 19.1±0.2°, 20.0±0.2°, 26.1±0.2°;

[0144] 7.1±0.2°, 9.3±0.2°, 13.8±0.2°, 14.3±0.2°, 15.5±0.2°, 19.1±0.2°, 20.0±0.2°, 22.5±0.2°;

[0145] 7.1±0.2°, 9.3±0.2°, 12.4±0.2°, 13.8±0.2°, 14.3±0.2°, 15.5±0.2°, 19.1±0.2°, 20.0±0.2°;

[0146] 7.1±0.2°, 9.3±0.2°, 12.4±0.2°, 13.8±0.2°, 14.3±0.2°, 15.5±0.2°, 19.1±0.2°, 20.0±0.2°, 22.5±0.2°;

[0147] 7.1±0.2°, 9.3±0.2°, 12.4±0.2°, 13.8±0.2°, 14.3±0.2°, 15.5±0.2°, 17.2±0.2°, 19.1±0.2°, 20.0±0.2°;

[0148] Most preferably, the X-ray powder diffraction pattern of crystal form I is basically as shown in Figure 13; the TGA-DSC pattern is shown in Figure 14;

[0149] The X-ray powder diffraction pattern of crystal form J includes at least one or more diffraction peaks located at 2θ of 9.1±0.2°, 13.6±0.2°, 15.3±0.2°, and 17.0±0.2°, preferably two, more preferably three; and even more preferably, it may also include at least one of 7.0±0.2°, 12.2±0.2°, 17.7±0.2°, 18.8±0.2°, 19.7±0.2°, and 22.2±0.2°, preferably two, three, four, five, or six.

[0150] More preferably, the X-ray powder diffraction pattern of crystal form J includes one or more diffraction peaks located at 2θ of 7.0±0.2°, 9.1±0.2°, 12.2±0.2°, 13.6±0.2°, 15.3±0.2°, 17.0±0.2°, 17.7±0.2°, 18.8±0.2°, 19.7±0.2°, and 22.2±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 14.1±0.2°, 21.6±0.2°, 22.7±0.2°, 25.9±0.2°, 26.4±0.2°, and 27.5±0.2°, preferably 2, 3, 4, 5, or 6 peaks.

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

[0152] 9.1±0.2°, 13.6±0.2°, 15.3±0.2°, 17.0±0.2°, 18.8±0.2°, 19.7±0.2°, 22.2±0.2°;

[0153] 9.1±0.2°, 13.6±0.2°, 15.3±0.2°, 17.0±0.2°, 17.7±0.2°, 19.7±0.2°, 22.2±0.2°;

[0154] 7.0±0.2°, 9.1±0.2°, 13.6±0.2°, 15.3±0.2°, 17.0±0.2°, 19.7±0.2°, 22.2±0.2°;

[0155] 7.0±0.2°, 9.1±0.2°, 13.6±0.2°, 15.3±0.2°, 17.0±0.2°, 17.7±0.2°, 19.7±0.2°;

[0156] 9.1±0.2°, 13.6±0.2°, 14.1±0.2°, 15.3±0.2°, 17.0±0.2°, 19.7±0.2°, 22.2±0.2°;

[0157] 9.1±0.2°, 13.6±0.2°, 15.3±0.2°, 17.0±0.2°, 17.7±0.2°, 18.8±0.2°, 19.7±0.2°, 22.2±0.2°;

[0158] 7.0±0.2°, 9.1±0.2°, 13.6±0.2°, 15.3±0.2°, 17.0±0.2°, 18.8±0.2°, 19.7±0.2°, 22.2±0.2°;

[0159] 7.0±0.2°, 9.1±0.2°, 12.2±0.2°, 13.6±0.2°, 15.3±0.2°, 17.0±0.2°, 19.7±0.2°, 22.2±0.2°;

[0160] 9.1±0.2°, 13.6±0.2°, 14.1±0.2°, 15.3±0.2°, 17.0±0.2°, 18.8±0.2°, 19.7±0.2°, 22.2±0.2°;

[0161] 9.1±0.2°, 12.2±0.2°, 13.6±0.2°, 15.3±0.2°, 17.0±0.2°, 17.7±0.2°, 18.8±0.2°, 19.7±0.2°, 22.2±0.2°;

[0162] 7.0±0.2°, 9.1±0.2°, 13.6±0.2°, 15.3±0.2°, 17.0±0.2°, 17.7±0.2°, 18.8±0.2°, 19.7±0.2°, 22.2±0.2°;

[0163] 7.0±0.2°, 9.1±0.2°, 12.2±0.2°, 13.6±0.2°, 15.3±0.2°, 17.0±0.2°, 17.7±0.2°, 18.8±0.2°, 19.7±0.2°;

[0164] Most preferably, the X-ray powder diffraction pattern of crystal form J is basically as shown in Figure 15; the TGA-DSC pattern is shown in Figure 16.

[0165] In certain embodiments of the present invention, the crystal form of the compound or its stereoisomer 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 crystal form A;

[0166] The X-ray powder diffraction pattern of crystal form A shows a diffraction peak at 2θ = 6.8 ± 0.2°; or at 7.2 ± 0.2°; or at 7.6 ± 0.2°; or at 9.9 ± 0.2°; or at 5.8 ± 0.2°; or at 9.3 ± 0.2°; or at 16.2 ± 0.2°. Or it has a diffraction peak at 16.7±0.2°; or it has a diffraction peak at 17.7±0.2°; or it has a diffraction peak at 19.9±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;

[0167] The X-ray powder diffraction pattern of crystal form A includes at least one or more diffraction peaks located at 2θ of 6.8±0.2°, 7.2±0.2°, 7.6±0.2°, and 9.9±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 5.8±0.2°, 9.3±0.2°, 16.2±0.2°, 16.7±0.2°, 17.7±0.2°, and 19.9±0.2°, preferably including two, three, four, five, or six such peaks;

[0168] More preferably, the X-ray powder diffraction pattern of crystal form A includes one or more diffraction peaks located at 6.8±0.2°, 7.2±0.2°, 7.6±0.2°, 9.9±0.2°, 5.8±0.2°, 9.3±0.2°, 16.2±0.2°, 16.7±0.2°, 17.7±0.2°, and 19.9±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 8, or 10 of these locations.

[0169] More preferably, the X-ray powder diffraction pattern of crystal form A may also include one or more diffraction peaks with 2θ values ​​of 11.2±0.2°, 13.9±0.2°, 17.5±0.2°, 18.3±0.2°, 19.0±0.2°, and 21.4±0.2°; preferably, it includes at least 2-3 peaks, or 4-5 peaks; more preferably, it includes any 2, 3, 4, 5, or 6 peaks.

[0170] For example, the X-ray powder diffraction pattern of crystal form A has diffraction peaks at the following positions with a 2θ value:

[0171] 5.8±0.2°, 6.8±0.2°, 7.2±0.2°, 7.6±0.2°, 9.3±0.2°, 9.9±0.2°, 16.2±0.2°;

[0172] 6.8±0.2°, 7.2±0.2°, 7.6±0.2°, 9.9±0.2°, 16.7±0.2°, 17.7±0.2°, 19.9±0.2°;

[0173] 6.8±0.2°, 7.2±0.2°, 7.6±0.2°, 9.9±0.2°, 11.2±0.2°, 13.9±0.2°, 17.5±0.2°;

[0174] 6.8±0.2°, 7.2±0.2°, 7.6±0.2°, 9.9±0.2°, 18.3±0.2°, 19.0±0.2°, 21.4±0.2;

[0175] 5.8±0.2°, 6.8±0.2°, 7.2±0.2°, 7.6±0.2°, 9.3±0.2°, 9.9±0.2°, 16.2±0.2°, 16.7±0.2°;

[0176] 6.8±0.2°, 7.2±0.2°, 7.6±0.2°, 9.9±0.2°, 16.2±0.2°, 16.7±0.2°, 17.7±0.2°, 19.9±0.2°;

[0177] 6.8±0.2°, 7.2±0.2°, 7.6±0.2°, 9.9±0.2°, 11.2±0.2°, 13.9±0.2°, 17.5±0.2°, 18.3±0.2°;

[0178] 6.8±0.2°, 7.2±0.2°, 7.6±0.2°, 9.9±0.2°, 17.5±0.2°, 18.3±0.2°, 19.0±0.2°, 21.4±0.2°;

[0179] 5.8±0.2°, 6.8±0.2°, 7.2±0.2°, 7.6±0.2°, 9.3±0.2°, 9.9±0.2°, 11.2±0.2°, 13.9±0.2°;

[0180] 6.8±0.2°, 7.2±0.2°, 7.6±0.2°, 9.9±0.2°, 17.7±0.2°, 19.9±0.2°, 19.0±0.2°, 21.4±0.2;

[0181] 5.8±0.2°, 6.8±0.2°, 7.2±0.2°, 7.6±0.2°, 9.9±0.2°, 19.9±0.2°, 11.2±0.2°, 21.4±0.2°;

[0182] 5.8±0.2°, 6.8±0.2°, 7.2±0.2°, 7.6±0.2°, 9.3±0.2°, 9.9±0.2°, 16.2±0.2°, 16.7±0.2°, 17.7±0.2°;

[0183] 6.8±0.2°, 7.2±0.2°, 7.6±0.2°, 9.3±0.2°, 9.9±0.2°, 16.2±0.2°, 16.7±0.2°, 17.7±0.2°, 19.9±0.2°;

[0184] 6.8±0.2°, 7.2±0.2°, 7.6±0.2°, 9.9±0.2°, 11.2±0.2°, 13.9±0.2°, 17.5±0.2°, 18.3±0.2°, 19.0±0.2°;

[0185] 6.8±0.2°, 7.2±0.2°, 7.6±0.2°, 9.9±0.2°, 13.9±0.2°, 17.5±0.2°, 18.3±0.2°, 19.0±0.2°, 21.4±0.2°;

[0186] Most preferably, the X-ray powder diffraction pattern of crystal form A is basically as shown in Figure 17; the TGA-DSC pattern is shown in Figure 18;

[0187] 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 crystal form B;

[0188] The X-ray powder diffraction pattern of crystal form B shows a diffraction peak at 2θ of 5.9 ± 0.2°; or at 9.3 ± 0.2°; or at 19.0 ± 0.2°; or at 21.3 ± 0.2°; or at 14.9 ± 0.2°; or at 16.8 ± 0.2°; or at 17.6 ± 0.2°. The diffraction peak is present at 22.3±0.2°; or at 22.7±0.2°; or at 25.1±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.

[0189] The X-ray powder diffraction pattern of crystal form B includes at least one or more diffraction peaks located at 2θ of 5.9±0.2°, 9.3±0.2°, 19.0±0.2°, and 21.3±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 14.9±0.2°, 16.8±0.2°, 17.6±0.2°, 22.3±0.2°, 22.7±0.2°, and 25.1±0.2°, preferably two, three, four, five, or six of these peaks.

[0190] More preferably, the X-ray powder diffraction pattern of crystal form B includes one or more diffraction peaks located at 5.9±0.2°, 9.3±0.2°, 14.9±0.2°, 16.8±0.2°, 17.6±0.2°, 19.0±0.2°, 21.3±0.2°, 22.3±0.2°, 22.7±0.2°, and 25.1±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 8, or 10 of these locations.

[0191] More preferably, the X-ray powder diffraction pattern of crystal form B may also include one or more diffraction peaks with 2θ values ​​of 10.6±0.2°, 11.7±0.2°, 17.8±0.2°, 19.6±0.2°, 22.9±0.2°, and 27.9±0.2°; preferably, it includes at least 2-3 peaks, or 4-5 peaks; more preferably, it includes any 2, 3, 4, 5, or 6 peaks.

[0192] For example, the X-ray powder diffraction pattern of crystal form B has diffraction peaks at the following positions with a 2θ value:

[0193] 5.9±0.2°、9.3±0.2°、14.9±0.2°、16.8±0.2°、17.6±0.2°、19.0±0.2°、21.3±0.2°；

[0194] 5.9±0.2°、9.3±0.2°、19.0±0.2°、21.3±0.2°、22.3±0.2°、22.7±0.2°、25.1±0.2°；

[0195] 5.9±0.2°、9.3±0.2°、10.6±0.2°、11.7±0.2°、17.8±0.2°、19.0±0.2°、21.3±0.2°；

[0196] 5.9±0.2°、9.3±0.2°、19.0±0.2°、21.3±0.2°、19.6±0.2°、22.9±0.2°、27.9±0.2°；

[0197] 5.9±0.2°、9.3±0.2°、14.9±0.2°、16.8±0.2°、17.6±0.2°、19.0±0.2°、21.3±0.2°、22.3±0.2°；

[0198] 5.9±0.2°、9.3±0.2°、17.6±0.2°、19.0±0.2°、21.3±0.2°、22.3±0.2°、22.7±0.2°、25.1±0.2°；

[0199] 5.9±0.2°、9.3±0.2°、10.6±0.2°、11.7±0.2°、17.8±0.2°、19.0±0.2°、19.6±0.2°、21.3±0.2°；

[0200] 5.9±0.2°、9.3±0.2°、19.0±0.2°、21.3±0.2°、17.8±0.2°、19.6±0.2°、22.9±0.2°、27.9±0.2°；

[0201] 5.9±0.2°、9.3±0.2°、10.6±0.2°、14.9±0.2°、19.0±0.2°、21.3±0.2°、25.1±0.2°、27.9±0.2°；

[0202] 5.9±0.2°、9.3±0.2°、11.7±0.2°、16.8±0.2°、17.6±0.2°、17.8±0.2°、19.0±0.2°、21.3±0.2°；

[0203] 5.9±0.2°, 9.3±0.2°, 14.9±0.2°, 16.8±0.2°, 19.0±0.2°, 21.3±0.2°, 22.9±0.2°, 27.9±0.2°;

[0204] 5.9±0.2°, 9.3±0.2°, 14.9±0.2°, 16.8±0.2°, 17.6±0.2°, 19.0±0.2°, 21.3±0.2°, 22.3±0.2°, 22.7±0.2°;

[0205] 5.9±0.2°, 9.3±0.2°, 16.8±0.2°, 17.6±0.2°, 19.0±0.2°, 21.3±0.2°, 22.3±0.2°, 22.7±0.2°, 25.1±0.2°;

[0206] 5.9±0.2°, 9.3±0.2°, 10.6±0.2°, 11.7±0.2°, 17.8±0.2°, 19.0±0.2°, 19.6±0.2°, 21.3±0.2°, 22.9±0.2°;

[0207] 5.9±0.2°, 9.3±0.2°, 11.7±0.2°, 17.8±0.2°, 19.0±0.2°, 19.6±0.2°, 21.3±0.2°, 22.9±0.2°, 27.9±0.2°;

[0208] Most preferably, the X-ray powder diffraction pattern of crystal form B is basically as shown in Figure 19; the TGA-DSC pattern is shown in Figure 20.

