Crystal form of IRAK inhibitor compound, and preparation method therefor and use thereof

Abstract

Provided in the present application are a crystal form of an IRAK inhibitor compound, a preparation method therefor and the use thereof. The crystal form relates to a crystal form B, a crystal form C, a crystal form D, a crystal form E, a crystal form F, a crystal form G, a crystal form H, a crystal form J, a crystal form K, a crystal form L, a crystal form M, a crystal form N, a crystal form O, a crystal form P, a crystal form Q, a crystal form R, a crystal form S and a crystal form T. The crystal form E prepared in the present application is a dihydrate of a compound (I), has good stability, can be stably stored under the conditions of high temperatures and a low relative humidity, and can be used for subsequent formulation research and development and pharmaceutical composition development.

Description

Crystalline form of IRAK inhibitor compound and preparation method and application thereof

[0001] Related applications

[0002] The present application claims priority to Chinese Patent Application No. 202410890692.5, filed on July 3, 2024, entitled "Crystalline form of IRAK inhibitor compound and preparation method and application thereof". TECHNICAL FIELD

[0003] The present application belongs to the field of drug crystal forms, and relates to a crystalline form of an IRAK inhibitor and a preparation method and application thereof, in particular to a polymorph of N-(1-(1-(acetylpiperidin-4-yl)azetidin-3-yl)-3-(difluoromethyl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-3-yl)pyridine amide and a hydrate and solvate thereof, and a preparation method and application of the polymorph. BACKGROUND

[0004] Interleukin-1 receptor-associated kinase (IRAK) is a family of serine / threonine protein kinases present in cells, which has four members: IRAK1, IRAK2, IRAK3 and IRAK4, and the common feature is to have a typical N-terminal death domain, which mediates the interaction between MyD88-family adaptor proteins and the central kinase domain, wherein: IRAK1 and IRAK4 have kinase activity. IRAK4 is a key factor downstream of the Toll-like receptor (TLR) / interleukin-1 receptor (IL-1R) mediated inflammatory signal transduction pathway, and the TLR cell exterior recognizes pathogen-specific molecules (such as lipopolysaccharide, polypeptide, viral DNA, etc.), and after binding with the ligand, the intracellular part recruits MyD88 to form a complex, activates IRAK1 autophosphorylation, and then activates the downstream serine / threonine kinase TAK1, activates the NF-κB and MAPK signaling pathways, and then produces pro-inflammatory cytokines, chemokines and destructive enzymes, and ultimately leads to the production of inflammatory response, mediating innate immunity. IL-1R is involved in host defense and hematopoiesis, and is a bridge connecting innate immunity and acquired immunity.

[0005] Studies have shown that overactivation of the IRAK4-dependent TLR / IL-1R signaling pathway is closely related to the development of rheumatoid arthritis, and many other studies have also confirmed that IRAK4 enzyme activation is closely related to the occurrence and development of diseases such as tumors, gout, systemic lupus erythematosus, multiple sclerosis, metabolic syndrome, atherosclerosis, myocardial infarction, sepsis, inflammatory bowel disease, asthma and allergy, etc.

[0006] At present, WO2020 / 043008A1 discloses a new compound (I) which can be effectively used as a medicine for preparing a medicine for treating IRAK-mediated and / or interleukin-1 receptor-related diseases, especially a medicine for treating and / or preventing IRAK-mediated and / or interleukin-1 receptor-related diseases, how to develop these compounds more suitable for the crystalline form of the medicine, especially to find a crystalline form which can exist stably, has improved hygroscopicity and / or drug efficacy, find a crystalline form which has good mechanical properties, such as good resistance to tabletting, dry grinding and wet granulation, no crystalline form transformation and no obvious decrease in crystallinity, so as to achieve good effect in the stage of medicine preparation and use, which is an urgent problem to be solved. SUMMARY

[0007] The following is a summary of the subject matter described in detail herein. This summary is not intended to limit the scope of the claims.

[0008] The present application provides a crystalline form of an IRAK inhibitor compound and a preparation method and application thereof, in particular, provides a polymorph of N-(1-(1-(acetylpiperidin-4-yl)azetidin-3-yl)-3-(difluoromethyl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-3-yl)pyridine amide (i.e. compound (I)) and a preparation method and application of the polymorph.

[0009] In one aspect, the present application provides a crystalline form B of compound (I), which is N-(1-(1-(acetylpiperidin-4-yl)azetidin-3-yl)-3-(difluoromethyl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-3-yl)pyridine amide as shown in the following figure:

[0010] The crystalline form B has characteristic peaks at 2θ angles of 13.49±0.20°, 19.10±0.20°, 20.74±0.20°, 23.32±0.20°, 26.18±0.20°, 29.58±0.20° in the X-ray diffraction spectrum.

[0011] In the present application, the crystalline form B is a methanol solvate of compound (I).

[0012] Preferably, the crystalline form B has a powder X-ray diffraction pattern as shown in Figure 1.

[0013] According to the embodiment of the present application, the differential scanning calorimeter (DSC) analysis of the crystalline form B shows that it starts to desolvate at 63°C and melts at 242.3°C.

[0014] According to embodiments of the present application, the thermal gravimetric analysis (TGA) of the crystalline Form B shows a weight loss of 3.0% at 170 °C.

[0015] Preferably, the crystalline Form B has DSC and TGA patterns as shown in Figure 3 and Figure 4.

[0016] The present application also provides a crystalline Form C of Compound (I), which has characteristic peaks on the X-ray diffraction pattern expressed in terms of 2 theta angle at 4.66 ± 0.20°, 15.57 ± 0.20°, 17.84 ± 0.20°, 18.68 ± 0.20°, 20.53 ± 0.20°, 23.21 ± 0.20°.

[0017] According to embodiments of the present application, the crystalline Form C is a monohydrate of Compound (I).

[0018] Preferably, the crystalline Form C has a powder X-ray diffraction pattern as shown in Figure 5.

[0019] According to embodiments of the present application, the differential scanning calorimeter (DSC) of the crystalline Form C shows onset of dehydration at 83 °C, and melting at 228.9 °C and 237.5 °C.

[0020] According to embodiments of the present application, the thermal gravimetric analysis (TGA) of the crystalline Form C shows a weight loss of 3.6% at 150 °C.

[0021] Preferably, the crystalline Form C has DSC and TGA patterns as shown in Figure 7 and Figure 8.

[0022] The present application also provides a crystalline Form D of Compound (I), which has characteristic peaks on the X-ray diffraction pattern expressed in terms of 2 theta angle at 12.50 ± 0.20°, 13.34 ± 0.20°, 18.12 ± 0.20°, 21.05 ± 0.20°, 24.62 ± 0.20°, 24.86 ± 0.20°.

[0023] According to embodiments of the present application, the crystalline Form D is a monohydrate of Compound (I).

[0024] Preferably, the crystalline Form D has a powder X-ray diffraction pattern as shown in Figure 9.

[0025] According to embodiments of the present application, the differential scanning calorimeter (DSC) of the crystalline Form D shows onset of dehydration at 66 °C, and melting at 238.4 °C and 244.0 °C.

[0026] According to embodiments of the present application, the thermal gravimetric analysis (TGA) of the crystalline Form D shows a weight loss of 4.3% at 130 °C.

[0027] Preferably, the Form D has DSC and TGA patterns as shown in FIG. 11 and FIG. 12.

[0028] The present application also provides Form E of Compound (I), which has characteristic peaks at 9.10 ± 0.20°, 12.52 ± 0.20°, 13.35 ± 0.20°, 18.15 ± 0.20°, 21.06 ± 0.20°, 24.88 ± 0.20° on the X-ray diffraction pattern expressed in terms of the 2θ angle.

[0029] According to embodiments of the present application, the Form E is a dihydrate of Compound (I).

[0030] Preferably, the Form E has powder X-ray diffraction pattern as shown in FIG. 13.

[0031] According to embodiments of the present application, the differential scanning calorimeter (DSC) of the Form E shows dehydration starting at 6 °C and 90 °C, a solid-solid transition peak at 189.2 °C after dehydration, and then melting at 239.2 °C.

[0032] According to embodiments of the present application, the thermogravimetric analysis (TGA) of the Form E shows a weight loss of 2.8% at 90 °C and a weight loss of 3.6% between 90 °C and 140 °C.

[0033] Preferably, the Form E has DSC and TGA patterns as shown in FIG. 15 and FIG. 16.

[0034] According to embodiments of the present application, the Form E is an irregularly shaped crystal. Preferably, the Form E has a particle size of about 5 μm to 20 μm (e.g., 5 μm, 8 μm, 10 μm, 13 μm, 15 μm, 18 μm, or 20 μm). Preferably, the Form E has a PLM (polarized light microscope) pattern as shown in FIG. 95.

[0035] The present application also provides Form F of Compound (I), which has characteristic peaks at 5.68 ± 0.20°, 15.42 ± 0.20°, 16.46 ± 0.20°, 20.79 ± 0.20°, 25.95 ± 0.20°, 26.21 ± 0.20° on the X-ray diffraction pattern expressed in terms of the 2θ angle.

[0036] According to embodiments of the present application, the Form F is a monohydrate of Compound (I).

[0037] Preferably, the Form F has powder X-ray diffraction pattern as shown in FIG. 17.

[0038] According to embodiments of the present application, the differential scanning calorimeter (DSC) of the Form F shows dehydration starting at 5 °C and melting at 239.1 °C.

[0039] According to embodiments of the present application, the thermal gravimetric analysis (TGA) of the crystalline Form F shows a weight loss of 1.3% at 80°C.

