Crystal forms of benzamide of pyrazolyl-amino-pyrimidinyl derivative, preparation method therefor and use thereof

Abstract

Disclosed are crystal forms of a benzamide of a pyrazolyl-amino-pyrimidinyl derivative, a preparation method therefor and the use thereof. Specifically, disclosed are a crystal form I and crystal form II of a compound shown as formula 2, or a crystal form III of a compound shown as formula 3, the crystal forms satisfying one or more of the following effect advantages: good physical and chemical properties, solid stability, good solubility, low hygroscopicity and good processibility in formulation processes.

Description

Crystal form, preparation method and application of benzamide of a pyrazolyl-amino-pyrimidinyl derivative

[0001] This application claims priority to Chinese patent application CN202410116499.6, filed on January 26, 2024, and to Chinese patent application CN202510007289.8, filed on January 2, 2025. The entire text of the aforementioned Chinese patent application is incorporated herein by reference. Technical Field

[0002] The present application relates to a crystalline form, preparation method and application of a benzamide of a pyrazolyl-amino-pyrimidinyl derivative. Background Art

[0003] JAK / STAT signaling begins with the binding of extracellular cytokines or growth factors to their corresponding transmembrane receptors. Cytokine-induced receptor subunits undergo homo- or heterodimerization, which brings JAKs into close proximity and alters their spatial structure, ultimately shifting the JAK kinase domain from an inhibitory form with no kinase activity to an activating form with kinase activity. This binding brings JAKs into close proximity with their receptors, leading to phosphorylation of both the JAKs themselves and the cytoplasmic receptor tails, creating potential docking sites for STAT monomers and recruiting and activating downstream signaling proteins. STATs are the primary substrates of JAKs. Receptors recruit inactive STAT monomers in the cytoplasm. JAKs phosphorylate the terminal tyrosine residues of STAT proteins, leading to the formation of homo- or heterodimers of phosphorylated STATs that rapidly translocate to the nucleus, inducing target gene transcription and ultimately regulating gene expression. JAK inhibitors play a crucial role in hematopoiesis and immune function by mediating signals from numerous cytokines and growth factors.

[0004] The activity of different small molecule kinase inhibitors that are currently marketed or in development

[0005] Preclinical study results indicate that the compound represented by Formula 2 has significant inhibitory effects on JAK1 and JAK2 at both the enzymatic and cellular levels. As can be seen from the data in the table above, the compound represented by Formula 2 has significantly better ability to simultaneously inhibit JAK1 and JAK2 than similar drugs currently in clinical research, and has the potential to become a best-in-class drug. Summary of the Invention

[0006] The present invention provides a crystalline form of a benzamide of a pyrazolyl-amino-pyrimidinyl derivative, a preparation method, and an application thereof. The crystalline form satisfies one or more of the following advantages: good physical and chemical properties, solid-state stability, good solubility, low hygroscopicity, and good processability in formulation processes.

[0007] The present invention provides a crystalline form I of a compound as shown in Formula 2;

[0008] The crystalline form I uses Cu-Kα radiation, and the X-ray powder diffraction pattern represented by 20 has diffraction peaks at the following positions: 7.337°±0.2°, 10.920°±0.2°, 13.787°±0.2°, 14.100°±0.2°, 16.423°±0.2°, 17.080°±0.2°, 19.806°±0.2°, and 19.975°±0.2°.

[0009] In one embodiment, the X-ray powder diffraction pattern of the crystalline form I expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 6.023°±0.2°, 10.650°±0.2°, 16.157°±0.2°, 18.201°±0.2°, 20.881°±0.2°, 24.596°±0.2°, 25.088°±0.2°, and 26.872°±0.2°.

[0010] In one embodiment, the X-ray powder diffraction pattern of the crystalline form I expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 10.014°±0.2°, 12.030°±0.2°, 12.617°±0.2°, 13.115±0.2°, 14.667°±0.2°, 18.917±0.2°, 29.662°±0.2°, 30.012°±0.2°, 31.021±0.2°, 35.994±0.2°, 38.847°±0.2°, and 41.459±0.2°.