[0209] 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 crystal form C;

[0210] The X-ray powder diffraction pattern of crystal form C shows a diffraction peak at 2θ of 8.0 ± 0.2°; or at 9.5 ± 0.2°; or at 11.5 ± 0.2°; or at 16.5 ± 0.2°; or at 9.7 ± 0.2°; or at 13.2 ± 0.2°; or at 14.4 ± 0.2°. The peak; or a diffraction peak at 18.8±0.2°; or a diffraction peak at 19.6±0.2°; or a diffraction peak at 22.3±0.2°; preferably including any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably including any 6, 7, 8, 9, or 10 of them;

[0211] The X-ray powder diffraction pattern of crystal form C includes at least one or more diffraction peaks located at 2θ of 8.0±0.2°, 9.5±0.2°, 11.5±0.2°, and 16.5±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 9.7±0.2°, 13.2±0.2°, 14.4±0.2°, 18.8±0.2°, 19.6±0.2°, and 22.3±0.2°, preferably two, three, four, five, or six of these peaks.

[0212] More preferably, the X-ray powder diffraction pattern of crystal form C includes one or more diffraction peaks located at 8.0±0.2°, 9.5±0.2°, 9.7±0.2°, 11.5±0.2°, 13.2±0.2°, 14.4±0.2°, 16.5±0.2°, 18.8±0.2°, 19.6±0.2°, and 22.3±0.2°; preferably, it includes diffraction peaks at any of the selected 4, 5, 6, 8, or 10 locations.

[0213] More preferably, the X-ray powder diffraction pattern of crystal form C may also include one or more diffraction peaks with 2θ values ​​of 15.1±0.2°, 16.2±0.2°, 21.0±0.2°, 21.9±0.2°, 25.2±0.2°, and 29.2±0.2°; preferably, it includes at least 2-3 peaks, or 4-5 peaks; more preferably, it includes any 2, 3, 4, 5, or 6 peaks.

[0214] For example, the X-ray powder diffraction pattern of crystal form C shows diffraction peaks at the following positions with a 2θ value:

[0215] 8.0±0.2°、9.5±0.2°、11.5±0.2°、16.5±0.2°、9.7±0.2°、13.2±0.2°、14.4±0.2°；

[0216] 8.0±0.2°、9.5±0.2°、11.5±0.2°、16.5±0.2°、18.8±0.2°、19.6±0.2°、22.3±0.2°；

[0217] 8.0±0.2°、9.5±0.2°、11.5±0.2°、16.5±0.2°、15.1±0.2°、16.2±0.2°、21.0±0.2°；

[0218] 8.0±0.2°、9.5±0.2°、11.5±0.2°、16.5±0.2°、21.9±0.2°、25.2±0.2°、29.2±0.2°；

[0219] 8.0±0.2°、9.5±0.2°、11.5±0.2°、16.5±0.2°、9.7±0.2°、13.2±0.2°、14.4±0.2°、18.8±0.2°；

[0220] 8.0±0.2°、9.5±0.2°、11.5±0.2°、16.5±0.2°、14.4±0.2°、18.8±0.2°、19.6±0.2°、22.3±0.2°；

[0221] 8.0±0.2°、9.5±0.2°、11.5±0.2°、16.5±0.2°、15.1±0.2°、16.2±0.2°、21.0±0.2°、21.9±0.2°；

[0222] 8.0±0.2°、9.5±0.2°、11.5±0.2°、16.5±0.2°、21.0±0.2°、21.9±0.2°、25.2±0.2°、29.2±0.2°；

[0223] 8.0±0.2°、9.5±0.2°、11.5±0.2°、16.5±0.2°、9.7±0.2°、13.2±0.2°、15.1±0.2°、16.2±0.2°；

[0224] 8.0±0.2°、9.5±0.2°、11.5±0.2°、16.5±0.2°、19.6±0.2°、22.3±0.2°、25.2±0.2°、29.2±0.2°；

[0225] 8.0±0.2°, 9.5±0.2°, 11.5±0.2°, 16.5±0.2°, 9.7±0.2°, 22.3±0.2°, 15.1±0.2°, 29.2±0.2°;

[0226] 8.0±0.2°, 9.5±0.2°, 11.5±0.2°, 16.5±0.2°, 9.7±0.2°, 13.2±0.2°, 14.4±0.2°, 18.8±0.2°, 19.6±0.2°;

[0227] 8.0±0.2°, 9.5±0.2°, 11.5±0.2°, 16.5±0.2°, 13.2±0.2°, 14.4±0.2°, 18.8±0.2°, 19.6±0.2°, 22.3±0.2°;

[0228] 8.0±0.2°, 9.5±0.2°, 11.5±0.2°, 16.5±0.2°, 15.1±0.2°, 16.2±0.2°, 21.0±0.2°, 21.9±0.2°, 25.2±0.2°;

[0229] 8.0±0.2°, 9.5±0.2°, 11.5±0.2°, 16.5±0.2°, 16.2±0.2°, 21.0±0.2°, 21.9±0.2°, 25.2±0.2°, 29.2±0.2°;

[0230] Most preferably, the X-ray powder diffraction pattern of crystal form C is basically as shown in Figure 21; the TGA-DSC pattern is shown in Figure 22.

[0231] In certain embodiments of the present invention, the 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 crystal form A, crystal form B, and crystal form The positions of the top ten diffraction peaks with the highest relative peak intensities in the X-ray powder diffraction patterns of crystal forms C, D, E, F, G, H, I, and J have a 2θ error of ±0.2° to ±0.5° compared with the corresponding positions of the diffraction peaks in Figures 1, 3, 4, 6, 8, 9, 11, 12, 13, and 15; preferably ±0.2° to ±0.3°, and most preferably ±0.2°.

[0232] In certain embodiments of the present invention, the positions of the top ten diffraction peaks with the highest relative intensities in the X-ray powder diffraction patterns of 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 crystal forms A, B, and C have a 2θ error of ±0.2° to ±0.5° compared with the corresponding positions of the diffraction peaks in Figures 17, 19, and 21, respectively; preferably ±0.2° to ±0.3°, and most preferably ±0.2°.

[0233] The present invention also provides a method for preparing the crystal form or eutectic of the compound or its stereoisomer as described above, which are methods one to three;

[0234] Method 1: Add the compound to a poor solvent, stir or slurry, and optionally centrifuge to obtain the corresponding crystal form;

[0235] Method 2: Dissolve the compound or a certain crystal form in a good solvent, optionally add seed crystals, stir or cool to crystallize, centrifuge to obtain the corresponding crystal form; preferably, the amount of seed crystals added is 0.05%-10%, more preferably 0.1%-6%, more preferably 1%-5%;

[0236] Method 3: Dissolve the compound or a certain crystal form in a good solvent, volatilize, and obtain the corresponding crystal form;

[0237] The unsuitable solvent is selected from one or more of acetone, ethyl acetate, isopropyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone, 3-pentanone, methyl tert-butyl ether, water, cyclohexane, and n-heptane; preferably one or more of water, methanol, ethanol, isopropanol, and acetone.

[0238] The good solvent is selected from one or more of dimethyl sulfoxide, acetic acid, methanol, acetone, ethanol, isopropanol, ethyl acetate, acetonitrile, 88% acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone, 3-pentanone, N-methylpyrrolidone, methyl isobutyl ketone, and water.

[0239] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the crystalline form or cocrystal of the compound described above or its stereoisomers, and one or more pharmaceutically acceptable carriers or excipients.

[0240] The present invention also provides the use of the crystalline form or eutectic of the compound or its stereoisomer as described above, 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.

[0241] The present invention also provides the use of the crystalline form or cocrystal of the compound or its stereoisomer as described above, or the pharmaceutical composition as described above, 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.

[0242] The present invention also provides a method for treating and / or preventing autoimmune diseases, comprising administering to a desired subject the crystalline or cocrystal form of the compound as described above or its stereoisomers, or the 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.

[0243] Detailed description of the invention

[0244] "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.

[0245] "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.

[0246] 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 (C1- 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... 1-6 The 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.

[0247] 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.

[0248] 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 having a carbon atom content of 3 to 20. 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 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.

[0249] 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 having a carbon atom content of 3 to 20. 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.

[0250] 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.

[0251] 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:

[0252] 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:

[0253] 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:

[0254] 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.

[0255] 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:

[0256] 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:

[0257] 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:

[0258] 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),

[0259] 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.

[0260] 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,

[0261] 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.

[0262] 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.

[0263] 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.

[0264] The term "alkylacyl" refers to -C(O)-alkyl, where the definition of alkyl is as described above.

[0265] 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,

[0266] 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.

[0267] 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.

[0268] The term "aminocarbonyl" refers to NH2-C(O)-.

[0269] 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.

[0270] 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.

[0271] 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.

[0272] "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).

[0273] 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.

[0274] "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.

[0275] "Stereoisomers" encompass all enantiomers / non-corresponding isomers / stereoisomers of the present invention, as well as enantiomers / non-corresponding isomers / stereoisomers enriched in this invention.

[0276] "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.

[0277] "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%.

[0278] "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.

[0279] "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.

[0280] 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

[0281] Figure 1 shows the XRPD spectrum of the free alkali crystal form A of compound A in Example 7.

[0282] Figure 2 shows the TGA-DSC spectrum of the free alkali crystal form A of compound A in Example 7.

[0283] Figure 3 shows the XRPD spectrum of the free alkali crystal form B of compound B in Example 7.

[0284] Figure 4 shows the XRPD spectrum of the free alkali crystal form C of compound C in Example 7.

[0285] Figure 5 shows the TGA-DSC spectrum of the free alkali crystal form C of compound C in Example 7.

[0286] Figure 6 shows the XRPD spectrum of the free alkali crystal form D of compound in Example 7.

[0287] Figure 7 shows the TGA-DSC spectrum of the free alkali crystal form D of compound 7 in Example 7.

[0288] Figure 8 shows the XRPD spectrum of the free alkali crystal form E of compound E in Example 7.

[0289] Figure 9 shows the XRPD spectrum of the free alkali crystal form F of compound F in Example 7.

[0290] Figure 10 shows the DSC spectrum of the free alkali crystal form F of compound 7 in Example 7.

[0291] Figure 11 shows the XRPD spectrum of the free alkali crystal form G of compound 7 in Example 7.

[0292] Figure 12 shows the XRPD spectrum of the free alkali crystal form H of compound 7 in Example 7.

[0293] Figure 13 shows the XRPD spectrum of the free alkali crystal form I of compound 7 in Example 7.

[0294] Figure 14 shows the TGA-DSC spectrum of the free alkali crystal form I of compound 7 in Example 7.

[0295] Figure 15 shows the XRPD spectrum of the free alkali crystal form J of compound J in Example 7.

[0296] Figure 16 shows the TGA-DSC spectrum of the free alkali crystal form J of compound J in Example 7.

[0297] Figure 17 shows the XRPD spectrum of the free alkali crystal form A of compound in Example 3.

[0298] Figure 18 shows the TGA-DSC spectrum of the free alkali crystal form A of compound A in Example 3.

[0299] Figure 19 shows the XRPD spectrum of the free alkali crystal form B of compound B in Example 3.

[0300] Figure 20 shows the TGA-DSC spectrum of the free alkali crystal form B of compound B in Example 3.

[0301] Figure 21 shows the XRPD spectrum of the free alkali crystal form C of compound C in Example 3.

[0302] Figure 22 shows the TGA-DSC spectrum of the free alkali crystal form C of compound C in Example 3. Detailed Implementation

[0303] 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.

[0304] I. Preparation of Compounds

[0305] Example

[0306] 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.

[0307] 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).

[0308] 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.

[0309] 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.

[0310] 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.

[0311] Preparation of Intermediate 1

[0312] Step 1: Preparation of tert-butyl (5-(2-methoxyacetyl)thiazolyl-2-yl)carbamate

[0313] 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] + .

[0314] Step 2: Preparation of tert-butyl(5-(1-((3-amino-2,2-difluoropropyl)amino)-2-methoxyethyl)thiazolyl-2-yl)carbamate

[0315] 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] + .

[0316] Step 3: Preparation of tert-butyl(5-(1-(5,5-difluoro-2-carbonyltetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)thiazolyl-2-yl)carbamate

[0317] 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] + .

[0318] Preparation of intermediate 2

[0319] Step 1: Preparation of tert-butyl (5-(1-hydroxy-2-methoxyethyl)thiazolyl-2-yl)carbamate

[0320] 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] +.

[0321] Step 2: Preparation of 1-(2-((tert-butoxycarbonyl)amino)thiazolyl)-2-methoxyethyl 4-methylbenzenesulfonate

[0322] 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] +.

[0323] Step 3: Preparation of tert-butyl(5-(1-(5,5-difluoro-2-carbonylpiperidin-1-yl)-2-methoxyethyl)thiazolyl-2-yl)carbamate

[0324] 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] + .

[0325] Preparation of intermediate 3

[0326] Step 1: Preparation of N-methoxy-N-methyl-2-morpholinoacetamide

[0327] 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] + .