[0040] Preferably, the crystalline Form F has DSC and TGA patterns as shown in Figure 19 and Figure 20.

[0041] The present application also provides a crystalline Form G of Compound (I), which has characteristic peaks on the X-ray diffraction pattern expressed in terms of 2 theta angle at 12.48±0.20°, 17.56±0.20°, 19.87±0.20°, 20.66±0.20°, 25.88±0.20°, 29.01±0.20°.

[0042] According to embodiments of the present application, the crystalline Form G is a DMF solvate of Compound (I).

[0043] Preferably, the crystalline Form G has powder X-ray diffraction pattern as shown in Figure 21.

[0044] According to embodiments of the present application, the differential scanning calorimeter (DSC) of the crystalline Form G shows onset of desolvation at 103°C, and after desolvation, melting at 243.0°C.

[0045] According to embodiments of the present application, the thermal gravimetric analysis (TGA) of the crystalline Form G shows a weight loss of 12.9% at 140°C.

[0046] Preferably, the crystalline Form G has DSC and TGA patterns as shown in Figure 23 and Figure 24.

[0047] The present application also provides a crystalline Form H of Compound (I), which has characteristic peaks on the X-ray diffraction pattern expressed in terms of 2 theta angle at 12.44±0.20°, 17.47±0.20°, 19.85±0.20°, 20.65±0.20°, 25.84±0.20°, 28.99±0.20°.

[0048] According to embodiments of the present application, the crystalline Form H is a dihydrate of Compound (I).

[0049] Preferably, the crystalline Form H has powder X-ray diffraction pattern as shown in Figure 25.

[0050] According to embodiments of the present application, the differential scanning calorimeter (DSC) of the crystalline Form H shows onset of dehydration at 104°C, and after dehydration, melting at 243.0°C.

[0051] According to embodiments of the present application, the thermal gravimetric analysis (TGA) of the crystalline Form H shows a weight loss of 12.9% at 140°C.

[0052] Preferably, the Form H has DSC and TGA patterns as shown in FIG. 27 and FIG. 28.

[0053] The present application also provides Form J of Compound (I), which has characteristic peaks at 7.80 ± 0.20°, 14.85 ± 0.20°, 19.95 ± 0.20°, 21.56 ± 0.20°, 21.75 ± 0.20°, 24.50 ± 0.20° on the X-ray diffraction pattern expressed in terms of the 2θ angle.

[0054] According to embodiments of the present application, the Form J is an anhydrate of Compound (I).

[0055] Preferably, the Form J has a powder X-ray diffraction pattern as shown in FIG. 29.

[0056] According to embodiments of the present application, the Form J has a differential scanning calorimeter (DSC) showing a melting at 243.8 °C.

[0057] According to embodiments of the present application, the Form J has a thermogravimetric analysis (TGA) showing a weight loss of 0.9% at 100 °C.

[0058] Preferably, the Form J has DSC and TGA patterns as shown in FIG. 31 and FIG. 32.

[0059] The present application also provides Form K of Compound (I), which has characteristic peaks at 13.49 ± 0.20°, 19.66 ± 0.20°, 19.94 ± 0.20°, 20.49 ± 0.20°, 26.21 ± 0.20°, 29.60 ± 0.20° on the X-ray diffraction pattern expressed in terms of the 2θ angle.

[0060] According to embodiments of the present application, the Form K is a monomethanol solvate of Compound (I).

[0061] Preferably, the Form K has a powder X-ray diffraction pattern as shown in FIG. 33.

[0062] According to embodiments of the present application, the Form K has a differential scanning calorimeter (DSC) showing a desolvation onset at 72 °C, followed by an endothermic peak at 203.8 °C, and finally a melting at 242.7 °C.

[0063] According to embodiments of the present application, the Form K has a thermogravimetric analysis (TGA) showing a weight loss of 3.1% at 120 °C.

[0064] Preferably, the Form K has DSC and TGA patterns as shown in FIG. 35 and FIG. 36.

[0065] The present application also provides a crystalline Form L of Compound (I), which has characteristic peaks in X-ray diffraction pattern expressed in 2θ angles at 5.68±0.20°, 11.15±0.20°, 15.43±0.20°, 20.55±0.20°, 22.34±0.20°, 23.26±0.20°.

[0066] According to embodiments of the present application, the crystalline Form L is a monohydrate of Compound (I).

[0067] Preferably, the crystalline Form L has a powder X-ray diffraction pattern as shown in Figure 37.

[0068] According to embodiments of the present application, the differential scanning calorimeter (DSC) of the crystalline Form L shows dehydration onset at 54°C, and after dehydration, melting at 239.2°C and 243.7°C.

[0069] According to embodiments of the present application, the thermogravimetric analysis (TGA) of the crystalline Form L shows 0.5% weight loss at 60°C, and 2.1% weight loss between 60°C and 220°C.

[0070] Preferably, the crystalline Form L has a DSC and TGA pattern as shown in Figure 39 and Figure 40.

[0071] The present application also provides a crystalline Form M of Compound (I), which has characteristic peaks in X-ray diffraction pattern expressed in 2θ angles at 4.68±0.20°, 10.66±0.20°, 18.69±0.20°, 19.81±0.20°, 21.90±0.20°, 24.24±0.20°.

[0072] According to embodiments of the present application, the crystalline Form M is a monoisopropyl acetate-monohydrate solvate of Compound (I).

[0073] Preferably, the crystalline Form M has a powder X-ray diffraction pattern as shown in Figure 41.

[0074] According to embodiments of the present application, the differential scanning calorimeter (DSC) of the crystalline Form M shows dehydration / solvent loss onset at 15°C and 96°C, and after dehydration / solvent loss, an endothermic peak at 186.6°C, followed by melting of the sample at 238.8°C and 242.2°C.

[0075] According to embodiments of the present application, the thermogravimetric analysis (TGA) of the crystalline Form M shows 2.0% weight loss at about 85°C, and 5.1% weight loss between 85°C and 220°C.

[0076] Preferably, the crystalline Form M has a DSC and TGA pattern as shown in Figure 43 and Figure 44.

[0077] The present application also provides crystalline Form N of Compound (I), which has characteristic peaks in X-ray diffraction pattern expressed in terms of 2 theta angle at 11.21 ± 0.20°, 15.59 ± 0.20°, 17.84 ± 0.20°, 20.38 ± 0.20°, 20.54 ± 0.20°, 23.24 ± 0.20°.

[0078] According to embodiments of the present application, the crystalline Form N is an anhydrate of Compound (I).

[0079] Preferably, the crystalline Form N has a powder X-ray diffraction pattern as shown in FIG. 45.

[0080] According to embodiments of the present application, the differential scanning calorimeter (DSC) of the crystalline Form N shows a melting at 240.5 °C.

[0081] According to embodiments of the present application, the thermogravimetric analysis (TGA) of the crystalline Form N shows a weight loss of 0.9% at 80 °C.

[0082] Preferably, the crystalline Form N has a DSC and TGA pattern as shown in FIG. 47 and FIG. 48.

[0083] The present application also provides crystalline Form O of Compound (I), which has characteristic peaks in X-ray diffraction pattern expressed in terms of 2 theta angle at 4.65 ± 0.20°, 15.64 ± 0.20°, 18.62 ± 0.20°, 21.53 ± 0.20°, 23.17 ± 0.20°, 24.02 ± 0.20°.

[0084] According to embodiments of the present application, the crystalline Form O is a 1,4-dioxane-monohydrate solvate of Compound (I).

[0085] Preferably, the crystalline Form O has a powder X-ray diffraction pattern as shown in FIG. 49.

[0086] According to embodiments of the present application, the differential scanning calorimeter (DSC) of the crystalline Form O shows a dehydration onset at 9 °C, followed by desolvation at 75 °C and 118 °C, and then the sample melts at 238.8 °C and 241.9 °C.

[0087] According to embodiments of the present application, the thermogravimetric analysis (TGA) of the crystalline Form O shows a weight loss of 1.4% at 75 °C, and a weight loss of 8.9% between 75 °C and 160 °C.

[0088] Preferably, the crystalline Form O has a DSC and TGA pattern as shown in FIG. 51 and FIG. 52.

[0089] The present application also provides a crystalline form P of Compound (I), which has characteristic peaks in X-ray diffraction pattern expressed in terms of 2 theta angle at 16.62±0.20°, 19.95±0.20°, 20.36±0.20°, 20.86±0.20°, 21.22±0.20°, 25.54±0.20°.

[0090] According to embodiments of the present application, the crystalline form P is a monohydrate of Compound (I).

[0091] Preferably, the crystalline form P has a powder X-ray diffraction pattern as shown in FIG. 53.

[0092] According to embodiments of the present application, the differential scanning calorimeter (DSC) of the crystalline form P shows dehydration starting at 13°C, and melting at 240.4°C after dehydration.

[0093] According to embodiments of the present application, the thermogravimetric analysis (TGA) of the crystalline form P shows a weight loss of 1.7% at 70°C.

[0094] Preferably, the crystalline form P has a DSC and TGA pattern as shown in FIG. 55 and FIG. 56.

[0095] The present application also provides a crystalline form Q of Compound (I), which has characteristic peaks in X-ray diffraction pattern expressed in terms of 2 theta angle at 18.73±0.20°, 21.76±0.20°, 22.00±0.20°, 22.26±0.20°, 23.43±0.20°, 24.19±0.20°.

[0096] According to embodiments of the present application, the crystalline form Q is a tetrahydrofuran solvate of Compound (I).

[0097] Preferably, the crystalline form Q has a powder X-ray diffraction pattern as shown in FIG. 57.