[0011] In one embodiment, the X-ray powder diffraction pattern of the crystalline form I expressed in 2θ angles has diffraction peaks as shown in the following table:

[0012] In one embodiment, the X-ray powder diffraction pattern of the crystalline form I expressed in 2θ angles is substantially as shown in FIG2 .

[0013] In one embodiment, the differential scanning calorimetry diagram of the crystalline form I has an endothermic peak at 195°C±2°C.

[0014] In one embodiment, the differential scanning calorimetry diagram of the crystalline form I has an endothermic peak at 195°C±2°C, and the heat of melting is 94 J / g.

[0015] In one embodiment, the differential scanning calorimetry diagram of the crystalline form I is substantially as shown in FIG4 .

[0016] In one embodiment, the thermogravimetric analysis of the Form I shows a weight loss of 0.26%±0.03% when heated to 150°C.

[0017] In one embodiment, the thermogravimetric analysis diagram of the crystalline form I is substantially as shown in FIG3 .

[0018] In one embodiment, the dynamic moisture adsorption analysis diagram of the crystalline form I is substantially as shown in FIG5 .

[0019] In one embodiment, the scanning electron microscope image of the crystalline form I is substantially as shown in FIG6 .

[0020] The present invention also provides a method for preparing the above-mentioned crystal form I, which comprises the following steps:

[0021] Methyl tert-butyl ether is added to a saturated tetrahydrofuran solution of the compound represented by Formula 2.

[0022] In a certain embodiment, the volume ratio of the tetrahydrofuran to the methyl tert-butyl ether is 1:4-1:10, preferably 1:5.

[0023] The present invention also provides a crystalline form II of the compound shown in Formula 2;

[0024] The crystalline form II uses Cu-Kα radiation, and the X-ray powder diffraction pattern expressed in 2θ has diffraction peaks at the following positions: 6.803°±0.2°, 12.477°±0.2°, 16.356°±0.2°, 20.669°±0.2°, 26.549°±0.2°, and 3.442°±0.2°.

[0025] In one embodiment, the X-ray powder diffraction pattern of the crystalline form II expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 21.020°±0.2°, 21.407°±0.2°, 27.919°±0.2°, 29.702°±0.2°, and 31.436°±0.2°.

[0026] In a certain embodiment, the X-ray powder diffraction pattern of the crystalline form II expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 13.614°±0.2°, 15.884°±0.2°, 18.046°±0.2°, 18.575°±0.2°, 20.037°±0.2°, 25.638°±0.2°, 27.449, 28.946°±0.2°, 30.657°±0.2°, 32.699°±0.2°, 33.006°±0.2°, 34.442°±0.2°, 37.155°±0.2°, 38.038°±0.2°, 40.171°±0.2°, and 40.676°±0.2°.

[0027] In one embodiment, the X-ray powder diffraction pattern of the crystalline form II expressed in 2θ angles has the diffraction peaks shown in the following table:

[0028] In one embodiment, the X-ray powder diffraction pattern of the crystalline form II expressed in 2θ angles is substantially as shown in FIG7 .

[0029] In one embodiment, the differential scanning calorimetry diagram of the crystalline form II has an endothermic peak at 188°C±2°C.

[0030] In one embodiment, the differential scanning calorimetry diagram of the crystalline form II has an endothermic peak at 188°C±2°C, and the heat of melting is 90 J / g.

[0031] In one embodiment, the differential scanning calorimetry diagram of the Form II is substantially as shown in FIG9 .

[0032] In one embodiment, the thermogravimetric analysis of the Form II shows no weight loss when heated to 150°C.

[0033] In one embodiment, the thermogravimetric analysis diagram of the Form II is substantially as shown in FIG8 .

[0034] In one embodiment, the dynamic moisture adsorption analysis diagram of the crystal form II is substantially as shown in FIG10 .

[0035] In one embodiment, the scanning electron microscope image of the crystal form II is substantially as shown in FIG11 .