[0328] Step 2: Preparation of tert-butyl(5-(2-morpholinoacetyl)thiazolyl-2-yl)carbamate

[0329] 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] + .

[0330] Step 3: Preparation of tert-butyl (5-(1-hydroxy-2-morpholinoethyl)thiazolyl-2-yl)carbamate

[0331] 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] + .

[0332] Preparation of intermediate 4

[0333] Step 1: Preparation of 1-(1-(2-aminothiazol-5-yl)-2-hydroxyethyl)-5,5-difluoropiperidin-2-one

[0334] 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] + .

[0335] Step 2: Preparation of tert-butyl(5-(1-(5,5-difluoro-2-oxopiridin-1-yl)-2-hydroxyethyl)thiazolyl-2-yl)carbamate

[0336] 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] + .

[0337] Step 3: Preparation of tert-butyl(5-(1-(5,5-difluoro-2-oxopiperidin-1-yl)-2-oxoethyl)thiazolyl-2-yl)carbamate

[0338] 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] + .

[0339] Preparation of Example 1

[0340] 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

[0341] 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] + .

[0342] Step 2: Preparation of nitrogen-[5-[1-(5,5-difluoro-2-carbonyl-hexahydropyrimidin-1-yl)-2-morpholino-ethyl]thiazolyl-2-yl]tert-butyl carbamate

[0343] 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] + .

[0344] 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

[0345] 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] + .

[0346] 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

[0347] 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%).

[0348] 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] + .

[0349] Preparation of Example 2

[0350] Step 1: Preparation of tert-butyl(5-(1-(5,5-difluoro-2-oxopiperidin-1-yl)-2-morpholinoethyl)thiazolyl-2-yl)carbamate

[0351] 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] + .

[0352] Step 2: Preparation of 1-(1-(2-aminothiazolyl-5-yl)-2-morpholinoethyl)-5,5-difluoropiperidin-2-one

[0353] 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] + .

[0354] 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

[0355] (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] + .

[0356] 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

[0357] 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] + .

[0358] 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

[0359] 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%).

[0360] 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] + .

[0361] Preparation of Example 3

[0362] Step 1: Preparation of tert-butyl(5-(1-(5,5-difluoro-2-oxopiridin-1-yl)-2-((R)-2-methylmorpholino)ethyl)thiazolyl-2-yl)carbamate

[0363] 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] + .

[0364] Step 2: Preparation of 1-(1-(2-aminothiazolyl-5-yl)-2-((R)-2-methylmorpholino)ethyl)-5,5-difluoropiperidin-2-one

[0365] 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] + .

[0366] 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

[0367] (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] + .

[0368] 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

[0369] 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] + .

[0370] 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

[0371] 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%).

[0372] 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] + .

[0373] Preparation of Example 4

[0374] Step 1: Preparation of tert-butyl(S)-2-((((trifluoromethyl)sulfonyl)oxo)methyl)morpholine-4-carboxylic acid ester

[0375] 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] + .

[0376] Step 2: Preparation of tert-butyl(S)-2-(fluoromethyl)morpholine-4-carboxylic acid ester

[0377] 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] + .

[0378] Step 3: Preparation of (S)-2-(fluoromethyl)morpholine

[0379] 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] + .

[0380] Step 4: Preparation of tert-butyl(5-(1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-hydroxyethyl)thiazolyl-2-yl)carbamate

[0381] 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] + .

[0382] Step 5: Preparation of tert-butyl(5-(1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-oxoethyl)thiazolyl-2-yl)carbamate

[0383] 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] + .

[0384] 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

[0385] 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]+.

[0386] Step 7: Preparation of 1-((R)-1-(2-aminothiazolyl-5-yl)-2-((S)-2-(fluoromethyl)morpholino)ethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one

[0387] 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]+.

[0388] 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

[0389] (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] + .

[0390] 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

[0391] 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] + .

[0392] 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

[0393] 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).

[0394] 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] + .

[0395] Preparation of Example 5

[0396] 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

[0397] 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] + .

[0398] Step 2: Preparation of 1-(1-(2-aminothiazolyl-5-yl)-2-((2R,5R)-2,5-dimethylmorpholino)ethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one

[0399] 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] + .

[0400] 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

[0401] (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] + .

[0402] 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

[0403] 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] + .

[0404] 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

[0405] 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).

[0406] 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] + .

[0407] Preparation of Example 6

[0408] 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

[0409] 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] + .

[0410] Step 2: Preparation of 1-(1-(2-aminothiazolyl-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)-5,5-difluorotetrahydropyrimidine-2(1H)-one

[0411] 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] + .

[0412] 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

[0413] (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] + .

[0414] 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

[0415] 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] + .

[0416] 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

[0417] 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%).

[0418] 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] + .

[0419] Preparation of Example 7

[0420] 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

[0421] 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] + .

[0422] Step 2: Preparation of 1-((R)-1-(2-aminothiazolyl-5-yl)-2-((R)-2-methylmorpholino)ethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one

[0423] 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%).

[0424] 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] + .

[0425] 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

[0426] (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] + .

[0427] 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

[0428] 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] + .

[0429] 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

[0430] 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%).

[0431] 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] + .

[0432] Preparation of Example 8

[0433] 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

[0434] 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 residue 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]+.

[0435] Step 2: Preparation of 1-((R)-1-(2-aminothiazolyl-5-yl)-2-((S)-3-methylmorpholino)ethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one

[0436] 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]+.

[0437] 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

[0438] (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] + .

[0439] 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

[0440] 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] + .

[0441] 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

[0442] 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%).

[0443] 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] + .

[0444] Preparation of Example 9

[0445] The preparation method of Example 9 is the same as that of Example 3.

[0446] 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).

[0447] Biological testing evaluation

[0448] 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.

[0449] 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.

[0450] 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.

[0451] 2. Experimental instruments and reagents:

[0452] 2.1 Instruments:

[0453] 2.2 Reagents:

[0454] 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.

[0455] 4. Experimental data processing methods:

[0456] 1) Inhibition rate (%): The inhibition rate is obtained by calculating the original data (OD450-OD570) according to the following formula.

[0457] 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.

[0458] 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.

[0459] The fitted calculation equation is Y = Bottom + (Top - Bottom) / (1 + 10^(LogIC)). 50 -X)*HillSlope))

[0460] 5. Experimental Results and Conclusions:

[0461] Table 1

[0462] 6. Conclusion: The compounds of this invention exhibit excellent competitive binding to human IL-17 receptor ligands.

[0463] Test Example 2: Determination of the inhibitory effect of the compound of the present invention on Groα secretion by HT-29 cells.

[0464] 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.

[0465] Experimental instruments and reagents:

[0466] instrument:

[0467] Reagents:

[0468] 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.

[0469] Experimental data processing method: GraphPad Prism 8.3.0 was used to analyze the data.

[0470] 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.

[0471] Curve fitting: Based on the inhibition rates (%) 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)).

[0472] Experimental results and conclusions:

[0473] Table 2

[0474] Conclusion: The compounds of the present invention show excellent inhibitory effects on the secretion of Groα by HT-29 cells.

[0475] Test Example 3, Pharmacokinetic determination of Wistar rats

[0476] 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.

[0477] 2. Experimental protocol

[0478] 2.1 Test drug: Prepared by the present invention example.

[0479] 2.2 Test animals: 3 female Wistar rats in each group, provided by Beijing Vital River Laboratory Animal Technology Co., Ltd., animal production license number (SCXK(Beijing)2021-0011).

[0480] 2.3 Drug preparation: Oral administration drug preparation: 30% PEG400 + 70% (10% Solutol) water

[0481] 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.

[0482] 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.

[0483] 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℃.

[0484] 2.6 Sample preparation:

[0485] 1) Add 250uL of acetonitrile to 50uL of plasma sample to precipitate, mix and centrifuge at 4000rpm at 4℃ for 20 minutes.

[0486] 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-4000Qtrap-Shimadzu Controller-CBM20A.

[0487] 2.7 Liquid Chromatography Analysis:

[0488] ●Column: Waters Xbridge C18 3.5um 2.1*50mm

[0489] ●Mobile phase: Solution A is a 0.1% formic acid aqueous solution, and Solution B is a 0.1% formic acid acetonitrile solution.

[0490] ● Flow rate: 0.6 mL / min

[0491] ●Eluting time: 0-3.5 minutes, eluent as follows:

[0492] 3. Experimental Results and Analysis: The pharmacokinetic results of the rat pharmacokinetic experiment are shown in Table 3 below, which contains pharmacokinetic parameters.

[0493] Table 3

[0494] 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 AUC and blood drug concentration.

[0495] Test Example 4. Pharmacokinetic determination in Beagle dogs

[0496] 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.

[0497] 2. Experimental protocol

[0498] 2.1 Test drug: The embodiments of the present invention, self-made.

[0499] 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).

[0500] 2.3 Drug preparation: Oral administration drug preparation: 30% PEG400 + 70% (10% Solutol) water

[0501] 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 dissolve it to clarity by ultrasonic treatment, then add 70% (10% Solutol) water to obtain a colorless and clear solution with a concentration of 0.6 mg / mL.

[0502] 2.4 Administration plan: 3 Beagle dogs in each group, male; after fasting overnight, they are respectively given PO, the dose is 3 mg / kg, and the administration volume is 5 mL / kg.

[0503] 2.5 Sample collection: After oral administration to Beagle dogs, blood is collected from the anterior limb vein or other suitable 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). The 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.

[0504] 2.6 Sample treatment:

[0505] 1) Add 40uL of plasma sample to 400uL of methanol for precipitation, mix and centrifuge at 4000rpm for 10 minutes.

[0506] 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+).

[0507] 2.7 Liquid Chromatography Analysis:

[0508] ●Column: ACQUITY UPLC HSS T3 1.8um 2.1*50mm

[0509] ●Mobile phase: Solution A is a 0.1% formic acid aqueous solution, and Solution B is a 0.1% formic acid acetonitrile solution.

[0510] ● Flow rate: 0.6 mL / min

[0511] ●Eluting time: 0-1.4 minutes, eluent as follows:

[0512] 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.

[0513] Test Example 5: Pharmacodynamic Experiment of the Compound in a 5% Imiquimod-induced Wistar Rat Psoriasis Model

[0514] 1. Experimental Objective: To evaluate the efficacy of the compound in a 5% imiquimod-induced Wistar rat model of psoriasis.

[0515] 2. Experimental Design

[0516] 2.1 Test reagents: In this embodiment of the invention, they were prepared in-house.

[0517] 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.

[0518] 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)

[0519] 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).

[0520] 2.5 Experimental Design Note: *30% PEG400 + 70% (10% Solutol) water; **0.5% CMC-Na / 1% Tween 80; ***PBS

[0521] 2.6 Experimental Procedure and Endpoint Sample Collection

[0522] 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).

[0523] 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;

[0524] 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.

[0525] Table 4. PASI Scoring Criteria

[0526] 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).

[0527] 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.

[0528] 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.

[0529] 2.7 Key indicators: body weight and PASI score of back skin from D1 to D7, and a photo taken at the end.

[0530] 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.

[0531] III. Study of Crystal Forms and Eutectic

[0532] 1.1 Experimental Apparatus

[0533] 1.1.1 Some parameters of physicochemical detection instruments

[0534] 1.2 Instruments and Liquid Chromatography Analysis Conditions

[0535] 1.2.1 Instruments and Equipment

[0536] 1.2.2 Chromatographic conditions

[0537] 1.2.3 Chromatographic conditions

[0538] 1. Preparation of the free base crystal form of the compound in Example 7

[0539] 1.1 Preparation of free alkali crystal form A

[0540] A. 200 mg of the free base amorphous compound from Example 7 was dissolved in 1 mL of 10% water / ethanol (v / v), stirred at 5°C to crystallize, filtered, and dried under vacuum. The resulting solid product was identified as crystal form A by X-ray powder diffraction.

[0541] B. 10 mg of the compound of crystal form I or free base amorphous form from Example 7 was added to 1 mL of 50% water / methanol (v / v), suspended at room temperature for 3 days, centrifuged, and the solid was dried under vacuum at 40°C to obtain a solid product, which was identified as crystal form A by X-ray powder diffraction.

[0542] C. Dissolve 10 mg of the compound A (crystal form) from Example 7 in the solvent in Table 5, stir overnight at 5°C, centrifuge, and dry the solid under vacuum at 40°C to obtain a solid product. X-ray powder diffraction analysis showed that it was crystal form A, i.e., not converted to crystal.

[0543] Table 5

[0544] D. 10 mg of the free base amorphous compound from Example 7 was dissolved in the solvent in Table 6 at room temperature or 40°C, and then evaporated and solidified at room temperature to obtain a solid product, which was identified as crystal form A by X-ray powder diffraction.

[0545] Table 6

[0546] E. 0.5 g of the free alkali amorphous product from Example 7 was placed in 2.5 ml of methanol (containing 10% water) and magnetically stirred at room temperature for 24 h. The resulting product was identified as crystal form A by X-ray powder diffraction.

[0547] F. At room temperature, 1g of free base amorphous material from Example 7 was dissolved in 10ml of methanol, 2.5ml of water was added, 1.5% of crystal form A seed crystals were added, and the crystals were cultured for 1 hour. Then, 17.5ml of water was added, and the mixture was stirred for 1 hour before filtration. The obtained product was identified as crystal form A by X-ray powder diffraction, with a yield of 90%.

[0548] G. Weigh 1003.29 mg of the free amorphous base from Example 7, add 5 ml of aqueous ethanol (10% water content) at room temperature, and sonicate to dissolve it completely; transfer the solution to a circulating water bath at 5°C, stir magnetically at 300 rpm for 20 min, add 1% seed crystal A 10 mg, and stir at a constant temperature for 4 h; filter, dry at 50°C overnight, and the obtained product (668.77 mg) was identified as crystal form A by X-ray powder diffraction, with a yield of 66.7%.