[0098] According to embodiments of the present application, the differential scanning calorimeter (DSC) of the crystalline form Q shows desolvation starting at 71°C, and melting at 229.9°C after desolvation, with a recrystallization peak at 231.4°C, followed by melting of the sample at 238.5°C and 242.4°C.

[0099] According to embodiments of the present application, the thermogravimetric analysis (TGA) of the crystalline form Q shows a weight loss of 1.5% at about 70°C, and a weight loss of 4.7% between 70°C and 150°C.

[0100] Preferably, the crystalline form Q has a DSC and TGA pattern as shown in FIG. 59 and FIG. 60.

[0101] The present application also provides a crystalline Form R of Compound (I), which has characteristic peaks in X-ray diffraction pattern expressed in terms of 2 theta angle at 4.66 ± 0.20°, 10.83 ± 0.20°, 18.78 ± 0.20°, 21.77 ± 0.20°, 23.27 ± 0.20°, 24.21 ± 0.20°.

[0102] According to embodiments of the present application, the crystalline Form R is a dihydrate of Compound (I).

[0103] Preferably, the crystalline Form R has a powder X-ray diffraction pattern as shown in FIG. 61.

[0104] According to embodiments of the present application, the differential scanning calorimeter (DSC) of the crystalline Form R shows dehydration onset at 14 °C and 89 °C, followed by sample melting at 240.5 °C and 243.8 °C.

[0105] According to embodiments of the present application, the thermogravimetric analysis (TGA) of the crystalline Form R shows 2.6% weight loss at 80 °C, and 3.6% weight loss between 80 °C and 130 °C.

[0106] Preferably, the crystalline Form R has a DSC and TGA pattern as shown in FIG. 63 and FIG. 64.

[0107] The present application also provides a crystalline Form S of Compound (I), which has characteristic peaks in X-ray diffraction pattern expressed in terms of 2 theta angle at 4.66 ± 0.20°, 5.57 ± 0.20°, 11.23 ± 0.20°, 17.89 ± 0.20°, 20.52 ± 0.20°, 23.30 ± 0.20°.

[0108] According to embodiments of the present application, the crystalline Form S is a dihydrate of Compound (I).

[0109] Preferably, the crystalline Form S has a powder X-ray diffraction pattern as shown in FIG. 65.

[0110] According to embodiments of the present application, the differential scanning calorimeter (DSC) of the crystalline Form S shows dehydration onset at 6 °C and 89 °C, followed by sample melting at 239.2 °C and 242.6 °C.

[0111] According to embodiments of the present application, the thermogravimetric analysis (TGA) of the crystalline Form S shows 2.7% weight loss at 80 °C, and 3.6% weight loss between 80 °C and 130 °C.

[0112] Preferably, the crystalline Form S has a DSC and TGA pattern as shown in FIG. 67 and FIG. 68.

[0113] The present application also provides a crystalline form T of Compound (I), which has characteristic peaks in X-ray diffraction pattern expressed in terms of 2 theta angle at 4.67 ± 0.20°, 12.95 ± 0.20°, 18.68 ± 0.20°, 21.42 ± 0.20°, 21.79 ± 0.20°, 24.17 ± 0.20°.

[0114] According to embodiments of the present application, the crystalline form T is a dihydrate of Compound (I).

[0115] Preferably, the crystalline form T has a powder X-ray diffraction pattern as shown in Figure 69.

[0116] According to embodiments of the present application, the differential scanning calorimeter (DSC) of the crystalline form T shows dehydration starting at 24 °C and 92 °C, and melting at 239.1 °C after dehydration.

[0117] According to embodiments of the present application, the thermogravimetric analysis (TGA) of the crystalline form T shows 2.5% weight loss at 90 °C, and 3.9% weight loss between 90 °C and 160 °C.

[0118] Preferably, the crystalline form T has a DSC and TGA pattern as shown in Figure 71 and Figure 72.

[0119] In another aspect, the present application also provides a method for preparing a polymorph of Compound (I).

[0120] According to embodiments of the present application, a method for preparing the crystalline form B comprises the following steps:

[0121] Compound (I) is mixed with methanol, heated and stirred until dissolved, cooled, and centrifuged to obtain the crystalline form B.

[0122] In the preparation of the crystalline form B, the mass-volume ratio of Compound (I) to methanol is 1 mg: (0.02-0.2) mL, for example, 1 mg:0.02 mL, 1 mg:0.05 mL, 1 mg:0.08 mL, 1 mg:0.1 mL, 1 mg:0.15 mL, or 1 mg:0.2 mL.

[0123] In the preparation of the crystalline form B, the temperature of heating is 50-70 °C, for example, 50 °C, 55 °C, 60 °C, 65 °C, or 70 °C.

[0124] In the preparation of the crystalline form B, the cooling is cooling to 0-5 °C (for example, 0 °C, 1 °C, 2 °C, 3 °C, 4 °C, or 5 °C) for 1-3 days (for example, 1 day, 1.5 days, 1.8 days, 2 days, 2.5 days, or 3 days) and then filtering.

[0125] The present application provides a method for preparing the crystalline form C, comprising the following steps:

[0126] Compound (I) is mixed with acetone, heated and stirred, and then cooled and stirred, centrifuged and filtered, and vacuum dried to obtain the crystal form C.

[0127] In the preparation of the crystal form C, the mass-volume ratio of compound (I) to acetone is 1 mg:(0.01-0.1) mL, for example, 1 mg:0.01 mL, 1 mg:0.02 mL, 1 mg:0.03 mL, 1 mg:0.05 mL, 1 mg:0.08 mL, or 1 mg:0.1 mL.

[0128] In the preparation of the crystal form C, the temperature of the heating is 50-70°C (for example, 50°C, 55°C, 60°C, 65°C, or 70°C) for 1-3 hours (for example, 1 hour, 1.5 hours, 2 hours, 2.5 hours, or 3 hours).

[0129] In the preparation of the crystal form C, the cooling is cooling to 20-25°C (for example, 20°C, 22°C, 24°C, or 25°C) and then continuing to stir for 1-3 days (for example, 1 day, 1.5 days, 1.8 days, 2 days, 2.5 days, or 3 days).

[0130] The present application provides a preparation method of the crystal form D, comprising the following steps:

[0131] Compound (I) is mixed with ethyl acetate, stirred at room temperature, centrifuged and filtered to obtain the crystal form D.

[0132] In the preparation of the crystal form D, the mass-volume ratio of compound (I) to ethyl acetate is 100 mg:(0.5-5) mL, for example, 100 mg:0.5 mL, 100 mg:0.8 mL, 100 mg:1 mL, 100 mg:1.5 mL, 100 mg:2 mL, 100 mg:3 mL, 100 mg:4 mL, or 100 mg:5 mL.

[0133] In the preparation of the crystal form D, the cooling is cooling to 20-25°C (for example, 20°C, 22°C, 24°C, or 25°C) and then continuing to stir for 1-3 days (for example, 1 day, 1.5 days, 1.8 days, 2 days, 2.5 days, or 3 days).

[0134] The present application provides a preparation method of the crystal form E, comprising the following steps:

[0135] Compound (I) is mixed with water, heated and stirred, centrifuged and filtered, and vacuum dried to obtain the crystal form E.

[0136] In the preparation of the crystalline form E, the mass-volume ratio of the compound (I) to water is 1 g:(5-30) mL, for example 1 g:5 mL, 1 g:8 mL, 1 g:10 mL, 1 g:15 mL, 1 g:20 mL, 1 g:25 mL, 1 g:28 mL or 1 g:30 mL.

[0137] In the preparation of the crystalline form E, the temperature of the heating and stirring is 30-40°C (for example 30°C, 33°C, 35°C, 37°C, 39°C or 40°C) and the stirring is performed for 16-30 hours (for example 16 hours, 18 hours, 20 hours, 22 hours, 25 hours, 28 hours or 30 hours).

[0138] In the preparation of the crystalline form E, the room temperature vacuum drying time is 20-30 min, for example 20 min, 22 min, 25 min, 28 min or 30 min.

[0139] The present application provides a preparation method of the crystalline form F, comprising the following steps:

[0140] The crystalline form E of compound (I) is heated to obtain the crystalline form F.

[0141] In the preparation of the crystalline form F, the crystalline form E is heated to remove one molecule of crystalline water to obtain the crystalline form F. Preferably, the heating is heating to 145-155°C (for example 145°C, 148°C, 150°C, 153°C or 155°C) and maintaining for 8-15 min (for example 8 min, 9 min, 10 min, 11 min, 12 min, 13 min, 14 min or 15 min).

[0142] The present application provides a preparation method of the crystalline form G, comprising the following steps:

[0143] Compound (I) is mixed with N,N-dimethylformamide, heated and stirred to dissolve completely, filtered, the mother liquor is cooled to precipitate solids, and centrifugal filtration is performed to obtain the crystalline form G.

[0144] In the preparation of the crystalline form G, the mass-volume ratio of the compound (I) to N,N-dimethylformamide is 100 mg:(4-5) mL, for example 100 mg:4 mL, 100 mg:4.3 mL, 100 mg:4.5 mL, 100 mg:4.8 mL or 100 mg:5 mL.

[0145] In the preparation of the crystalline form G, the temperature of the heating and stirring is 50-60°C, for example 50°C, 55°C, 58°C or 60°C.

[0146] In the preparation of the crystalline form G, the mother liquor is cooled to 2-8°C (for example 2°C, 4°C, 5°C, 7°C or 8°C) and maintained for 1-3 days (for example 1 day, 1.5 days, 1.8 days, 2 days, 2.5 days or 3 days).