[0036] The present invention also provides a method for preparing Form II, which comprises the following steps:

[0037] The following temperature program was performed on a butanone solution of the compound represented by Formula 2:

[0038] Equilibrate at 25°C for 10 min → heat up to 50°C at 2.5°C / min;

[0039] → Equilibrate at 50℃ for 30min → Cool down to 5℃ at 1℃ / min;

[0040] → Equilibrate at 5℃ for 30min → Raise the temperature to 50℃ at 1.8℃ / min;

[0041] → Equilibrate at 50℃ for 30min → Cool down to 5℃ at 1℃ / min;

[0042] → Equilibrate at 5℃ for 30min → Raise the temperature to 25℃ at 2℃ / min;

[0043] →Equilibrate at 25℃ for 10 minutes.

[0044] In one embodiment, the concentration of the butanone solution of the compound represented by Formula 2 is 40-60 g / L, for example, 54 g / L.

[0045] In one embodiment, the temperature program is cycled twice.

[0046] The present invention also provides a crystalline form III of the compound shown in Formula 3;

[0047] The crystalline form III uses Cu-Kα radiation, and the X-ray powder diffraction pattern expressed in 2θ has diffraction peaks at the following positions: 6.537°±0.2°, 17.566°±0.2°, 20.536°±0.2°, and 27.163°±0.2°.

[0048] In a certain embodiment, the X-ray powder diffraction pattern of the crystalline form III expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 12.516°±0.2°, 23.079°±0.2°, 24.834°±0.2°, and 26.134°±0.2°.

[0049] In one embodiment, the X-ray powder diffraction pattern of the crystalline form III expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 13.128°±0.2°, 14.504°±0.2°, 27.775°±0.2°, 29.340°±0.2°, 32.327°±0.2°, and 33.266°±0.2°.

[0050] In one embodiment, the X-ray powder diffraction pattern of the crystalline form III expressed in 2θ angles has the diffraction peaks shown in the following table:

[0051] In one embodiment, the X-ray powder diffraction pattern of the Form III expressed in 2θ angles is substantially as shown in FIG12 .

[0052] In one embodiment, the differential scanning calorimetry diagram of the crystalline form III has an endothermic peak at 84°C±2°C.

[0053] In one embodiment, the differential scanning calorimetry diagram of the crystalline form III has an endothermic peak at 84°C±2°C, and the heat of melting is 34 J / g.

[0054] In one embodiment, the differential scanning calorimetry diagram of the crystalline form III has an endothermic peak at 174°C±2°C.

[0055] In one embodiment, the differential scanning calorimetry diagram of the crystalline form III has an endothermic peak at 174°C±2°C, and the heat of melting is 43 J / g.

[0056] In one embodiment, the differential scanning calorimetry diagram of the crystalline form III has an endothermic peak at 184°C±2°C.

[0057] In one embodiment, the differential scanning calorimetry diagram of the crystalline form III has an endothermic peak at 184°C±2°C, and the heat of melting is 22 J / g.

[0058] In one embodiment, the differential scanning calorimetry diagram of the crystalline form III has an endothermic peak at 193°C±2°C.

[0059] In one embodiment, the differential scanning calorimetry diagram of the crystalline form III has an endothermic peak at 193°C±2°C, and the heat of melting is 20 J / g.

[0060] In one embodiment, the differential scanning calorimetry diagram of the Form III is substantially as shown in FIG14 .

[0061] In one embodiment, the thermogravimetric analysis of the Form III shows a weight loss of 1.6±0.1% when heated to 150°C.

[0062] In one embodiment, the thermogravimetric analysis diagram of the Form III is substantially as shown in FIG13 .

[0063] In one embodiment, the dynamic moisture adsorption analysis diagram of the crystalline form III is substantially as shown in FIG15 .

[0064] In one embodiment, the scanning electron microscope image of the Form III is substantially as shown in FIG16 .

[0065] The present invention also provides a method for preparing Form III, which comprises the following steps:

[0066] Water is added to a saturated tetrahydrofuran solution of the compound represented by Formula 2 until solid precipitates.