[0549] The XRPD spectrum of crystal form A is shown in Figure 1, and the positions of its characteristic peaks are shown in Table 7. The TGA-DSC spectrum of crystal form A is shown in Figure 2. The DSC spectrum shows that the endothermic peaks are at 47.65℃ and 197.84℃, and the TGA spectrum shows that the weight loss is approximately 1.27% from 30℃ to 100℃.

[0550] Table 7

[0551] 1.2 Preparation of Free Alkali Crystal Form B

[0552] 30 mg of the free amorphous base from Example 7 was dissolved in 0.04 mL of acetone, stirred at 5 °C for 2 h to crystallize, centrifuged, and the wet product was identified as crystal form B by X-ray powder diffraction. The XRPD spectrum of crystal form B is shown in Figure 3, and the positions of its characteristic peaks are shown in Table 8.

[0553] Table 8

[0554] 1.3 Preparation of free alkali crystal form C

[0555] 10 mg of compound A (crystal form) from Example 7 was dissolved in 0.2 mL of methanol and allowed to slowly evaporate at 5 °C to precipitate a solid product, which was identified as crystal form C by X-ray powder diffraction. The XRPD spectrum of crystal form C is shown in Figure 4, and its characteristic peak positions are shown in Table 9. The TGA-DSC spectrum of crystal form C is shown in Figure 5. The DSC spectrum shows that the endothermic peaks are at 176.13 °C and 199.20 °C, and the TGA spectrum shows a weight loss of 1.02% from 30 °C to 110 °C.

[0556] Table 9

[0557] 1.4 Preparation of Free Alkali Crystal Form D

[0558] 10 mg of compound I (from Example 7) was added to 1 mL of methyl tert-butyl ether, stirred at room temperature for 3 days, centrifuged, and dried under vacuum to obtain a solid product, which was identified as crystal form D by X-ray powder diffraction. The XRPD spectrum of crystal form D is shown in Figure 6, and its characteristic peak positions are shown in Table 10. The TGA-DSC spectrum of crystal form D is shown in Figure 7. The DSC spectrum shows that the endothermic peaks are at 143.47 °C and 149.31 °C, and the TGA spectrum shows that the weight loss is 8.72% from 30 °C to 150 °C.

[0559] Table 10

[0560] 1.5 Preparation of Free Alkali Crystal Form E

[0561] A. 10 mg of compound I from Example 7 was dissolved in 1 mL of 10% water / isopropanol (v / v) at 40°C and allowed to evaporate and solidify at room temperature to obtain a solid product, which was identified as crystal form E by X-ray powder diffraction.

[0562] B. 10 mg of the compound of crystal form I in Example 7 was added to 1 mL of the solvent in Table 11, stirred at room temperature for 3 days, centrifuged, and the solid was dried under vacuum at 40°C to obtain a solid product, which was identified as crystal form E by X-ray powder diffraction.

[0563] Table 11

[0564] The XRPD spectrum of crystal form E is shown in Figure 8, and the positions of its characteristic peaks are shown in Table 12.

[0565] Table 12

[0566] 1.6 Preparation of Free Alkali Crystal Form F

[0567] A. 10 mg of the compound I from Example 7 was added to 1 mL of isopropanol, stirred at room temperature for 3 days, centrifuged, and the solid was dried under vacuum at 40 °C to obtain a solid product, which was identified as crystal form F by X-ray powder diffraction.

[0568] B. 10 mg of the compound I crystal form shown in Example 7 was added to 1 mL of the solvent in Table 13, suspended at room temperature for 3 days, centrifuged, and the solid was dried under vacuum at 40°C to obtain a solid product, which was identified as crystal form F by X-ray powder diffraction.

[0569] Table 13

[0570] C. 10 mg of the compound I from Example 7 was dissolved in the solvent in Table 14 at room temperature or 40°C, and then evaporated and solidified at room temperature to obtain a solid product, which was identified as crystal form F by X-ray powder diffraction.

[0571] Table 14

[0572] The XRPD spectrum of crystal form F is shown in Figure 9, and the positions of its characteristic peaks are shown in Table 15. The DSC spectrum of crystal form F is shown in Figure 10, and the spectrum shows that the endothermic peak has a peak value of 147.42℃.

[0573] Table 15

[0574] 1.7 Preparation of Free Alkali Crystal Form G

[0575] 10 mg of compound I from Example 7 was dissolved in 1 mL of 2-methyltetrahydrofuran and allowed to evaporate and solidify at room temperature. The resulting product was identified as crystal form G by X-ray powder diffraction. The XRPD spectrum of crystal form G is shown in Figure 11, and the positions of its characteristic peaks are shown in Table 16.

[0576] Table 16

[0577] 1.8 Preparation of free alkali crystal form H

[0578] 10 mg of compound I from Example 7 was dissolved in 1 mL of methyl isobutyl ketone and allowed to evaporate and solidify at room temperature to obtain a solid product, which was identified as crystal form H by X-ray powder diffraction. The XRPD spectrum of crystal form H is shown in Figure 12, and the positions of its characteristic peaks are shown in Table 17.

[0579] Table 17

[0580] 1.9 Preparation of Free Alkali Crystal Form I

[0581] A. Weigh 6g of the free base amorphous compound from Example 7, add 30ml of ethanol / water (9 / 1) (v / v), stir at 60℃ to dissolve, filter, cool to room temperature, stir for 1h, add 60ml of purified water, stir for 12h, filter, dry in a 50℃ forced-air drying oven for 24h to obtain a solid product, which was identified as crystal form I by X-ray powder diffraction.

[0582] B. Weigh 0.7 g of the free base amorphous compound from Example 7, add 11 ml of acetone / water (7 / 1) (v / v), stir at 60°C until dissolved, filter, cool to room temperature, and stir for 1 h. Filter again, dry in a 50°C forced-air drying oven for 24 h to obtain a solid product, which was identified as crystal form I by X-ray powder diffraction.

[0583] The XRPD spectrum of crystal form I is shown in Figure 13, and the positions of its characteristic peaks are shown in Table 18. The TGA-DSC spectrum of crystal form I is shown in Figure 14. The DSC spectrum shows that the endothermic peaks are at 45.48℃ and 138.80℃, and the TGA spectrum shows that the weight loss is approximately 1.98% between 30℃ and 110℃.

[0584] Table 18

[0585] 1.10 Preparation of Free Alkali Crystal Form J

[0586] A. Weigh 1g of the free base amorphous compound from Example 7, add 1ml of dimethyl sulfoxide (DMSO), heat to dissolve, cool to room temperature, add 30ml of purified water, stir for 12h, filter, and dry in a 50℃ forced-air drying oven for 24h to obtain a solid product, which is identified as crystal form J by X-ray powder diffraction.

[0587] B. Weigh 1 g of the free base amorphous compound from Example 7, add 1 ml of N,N-dimethylformamide (DMF), heat to dissolve, cool to room temperature, add 20 ml of purified water, stir for 12 h, filter, and dry in a 50°C oven for 24 h to obtain a solid product, which is identified as crystal form J by X-ray powder diffraction.

[0588] The XRPD spectrum of crystal form J is shown in Figure 15, and the positions of its characteristic peaks are shown in Table 19. The TGA-DSC spectrum of crystal form J is shown in Figure 16. The DSC spectrum shows that the endothermic peaks are at 112.28℃ and 115.77℃, and the TGA spectrum shows that the weight loss is approximately 6.90% between 30℃ and 150℃.

[0589] Table 19

[0590] 2. Preparation of the free base crystal form of the compound in Example 3

[0591] 2.1 Preparation of free alkali crystal form A

[0592] Weigh 100 mg of free amorphous alkali from Example 3, add 1 mL of methyl tert-butyl ether, stir magnetically at 50°C for 5 hours, then stir magnetically at room temperature for 48 hours, filter, and vacuum dry the solid at 50°C for 24 hours. XRPD analysis showed that it was crystal form A.

[0593] The XRPD spectrum of crystal form A is shown in Figure 17, and the positions of its characteristic peaks are shown in Table 20. The TGA-DSC spectrum of crystal form A is shown in Figure 18.

[0594] Table 20

[0595] 2.2 Preparation of Free Alkali Crystal Form B

[0596] Method 1:

[0597] Weigh 200 mg of the free amorphous base from Example 3, add 1 mL of anhydrous ethanol, and dissolve by magnetic stirring at room temperature. After clarification, a solid gradually precipitates out. Stir for 1 hour. Add 1 mL of purified water to the above suspension within 2 minutes, and continue magnetic stirring overnight. Filter, and vacuum dry the solid at 50°C for 24 hours. XRPD analysis shows it to be crystalline form B.

[0598] Method 2

[0599] Weigh 3g of the free amorphous base from Example 3, add 30mL of isopropyl ether and 1mL of anhydrous ethanol, stir magnetically at 50°C for 5h, then stir magnetically at room temperature for 2h, filter, and vacuum dry the solid at 50°C for 24h. XRPD analysis showed that it was crystal form B.

[0600] Method 3

[0601] Weigh 1.2g of free alkali amorphous material from Example 3, add 6mL of ethanol, stir at room temperature for 20 minutes, then add 6mL of water, add 2% seed crystals, incubate at room temperature overnight, then add 6mL of water, stir at room temperature for 4 hours, cool to 10°C, stir for 2 hours, filter, and vacuum dry at 50°C for 12 hours. The yield is 80%, and XRPD analysis shows it to be crystal form B.

[0602] Method 4

[0603] Weigh 1g of free base amorphous material from Example 3, add 15mL of isopropyl ether and 1mL of ethanol, heat to 50°C, add 1% seed crystals, stir for 5 hours, cool to room temperature, stir for 2 hours, filter, dry in a forced-air environment at 50°C for 14 hours, and XRPD test shows it to be crystal form B.

[0604] Method 5

[0605] Weigh 1g of free base amorphous material from Example 3, add 10mL of acetone, heat to 50°C, then add 10mL of water, add 1% seed crystals, keep warm and stir for 1 hour, cool to room temperature, then add 20mL of water, stir at room temperature for 16 hours, filter, vacuum dry at 40°C for 20 hours, and XRPD test shows it to be crystal form B.

[0606] Method 6

[0607] Weigh 1g of free alkali amorphous material from Example 3, add 10mL of methanol, stir at room temperature for 20 minutes, then add 10mL of water, add 1% seed crystals, stir at room temperature for 48 hours, then add 20mL of water, continue stirring for 2 hours, filter, dry in a forced-air environment at 60℃ for 20 hours, and XRPD analysis shows it to be crystal form B.

[0608] The XRPD spectrum of crystal form B is shown in Figure 19, and the positions of its characteristic peaks are shown in Table 21. The TGA-DSC spectrum of crystal form B is shown in Figure 20.

[0609] Table 21

[0610] 2.3 Preparation of free alkali crystal form C

[0611] Weigh 40 mg of free amorphous base from Example 3, add 80 μL of methanol, stir magnetically at room temperature to dissolve and clarify, then add 400 μL of n-heptane to precipitate a solid, let stand overnight at 4°C, and then centrifuge. The obtained solid was detected by XRPD as crystalline form C.

[0612] The XRPD spectrum of crystal form C is shown in Figure 21, and the positions of its characteristic peaks are shown in Table 22. The TGA-DSC spectrum of crystal form C is shown in Figure 22.

[0613] Table 22

[0614] 3. Example 7: Determination of the hygroscopicity of the free alkali crystal form

[0615] 3.1 Experimental objective: To investigate the hygroscopicity of different crystal forms under different relative humidity conditions, and to provide a basis for crystal form screening and storage.

[0616] 3.2 Experimental Procedure:

[0617] 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%.

[0618] 3.3 Experimental Results:

[0619] 1) DVS testing showed that crystal form A had a moisture absorption weight gain of about 2.6% under normal storage conditions (i.e., 25℃, 60%RH); under accelerated testing conditions (i.e., 70%RH), the moisture absorption weight gain was about 2.8%; under extreme conditions (90%RH), the moisture absorption weight gain was about 3.5%; after DVS testing, the crystal form was retested and no change was observed.

[0620] 2) DVS testing showed that crystal form I had a moisture absorption weight gain of about 6.9% under normal storage conditions (i.e., 25℃, 60%RH); under accelerated experimental conditions (i.e., 70%RH), the moisture absorption weight gain was about 8.6%; under extreme conditions (90%RH), the moisture absorption weight gain was about 11.0%; after DVS testing, the crystal form was retested and no change was observed.

[0621] 4. Example 7: Stability Study of Free Alkali Crystal Form

[0622] 4.1 Influencing Factors

[0623] In Example 7, free alkali crystal form A and free alkali crystal form I were laid out flat in the open, and the stability of the samples was investigated under the following conditions: high temperature (40℃ and 60℃), high humidity (RH 75%, RH 92.5%) and light irradiation. The sampling period was 30 days (chromatographic conditions 1.2.2).

[0624] Table 21

[0625] in conclusion:

[0626] Experiments on influencing factors showed that free alkali crystalline form A exhibited good physical and chemical stability after 30 days under high humidity (75% RH, 92.5% RH) and light conditions, and good physical stability after 30 days under high temperature (40℃, 60℃) conditions, although its chemical purity decreased. Free alkali crystalline form I also exhibited good physical stability after 30 days under high temperature (40℃, 60℃) and light conditions, although its chemical purity decreased. Under high humidity (75% RH, 92.5% RH) conditions, it maintained good physical and chemical stability after 30 days.

[0627] 4.2 Long-term / Accelerated Stability

[0628] The stability of free alkali crystal form A and crystal form I was investigated under conditions of 25℃ / 60%RH and 40℃ / 75%RH, respectively (chromatographic conditions 1.2.2).

[0629] Table 22

[0630] Conclusion: Long-term accelerated experiments show that free alkali crystal form A and crystal form I have good physical and chemical stability under conditions of 25℃ / 60%RH and 40℃ / 75%RH for 1-2 months.