[0147] The present application provides a preparation method of the crystalline form H, comprising the following steps:

[0148] Compound (I) is mixed with a mixed solvent (N,N-dimethylformamide and acetone), heated and stirred to dissolve completely, filtered, the mother liquor is cooled to precipitate solids, and centrifugal filtration is performed to obtain the crystalline form H.

[0149] In the preparation of the crystalline form H, the mixed solvent is a mixture of N,N-dimethylformamide and acetone.

[0150] In the preparation of the crystalline form H, the volume ratio of N,N-dimethylformamide to acetone in the mixed solvent is 1:3-1:5, for example 1:3, 1:3.3, 1:3.5, 1:3.8, 1:4, 1:4.3, 1:4.5, 1:4.8 or 1:5.

[0151] In the preparation of the crystalline form H, the mass-volume ratio of compound (I) to the mixed solvent is 100 mg:(20-25) mL, for example 100 mg:20 mL, 100 mg:21 mL, 100 mg:22 mL, 100 mg:23 mL, 100 mg:24 mL or 100 mg:25 mL.

[0152] In the preparation of the crystalline form H, the temperature of the heating and stirring is 50-60°C, for example 50°C, 55°C, 58°C or 60°C.

[0153] In the preparation of the crystalline form H, the mother liquor is cooled to 0-5°C (for example 0°C, 1°C, 2°C, 3°C, 4°C or 5°C) and maintained for 3-5 hours (for example 3 hours, 3.5 hours, 4 hours, 4.5 hours or 5 hours).

[0154] The present application provides a preparation method of the crystalline form J, comprising the following steps:

[0155] The crystalline form E of compound (I) is heated to obtain the crystalline form J.

[0156] In the preparation of the crystalline form J, the crystalline form E is heated to remove two molecules of crystal water to obtain the crystalline form J. Preferably, the heating is heating to 210-220°C (for example 210°C, 215°C, 218°C or 220°C) and maintaining for 8-15 minutes (for example 8 minutes, 10 minutes, 12 minutes, 14 minutes or 15 minutes).

[0157] The present application provides a preparation method of the crystalline form K, comprising the following steps:

[0158] Compound (I) is mixed with methanol, suspended at room temperature, centrifuged and filtered to obtain the crystal form K.

[0159] In the preparation of the crystal form K, the mass-volume ratio of the compound (I) to methanol is 100 mg:(0.5-2) mL, for example 100 mg:0.5 mL, 100 mg:0.8 mL, 100 mg:1 mL, 100 mg:1.3 mL, 100 mg:1.5 mL, 100 mg:1.8 mL or 100 mg:2 mL.

[0160] In the preparation of the crystal form K, the suspension at room temperature is suspended at 25°C for 1-2 weeks, for example 1 week, 9 days, 10 days, 12 days or 2 weeks.

[0161] The present application provides a preparation method of the crystal form L, comprising the following steps:

[0162] Compound (I) is mixed with ethyl acetate, suspended for multiple times in a temperature cycle, centrifuged and filtered to obtain the crystal form L.

[0163] In the preparation of the crystal form L, the mass-volume ratio of the compound (I) to ethyl acetate is 100 mg:(0.5-2) mL, for example 100 mg:0.5 mL, 100 mg:0.8 mL, 100 mg:1 mL, 100 mg:1.30 mL, 100 mg:1.50 mL, 100 mg:1.8 mL or 100 mg:2 mL.

[0164] In the preparation of the crystal form L, the temperature range of the temperature cycle is 0-60°C, for example 5-50°C. In the present application, the temperature cycle refers to the temperature rising from the initial temperature to the highest temperature and then falling back to the initial temperature.

[0165] In the preparation of the crystal form L, the rate of the temperature cycle is 0.05-0.2°C / min, for example 0.05°C / min, 0.08°C / min, 0.1°C / min, 0.15°C / min, 0.18°C / min or 0.2°C / min.

[0166] In the preparation of the crystal form L, the number of temperature cycles is 3-5 times, for example 3 times, 4 times or 5 times.

[0167] The present application provides a preparation method of the crystal form M, comprising the following steps:

[0168] Compound (I) is mixed with isopropyl acetate, suspended for multiple times in a temperature cycle, centrifuged and filtered to obtain the crystal form M.

[0169] In the preparation of the crystalline form M, the mass-volume ratio of the compound (I) to isopropyl acetate is 100 mg:(0.5-2) mL, for example 100 mg:0.5 mL, 100 mg:0.8 mL, 100 mg:1 mL, 100 mg:1.3 mL, 100 mg:1.5 mL, 100 mg:1.8 mL or 100 mg:2 mL.

[0170] In the preparation of the crystalline form M, the temperature range of the temperature cycle is 0-60°C, for example 5-50°C.

[0171] In the preparation of the crystalline form M, the rate of the temperature cycle is 0.05-0.2°C / min, for example 0.05°C / min, 0.08°C / min, 0.1°C / min, 0.15°C / min, 0.18°C / min or 0.2°C / min.

[0172] In the preparation of the crystalline form M, the number of temperature cycles is 8-12, for example 8, 9, 10, 11 or 12.

[0173] The present application provides a preparation method of the crystalline form N, comprising the following steps:

[0174] Compound (I) is mixed with acetonitrile, and the suspension is subjected to multiple temperature cycles, and centrifugal filtration to obtain the crystalline form N.

[0175] In the preparation of the crystalline form N, the mass-volume ratio of the compound (I) to acetonitrile is 100 mg:(0.5-2) mL, for example 100 mg:0.5 mL, 100 mg:0.8 mL, 100 mg:1 mL, 100 mg:1.3 mL, 100 mg:1.5 mL, 100 mg:1.8 mL or 100 mg:2 mL.

[0176] In the preparation of the crystalline form N, the temperature range of the temperature cycle is 0-60°C, for example 5-50°C.

[0177] In the preparation of the crystalline form N, the rate of the temperature cycle is 0.05-0.2°C / min, for example 0.05°C / min, 0.08°C / min, 0.1°C / min, 0.15°C / min, 0.18°C / min or 0.2°C / min.

[0178] In the preparation of the crystalline form N, the number of temperature cycles is 3-5, for example 3, 4 or 5.

[0179] The present application provides a preparation method of the crystalline form O, comprising the following steps:

[0180] The compound (I) is mixed with dioxane, and the temperature is cycled up and down for multiple times to obtain the crystal form O.

[0181] In the preparation of the crystal form O, the mass-volume ratio of the compound (I) to dioxane is 100 mg:(0.5-2) mL, for example, 100 mg:0.5 mL, 100 mg:0.8 mL, 100 mg:1 mL, 100 mg:1.3 mL, 100 mg:1.5 mL, 100 mg:1.8 mL, or 100 mg:2 mL.

[0182] In the preparation of the crystal form O, the temperature range of the temperature cycling is 0-60°C, for example, 5-50°C.

[0183] In the preparation of the crystal form O, the rate of the temperature cycling is 0.05-0.2°C / min, for example, 0.05°C / min, 0.08°C / min, 0.1°C / min, 0.15°C / min, 0.18°C / min, or 0.2°C / min.

[0184] In the preparation of the crystal form O, the number of temperature cycling is 8-12 times, for example, 8 times, 9 times, 10 times, 11 times, or 12 times.

[0185] The application provides a preparation method of the crystal form P, comprising the following steps:

[0186] The compound (I) is mixed with acetonitrile, heated and stirred, and centrifuged to obtain the crystal form P.

[0187] In the preparation of the crystal form P, the mass-volume ratio of the compound (I) to acetonitrile is 100 mg:(0.5-2) mL, for example, 100 mg:0.5 mL, 100 mg:0.8 mL, 100 mg:1 mL, 100 mg:1.3 mL, 100 mg:1.5 mL, 100 mg:1.8 mL, or 100 mg:2 mL.

[0188] In the preparation of the crystal form P, the temperature for heating and stirring is 50-70°C (for example, 50°C, 55°C, 58°C, 60°C, 65°C, 68°C, or 70°C), and the stirring time is 1-2 days (for example, 1 day, 1.2 days, 1.5 days, 1.8 days, or 2 days).

[0189] The application provides a preparation method of the crystal form Q, comprising the following steps:

[0190] The compound (I) is mixed with tetrahydrofuran, and the temperature is cycled up and down for multiple times to obtain the crystal form Q.

[0191] In the preparation of the crystalline form Q, the mass-volume ratio of the compound (I) to tetrahydrofuran is 100 mg:(0.5-2) mL, for example 100 mg:0.5 mL, 100 mg:0.8 mL, 100 mg:1 mL, 100 mg:1.3 mL, 100 mg:1.5 mL, 100 mg:1.8 mL or 100 mg:2 mL.

[0192] In the preparation of the crystalline form Q, the temperature range of the temperature cycle is 0-60°C, for example 5-50°C.

[0193] In the preparation of the crystalline form Q, the rate of the temperature cycle is 0.05-0.2°C / min, for example 0.05°C / min, 0.08°C / min, 0.1°C / min, 0.15°C / min, 0.18°C / min or 0.2°C / min.

[0194] In the preparation of the crystalline form Q, the number of temperature cycles is 8-12, for example 8, 9, 10, 11 or 12.

[0195] The present application provides a preparation method of the crystalline form R, comprising the following steps:

[0196] The compound (I) is mixed with ethanol, and the suspension is subjected to multiple temperature cycles, and centrifugal filtration to obtain the crystalline form R.