[0067] Preferably, the volume ratio of the tetrahydrofuran to the water is 1:4-1:10, preferably 1:5.

[0068] The present invention also provides a pharmaceutical composition comprising one or more of the above-mentioned crystalline form I, crystalline form II and crystalline form III, and pharmaceutical excipients.

[0069] The present invention also provides a use of the above-mentioned crystal form I, crystal form II or the above-mentioned pharmaceutical composition in the preparation of a drug for treating and / or preventing diseases associated with JAK kinase.

[0070] In one embodiment, the disease associated with JAK kinase is inflammatory bowel disease, psoriasis, vitiligo, atopic dermatitis, systemic lupus erythematosus, asthma, diabetic nephropathy, chronic myeloid leukemia (CML), essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis (MF), breast cancer or ovarian cancer.

[0071] The term “substantially” means that the positions of the peaks in the graph may vary slightly with slight variations in the measuring equipment, measuring conditions, and batches of the product to be measured, and are not to be regarded as absolute values.

[0072] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0073] The reagents and raw materials used in the present invention are commercially available.

[0074] The positive progress of the present invention is that the crystalline form provided in the present application has good physical and chemical properties, good high temperature (e.g., 60°C) and high humidity (75% RH) stability, good solubility, low hygroscopicity, uniform particle size distribution, good solid form and formulation processability, and good development prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0075] Figure 1 is the XRPD spectrum of the amorphous powder.

[0076] Figure 2 is the XRPD spectrum of Form I.

[0077] FIG3 is a TGA spectrum of Form I.

[0078] Figure 4 is the DSC spectrum of Form I

[0079] Figure 5 is a DVS spectrum of Form I.

[0080] FIG6 is a SEM image of Form I.

[0081] FIG7 is an XRPD spectrum of Form II.

[0082] FIG8 is a TGA spectrum of Form II.

[0083] FIG9 is a DSC spectrum of Form II.

[0084] FIG10 is a DVS spectrum of Form II.

[0085] FIG11 is a SEM image of Form II.

[0086] FIG12 is an XRPD spectrum of Form III.

[0087] FIG13 is a TGA spectrum of Form III.

[0088] FIG14 is a DSC spectrum of Form III.

[0089] FIG15 is a DVS spectrum of Form III.

[0090] FIG16 is a SEM image of Form III. DETAILED DESCRIPTION

[0091] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0092] 1. Analytical methods

[0093] 1.1 X-ray powder diffraction (XRPD)

[0094] Crystalline analysis of the samples was performed using an X-ray powder diffractometer. The 2θ scanning angle was from 3° ± 0.2° to 42° ± 0.2°, with a scanning step size of 0.02° ± 0.2° and a scanning time of 0.2 s per step. The light tube voltage and current were 40 kV and 40 mA, respectively. During sample preparation, an appropriate amount of sample was placed on a sample tray and flattened with a glass slide or other tool to ensure a smooth surface.

[0095] 1.2 Thermogravimetric analysis (TGA)

[0096] The samples were analyzed using a TA Instruments TGA Discovery 550. The samples were placed in a tared aluminum pan, which was automatically weighed by the system. The sample was then heated to the specified temperature at a rate of 10°C / min under nitrogen.

[0097] 1.3 Differential Scanning Calorimetry (DSC)

[0098] The samples were analyzed using a TA Instruments Discovery DSC 25. The weighed samples were placed in a sample tray, and the sample was heated to the specified temperature at a rate of 10°C / min under the protection of nitrogen (50 ml / min).

[0099] 1.4 Dynamic Water Sorption Analysis (DVS)

[0100] Samples were analyzed using Intrinsic DVS (System Measurement System UK). The test sample size was approximately 20-30 mg. The test chamber temperature was controlled at 25 ± 1°C, and the relative humidity was increased from 0% to 90% and then decreased to 0% at a rate of 10% / h. Mass data was recorded every 20 seconds.

[0101] 1.5 Scanning electron microscopy (SEM)

[0102] The sample was analyzed using Phenompure+. After being gold-sprayed, the sample was placed in the instrument for testing. The magnification was adjusted to 400x to capture the sample's crystal habit.