[0631] 5. Hygroscopicity test of free alkali crystal form in Example 3

[0632] 5.1 Experimental Objective: To investigate the hygroscopicity of the free alkali crystal form of the compound under different relative humidity conditions, and to provide a basis for the screening and storage of stable crystal forms of the compound.

[0633] 5.2 Experimental Procedure: The free alkali 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 increase in weight 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%.

[0634] 5.3 Experimental Results:

[0635] The free alkali crystalline form B gains 0.3691% in weight upon moisture absorption at 80% RH, exhibiting slight hygroscopicity. After two cycles of moisture absorption and desorption at 0-95% relative humidity, the XRPD spectrum of the free alkali crystalline form B remained unchanged, indicating that the crystal form did not transform.

[0636] 6. Example 3: Solid stability experiment of free alkali crystal form

[0637] 6.1 Experimental Objective: To investigate the physicochemical stability of free base 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 stable crystal forms of the compound.

[0638] 6.2 Experimental Scheme

[0639] Approximately 1 mg of free alkali 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 related substances were calculated by peak area normalization method (chromatographic conditions are shown in 1.2.3).

[0640] Conclusion: The crystal form of this invention exhibits good physical and chemical stability.

Claims

1. A crystalline form of a compound of Formula (I) or a stereoisomer thereof, ###0001### Formula (I) ​ 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 heterocyclyl, C 6-10 aryl, 5-10 membered 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-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; 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.

2. The crystalline form of the compound or stereoisomer thereof according to claim 1, 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 heterocyclyl, more preferably a 5-6 membered heterocyclyl; preferably, ring E is selected from R 2-1-1 each independently is selected from hydrogen, deuterium, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1- 3hydroxyalkyl, C 1-3 heteroalkyl, C 1-3 haloheteroalkyl, preferably methyl, ethyl, methoxy, F, -CHF2, -CH2F, -CF3, -CH2CHF2, -CHF2CH3, -CH2CF3, -CH2OCH3, -CH2OCF3, or OCF3; R 4-1-1 each independently is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy; preferably methyl or F; each R1is independently selected from hydrogen, deuterium, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy; preferably methyl or F.

3. The crystalline form of the compound or a stereoisomer thereof according to claim 1 or 2, characterized in that, The compounds are shown below:

4. The crystalline form of the compound or a stereoisomer thereof according to any one of claims 1 to 3, characterized in that, 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.

5. The crystalline form of the compound or stereoisomer thereof according to any one of claims 1 to 4, 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 crystal form A; The X-ray powder diffraction pattern of crystal form A shows a diffraction peak at 2θ of 6.0 ± 0.2°; or at 9.3 ± 0.2°; or at 10.6 ± 0.2°; or at 14.5 ± 0.2°; or at 16.3 ± 0.2°; or at 17.8 ± 0.2°; or at 19.3 ± 0.2°. The diffraction peak is present at 20.0±0.2°; or at 21.6±0.2°; or at 23.1±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 crystal form B; The X-ray powder diffraction pattern of crystal form B shows a diffraction peak at 2θ of 5.5 ± 0.2°; or at 5.9 ± 0.2°; or at 11.1 ± 0.2°; or at 18.5 ± 0.2°; or at 19.4 ± 0.2°; or at 22.4 ± 0.2°; or at 23.0 ± 0.2°. The diffraction peak is present at 24.0±0.2°; or at 25.9±0.2°; or at 26.7±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. 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 crystal form C; The X-ray powder diffraction pattern of crystal form C shows a diffraction peak at 2θ of 5.9 ± 0.2°; or at 9.1 ± 0.2°; or at 12.9 ± 0.2°; or at 14.4 ± 0.2°; or at 16.3 ± 0.2°; or at 18.9 ± 0.2°; or at 19.6 ± 0.2°. The diffraction peak is present at 20.8±0.2°; or at 23.3±0.2°; or at 29.0±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. 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 crystal form D; The X-ray powder diffraction pattern of crystal form D shows a diffraction peak at 2θ of 6.8 ± 0.2°; or at 9.1 ± 0.2°; or at 11.8 ± 0.2°; or at 13.3 ± 0.2°; or at 15.0 ± 0.2°; or at 17.0 ± 0.2°; or at 18.2 ± 0.2°. The diffraction peak is present at 19.2±0.2°; or at 21.9±0.2°; or at 26.9±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 crystal form E; the X-ray powder diffraction pattern of the crystalline Form E has a diffraction peak at 2-theta = 9.2+0.2°; or has a diffraction peak at 12.1+0.2°; or has a diffraction peak at 13.5+0.2°; or has a diffraction peak at 14.0+0.2°; or has a diffraction peak at 15.2+0.2°; or has a diffraction peak at 17.1+0.2°; or has a diffraction peak at 18.6+0.2°; or has a diffraction peak at 19.5+0.2°; or has a diffraction peak at 22.2+0.2°; or has a diffraction peak at 26.1+0.2°; preferably comprising any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, or 8-10 of the above diffraction peaks; more preferably comprising any 6, 7, 8, 9 or 10 of the above diffraction peaks; or it is N-((S)-2-((5-((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2- ((R)-2-methylmorpholino)ethyl)thiazol-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2- oxoehtyl)-1-fluorocyclopropane-1-carboxamide crystalline Form F; the X-ray powder diffraction pattern of the crystalline Form F has a diffraction peak at 2-theta = 7.0+0.2°; or has a diffraction peak at 9.2+0.2°; or has a diffraction peak at 12.2+0.2°; or has a diffraction peak at 13.5+0.2°; or has a diffraction peak at 14.1+0.2°; or has a diffraction peak at 15.3+0.2°; or has a diffraction peak at 17.0+0.2°; or has a diffraction peak at 18.7+0.2°; or has a diffraction peak at 19.6+0.2°; or has a diffraction peak at 22.2+0.2°; preferably comprising any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, or 8-10 of the above diffraction peaks; more preferably comprising any 6, 7, 8, 9 or 10 of the above diffraction peaks; or it is N-((S)-2-((5-((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2- ((R)-2-methylmorpholino)ethyl)thiazol-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2- oxoehtyl)-1-fluorocyclopropane-1-carboxamide crystalline Form G; the X-ray powder diffraction pattern of the crystalline form G has a diffraction peak at 9.1±0.2°; or has a diffraction peak at 12.2±0.2°; or has a diffraction peak at 13.5±0.2°; or has a diffraction peak at 15.1±0.2°; or has a diffraction peak at 16.9±0.2°; or has a diffraction peak at 18.5±0.2°; or has a diffraction peak at 19.5±0.2°; or has a diffraction peak at 22.0±0.2°; or has a diffraction peak at 22.6±0.2°; or has a diffraction peak at 26.1±0.2°; preferably comprising any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, or 8-10 of the above diffraction peaks; more preferably comprising any 6, 7, 8, 9 or 10 of the above diffraction peaks; or it is N-((S)-2-((5-((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2- ((R)-2-methylmorpholino)ethyl)thiazol-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2- oxoehtyl)-1-fluorocyclopropane-1-carboxamide crystalline form H; the X-ray powder diffraction pattern of the crystalline form H has a diffraction peak at 6.9±0.2°; or has a diffraction peak at 9.0±0.2°; or has a diffraction peak at 12.0±0.2°; or has a diffraction peak at 13.3±0.2°; or has a diffraction peak at 13.9±0.2°; or has a diffraction peak at 15.0±0.2°; or has a diffraction peak at 16.7±0.2°; or has a diffraction peak at 18.5±0.2°; or has a diffraction peak at 19.4±0.2°; or has a diffraction peak at 21.8±0.2°; preferably comprising any 2-5, or 3-5, or 3-6, or 3-8, or 5 -8, or 6-8, or 8-10 of the above diffraction peaks; or it is N-((S)-2-((S)-5-((R)-1-(5,5-difluoro-2-oxotetrathydropyrimidin-1(2H)-yl)-2- ((R)-2- methylmorpholino)ethyl)thiazol-2-yl)amino)-1- ((1r,4S)-4-methylcyclohexyl)-2- oxoe yl)-1-fluorocyclopropane-1-carboxamide crystalline form I; the X-ray powder diffraction pattern of the crystalline Form I has a diffraction peak at 7.1±0.2°; or has a diffraction peak at 9.3±0.2°; or has a diffraction peak at 12.4±0.2°; or has a diffraction peak at 13.8±0.2°; or has a diffraction peak at 14.3±0.2°; or has a diffraction peak at 15.5±0.2°; or has a diffraction peak at 17.2±0.2°; or has a diffraction peak at 19.1±0.2°; or has a diffraction peak at 20.0±0.2°; or has a diffraction peak at 22.5±0.2°; preferably contains any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, or 8-10 of the above diffraction peaks; more preferably contains any 6, 7, 8, 9 or 10 of the above diffraction peaks; or it is N-((S)-2-((5-((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazol-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide crystalline Form J; the X-ray powder diffraction pattern of the crystalline Form J has a diffraction peak at 7.0±0.2°; or has a diffraction peak at 9.1±0.2°; or has a diffraction peak at 12.2±0.2°; or has a diffraction peak at 13.6±0.2°; or has a diffraction peak at 15.3±0.2°; or has a diffraction peak at 17.0±0.2°; or has a diffraction peak at 17.7±0.2°; or has a diffraction peak at 18.8±0.2°; or has a diffraction peak at 19.7±0.2°; or has a diffraction peak at 22.2±0.2°; preferably contains any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, or 8-10 of the above diffraction peaks; more preferably contains any 6, 7, 8, 9 or 10 of the above diffraction peaks.