[0197] In the preparation of the crystalline form R, the mass-volume ratio of the compound (I) to ethanol is 100 mg:(0.5-2) mL, for example 100 mg:0.5 mL, 100 mg:0.8 mL, 100 mg:1 mL, 100 mg:1.3 mL, 100 mg:1.5 mL, 100 mg:1.8 mL or 100 mg:2 mL.

[0198] In the preparation of the crystalline form R, the temperature range of the temperature cycle is 0-60°C, for example 5-50°C.

[0199] In the preparation of the crystalline form R, the rate of the temperature cycle is 0.05-0.2°C / min, for example 0.05°C / min, 0.08°C / min, 0.1°C / min, 0.15°C / min, 0.18°C / min or 0.2°C / min.

[0200] In the preparation of the crystalline form R, the number of temperature cycles is 3-5, for example 3, 4 or 5.

[0201] The present application provides a preparation method of the crystalline form S, comprising the following steps:

[0202] The compound (I) is mixed with acetone, and the suspension is subjected to multiple temperature cycles, and centrifugal filtration to obtain the crystalline form S.

[0203] In the preparation of the crystalline form S, the mass-volume ratio of the compound (I) to acetone is 100 mg:(0.5-2) mL, for example 100 mg:0.5 mL, 100 mg:0.8 mL, 100 mg:1 mL, 100 mg:1.3 mL, 100 mg:1.5 mL, 100 mg:1.8 mL or 100 mg:2 mL.

[0204] In the preparation of the crystalline form S, the temperature range of the temperature cycle is 0-60°C, for example 5-50°C.

[0205] In the preparation of the crystalline form S, the rate of the temperature cycle is 0.05-0.2°C / min, for example 0.05°C / min, 0.08°C / min, 0.1°C / min, 0.15°C / min, 0.18°C / min or 0.2°C / min.

[0206] In the preparation of the crystalline form S, the number of temperature cycles is 3-5, for example 3, 4 or 5.

[0207] The application provides a preparation method of the crystalline form T, comprising the following steps:

[0208] Compound (I) is mixed with a mixed solvent, and the suspension is mixed by temperature cycle for multiple times, and centrifugal filtration to obtain the crystalline form T.

[0209] In the preparation of the crystalline form T, the mixed solvent is a mixture of dimethyl sulfoxide and isopropanol.

[0210] In the preparation of the crystalline form T, the volume ratio of dimethyl sulfoxide to isopropanol in the mixed solvent is 1:3-1:5, for example 1:3, 1:3.3, 1:3.5, 1:3.8, 1:4, 1:4.3, 1:4.5, 1:4.8 or 1:5.

[0211] In the preparation of the crystalline form T, the mass-volume ratio of the compound (I) to the mixed solvent is 100 mg:(0.5-2) mL, for example 100 mg:0.5 mL, 100 mg:0.8 mL, 100 mg:1 mL, 100 mg:1.3 mL, 100 mg:1.5 mL, 100 mg:1.8 mL or 100 mg:2 mL.

[0212] In the preparation of the crystalline form T, the temperature range of the temperature cycle is 0-60°C, for example 5-50°C.

[0213] In the preparation of Form T, the rate of the temperature cycle is 0.05-0.2°C / min, for example, it can be 0.05°C / min, 0.08°C / min, 0.1°C / min, 0.15°C / min, 0.18°C / min or 0.2°C / min.

[0214] In the preparation of Form T, the number of temperature cycle is 8-12 times, for example, 8 times, 9 times, 10 times, 11 times or 12 times.

[0215] The present application also provides a preservation condition method of Form E, wherein the Form E is placed under the condition of relative humidity less than 93% RH, for example, less than 75% RH.

[0216] Preferably, according to the preservation method of Form E, the temperature of the placement can be room temperature to 40°C, for example, 20-40°C, for example, 20°C, 25°C, 30°C, 35°C or 40°C.

[0217] The present application also provides a pharmaceutical composition comprising any one of Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form J, Form K, Form L, Form M, Form N, Form O, Form P, Form Q, Form R, Form S or Form T of Compound (I) or a combination of at least two thereof, and optionally present pharmaceutically acceptable pharmaceutical adjuvant.

[0218] The present application also provides a preparation comprising any one of Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form J, Form K, Form L, Form M, Form N, Form O, Form P, Form Q, Form R, Form S or Form T of Compound (I) or a combination of at least two thereof, and optionally present pharmaceutically acceptable pharmaceutical adjuvant.

[0219] The present application also provides the use of Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form J, Form K, Form L, Form M, Form N, Form O, Form P, Form Q, Form R, Form S or Form T of Compound (I) or the pharmaceutical composition as described above in the preparation of a drug for preventing and / or treating IRAK-mediated diseases or disorders.

[0220] According to embodiments of the present application, the IRAK-mediated disease or disorder is selected from the group consisting of autoimmune diseases; inflammatory diseases; pain diseases; diseases of the respiratory tract, airways and lung; lung inflammation and injury; pulmonary hypertension; gastrointestinal diseases; allergic diseases; infectious diseases; trauma and tissue injury diseases; fibrotic diseases; eye diseases; joint, muscle and bone diseases; skin diseases; kidney diseases; hematopoietic system diseases; liver diseases; oral cavity diseases; metabolic diseases, heart diseases; vascular diseases; neuroinflammatory diseases; neurodegenerative diseases; sepsis; genetic diseases; and cancer. Among them, the autoimmune diseases and inflammatory diseases are selected from the group consisting of systemic lupus erythematosus, lupus nephritis, arthritis, hidradenitis suppurativa, psoriasis, Crohn's disease, atopic dermatitis, gout, cryopyrin-associated periodic syndromes, chronic kidney disease or acute kidney injury, chronic obstructive pulmonary disease, asthma, bronchospasm, and graft-versus-host disease. Among them, the cancer is selected from the group consisting of breast cancer, small cell lung cancer, non-small cell lung cancer, bronchioloalveolar carcinoma, prostate cancer, bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal tissue cancer, esophageal cancer, ovarian cancer, pancreatic cancer, colorectal cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical and vaginal cancer, leukemia, multiple myeloma and lymphoma. Preferably, the IRAK-mediated disease or disorder is selected from the group consisting of tumor, rheumatoid arthritis, systemic lupus erythematosus, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, inflammatory bowel disease, asthma and allergy, etc.

[0221] The present application also provides a method for preventing and / or treating an IRAK-mediated disease or disorder, comprising administering to an individual in need thereof a therapeutically effective amount of the crystalline Form B, the crystalline Form C, the crystalline Form D, the crystalline Form E, the crystalline Form F, the crystalline Form G, the crystalline Form H, the crystalline Form J, the crystalline Form K, the crystalline Form L, the crystalline Form M, the crystalline Form N, the crystalline Form O, the crystalline Form P, the crystalline Form Q, the crystalline Form R, the crystalline Form S, the crystalline Form T of Compound (I) as described above, or the pharmaceutical composition, or the preparation.

[0222] In some embodiments, the IRAK is selected from the group consisting of IRAK4 and / or IRAK1-related kinases.

[0223] The present application also provides a method for preventing and / or treating an interleukin-1 receptor-associated disease, comprising administering to an individual in need thereof a therapeutically effective amount of the crystalline Form B, the crystalline Form C, the crystalline Form D, the crystalline Form E, the crystalline Form F, the crystalline Form G, the crystalline Form H, the crystalline Form J, the crystalline Form K, the crystalline Form L, the crystalline Form M, the crystalline Form N, the crystalline Form O, the crystalline Form P, the crystalline Form Q, the crystalline Form R, the crystalline Form S, the crystalline Form T of Compound (I) as described above, or the pharmaceutical composition, or the preparation.

[0224] According to the embodiments of the present application, the disease or disorder associated with interleukin-1 receptor-associated kinase is selected from the group consisting of tumor, gout, rheumatoid arthritis, systemic lupus erythematosus, hidradenitis suppurativa, multiple sclerosis, metabolic syndrome, atherosclerosis, myocardial infarction, sepsis, inflammatory bowel disease, asthma and allergy, and the like.

[0225] The methods of the present application can be administered alone, or in combination with one, two or more crystalline forms of Compound (I) of the present application, and one, two or more other chemotherapeutic agents. The administration of the multiple agents can be simultaneous or sequential.

[0226] Definitions and explanations of terms

[0227] Various terms and phrases used in the present application have the ordinary meanings as understood by those skilled in the art, even though the present application desires to set forth herein more detailed explanations and interpretations of these terms and phrases, in the event that there is any inconsistency between the meanings of the terms and phrases set forth herein and the ordinary meanings, the meanings set forth herein shall prevail.

[0228] The polymorphs of Compound (I) of the present application include non-solvate (anhydrous), hydrate and solvate crystalline forms of Compound (I).

[0229] The polymorphs of Compound (I) of the present application have X-ray powder diffraction characteristic peaks expressed in terms of 2 theta angles, wherein “±0.20°” is the allowable measurement error range.

[0230] The polymorphs of Compound (I) of the present application can be used in combination with other active ingredients, provided that it does not produce any other adverse effects, such as allergic reactions.

[0231] The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

[0232] The polymorphs of Compound (I) of the present application can be prepared into suitable pharmaceutical compositions using known pharmaceutical carriers by those skilled in the art. The pharmaceutical compositions can be specially formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration. The pharmaceutical compositions can be formulated into various dosage forms for ease of administration, such as oral preparations (e.g., tablets, capsules, solutions, or suspensions), injectable preparations (e.g., injectable solutions or suspensions, or injectable dry powder which can be used immediately before injection by adding a pharmaceutical solvent), and rectal preparations.

[0233] The term "therapeutically and / or prophylactically effective amount" as used herein is an amount of a drug or pharmaceutical agent that elicits the biological or medical response of a living multi-cellular organism, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or other.