[0103] Example 1 Preparation and Characterization of Form I

[0104] To a saturated tetrahydrofuran solution of 0.6 ml (62.4 mg) of the compound represented by Formula 2 (prepared as an amorphous powder using Example 111 of compound patent CN113227074A, whose XRPD pattern expressed in 2θ angles using Cu-Kα radiation is shown in FIG1 ) was prepared, 3 ml of methyl tert-butyl ether was added, and the mixture was filtered to obtain Form I.

[0105] Characterization of Form I

[0106] The XRPD pattern of Form I using Cu-Kα radiation, expressed in 2θ angles, is shown in Figure 2, and the specific data are shown in the table below. TGA analysis results are shown in Figure 3, showing a 0.26% weight loss when heated to 150°C. DSC analysis results of Form I are shown in Figure 4, indicating an endothermic peak at 195°C with an enthalpy of 93 J / g. DVS analysis results of Form I are shown in Figure 5. Form I is an anhydrous crystalline form. A SEM scan of Form I is generally shown in Figure 6.

[0107] Example 2 Preparation and Characterization of Form II

[0108] To a glass vial, the compound of Formula 2 (53.8 mg) (prepared with reference to Example 111 of compound patent CN113227074A) and butanone (1 ml) were added. The resulting solution was subjected to the following temperature program using a crystal 16, cycled twice, and filtered to obtain Form II.

[0109] Equilibrate at 25℃ for 10min→heat up to 50℃ at 2.5℃ / min

[0110] → Equilibrate at 50℃ for 30min → Cool down to 5℃ at 1℃ / min

[0111] → Equilibrate at 5℃ for 30min → Raise the temperature to 50℃ at 1.8℃ / min

[0112] → Equilibrate at 50℃ for 30min → Cool down to 5℃ at 1℃ / min

[0113] → Equilibrate at 5℃ for 30min → Raise the temperature to 25℃ at 2℃ / min

[0114] →Equilibrate at 25℃ for 10 minutes.

[0115] Characterization of Form II

[0116] The XRPD pattern of Form II using Cu-Kα radiation, expressed in 2θ angles, is shown in Figure 7, and the specific data are shown in the table below. TGA analysis results are shown in Figure 8, showing no weight loss when heated to 150°C. DSC analysis results of Form II are shown in Figure 9, revealing an endothermic peak at 189°C with an enthalpy of 91 J / g. DVS analysis results of Form II are shown in Figure 10. Form II is an anhydrous crystalline form. A SEM scan of Form II is generally shown in Figure 11.

[0117] Example 3 Preparation and Characterization of Form III

[0118] Prepare 0.6 ml (62.4 mg) of a saturated tetrahydrofuran solution of the compound shown in Formula 2 (prepared with reference to Example 111 of compound patent CN113227074A), add 3 ml of water, and filter to obtain Form III.

[0119] Characterization of Form III

[0120] The XRPD pattern of Form III using Cu-Kαα radiation, expressed in 2θ angles, is shown in Figure 12, with specific data in the table below. TGA analysis results are shown in Figure 13, showing a 1.6% weight loss when heated to 150°C. DSC analysis results of Form III are shown in Figure 14, revealing an endothermic peak at 173°C with an enthalpy of 41 J / g. DVS analysis results of Form III are shown in Figure 15. Form III is a hemihydrate. A SEM scan of Form III is generally shown in Figure 16.

[0121] The comparison of the physical and chemical properties of the three crystal forms is shown in the following table:

[0122] Form II has no weight loss before 150°C and has the lowest hygroscopicity, and is non-hygroscopic. Form I also has low weight loss and slight hygroscopicity, and is suitable for further process development.

[0123] *At 25±1°C and 80±2% RH (Ph. Eur. 6.0).

[0124] Example 4 Crystallization Experiment

[0125] Crystallization experiments were conducted under eight different solvent conditions. Equal amounts of the three crystalline forms were added to a vial, followed by a certain amount of solvent and stirring under different conditions. The experimental parameters and results are listed in the table below. The results show that in aqueous systems, the crystals transform into Form III, in isopropanol and acetonitrile systems, they transform into Form II, in methanol, they transform into Form I, and in methyl tert-butyl ether, they form a mixture of Forms I and II.