6. The crystalline form of the compound or stereoisomer thereof according to claim 5, characterized in that, the X-ray powder diffraction pattern of the crystalline Form A contains at least one diffraction peak at 9.3±0.2°, 16.3±0.2°, 19.3±0.2° and 21.6±0.2°, preferably contains 2 of them, more preferably contains 3 or 4 of them; further preferably, it can also contain at least one of 6.0±0.2°, 10.6±0.2°, 14.5±0.2°, 17.8±0.2°, 20.0±0.2° and 23.1±0.2°, preferably contains 2, 3, 4, 5 or 6 of them; Further preferably, the X-ray powder diffraction pattern of said Form A comprises one or more peaks at 6.0±0.2°, 9.3±0.2°, 10.6±0.2°, 14.5±0.2°, 16.3±0.2°, 17.8±0.2°, 19.3±0.2°, 20.0±0.2°, 21.6±0.2° and 23.1±0.2°; preferably, comprises any 4, 5, 6, 8 or 10 thereof; More preferably, the X-ray powder diffraction pattern of said Form A can further comprise one or more peaks at 2-theta of 12.0±0.2°, 13.4±0.2°, 17.1±0.2°, 20.4±0.2° and 25.9±0.2°; preferably, at least 2-3 or 4-5 thereof; more preferably, any 2, 3, 4 or 5 thereof; For example, the X-ray powder diffraction pattern of said Form A has peaks at 2-theta at the following positions: 6.0±0.2°、9.3±0.2°、10.6±0.2°、16.3±0.2°、19.3±0.2°、21.6±0.2°、23.1±0.2°； 9.3±0.2°、10.6±0.2°、16.3±0.2°、19.3±0.2°、20.0±0.2°、21.6±0.2°、23.1±0.2°； 6.0±0.2°、9.3±0.2°、10.6±0.2°、16.3±0.2°、19.3±0.2°、20.0±0.2°、21.6±0.2°； 6.0±0.2°、9.3±0.2°、10.6±0.2°、16.3±0.2°、19.3±0.2°、20.0±0.2°、21.6±0.2°、23.1±0.2°； 6.0±0.2°、9.3±0.2°、10.6±0.2°、16.3±0.2°、17.8±0.2°、19.3±0.2°、21.6±0.2°、23.1±0.2°； 6.0±0.2°、9.3±0.2°、10.6±0.2°、14.5±0.2°、16.3±0.2°、19.3±0.2°、21.6±0.2°、23.1±0.2°； 6.0±0.2°、9.3±0.2°、10.6±0.2°、16.3±0.2°、17.8±0.2°、19.3±0.2°、21.6±0.2°、23.1±0.2°； 6.0±0.2°、9.3±0.2°、10.6±0.2°、16.3±0.2°、17.8±0.2°、19.3±0.2°、20.0±0.2°、21.6±0.2°、23.1±0.2°； 6.0±0.2°、9.3±0.2°、10.6±0.2°、14.5±0.2°、16.3±0.2°、17.8±0.2°、19.3±0.2°、21.6±0.2°、23.1±0.2°； 6.0±0.2°、9.3±0.2°、10.6±0.2°、14.5±0.2°、16.3±0.2°、19.3±0.2°、20.0±0.2°、21.6±0.2°、23.1±0.2°； Most preferably, the X-ray powder diffraction pattern of said Form A is substantially as shown in Figure 1; and the TGA-DSC pattern is as shown in Figure 2; The X-ray powder diffraction pattern of said Form B comprises at least one peak at 2-theta of 5.5±0.2°, 11.1±0.2°, 18.5±0.2° and 19.4±0.2°, preferably 2 thereof, more preferably 3 thereof; further preferably, can further comprise at least one peak at 2-theta of 5.9±0.2°, 22.4±0.2°, 23.0±0.2°, 24.0±0.2°, 25.9±0.2° and 26.7±0.2°, preferably 2, 3, 4 or 5 thereof; Further preferably, the X-ray powder diffraction pattern of said p-toluenesulfonic acid salt Form B comprises one or more peaks at 2-theta of 5.5±0.2°, 5.9±0.2°, 11.1±0.2°, 18. 5±0.2°, 19.4±0.2°, 22.4±0.2°, 23. 0±0.2°, 24.0±0.2°, 25.9±0.2° and 26.7±0.2°; preferably, comprises any 4, 5, 6,7, 8 or 10 thereof; For example, the X-ray powder diffraction pattern of Form B has peaks at 2-theta at the following positions: 5.5±0.2°、5.9±0.2°、11.1±0.2°、18.5±0.2°、19.4±0.2°、24.0±0.2°、25.9±0.2°； 5.5±0.2°、5.9±0.2°、18.5±0.2°、19.4±0.2°、22.4±0.2°、25.9±0.2°、26.7±0.2°； 5.5±0.2°、5.9±0.2°、18.5±0.2°、19.4±0.2°、24.0±0.2°、25.9±0.2°、26.7±0.2°； 5.5±0.2°、5.9±0.2°、11.1±0.2°、18.5±0.2°、19.4±0.2°、22.4±0.2°、24.0±0.2°、25.9±0.2°； Most preferably, the X-ray powder diffractogram of said Form B is substantially as shown in Figure 3; The X-ray powder diffraction pattern of said Form C comprises at least one peak at 2-theta of 5.9±0.2°, 9.1±0.2°, 18.9±0.2° and 19.6±0.2°, preferably 2 thereof, more preferably 3 thereof; further preferably can further comprise at least one peak at 2-theta of 12.9±0.2°, 14.4±0.2°, 16.3±0.2°, 20.8±0.2°, 23.3±0.2° and 29.0±0.2°, preferably 2, 3, 4, 5 or 6 thereof; Further preferably, the X-ray powder diffraction pattern of said Form C comprises one or more of the diffraction peaks at 2-theta 5.9±0.2°, 9.1±0.2°, 12.9±0.2°, 14.4±0.2°, 16.3±0.2°, 18.9±0.2°, 19.6±0.2°, 20.8±0.2°, 23.3±0.2° and 29.0±0.2°; preferably, 4, 5, 6, 7, 8 or 10 of them; further preferably, it can also comprise at least one of 2-theta 11.9±0.2°, 14.7±0.2°, 17.0±0.2°, 17.7±0.2°, 22.4±0.2° and 25.4±0.2°, preferably 2, 3, 4, 5 or 6 of them; For example, the X-ray powder diffraction pattern of Form C has diffraction peaks at 2-theta of the following positions: 5.9±0.2°、9.1±0.2°、16.3±0.2°、18.9±0.2°、19.6±0.2°、20.8±0.2°、23.3±0.2°； 5.9±0.2°、9.1±0.2°、16.3±0.2°、18.9±0.2°、19.6±0.2°、23.3±0.2°、29.0±0.2°； 5.9±0.2°、9.1±0.2°、14.4±0.2°、16.3±0.2°、18.9±0.2°、19.6±0.2°、23.3±0.2°； 5.9±0.2°、9.1±0.2°、14.4±0.2°、16.3±0.2°、18.9±0.2°、19.6±0.2°、20.8±0.2°、23.3±0.2°； 5.9±0.2°、9.1±0.2°、14.4±0.2°、16.3±0.2°、18.9±0.2°、19.6±0.2°、23.3±0.2°、29.0±0.2°； 5.9±0.2°、9.1±0.2°、14.4±0.2°、16.3±0.2°、18.9±0.2°、19.6±0.2°、20.8±0.2°、23.3±0.2°、29.0±0.2°； 5.9±0.2°、9.1±0.2°、12.9±0.2°、14.4±0.2°、16.3±0.2°、18.9±0.2°、19.6±0.2°、20.8±0.2°、23.3±0.2°； Most preferably, the X-ray powder diffraction pattern of said Form C is substantially as shown in Figure 4; the TGA-DSC pattern is shown in Figure 5; The X-ray powder diffraction pattern of said Form D comprises at least one or more of the diffraction peaks at 2-theta 13.3±0.2°, 15.0±0.2°, 18.2±0.2° and 21.9±0.2°, preferably 2 of them, more preferably 3 of them; further preferably, it can also comprise at least one of 2-theta 6.8±0.2°, 9.1±0.2°, 11.8±0.2°, 17.0±0.2°, 19.2±0.2° and 26.9±0.2°, preferably 2, 3, 4, 5 or 6 of them; Further preferably, the X-ray powder diffraction pattern of said Form D comprises one or more of the diffraction peaks at 2-theta 6.8±0.2°, 9.1±0.2°, 11.8±0.2°, 13.3±0.2°, 15.0±0.2°, 17.0±0.2°, 18.2±0.2°, 19.2±0.2°, 21.9±0.2° and 26.9±0.2°; preferably, 4, 5, 6, 7, 8 or 10 of them; further preferably, it can also comprise at least one of 2-theta 13.7±0.2°, 22.9±0.2°, 24.8±0.2°, 25.6±0.2°, 25.9±0.2° and 27.7±0.2°, preferably 2, 3, 4, 5 or 6 of them; For example, the X-ray powder diffraction pattern of Form D has diffraction peaks at 2-theta of the following positions: 9.1±0.2°、13.3±0.2°、15.0±0.2°、17.0±0.2°、18.2±0.2°、19.2±0.2°、21.9±0.2°； 13.3±0.2°、15.0±0.2°、17.0±0.2°、18.2±0.2°、19.2±0.2°、21.9±0.2°、26.9±0.2°； 6.8±0.2°、13.3±0.2°、15.0±0.2°、17.0±0.2°、18.2±0.2°、19.2±0.2°、21.9±0.2°； 9.1±0.2°、11.8±0.2°、13.3±0.2°、15.0±0.2°、17.0±0.2°、18.2±0.2°、19.2±0.2°、21.9±0.2°； 9.1±0.2°、13.3±0.2°、15.0±0.2°、17.0±0.2°、18.2±0.2°、19.2±0.2°、21.9±0.2°、26.9±0.2°； 6.8±0.2°、9.1±0.2°、13.3±0.2°、15.0±0.2°、17.0±0.2°、18.2±0.2°、19.2±0.2°、21.9±0.2°； Most preferably, the X-ray powder diffraction pattern of said Form D is substantially as shown in Figure 6; the TGA-DSC pattern is shown in Figure 7; The X-ray powder diffraction pattern of the crystal form E comprises at least one or more diffraction peaks at 2-theta of 9.2±0.2°, 13.5±0.2°, 15.2±0.2° and 18.6±0.2°, preferably comprises 2 of them, more preferably comprises 3 of them; further preferably, it can also comprise at least one of 2-theta of 12.1±0.2°, 14.0±0.2°, 17.1±0.2°, 19.5±0.2°, 22.2±0.2° and 26.1±0.2°, preferably comprises 2, 3, 4, 5 or 6 of them; Further preferably, the X-ray powder diffraction pattern of the crystal form E comprises one or more diffraction peaks at 2-theta of 9.2±0.2°, 12.1±0.2°, 13.5±0.2°, 14.0±0.2°, 15.2±0.2°, 17.1±0.2°, 18.6±0.2°, 19.5±0.2°, 22.2±0.2° and 26.1±0.2°; preferably, it comprises 4, 5, 6, 7, 8 or 10 optional diffraction peaks; further preferably, it can also comprise at least one of 2-theta of 7.0±0.2°, 18.0±0.2°, 22.9±0.2°, 24.4±0.2°, 25.4±0.2° and 27.3±0.2°, preferably comprises 2, 3, 4, 5 or 6 of them; For example, the X-ray powder diffraction pattern of the crystal form E has diffraction peaks at 2-theta of the following positions: 9.2±0.2°、13.5±0.2°、14.0±0.2°、15.2±0.2°、17.1±0.2°、18.6±0.2°、19.5±0.2°； 9.2±0.2°、13.5±0.2°、15.2±0.2°、17.1±0.2°、18.6±0.2°、19.5±0.2°、22.2±0.2°； 9.2±0.2°、12.1±0.2°、13.5±0.2°、15.2±0.2°、17.1±0.2°、18.6±0.2°、19.5±0.2°； 7.0±0.2°、9.2±0.2°、13.5±0.2°、14.0±0.2°、15.2±0.2°、17.1±0.2°、18.6±0.2°、19.5±0.2°； 9.2±0.2°、12.1±0.2°、13.5±0.2°、14.0±0.2°、15.2±0.2°、17.1±0.2°、18.6±0.2°、19.5±0.2°； 9.2±0.2°、12.1±0.2°、13.5±0.2°、15.2±0.2°、17.1±0.2°、18.6±0.2°、19.5±0.2°、22.2±0.2°； 9.2±0.2°、13.5±0.2°、14.0±0.2°、15.2±0.2°、17.1±0.2°、18.6±0.2°、19.5±0.2°、22.2±0.2°； 9.2±0.2°、12.1±0.2°、13.5±0.2°、14.0±0.2°、15.2±0.2°、17.1±0.2°、18.6±0.2°、19.5±0.2°、22.2±0.2°； Most preferably, the X-ray powder diffraction pattern of the crystal form E is substantially as shown in Figure 8; The X-ray powder diffraction pattern of the crystal form F comprises at least one or more diffraction peaks at 2-theta of 9.2+0.2°, 13.5+0.2°, 15.3+0.2° and 22.2+0.2°, preferably comprises 2 of them, more preferably comprises 3 of them; Further preferably, the X-ray powder diffraction pattern of the crystal form F comprises one or more diffraction peaks at 2-theta of 7.0+0.2°, 9.2+0.2°, 12.2+0.2°, 13.5+0.2°, 14.1+0.2°, 15.3+0.2°, 17.0+0.2°, 18.7+0.2°, 19.6+0.2° and 22.2+0.2°; preferably, it comprises 4, 5, 6, 8 or 10 optional diffraction peaks; further preferably, it can also comprise at 2-theta of 17.9+0.2°, 22.8+0.2°, 25.6+0.2°, 26.0+0.2°, 26.3+0.2° and 27.4+0.2°, preferably comprises 2, 3, 4, 5 or For example, the X-ray powder diffraction pattern of crystalline Form F has diffraction peaks at about the following positions 2Q: 9.2±0.2°、13.5±0.2°、15.3±0.2°、17.0±0.2°、18.7±0.2°、19.6±0.2°、22.2±0.2； 7.0±0.2°、9.2±0.2°、13.5±0.2°、15.3±0.2°、17.0±0.2°、19.6±0.2°、22.2±0.2； 9.2±0.2°、13.5±0.2°、14.1±0.2°、15.3±0.2°、17.0±0.2°、19.6±0.2°、22.2±0.2； 9.2±0.2°、13.5±0.2°、14.1±0.2°、15.3±0.2°、17.0±0.2°、18.7±0.2°、19.6±0.2°、22.2±0.2； 7.0±0.2°、9.2±0.2°、113.5±0.2°、14.1±0.2°、15.3±0.2°、17.0±0.2°、19.6±0.2°、22.2±0.2； 9.2±0.2°、12.2±0.2°、13.5±0.2°、14.1±0.2°、15.3±0.2°、17.0±0.2°、19.6±0.2°、22.2±0.2； 7.0±0.2°、9.2±0.2°、13.5±0.2°、14.1±0.2°、15.3±0.2°、17.0±0.2°、18.7±0.2°、19.6±0.2°、22.2±0.2； 9.2±0.2°、12.2±0.2°、13.5±0.2°、14.1±0.2°、15.3±0.2°、17.0±0.2°、18.7±0.2°、19.6±0.2°、22.2±0.2； Most preferably, the X-ray powder diffraction pattern of said crystalline Form F is substantially as shown in Figure 9; and the DSC pattern is as shown in Figure 10; The X-ray powder diffraction pattern of said crystalline Form G comprises at least one, preferably two, more preferably three, diffraction peaks at about 2Q values of 15.1 ± 0.2°, 16.9 ± 0.2°, 18.5 ± 0.2° and 19.5 ± 0.2°; further preferably, it can also comprise at least one, preferably two, three, four, five or six, of the 2Q values of 9.1 ± 0.2°, 12.2 ± 0.2°, 13.5 ± 0.2°, 22.0 ± 0.2°, 22.6 ± 0.2° and 26.1 ± 0.2°; Further preferably, the X-ray powder diffraction pattern of said crystalline Form G comprises one or more of the diffraction peaks at about 2Q values of 9.1 ± 0.2°, 12.2 ± 0.2°, 13.5 ± 0.2°, 15.1 ± 0.2°, 16.9 ± 0.2°, 18.5 ± 0.2°, 19.5 ± 0.2°, 22.0 ± 0.2°, 22.6 ± 0.2° and 26.1 ± 0.2°; preferably, it comprises optionally four, five, six, seven, eight or ten of these peaks; further preferably, it can also comprise at least one, preferably two, three, four, five or six, of the 2Q values of 25.1 ± 0.2°, 25.5 ± 0.2°, 25.7 ± 0.2°, 27.1 ± 0.2°, 33.0 ± 0.2° and 37.1 ± 0.2°; For example, the X-ray powder diffraction pattern of crystalline Form G has diffraction peaks at about the following positions 2Q: 9.1±0.2°、12.2±0.2°、15.1±0.2°、16.9±0.2°、18.5±0.2°、19.5±0.2°、22.0±0.2°； 15.1±0.2°、16.9±0.2°、18.5±0.2°、19.5±0.2°、22.0±0.2°、22.6±0.2°、26.1±0.2°； 9.1±0.2°、12.2±0.2°、13.5±0.2°、15.1±0.2°、16.9±0.2°、18.5±0.2°、19.5±0.2°； 9.1±0.2°、12.2±0.2°、13.5±0.2°、15.1±0.2°、16.9±0.2°、18.5±0.2°、19.5±0.2°、22.0±0.2°； 9.1±0.2°、12.2±0.2°、15.1±0.2°、16.9±0.2°、18.5±0.2°、19.5±0.2°、22.0±0.2°、26.1±0.2°； 9.1±0.2°、12.2±0.2°、13.5±0.2°、15.1±0.2°、16.9±0.2°、18.5±0.2°、19.5±0.2°、22.0±0.2°、22.6±0.2°； 9.1±0.2°、12.2±0.2°、15.1±0.2°、16.9±0.2°、18.5±0.2°、19.5±0.2°、22.0±0.2°、22.6±0.2°、26.1±0.2°； Most preferably, the X-ray powder diffraction pattern of said crystalline Form G is substantially as shown in Figure 11; The X-ray powder diffraction pattern of said crystalline Form H comprises at least one, preferably two, more preferably three, diffraction peaks at about 2Q values of 12.0 ± 0.2°, 15.0 ± 0.2°, 18.5 ± 0.2° and 19.4 ± 0.2°; further preferably, it can also comprise at least one, preferably two, three, four, five or six, of the 2Q values of 6.9 ± 0.2°, 9.0 ± 0.2°, 13.3 ± 0.2°, 13.9 ± 0.2°, 16.7 ± 0.2° and 21.8 ± 0.2°; Further preferably, the X-ray powder diffraction pattern of said Form H comprises one or more of the diffraction peaks at 2-theta 6.9±0.2°, 9.0±0.2°, 12.0±0.2°, 13.3±0.2°, 13.9±0.2°, 15.0±0.2°, 16.7±0.2°, 18.5±0.2°, 19.4±0.2° and 21.8±0.2°; preferably, 4, 5, 6, 7, 8 or 10 of the diffraction peaks are optionally included; further preferably, it can also include at least one of 2-theta 21.0±0.2°, 24.9±0.2°, 25.3±0.2°, 25.9±0.2°, 26.9±0.2° and 32.8±0.2°, preferably 2, 3, 4, 5 or 6 of them are included; For example, the X-ray powder diffraction pattern of Form H has diffraction peaks at 2-theta of the following positions: 6.9±0.2°、12.0±0.2°、13.3±0.2°、13.9±0.2°、15.0±0.2°、18.5±0.2°、19.4±0.2°； 12.0±0.2°、13.3±0.2°、13.9±0.2°、15.0±0.2°、18.5±0.2°、19.4±0.2°、21.8±0.2°； 12.0±0.2°、13.3±0.2°、13.9±0.2°、15.0±0.2°、16.7±0.2°、18.5±0.2°、19.4±0.2°； 6.9±0.2°、9.0±0.2°、12.0±0.2°、13.3±0.2°、13.9±0.2°、15.0±0.2°、18.5±0.2°、19.4±0.2°； 12.0±0.2°、13.3±0.2°、13.9±0.2°、15.0±0.2°、16.7±0.2°、18.5±0.2°、19.4±0.2°、21.8±0.2°； 6.9±0.2°、12.0±0.2°、13.3±0.2°、13.9±0.2°、15.0±0.2°、18.5±0.2°、19.4±0.2°、21.8±0.2°； 6.9±0.2°、9.0±0.2°、12.0±0.2°、13.3±0.2°、13.9±0.2°、15.0±0.2°、18.5±0.2°、19.4±0.2°、21.8±0.2°； Most preferably, the X-ray powder diffraction pattern of said Form H is substantially as shown in Figure 12; The X-ray powder diffraction pattern of said Form I comprises at least one or more of the diffraction peaks at 2-theta 7.1±0.2°, 13.8±0.2°, 14.3±0.2° and 15.5±0.2°, preferably 2 of them, more preferably 3 of them; further preferably, it can also include at least one of 9.3±0.2°, 12.4±0.2°, 17.2±0.2°, 19.1±0.2°, 20.0±0.2° and 22.5±0.2°, preferably 2, 3, 4, 5 or 6 of them are included; Further preferably, the X-ray powder diffraction pattern of said Form I comprises one or more of the diffraction peaks at 2-theta 7.1±0.2°, 9.3±0.2°, 12.4±0.2°, 13.8±0.2°, 14.3±0.2°, 15.5±0.2°, 17.2±0.2°, 19.1±0.2°, 20.0±0.2° and 22.5±0.2°; preferably, 4, 5, 6, 7, 8 or 10 of diffraction peaks are optionally included; further preferably, it can also include at least one of 21.6±0.2°, 21.8±0.2°, 25.8±0.2°, 26.1±0.2°, 26.8±0.2° and 33.9±0.2° of 2-theta, preferably 2, 3, 4, 5 or 6 of them are contained; For example, the X-ray powder diffraction pattern of Form I has diffraction peaks at 2-theta of the following positions: 7.1±0.2°、9.3±0.2°、13.8±0.2°、14.3±0.2°、15.5±0.2°、19.1±0.2°、20.0±0.2°； 7.1±0.2°、9.3±0.2°、13.8±0.2°、14.3±0.2°、15.5±0.2°、26.1±0.2°、26.8±0.2°； 7.1±0.2°、9.3±0.2°、12.4±0.2°、13.8±0.2°、14.3±0.2°、15.5±0.2°、22.5±0.2°； 7.1±0.2°、9.3±0.2°、13.8±0.2°、14.3±0.2°、15.5±0.2°、19.1±0.2°、22.5±0.2°； 7.1±0.2°、9.3±0.2°、13.8±0.2°、14.3±0.2°、15.5±0.2°、19.1±0.2°、20.0±0.2°、26.1±0.2°； 7.1±0.2°、9.3±0.2°、13.8±0.2°、14.3±0.2°、15.5±0.2°、19.1±0.2°、20.0±0.2°、22.5±0.2°； 7.1±0.2°、9.3±0.2°、12.4±0.2°、13.8±0.2°、14.3±0.2°、15.5±0.2°、19.1±0.2°、20.0±0.2°； 7.1±0.2°、9.3±0.2°、12.4±0.2°、13.8±0.2°、14.3±0.2°、15.5±0.2°、19.1±0.2°、20.0±0.2°、22.5±0.2°； 7.1±0.2°、9.3±0.2°、12.4±0.2°、13.8±0.2°、14.3±0.2°、15.5±0.2°、17.2±0.2°、19.1±0.2°、20.0±0.2°； Most preferably, the X- ray powder diffraction pattern of said Form I is substantially as shown in Figure 13; the TGA-DSC pattern is shown in Figure 14; the X-ray powder diffraction pattern of the crystalline form J comprises at least one, preferably 2, more preferably 3, of the diffraction peaks at 2-theta 9.1+0.2°, 13.6+0.2°, 15.3+0.2° and 17.0+0.2°; further preferably, it can also comprise at least one, preferably 2, 3, 4, 5 or 6, of the diffraction peaks at 2-theta 7.0+0.2°, 12.2+0.2°, 17.7+0.2°, 18.8+0.2°, 19.7+0.2° and 22.2+0.2°; Further preferably, the X-ray powder diffraction pattern of the crystalline form J comprises at least one, preferably 2, more preferably 3, of the diffraction peaks at 2-theta 9.1+0.2°, 13.6+0.2°, 15.3+0.2° and 17.0+0.2°; further preferably, it can also comprise at least one, preferably 2, 3, 4, 5 or 6, of the diffraction peaks at 2-theta 7.0+0.2°, 12.2+0.2°, 17.7+0.2°, 18.8+0.2°, 19.7+0.2° and 22.2+0.2°; For example, the X-ray powder diffraction pattern of the crystalline form J has diffraction peaks at 2-theta of: 9.1±0.2°、13.6±0.2°、15.3±0.2°、17.0±0.2°、18.8±0.2°、19.7±0.2°、22.2±0.2°； 9.1±0.2°、13.6±0.2°、15.3±0.2°、17.0±0.2°、17.7±0.2°、19.7±0.2°、22.2±0.2°； 7.0±0.2°、9.1±0.2°、13.6±0.2°、15.3±0.2°、17.0±0.2°、19.7±0.2°、22.2±0.2°； 7.0±0.2°、9.1±0.2°、13.6±0.2°、15.3±0.2°、17.0±0.2°、17.7±0.2°、19.7±0.2°； 9.1±0.2°、13.6±0.2°、14.1±0.2°、15.3±0.2°、17.0±0.2°、19.7±0.2°、22.2±0.2°； 9.1±0.2°、13.6±0.2°、15.3±0.2°、17.0±0.2°、17.7±0.2°、18.8±0.2°、19.7±0.2°、22.2±0.2°； 7.0±0.2°、9.1±0.2°、13.6±0.2°、15.3±0.2°、17.0±0.2°、18.8±0.2°、19.7±0.2°、22.2±0.2°； 7.0±0.2°、9.1±0.2°、12.2±0.2°、13.6±0.2°、15.3±0.2°、17.0±0.2°、19.7±0.2°、22.2±0.2°； 9.1±0.2°、13.6±0.2°、14.1±0.2°、15.3±0.2°、17.0±0.2°、18.8±0.2°、19.7±0.2°、22.2±0.2°； 9.1±0.2°、12.2±0.2°、13.6±0.2°、15.3±0.2°、17.0±0.2°、17.7±0.2°、18.8±0.2°、19.7±0.2°、22.2±0.2°； 7.0±0.2°、9.1±0.2°、13.6±0.2°、15.3±0.2°、17.0±0.2°、17.7±0.2°、18.8±0.2°、19.7±0.2°、22.2±0.2°； 7.0±0.2°、9.1±0.2°、12.2±0.2°、13.6±0.2°、15.3±0.2°、17.0±0.2°、17.7±0.2°、18.8±0.2°、19.7±0.2°； Most preferably, the X-ray powder diffraction pattern of the crystalline form J is substantially as shown in Figure 15; and the TGA-DSC pattern is as shown in Figure 16.