[0234] The total daily dosage of the polymorphs of compound (I) and pharmaceutical compositions of the present application actually administered will, of course, be decided by the attending physician within the scope of sound medical judgment. For any particular patient, the specific therapeutically effective dose level will depend on a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. For example, it is typical practice to initiate treatment with lower dosages than required to achieve the desired therapeutic effect and to gradually increase the dosage to achieve the desired effect.

[0235] The present application has the following advantages over the prior art:

[0236] (1) The present application provides a plurality of crystal forms of compound (I) and a preparation method thereof. The preparation method is simple, easy to implement, has mild reaction conditions, and has high product yield. In addition, multiple purifications are not required, the operation is safe and environmentally friendly, and is conducive to the industrialized production of the polymorphs.

[0237] (2) The plurality of crystal forms prepared by the present application have good stability and can be stably stored at high temperatures and under low relative humidity conditions. For example, the crystal form E is physically and chemically stable when placed at 60°C (closed) for one week, and is physically and chemically stable when placed at 40°C / 75% RH (open) for one week; the crystal form E is physically and chemically stable at 25°C and 93% RH or less.

[0238] In addition, the crystal forms described in the present application have good flowability, are easy to pulverize, and are relatively easy to prepare pharmaceutical compositions. Finally, the plurality of crystal forms prepared by the present application have high purity and few impurities.

[0239] Other aspects can become apparent from the following drawings and detailed description. BRIEF DESCRIPTION OF DRAWINGS

[0240] Figure 1 is an XRPD pattern of crystal form B in Example 1.

[0241] Figure 2 is an H-NMR pattern of crystal form B in Example 1. 1 H-NMR pattern.

[0242] Figure 3 is a DSC pattern of crystal form B in Example 1.

[0243] Figure 4 is a TGA pattern of Form B in Example 1.

[0244] Figure 5 is an XRPD pattern of Form C in Example 2.

[0245] Figure 6 is a 1 H-NMR pattern of Form C in Example 2.

[0246] Figure 7 is a DSC pattern of Form C in Example 2.

[0247] Figure 8 is a TGA pattern of Form C in Example 2.

[0248] Figure 9 is an XRPD pattern of Form D in Example 3.

[0249] Figure 10 is a 1 H-NMR pattern of Form D in Example 3.

[0250] Figure 11 is a DSC pattern of Form D in Example 3.

[0251] Figure 12 is a TGA pattern of Form D in Example 3.

[0252] Figure 13 is an XRPD pattern of Form E in Example 4.

[0253] Figure 14 is a 1 H-NMR pattern of Form E in Example 4.

[0254] Figure 15 is a DSC pattern of Form E in Example 4.

[0255] Figure 16 is a TGA pattern of Form E in Example 4.

[0256] Figure 17 is an XRPD pattern of Form F in Example 5.

[0257] Figure 18 is a 1 H-NMR pattern of Form F in Example 5.

[0258] Figure 19 is a DSC pattern of Form F in Example 5.

[0259] Figure 20 is a TGA pattern of Form F in Example 5.

[0260] Figure 21 is an XRPD pattern of Form G in Example 6.

[0261] Figure 22 is a 1 H-NMR pattern of Form G in Example 6.

[0262] Figure 23 is a DSC pattern of Form G in Example 6.

[0263] Figure 24 is a TGA pattern of Form G in Example 6.

[0264] Figure 25 is an XRPD pattern of Form H in Example 7.

[0265] Figure 26 is a 1 H-NMR pattern of Form H in Example 7.

[0266] Figure 27 is a DSC pattern of Form H in Example 7.

[0267] Figure 28 is a TGA pattern of Form H in Example 7.

[0268] Figure 29 is an XRPD pattern of a mixture of Form J + small amount of Form P in Example 8.

[0269] Figure 30 is a 1 H-NMR pattern of a mixture of Form J + small amount of Form P in Example 8.

[0270] Figure 31 is a DSC pattern of a mixture of Form J + small amount of Form P in Example 8.

[0271] Figure 32 is a TGA pattern of a mixture of Form J + small amount of Form P in Example 8.

[0272] Figure 33 is an XRPD pattern of Form K in Example 9.

[0273] Figure 34 is a 1 H-NMR pattern of Form K in Example 9.

[0274] Figure 35 is a DSC pattern of Form K in Example 9.

[0275] Figure 36 is a TGA pattern of Form K in Example 9.

[0276] Figure 37 is an XRPD pattern of Form L in Example 10.

[0277] Figure 38 is a 1 H-NMR pattern of Form L in Example 10.

[0278] Figure 39 is a DSC pattern of Form L in Example 10.

[0279] Figure 40 is a TGA pattern of Form L in Example 10.

[0280] Figure 41 is an XRPD pattern of Form M in Example 11.

[0281] Figure 42 is a 1 H-NMR pattern of Form M in Example 11.

[0282] Figure 43 is a DSC pattern of Form M in Example 11.

[0283] Figure 44 is a TGA profile of Form M in Example 11.

[0284] Figure 45 is an XRPD profile of Form N in Example 12.

[0285] Figure 46 is a 1 H-NMR profile of Form N in Example 12.

[0286] Figure 47 is a DSC profile of Form N in Example 12.

[0287] Figure 48 is a TGA profile of Form N in Example 12.

[0288] Figure 49 is an XRPD profile of Form O in Example 13.

[0289] Figure 50 is a 1 H-NMR profile of Form O in Example 13.

[0290] Figure 51 is a DSC profile of Form O in Example 13.

[0291] Figure 52 is a TGA profile of Form O in Example 13.

[0292] Figure 53 is an XRPD profile of Form P in Example 14.

[0293] Figure 54 is a 1 H-NMR profile of Form P in Example 14.

[0294] Figure 55 is a DSC profile of Form P in Example 14.

[0295] Figure 56 is a TGA profile of Form P in Example 14.

[0296] Figure 57 is an XRPD profile of Form Q in Example 15.

[0297] Figure 58 is a 1 H-NMR profile of Form Q in Example 15.

[0298] Figure 59 is a DSC profile of Form Q in Example 15.

[0299] Figure 60 is a TGA profile of Form Q in Example 15.

[0300] Figure 61 is an XRPD profile of Form R in Example 16.

[0301] Figure 62 is a 1 H-NMR profile of Form R in Example 16.

[0302] Figure 63 is a DSC profile of Form R in Example 16.

[0303] Figure 64 is a TGA pattern of Form R in Example 16.

[0304] Figure 65 is an XRPD pattern of Form S in Example 17.

[0305] Figure 66 is a 1 H-NMR pattern of Form S in Example 17.

[0306] Figure 67 is a DSC pattern of Form S in Example 17.

[0307] Figure 68 is a TGA pattern of Form S in Example 17.

[0308] Figure 69 is an XRPD pattern of Form T in Example 18.

[0309] Figure 70 is a 1 H-NMR pattern of Form T in Example 18.

[0310] Figure 71 is a DSC pattern of Form T in Example 18.

[0311] Figure 72 is a TGA pattern of Form T in Example 18.

[0312] Figure 73 is an XRPD overlay of samples from water activity experiment at 25 °C in Example 19 - 1.

[0313] Figure 74 is an XRPD overlay of samples from water activity experiment at 25 °C in Example 19 - 2.

[0314] Figure 75 is an XRPD overlay of samples from water activity experiment at 25 °C in Example 19 - 3.

[0315] Figure 76 is an XRPD overlay of samples from VT-XRPD test in Example 20.

[0316] Figure 77 is an XRPD pattern of Experiment Number H1 in Example 21.

[0317] Figure 78 is a DSC pattern of Experiment Number H1 in Example 21.

[0318] Figure 79 is a TGA pattern of Experiment Number H1 in Example 21.

[0319] Figure 80 is a 1 H-NMR pattern of Experiment Number H1 in Example 21.

[0320] Figure 81 is an XRPD pattern of Experiment Number H2 in Example 21.

[0321] Figure 82 is an XRPD pattern of Experiment Number H3 in Example 21.

[0322] Figure 83 is an XRPD pattern of Example 21, Experiment Number H4.

[0323] Figure 84 is an XRPD pattern of Example 21, Experiment Number H5.

[0324] Figure 85 is a DSC pattern of Example 21, Experiment Number H5.

[0325] Figure 86 is a TGA pattern of Example 21, Experiment Number H5.

[0326] Figure 87 is a H-NMR pattern of Example 21, Experiment Number H5. 1

[0327] Figure 88 is an XRPD overlay of the sample obtained after solid stability evaluation of Form E in Example 22.

[0328] Figure 89 is an XRPD overlay of the sample of residual solid obtained after solubility testing of Form E in Example 23.

[0329] Figure 90 is a DVS test pattern of Form E at 25 °C in Example 24.

[0330] Figure 91 is an XRPD pattern of the sample of residual solid obtained after DVS testing in Example 24.

[0331] Figure 92 is an XRPD overlay of the sample obtained after simulated tabletting of Form E in Example 25.

[0332] Figure 93 is an XRPD overlay of the sample obtained after simulated dry granulation of Form E in Example 25.

[0333] Figure 94 is an XRPD overlay of the sample obtained after simulated wet granulation of Form E in Example 25.

[0334] Figure 95 is a PLM pattern of Form E in Example 4 (scale 50 μιη).

[0335] Figure 96 is a DSC pattern of Form A in the initial crystalline form characterization of Compound (I).

[0336] Figure 97 is a TGA pattern of Form A in the initial crystalline form characterization of Compound (I).