[0126] Example 5 Stability Test

[0127] The stability of the three crystalline forms was tested under specific temperature and humidity conditions. 10 mg of the solids listed in the table below were placed in 2 ml glass vials and transferred to a stability chamber. The experimental conditions were: 40°C / 75% RH, 60°C. Samples were removed at designated times for XRPD analysis. The results, shown in the table below, demonstrate that the three crystalline forms are stable at 40°C / 75% RH, 60°C for at least six days.

[0128] Example 6 Solubility Experiment

[0129] This experiment determined the solubility of three crystal forms in water and simulated liquids (SGF, FaSSIF, and FeSSIF) at 37°C. After mixing 20 mg of the solid with the solvent and stirring at 37°C for a certain period of time, the sample was filtered and the filtrate was used for HPLC content detection (LOQ = 0.0005 mg / mL), and the solid was used for XRPD crystal form detection. The solubility determination results are shown in the table below. The results show that the solubility of crystal form I is the best in all three simulated liquids, and the solubility of crystal form II is higher than that of crystal form III in all three simulated liquids. The crystal form of the solid obtained at 2h and 10h did not change.

[0130] N / A: Insufficient solid obtained for XRPD testing.

Claims

1. Polymorph I of the compound shown in Formula 2, Polymorph II of the compound shown in Formula 2 or Polymorph III of the compound shown in Formula 3, characterized in that: It is selected from Polymorph I, Polymorph II or Polymorph III; Polymorph I of the compound represented by Formula 2, whose X-ray powder diffraction pattern expressed in 2θ using Cu-Kα radiation has diffraction peaks at the following positions: 7.337°±0.2°, 10.920°±0.2°, 13.787°±0.2°, 14.100°±0.2°, 16.423°±0.2°, 17.080°±0.2°, 19.806°±0.2°, 19.975°±0.2°; Polymorph II of the compound represented by Formula 2, whose X-ray powder diffraction pattern expressed in 2θ using Cu-Kα radiation has diffraction peaks at the following positions: 6.803°±0.2°, 12.477°±0.2°, 16.356°±0.2°, 20.669°±0.2°, 26.549°±0.2°, 3.442°±0.2°; Polymorph III of the compound represented by Formula 3, whose X-ray powder diffraction pattern expressed in 2θ using Cu-Kα radiation has diffraction peaks at the following positions: 6.537°±0.2°, 17.566°±0.2°, 20.536°±0.2°, 27.163°±0.2°.

2. The crystalline form I of the compound represented by Formula 2, the crystalline form II of the compound represented by Formula 2, or the crystalline form III of the compound represented by Formula 3 as claimed in claim 1, characterized in that, It satisfies one or more of the following conditions: (1) For the said Polymorph I, whose X-ray powder diffraction pattern expressed in 2θ using Cu-Kα radiation also has diffraction peaks at the following positions: 6.023°±0.2°, 10.650°±0.2°, 16.157°±0.2°, 18.201°±0.2°, 20.881°±0.2°, 24.596°±0.2°, 25.088°±0.2°, 26.872°±0.2°; (2) For the said Polymorph II, whose X-ray powder diffraction pattern expressed in 2θ using Cu-Kα radiation also has diffraction peaks at the following positions: 21.020°±0.2°, 21.407°±0.2°, 27.919°±0.2°, 29.702°±0.2°, 31.436°±0.2°; (3) For the said Polymorph III, whose X-ray powder diffraction pattern expressed in 2θ using Cu-Kα radiation also has diffraction peaks at the following positions: 12.516°±0.2°, 23.079°±0.2°, 24.834°±0.2°, 26.134°±0.2°.