7. The crystalline form of the compound or stereoisomer thereof according to any one of claims 1 to 4, characterized in that, which is N-((S)-2-((5-((R)-1-(5,5-difluoro-2-oxopiperidin-1-yl)-2-((R)-2-methylmorpholino)ethyl)thiazol-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-(ethyl-d5)-1H-pyrazole-5-carboxamide crystalline form A; The X-ray powder diffraction pattern of the crystalline form A has a diffraction peak at 2-theta 6.8+0.2°; or at 7.2+0.2°; or at 7.6+0.2°; or at 9.9+0.2°; or at 5.8+0.2°; or at 9.3+0.2°; or at 16.2+0.2°; or at 16.7+0.2°; or at 17.7+0.2°; or at 19.9+0.2°; preferably comprising any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, or 8-10 of the above diffraction peaks; more preferably comprising any 6, 7, 8, 9 or 10 of the above diffraction peaks; The X-ray powder diffraction pattern of the crystal form A contains at least one or more diffraction peaks at 2-theta of 6.8±0.2°, 7.2±0.2°, 7.6±0.2° and 9.9±0.2°, preferably contains two of them, more preferably contains three or four of them; further preferably, it can also contain at least one of 2-theta of 5.8±0.2°, 9.3±0.2°, 16.2±0.2°, 16.7±0.2°, 17.7±0.2° and 19.9±0.2°, preferably contains two, three, four, five or six of them; Further preferably, the X-ray powder diffraction pattern of the crystal form A contains one or more diffraction peaks at 2-theta of 6.8±0.2°, 7.2±0.2°, 7.6±0.2°, 9.9±0.2°, 5.8±0.2°, 9.3±0.2°, 16.2±0.2°, 16.7±0.2°, 17.7±0.2° and 19.9±0.2°; preferably, contains any four, five, six, eight or ten of them with diffraction peaks; Further preferably, the X-ray powder diffraction pattern of the crystal form A can also contain one or more diffraction peaks at 2-theta of 11.2±0.2°, 13.9±0.2°, 17.5±0.2°, 18.3±0.2°, 19.0±0.2° and 21.4±0.2°; preferably, contains any two to three of them, or four to five of them; further preferably, contains any two, three, four, five or six of them; For example, the X-ray powder diffraction pattern of the crystal form A has diffraction peaks at 2-theta of the following positions: 5.8±0.2°、6.8±0.2°、7.2±0.2°、7.6±0.2°、9.3±0.2°、9.9±0.2°、16.2±0.2°； 6.8±0.2°、7.2±0.2°、7.6±0.2°、9.9±0.2°、16.7±0.2°、17.7±0.2°、19.9±0.2°； 6.8±0.2°、7.2±0.2°、7.6±0.2°、9.9±0.2°、11.2±0.2°、13.9±0.2°、17.5±0.2°； 6.8±0.2°、7.2±0.2°、7.6±0.2°、9.9±0.2°、18.3±0.2°、19.0±0.2°、21.4±0.2； 5.8±0.2°、6.8±0.2°、7.2±0.2°、7.6±0.2°、9.3±0.2°、9.9±0.2°、16.2±0.2°、16.7±0.2°； 6.8±0.2°、7.2±0.2°、7.6±0.2°、9.9±0.2°、16.2±0.2°、16.7±0.2°、17.7±0.2°、19.9±0.2°； 6.8±0.2°、7.2±0.2°、7.6±0.2°、9.9±0.2°、11.2±0.2°、13.9±0.2°、17.5±0.2°、18.3±0.2°； 6.8±0.2°、7.2±0.2°、7.6±0.2°、9.9±0.2°、17.5±0.2°、18.3±0.2°、19.0±0.2°、21.4±0.2； 5.8±0.2°、6.8±0.2°、7.2±0.2°、7.6±0.2°、9.3±0.2°、9.9±0.2°、11.2±0.2°、13.9±0.2°； 6.8±0.2°、7.2±0.2°、7.6±0.2°、9.9±0.2°、17.7±0.2°、19.9±0.2°、19.0±0.2°、21.4±0.2； 5.8±0.2°、6.8±0.2°、7.2±0.2°、7.6±0.2°、9.9±0.2°、19.9±0.2°、11.2±0.2°、21.4±0.2； 5.8±0.2°、6.8±0.2°、7.2±0.2°、7.6±0.2°、9.3±0.2°、9.9±0.2°、16.2±0.2°、16.7±0.2°、17.7±0.2°； 6.8±0.2°、7.2±0.2°、7.6±0.2°、9.3±0.2°、9.9±0.2°、16.2±0.2°、16.7±0.2°、17.7±0.2°、19.9±0.2°； 6.8±0.2°、7.2±0.2°、7.6±0.2°、9.9±0.2°、11.2±0.2°、13.9±0.2°、17.5±0.2°、18.3±0.2°、19.0±0.2°； 6.8±0.2°、7.2±0.2°、7.6±0.2°、9.9±0.2°、13.9±0.2°、17.5±0.2°、18.3±0.2°、19.0±0.2°、21.4±0.2； Most preferably, the X-ray powder diffraction pattern of the crystal form A is substantially as shown in Figure 17; the TGA-DSC pattern is as shown in Figure 18; Or it is N-((S)-2-((5-((R)-1-(5,5-difluoro-2-oxopiperidin-1-yl)-2-((R)-2-methylmorpholino)ethyl)thiazol-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-(ethyl-d5)-1H-pyrazole-5-carboxamide crystal form B; The X-ray powder diffraction pattern of the crystal form B has a diffraction peak at 2-theta of 5.9±0.2°; or at 9.3±0.2°; or at 19.0±0.2°; or at 21.3±0.2°; or at 14.9±0.2°; or at 16.8±0.2°; or at 17.6±0.2°; or at 22.3±0.2°; or at 22.7±0.2°; or at 25.1±0.2°; preferably, contains any two to five of them, or three to five of them, or three to six of them, or three to eight of them, or five to eight of them, or six to eight of them, or eight to ten of them; more preferably, contains any six, seven, eight, nine or ten of them; the X-ray powder diffraction pattern of the crystalline Form B comprises at least one, preferably two, more preferably three, and even more preferably four, of the peaks at 5.9±0.2°, 9.3±0.2°, 14.9±0.2°, 16.8±0.2°, 17.6±0.2°, 19.0±0.2°, 21.3±0.2°, 22.3±0.2°, 22.7±0.2°, and 25.1±0.2° in terms of 2-theta; the X-ray powder diffraction pattern of the crystalline Form B comprises at least one, preferably two, more preferably three, and even more preferably four, of the peaks at 5.9±0.2°, 9.3±0.2°, 14.9±0.2°, 16.8±0.2°, 17.6±0.2°, 19.0±0.2°, 21.3±0.2°, 22.3±0.2°, 22.7±0.2°, and 25.1±0.2° in terms of 2-theta; the X-ray powder diffraction pattern of the crystalline Form B further comprises at least one, preferably two, more preferably three, and even more preferably four, of the peaks at 10.6±0.2°, 11.7±0.2°, 17.8±0.2°, 19.6±0.2°, 22.9±0.2°, and 27.9±0.2° in terms of 2-theta; For example, the X-ray powder diffraction pattern of the crystalline Form B comprises peaks at the following positions in terms of 2-theta: 5.9±0.2°、9.3±0.2°、14.9±0.2°、16.8±0.2°、17.6±0.2°、19.0±0.2°、21.3±0.2°； 5.9±0.2°、9.3±0.2°、19.0±0.2°、21.3±0.2°、22.3±0.2°、22.7±0.2°、25.1±0.2°； 5.9±0.2°、9.3±0.2°、10.6±0.2°、11.7±0.2°、17.8±0.2°、19.0±0.2°、21.3±0.2°； 5.9±0.2°、9.3±0.2°、19.0±0.2°、21.3±0.2°、19.6±0.2°、22.9±0.2°、27.9±0.2°； 5.9±0.2°、9.3±0.2°、14.9±0.2°、16.8±0.2°、17.6±0.2°、19.0±0.2°、21.3±0.2°、22.3±0.2°； 5.9±0.2°、9.3±0.2°、17.6±0.2°、19.0±0.2°、21.3±0.2°、22.3±0.2°、22.7±0.2°、25.1±0.2°； 5.9±0.2°、9.3±0.2°、10.6±0.2°、11.7±0.2°、17.8±0.2°、19.0±0.2°、19.6±0.2°、21.3±0.2°； 5.9±0.2°、9.3±0.2°、19.0±0.2°、21.3±0.2°、17.8±0.2°、19.6±0.2°、22.9±0.2°、27.9±0.2°； 5.9±0.2°、9.3±0.2°、10.6±0.2°、14.9±0.2°、19.0±0.2°、21.3±0.2°、25.1±0.2°、27.9±0.2°； 5.9±0.2°、9.3±0.2°、11.7±0.2°、16.8±0.2°、17.6±0.2°、17.8±0.2°、19.0±0.2°、21.3±0.2°； 5.9±0.2°、9.3±0.2°、14.9±0.2°、16.8±0.2°、19.0±0.2°、21.3±0.2°、22.9±0.2°、27.9±0.2°； 5.9±0.2°、9.3±0.2°、14.9±0.2°、16.8±0.2°、17.6±0.2°、19.0±0.2°、21.3±0.2°、22.3±0.2°、22.7±0.2°； 5.9±0.2°、9.3±0.2°、16.8±0.2°、17.6±0.2°、19.0±0.2°、21.3±0.2°、22.3±0.2°、22.7±0.2°、25.1±0.2°； 5.9±0.2°、9.3±0.2°、10.6±0.2°、11.7±0.2°、17.8±0.2°、19.0±0.2°、19.6±0.2°、21.3±0.2°、22.9±0.2°； 5.9±0.2°、9.3±0.2°、11.7±0.2°、17.8±0.2°、19.0±0.2°、19.6±0.2°、21.3±0.2°、22.9±0.2°、27.9±0.2°； Most preferably, the X-ray powder diffraction pattern of the crystalline Form B is substantially as shown in Figure 19; and the TGA-DSC pattern is substantially as shown in Figure 20; or a crystalline Form C of N-((S)-2-((5-((R)-1-(5,5-difluoro-2-oxopiperidin-1-yl)-2- ((R)-2-methylmorpholino)ethyl)thiazol-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2- oxoehtyl)-1-(ethyl-d5)-1H-pyrazole-5-carboxamide; The X-ray powder diffraction pattern of the crystal form C has a diffraction peak at 8.0±0.2°; or has a diffraction peak at 9.5±0.2°; or has a diffraction peak at 11.5±0.2°; or has a diffraction peak at 16.5±0.2°; or has a diffraction peak at 9.7±0.2°; or has a diffraction peak at 13.2±0.2°; or has a diffraction peak at 14.4±0.2°; or has a diffraction peak at 18.8±0.2°; or has a diffraction peak at 19.6±0.2°; or has a diffraction peak at 22.3±0.2°; preferably comprising any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, or 8-10 of the above diffraction peaks; more preferably comprising any 6, 7, 8, 9 or 10 of the above diffraction peaks; The X-ray powder diffraction pattern of the crystal form C has at least one diffraction peak at 8.0±0.2°, 9.5±0.2°, 11.5±0.2° and 16.5±0.2°, preferably comprising 2 of them, more preferably comprising 3 or 4 of them; further preferably, it can also comprise at least one of 9.7±0.2°, 13.2±0.2°, 14.4±0.2°, 18.8±0.2°, 19.6±0.2° and 22.3±0.2°, preferably comprising 2, 3, 4, 5 or 6 of them; Further preferably, the X-ray powder diffraction pattern of the crystal form C comprises one or more diffraction peaks at 8.0±0.2°, 9.5±0.2°, 9.7±0.2°, 11.5±0.2°, 13.2±0.2°, 14.4±0.2°, 16.5±0.2°, 18.8±0.2°, 19.6±0.2° and 22.3±0.2°; preferably comprising 4, 5, 6, 8 or 10 of them optionally; More preferably, the X-ray powder diffraction pattern of the crystal form C can also comprise one or more diffraction peaks at 15.1±0.2°, 16.2±0.2°, 21.0±0.2°, 21.9±0.2°, 25.2±0.2° and 29.2±0.2°; preferably comprising any 2-3, or 4-5 of them; further preferably, comprising any 2, 3, 4, 5 or 6 of them; For example, the X-ray powder diffraction pattern of the crystal form C has diffraction peaks at 2θ of the following positions: 8.0±0.2°、9.5±0.2°、11.5±0.2°、16.5±0.2°、9.7±0.2°、13.2±0.2°、14.4±0.2°； 8.0±0.2°、9.5±0.2°、11.5±0.2°、16.5±0.2°、18.8±0.2°、19.6±0.2°、22.3±0.2°； 8.0±0.2°、9.5±0.2°、11.5±0.2°、16.5±0.2°、15.1±0.2°、16.2±0.2°、21.0±0.2°； 8.0±0.2°、9.5±0.2°、11.5±0.2°、16.5±0.2°、21.9±0.2°、25.2±0.2°、29.2±0.2°； 8.0±0.2°、9.5±0.2°、11.5±0.2°、16.5±0.2°、9.7±0.2°、13.2±0.2°、14.4±0.2°、18.8±0.2°； 8.0±0.2°、9.5±0.2°、11.5±0.2°、16.5±0.2°、14.4±0.2°、18.8±0.2°、19.6±0.2°、22.3±0.2°； 8.0±0.2°、9.5±0.2°、11.5±0.2°、16.5±0.2°、15.1±0.2°、16.2±0.2°、21.0±0.2°、21.9±0.2°； 8.0±0.2°、9.5±0.2°、11.5±0.2°、16.5±0.2°、21.0±0.2°、21.9±0.2°、25.2±0.2°、29.2±0.2°； 8.0±0.2°、9.5±0.2°、11.5±0.2°、16.5±0.2°、9.7±0.2°、13.2±0.2°、15.1±0.2°、16.2±0.2°； 8.0±0.2°、9.5±0.2°、11.5±0.2°、16.5±0.2°、19.6±0.2°、22.3±0.2°、25.2±0.2°、29.2±0.2°； 8.0±0.2°、9.5±0.2°、11.5±0.2°、16.5±0.2°、9.7±0.2°、22.3±0.2°、15.1±0.2°、29.2±0.2°； 8.0±0.2°、9.5±0.2°、11.5±0.2°、16.5±0.2°、9.7±0.2°、13.2±0.2°、14.4±0.2°、18.8±0.2°、19.6±0.2°； 8.0±0.2°、9.5±0.2°、11.5±0.2°、16.5±0.2°、13.2±0.2°、14.4±0.2°、18.8±0.2°、19.6±0.2°、22.3±0.2°； 8.0±0.2°、9.5±0.2°、11.5±0.2°、16.5±0.2°、15.1±0.2°、16.2±0.2°、21.0±0.2°、21.9±0.2°、25.2±0.2°； 8.0±0.2°、9.5±0.2°、11.5±0.2°、16.5±0.2°、16.2±0.2°、21.0±0.2°、21.9±0.2°、25.2±0.2°、29.2±0.2°； Most preferably, the X-ray powder diffraction pattern of the crystal form C is substantially as shown in Figure 21; and the TGA-DSC pattern is substantially as shown in Figure 22.