[0337] Figure 98 is a H-NMR pattern of Form A in the initial crystalline form characterization of Compound (I). 1

[0338] Figure 99 is an XRPD overlay of Form A with Forms D and E in the initial crystalline form characterization of Compound (I). DETAILED DESCRIPTION

[0339] ​​The technical solutions of the present application are further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments are only used to help understand the present application, and should not be regarded as specific limitations on the present application.

[0340] Unless otherwise specified, all materials / reagents were obtained from commercial vendors without further purification.

[0341] In the embodiments of the present application, the instrument used for the X-ray powder diffraction test is Bruker D8 Advance, and the radiation source is Cu / K-Alpha1 The angle range is 2-40°. The differential scanning calorimeter (DSC) is TA Instruments Discovery 2500, the temperature range is ~30 to 250℃, and the heating rate is 10℃ / min. The thermal gravimetric analyzer (TGA) is TA Instruments Discovery 5500, the sample pan is an aluminum pan (open), the starting temperature is ambient temperature (lower than 35℃), the ending temperature is 150-300℃, and the heating rate is 10℃ / min. The dynamic water vapor sorption instrument (DVS) is SMS Intrinsic, the temperature is 25℃, the solvent is water, and the nitrogen flow rate is 200sccm. The nuclear magnetic resonance instrument (NMR) is Bruker Avance-AV 400M (for 1 H-NMR), the number of scans is 8, and the temperature is 297.6K. The Karl Fischer titrator (KF) is Metrohm 851 / 885 system, the method is coulometric method, the cell temperature is 150℃, the extraction time is 120s, and the nitrogen flow rate is 50mL / min. The polarized light microscope (PLM) is Leica DM4 P, the method is cross-polarized light, and silicon oil is added dropwise. The high performance liquid chromatograph (HPLC) is SHIMADZU LC-40, the wavelength is 255nm, the chromatographic column is Agilent Zorbax XDB-C18 150mm 4.6mm 3.5μm, and the detector is DAD.

[0342] Preparation of compound (I)

[0343] The synthesis route of compound (I) is as follows:

[0344] First step: compound 3 6-(1H-pyrazol-3-yl)picolinic acid

[0345] In a 1000 mL round bottom flask, 1-(tetrahydropyranyl)-1H-pyrazole-5-boronic acid pinacol ester (15.3 g, 55.0 mmol), 6-bromo-2-pyridinecarboxylic acid (10.1 g, 50.0 mmol), Pd(PPh3)4(1.0 g, 0.86 mmol), Na2CO3(10.6 g, 100.0 mmol), dioxane (300 mL) and H2O (60 mL) were added and the reaction mixture was heated to 80 °C for 16 h under nitrogen atmosphere. After completion of the reaction, the reaction mixture was extracted with EtOAc. The aqueous phase was adjusted to pH = 3 with 4 M HCl and the solid was allowed to separate. The solid was stirred for 0.5 h and filtered. The solid was washed with H2O and acetonitrile to obtain 9.0 g of white solid in 95% yield. LCMS (ESI): m / z = 190 (M+H) + .

[0346] Second Step: Compound 5 tert-butyl 3-(p-toluenesulfonyloxy)azetidine-1-carboxylate

[0347] In a 500 mL round bottom flask, N-Boc-3-hydroxyazetidine (50.0 g, 289.0 mmol) was dissolved in CH2Cl2(500 mL) and cooled in an ice bath. To the solution was added p-toluenesulfonyl chloride (54.9 g, 289.0 mmol) and pyridine (27.4 g, 347.0 mmol) and the reaction mixture was allowed to warm to room temperature and stirred for 36 h. After completion of the reaction, the reaction mixture was diluted with water and the phases were separated. The aqueous phase was extracted with CH2Cl2. The combined organic phases were washed with 5% NaHCO3solution and saturated NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EtOAc (v / v) = 30:1) to obtain 86.5 g of the product in 92% yield. LCMS (ESI): m / z = 328 (M+H) + .

[0348] Third Step: Compound 7 ethyl 1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-4-nitro-1H-pyrazole-3-carboxylate

[0349] In a 500 mL three-necked round-bottom flask, 4-nitro-lH-pyrazole-3-carboxylic acid ethyl ester (22.0 g, 118.9 mmol), DMSO (200 mL) and K2CO3(19.7 g, 142.7 mmol) were added and stirred at room temperature for 0.5 h. The reaction was heated to 100 °C and a solution of tert-butyl 3-(p-tolylsulfonyloxy)azetidine-l-carboxylate (38.9 g, 118.9 mmol) in DMSO (40 mL) was added dropwise. The reaction was stirred for 6 h. After completion of the reaction, the reaction was diluted with water and extracted with EtOAc. The organic layers were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EtOAc (v / v) = 3: 1) to give 20.5 g in 51% yield. LCMS (ESI): m / z = 341 (M+H) + .

[0350] Fourth Step: Compound 8 tert-Butyl 3-(3-formyl-4-nitro-lH-pyrazol-l- yl)azetidine-l-carboxylate

[0351] In a 500 mL three-necked round-bottom flask equipped with a thermometer, l-(l-(tert-butoxycarbonyl)azetidin-3-yl)-4-nitro-lH-pyrazole-3-carboxylic acid ethyl ester (20.5 g, 60.3 mmol) was dissolved in THF (200 mL) and cooled in a dry ice / acetone bath. A 1 M solution of DIBAL-H in hexane (150 mL) was added slowly to the solution at a temperature below -65 °C. After the addition was complete, the reaction was poured into saturated NH4Cl solution (500 mL) and stirred. The mixture was filtered and the filtrate was extracted with EtOAc. The organic layers were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EtOAc (v / v) = 2: 1) to give 12.6 g in 71% yield. LCMS (ESI): m / z = 315 (M+H2O+H) + .

[0352] Fifth Step: Compound 9 tert-Butyl 3-(3-(difluoromethyl)-4-nitro-lH-pyrazol-l- yl)azetidine-l-carboxylate

[0353] In a 250 mL round bottom flask, 3-(3-formyl-4-nitro-lH-pyrazol-l- yl)azetidine-l-carboxylate tert-butyl ester (12.6 g, 42.6 mmol) was dissolved in CH2Cl2(150 mL) and cooled in an ice water bath. Diethylaminosulfur trifluoride (DAST, 17.1 g, 106.5 mmol) was added dropwise slowly and the temperature was maintained for 1 h. After the reaction was completed, the reaction mixture was neutralized with 5% NaHC03 aqueous solution and extracted with CH2Cl2. The organic layers were combined and washed with saturated NaCl solution, dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EtOAc (v / v) = 3: 1) to give 7.5 g in 55% yield. LCMS (ESI): m / z = 319 (M+H) + .

[0354] Step 6: Compound 11 tert-butyl 4-(3-(3-(difluoromethyl)-4-nitro-lH-pyrazol-l- yl)azetidin-l-yl)piperidine-l-carboxylate

[0355] In a 250 mL round bottom flask, 3-(3-(difluoromethyl)-4-nitro-lH-pyrazol-l- yl)azetidine-l-carboxylate tert-butyl ester (15.9 g, 50.0 mmol) was dissolved in CH2Cl2(100 mL) and trifluoroacetic acid (30 mL) was added. The reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, the solvent and trifluoroacetic acid were removed by distillation under reduced pressure. The residue was dissolved in CH2Cl2(200 mL) and the pH was adjusted to 8 with Et3N. N-Boc-4-piperidone (10.0 g, 50.0 mmol) and NaBH(OAc)3(31.8 g, 150.0 mmol) were added to the solution and the reaction mixture was stirred at room temperature for 16 h. After the reaction was completed, the reaction mixture was diluted with water and the pH was adjusted to basic with 5% NaHC03 aqueous solution. The mixture was extracted with CH2Cl2and the organic layers were combined and washed with saturated NaCl solution, dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EtOAc (v / v) = 3: 1) to give 18.4 g in 92% yield. LCMS (ESI): m / z = 424 (M+Na) + .

[0356] Step 7: Compound 12 l-(4-(3-(3-(difluoromethyl)-4-nitro-lH-pyrazol-l- yl)azetidin-l-yl)piperidin-l-yl)ethanone

[0357] In a 500 mL round bottom flask, 4-(3-(3-(difluoromethyl)-4-nitro-lH-pyrazol-l- yl)azetidin-l-yl)piperidine-l-carboxylic acid tert-butyl ester (20.0 g, 50.0 mmol) was dissolved in CH2Cl2(150 mL), trifluoroacetic acid (40 mL) was added, and the reaction was stirred at room temperature for 1 h. After the reaction was completed, the solvent and trifluoroacetic acid were removed by distillation under reduced pressure. The residue was dissolved in water, and Na2CO3was added to adjust the pH to 14. The mixture was extracted with CH2Cl2. The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was dissolved in CH2Cl2(300 mL), cooled in an ice water bath, and DIEA (12.9 g, 100.0 mmol) was added, followed by dropwise addition of a solution of acetyl chloride (3.9 g, 50.0 mmol) in CH2Cl2(80 mL). The reaction was stirred for 0.5 h while maintaining the temperature. After the reaction was completed, the mixture was diluted with water, extracted with CH2Cl2, and the combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (PE:EtOAc (v / v) = 1:1) to give 15.2 g in 89% yield. LCMS (ESI): m / z = 344 (M+H) + .