3. The crystalline form I of the compound represented by Formula 2, the crystalline form II of the compound represented by Formula 2, or the crystalline form III of the compound represented by Formula 3 according to claim 2, characterized in that, It satisfies one or more of the following conditions: (1) For the said Polymorph I, whose X-ray powder diffraction pattern expressed in 2θ using Cu-Kα radiation also has diffraction peaks at the following positions: 10.014°±0.2°, 12.030°±0.2°, 12.617°±0.2°, 13.115±0.2°, 14.667°±0.2°, 18.917±0.2°, 29.662°±0.2°, 30.012°±0.2°, 31.021±0.2°, 35.994±0.2°, 38.847°±0.2°, 41.459±0.2°; (2) The differential scanning calorimetry (DSC) curve of Polymorph I has an endothermic peak at 195°C ± 2°C; (3) The thermogravimetric analysis (TGA) curve of Polymorph I shows a weight loss of 0.26% ± 0.03% when heated to 150°C; (4) For Polymorph II, using Cu-Kα radiation, the X-ray powder diffraction pattern in terms of 2θ has diffraction peaks at the following positions: 13.614° ± 0.2°, 15.884° ± 0.2°, 18.046° ± 0.2°, 18.575° ± 0.2°, 20.037° ± 0.2°, 25.638° ± 0.2°, 27.449, 28.946° ± 0.2°, 30.657° ± 0.2°, 32.699° ± 0.2°, 33.006° ± 0.2°, 34.442° ± 0.2°, 37.155° ± 0.2°, 38.038° ± 0.2°, 40.171° ± 0.2°, 40.676° ± 0.2°; (5) The DSC curve of Polymorph II has an endothermic peak at 188°C ± 2°C; (6) The TGA curve of Polymorph II shows no weight loss when heated to 150°C; (7) For Polymorph III, using Cu-Kα radiation, the X-ray powder diffraction pattern in terms of 2θ has diffraction peaks at the following positions: 13.128° ± 0.2°, 14.504° ± 0.2°, 27.775° ± 0.2°, 29.340° ± 0.2°, 32.327° ± 0.2°, 33.266° ± 0.2°; (8) The DSC curve of Polymorph III has an endothermic peak at 84°C ± 2°C (9) The DSC curve of Polymorph III has an endothermic peak at 174°C ± 2°C; (10) The DSC curve of Polymorph III has an endothermic peak at 184°C ± 2°C; (11) The DSC curve of Polymorph III has an endothermic peak at 193°C ± 2°C; (12) The TGA curve of Polymorph III shows a weight loss of 1.6% ± 0.1% when heated to 150°C.

4. The crystalline form I of the compound shown in Formula 2, the crystalline form II of the compound shown in Formula 2, or the crystalline form III of the compound shown in Formula 3 as claimed in claim 3, wherein It satisfies one or more of the following conditions: (1) The crystalline form I has characteristic peaks and relative intensities in the X-ray powder diffraction pattern expressed in 2θ using Cu-Kα radiation as shown in the following table: (2) The DSC curve of Polymorph I has an endothermic peak at 195°C ± 2°C, and the heat of fusion is 94 J / g; (3) For the crystalline form II, the characteristic peaks and relative intensities of the X-ray powder diffraction pattern expressed in 2θ using Cu-Kα radiation are as follows in the table: (4) The DSC curve of Polymorph II has an endothermic peak at 188°C ± 2°C, and the heat of fusion is 90 J / g; (5) For the crystalline form III, the characteristic peaks and relative intensities of the X-ray powder diffraction pattern expressed in 2θ using Cu-Kα radiation are as follows in the table: (6) The DSC curve of Polymorph III has an endothermic peak at 84°C ± 2°C, and the heat of fusion is 34 J / g; (7) The DSC curve of Polymorph III has an endothermic peak at 174°C ± 2°C, and the heat of fusion is 43 J / g; (8) The DSC curve of Polymorph III has an endothermic peak at 184°C ± 2°C, and the heat of fusion is 22 J / g; (9) The DSC curve of Polymorph III has an endothermic peak at 193°C ± 2°C, and the heat of fusion is 20 J / g.