8. The crystalline form of the compound or a stereoisomer thereof according to any one of claims 5 to 7, wherein, The relative peak intensity of the diffraction peak position in the X-ray powder diffraction pattern of N-((S)-2-((5-((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)thiazol-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-fluorocyclopropane-1-carboxamide Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J is the top ten, and the 2θ error of the diffraction peak position corresponding to the position of Figure 1, Figure 3, Figure 4, Figure 6, Figure 8, Figure 9, Figure 11, Figure 12, Figure 13, Figure 15 is ±0.2°-±0.5°; preferably ±0.2°-±0.3°, most preferably ±0.2°. Or the relative peak intensity of the diffraction peak position in the X-ray powder diffraction pattern of N -((S)-2-((5-((R)-1-(5,5-difluor-2-oxopiperidin-1-yl)-2-((R)-2-methylmorpholino)ethyl)thiazol -2-yl)amino)-1-((1r,4S)-4-methyl cyclohexyl)-2-oxoethyl)-1-(ethyl-d5)-1H-pyrazole-5-carboxamide Form A, Form B and Form C is the top ten, and the 2θ error of the diffraction peak position corresponding to Figure 17, Figure 19 and Figure 21 is ±0.2°-±0.5°; preferably ±0.2° -±0.3°, most preferably ±0.2°.

9. A process for preparing a crystalline form of a compound of any one of claims 1-8, or a stereoisomer thereof, comprising: It is method one to three; Method one: the compound or certain crystal form is added to a poor solvent, stirred or beaten, optionally centrifuged, to obtain the corresponding crystal form; Method two: the compound or certain crystal form is dissolved in a good solvent, optionally, seed crystal is added, stirred or cooled to crystallize, centrifuged, to obtain the corresponding crystal form; preferably, the amount of seed crystal added is 0.05%-10%, preferably 0.1%-6%, more preferably 1%-5%; Method three: the compound or certain crystal form is dissolved in a good solvent, and the corresponding crystal form is obtained by volatilization; The poor solvent is selected from one or more of acetone, ethyl acetate, isopropyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, methanol, n-propanol, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, t-butanol, 2-butanone, 3-pentanone, methyl tert-butyl ether, water, cyclohexane, n-heptane; preferably one or more of water, methanol, ethanol, isopropanol, acetone; The good solvent is selected from one or more of dimethyl sulfoxide, acetic acid, methanol, acetone, ethanol, isopropanol, ethyl acetate, acetonitrile, 88% acetone, tetrahydrofuran, 2-methyltetra-hydrofuran, dichloromethane, 1,4-dioxane, benzene toluene, isopropanol, n-butanol, isobutanol, N,N-dimethy formamide, N,N-dimethylacetamide, n-propanol, t-butanol, 10. A pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of a compound according to any one of claims 1 to 8, or a stereoisomer thereof, and one or more pharmaceutically acceptable carriers or excipients.

11. Use of a crystalline form of a compound according to any one of claims 1 to 8, or a stereoisomer thereof, of a pharmaceutical composition according to claim 10 for the manufacture of a medicament for the treatment and / or prevention of an IL-17 related disease, in particular for the treatment and / or prevention of an IL-17A related disease.

12. Use of a crystalline form of a compound according to any one of claims 1 to 8, or a stereoisomer thereof, of a pharmaceutical composition according to claim 10 for the manufacture of a medicament for the treatment and / or prevention of an autoimmune disease; preferably the autoimmune disease is selected from psoriasis, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, psoriatic arthritis, ankylosing spondylitis, hidradenitis suppurativa, rheumatoid arthritis, palmoplantar pustulosis, spondyloarthritis and non-infectious uveitis.

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