5. The polymorphic form I of the compound represented by Formula 2, the polymorphic form II of the compound represented by Formula 2, or the polymorphic form III of the compound represented by Formula 3 according to claim 4, characterized in that, It satisfies one or more of the following conditions: (1) The described Form I has an X-ray powder diffraction pattern expressed in terms of 2θ angle using Cu-Kα radiation, which is substantially as shown in Figure 2; (2) The thermogravimetric analysis diagram of the described Form I is substantially as shown in Figure 3; (3) The differential scanning calorimetry diagram of the described Form I is substantially as shown in Figure 4; (4) The dynamic moisture sorption analysis diagram of the described Form I is substantially as shown in Figure 5; (5) The scanning electron microscope image of the described Form I is substantially as shown in Figure 6; (6) The X-ray powder diffraction pattern of the described Form II expressed in terms of 2θ angle is substantially as shown in Figure 7; (7) The thermogravimetric analysis diagram of the described Form II is substantially as shown in Figure 8; (8) The differential scanning calorimetry diagram of the described Form II is substantially as shown in Figure 9; (9) The dynamic moisture sorption analysis diagram of the described Form II is substantially as shown in Figure 10; (10) The scanning electron microscope image of the described Form II is substantially as shown in Figure 11; (11) The X-ray powder diffraction pattern of the described Form III expressed in terms of 2θ angle is substantially as shown in Figure 12; (12) The thermogravimetric analysis diagram of the described Form III is substantially as shown in Figure 13; (13) The differential scanning calorimetry diagram of the described Form III is substantially as shown in Figure 14; (14) The dynamic moisture sorption analysis diagram of the described Form III is substantially as shown in Figure 15; (15) The scanning electron microscope image of the described Form III is substantially as shown in Figure 16.

6. A method for preparing polymorph I as described in any one of claims 1-5, characterized in that, It includes the following steps: Methyl tert-butyl ether is added to the saturated tetrahydrofuran solution of the compound shown in Formula 2; preferably, the volume ratio of the tetrahydrofuran to the methyl tert-butyl ether is 1:4 - 1:10, and preferably 1:

5.

7. A method for preparing polymorph II as described in any one of claims 1-5, characterized in that, It includes the following steps: The following temperature program is carried out on the butanone solution of the compound shown in Formula 2; Equilibrate at 25°C for 10 min → Heat up to 50°C at a rate of 2.5°C / min; → Equilibrate at 50°C for 30 min → Cool down to 5°C at a rate of 1°C / min; → Equilibrate at 5°C for 30 min → Heat up to 50°C at a rate of 1.8°C / min; → Equilibrate at 50°C for 30 min → Cool down to 5°C at a rate of 1°C / min; → Equilibrate at 5°C for 30 min → Heat up to 25°C at a rate of 2°C / min; → Equilibrate at 25°C for 10 min; Among them, the concentration of the butanone solution of the compound shown in Formula 2 can be 40 - 60 g / L, such as 54 g / L; Preferably, the temperature program is cycled twice.

8. A method for preparing polymorph III as described in any one of claims 1-5, characterized in that, It includes the following steps: Water is added to the saturated tetrahydrofuran solution of the compound shown in Formula 2; preferably, the volume ratio of the tetrahydrofuran to the water is 1:4 - 1:10, and preferably 1:

5.

9. A crystal form of a compound represented by Formula 2 or Formula 3, characterized in that, It is prepared by the preparation method described in any one of claims 6-8; 10. A pharmaceutical composition, which includes the crystal form as described in any one of claims 1 - 5 or the crystal form as described in claim 9, and pharmaceutical excipients.

11. Use of a substance X in the preparation of a medicament for treating and / or preventing a disease associated with JAK kinase, wherein the substance X is the crystal form described in any one of claims 1-5 or the crystal form described in claim 9, or the pharmaceutical composition described in claim 10; preferably, the disease associated with JAK kinase is autoinflammatory bowel disease, psoriasis, vitiligo, atopic dermatitis, systemic lupus erythematosus, asthma, diabetic nephropathy, chronic myeloid leukemia, essential thrombocythemia, polycythemia vera, myelofibrosis, breast cancer or ovarian cancer.

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