[0358] Eighth Step: Compound 13 l-(4-(3-(4-amino-3-(difluoromethyl)-lH-pyrazol-l-yl)azetidin-l- yl)piperidin-l-yl)ethanone

[0359] In a 100 mL round bottom flask equipped with a hydrogen balloon, l-(4-(3-(3- (difluoromethyl)-4-nitro-lH-pyrazol-l-yl)azetidin-l-yl)piperidin-l-yl)ethanone (10.0 g, 29.2 mmol) was dissolved in MeOH (50 mL), and Pd / C (10% wet powder, 50 wt% moisture, 2.5 g) was added. The reaction was stirred at room temperature for 4 h. After the reaction was completed, the mixture was filtered, and the residue was washed with MeOH. The filtrate was concentrated under reduced pressure to give 8.6 g in 94% yield, which was used directly in the next step. LCMS (ESI): m / z = 314 (M+H) + .

[0360] Ninth Step: Compound (I) N-(l-(l-(l-acetylpiperidin-4-yl)azetidin-3-yl)-3- (difluoromethyl)-lH-pyrazol-4-yl)-6-(lH-pyrazol-3-yl)-2-pyridinecarboxamide

[0361] In a 250 mL round-bottom flask, was added 1-(4-(3-(4-amino-3-(difluoromethyl)-1H- pyrazol-1-yl)azetidin-1-yl)piperidin-1-yl)ethanone (6.3 g, 20.0 mmol), 6-(1H-pyrazol-3-yl)- 2-pyridinecarboxylic acid (3.8 g, 20.0 mmol), DMAP (4.9 g, 40.0 mmol) and CH2Cl2(100 mL), followed by the addition of EDCI (4.2 g, 22 mmol). The reaction was stirred at room temperature for 12 h. After the reaction was completed, the reaction was diluted with water, extracted with CH2Cl2, the organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (CH2Cl2:MeOH:Et3N (v / v / v) = 150:10:0.16) to give compound (I) 8.4 g, in 87% yield. LCMS (ESI): m / z = 485 (M+H) + .

[0362] Characterization of the initial crystalline form of compound (I)

[0363] Compound (I) was characterized by HPLC, XRPD, DSC, TGA, 1 HNMR, KF. According to the KF test results, it was shown to contain about 0.7 equivalent of water. HPLC showed that its chemical purity was 99.9%. DSC showed that it began to lose water at 85°C with an enthalpy of about 38 J / g, and after dehydration, it melted at Tonset 229.1°C and recrystallized at Tonset 231.9°C. Then, there were two melting points, Tonset 238.1°C and 242.1°C, respectively (Figure 96). TGA showed that it lost 1.3% at 80°C, and 1.9% between 80°C and 135°C (Figure 97). 1 H-NMR showed no solvent residue was detected (Figure 98). Water activity competition experiment (Example 19) showed that the initial crystalline form of compound (I) was converted to crystalline form E at 25°C, a.w. = 0.2-1 (Figures 73 and 74). In addition, combined with subsequent experimental results and XRPD, it was determined that the initial crystalline form of compound (I) was a physical mixture of crystalline form E and crystalline form D (Figure 99), and thus the initial crystalline form of compound (I) was defined as crystalline form A, which was a mixed crystal.

[0364] Example 1: Preparation of crystalline form B

[0365] Take 30 mg of the above compound (I), add 1.5 mL of methanol and dissolve at 50°C. The resulting solution is filtered through a 0.45 μm nylon filter to obtain a clear solution. The resulting clear solution is cooled to 5°C at a rate of 0.1°C / min and maintained at 5°C for 3 days. The resulting suspension is filtered by centrifugation at 14,000 rpm in a 0.45 μm nylon filter tube to obtain a white powder of Form B (17 mg).

[0366] Form B is characterized by XRPD, DSC, TGA, 1 HNMR, KF. Form B is a methanol solvate with high crystallinity. The XRPD characteristic peak position and intensity are shown in Table 1 and the XRPD pattern is shown in Figure 1. 1 H-NMR shows that it contains 0.5 equivalent (3% by weight) of methanol (Figure 2). DSC shows that it starts to desolvate at 63°C with an enthalpy of 32 J / g, and after desolvation the sample melts at Tonset of 242.3°C with a melting enthalpy of 109 J / g (Figure 3). TGA shows a weight loss of about 3.0% at 170°C (Figure 4). According to KF test results, it contains 0.1 equivalent (0.5% by weight) of water.

[0367] The XRPD pattern of Form B is shown in the X-ray powder diffraction pattern in terms of 2Θ angle, and the 2Θ values are shown in Table 1:

[0368] Table 1 XRPD characteristic peaks of Form B

[0369] Example 2: Preparation of Form C

[0370] Take 50 mg of compound (I), add 1 mL of acetone in a 2 mL glass bottle. The resulting sample is suspended at 50°C for 2 hours, then naturally cooled to 25°C and suspended at 25°C for 3 days. The resulting suspension is centrifuged through a 0.45 μm nylon filter at 14,000 rpm, and the resulting solid is dried at 50°C under vacuum for 2 hours to obtain a white powder of Form C (36 mg).

[0371] Form C is characterized by XRPD, DSC, TGA, 1 HNMR, KF. Form C is a hydrate with high crystallinity. The XRPD characteristic peak position and intensity are shown in Table 2 and the XRPD pattern is shown in Figure 5. 1H-NMR showed that it contained 0.01 equivalent (0.1% by weight) of acetone (Figure 6). DSC showed that it started to lose water at 83°C with an enthalpy of 15 J / g, and after losing water, the sample melted at Tonset of 228.9°C and 237.5°C with melting enthalpy of 92 J / g and 9 J / g, respectively (Figure 7). TGA showed a weight loss of 3.6% at 150°C (Figure 8). According to KF test, it contained 0.5 equivalent (1.8% by weight) of water.

[0372] The XRPD pattern of crystalline Form C is shown in Figure 2, which is an X-ray powder diffraction pattern in terms of 2 theta angle, and the 2 theta values are shown in Table 2.

[0373] Table 2. XRPD characteristic peaks of crystalline Form C

[0374] Example 3: Preparation of crystalline Form D

[0375] 100 mg of compound (I) was weighed into a 2 mL glass bottle. 1 mL of ethyl acetate was added, and stirred at 25°C for 1 day. The resulting suspension was filtered by centrifuging with a 0.45 μm nylon filter tube at 14,000 rpm. Crystalline Form D white powder (89 mg) was prepared.

[0376] XRPD, DSC, TGA, 1 HNMR, KF were performed on crystalline Form D. Crystalline Form D is a monohydrate with high crystallinity. The XRPD characteristic peak position and intensity are shown in Table 3, and the XRPD pattern is shown in Figure 9. 1 H-NMR showed that no solvent residue was detected (Figure 10). DSC showed that it started to lose water at 66°C with an enthalpy of 67 J / g, and after losing water, the sample melted at Tonset of 238.4°C and 244.0°C with melting enthalpy of 7 J / g and 95 J / g, respectively (Figure 11). TGA showed a weight loss of 4.3% at 130°C (Figure 12). According to KF test, it contained 0.7 equivalent (2.5% by weight) of water.

[0377] The XRPD pattern of crystalline Form D is shown in Figure 3, which is an X-ray powder diffraction pattern in terms of 2 theta angle, and the 2 theta values are shown in Table 3.

[0378] Table 3. XRPD characteristic peaks of crystalline Form D

[0379] Example 4: Preparation of crystalline Form E

[0380] Take 1.2 g of compound (I) and place it in a 40 mL glass bottle. Add 20 mL of water and stir at 37°C for 20 hours. Centrifuge the resulting suspension using a 0.45 μm nylon filter cartridge at 4,000 rpm. Dry under vacuum for 25 minutes at room temperature. A white powder of Form E (1.14 g) is obtained with a purity of 99.6% by HPLC.

[0381] Form E is characterized by XRPD, DSC, TGA, 1 HNMR, PLM, KF. Form E is a dihydrate with high crystallinity. The XRPD characteristic peak position and intensity are shown in Table 4 and the XRPD pattern is shown in Figure 13. 1 H-NMR shows no solvent residue detected (Figure 14). DSC shows it starts to lose water at 6°C and 90°C with enthalpy values of 52 J / g and 96 J / g, respectively, and after the loss of water, there is a solid-solid transition peak with an enthalpy of 3 J / g at Tonset of 189.2°C, followed by melting at Tonset of 239.2°C with a melting enthalpy of 101 J / g (Figure 15). TGA shows a weight loss of 2.8% at 90°C and 3.6% between 90°C and 140°C (Figure 16). According to the KF test result, it contains 1.9 equivalents (6.5% by weight) of water. PLM (polarized light microscopy) shows that this batch of Form E is about 5 μm to 20 μm irregularly shaped crystals (Figure 95). Form E is also characterized by XRD (single crystal diffraction) which shows it is a dihydrate.

[0382] The XRPD pattern of Form E is shown in Figure 13, which is the X-ray powder diffraction pattern in terms of 2 theta angle, and the 2 theta values are shown in Table 4:

[0383] Table 4 XRPD characteristic peaks of Form E

[0384] Example 5: Preparation of Form F

[0385] Take 31 mg of Form E and place it in a glass bottle for KF testing. Heat at 150°C for 10 minutes under nitrogen. A white powder of Form F (30 mg) is obtained.

[0386] Form F is characterized by XRPD, DSC, TGA, 1 HNMR, KF. Form F is a monohydrate with medium crystallinity. The XRPD characteristic peak position and intensity are shown in Table 5 and the XRPD pattern is shown in Figure 17. 1H-NMR showed no solvent residue was detected. DSC showed it started to lose solvent at 103°C with an enthalpy of 116 J / g, and after losing solvent it melted at Tonset of 243.0°C with a melting enthalpy of 102 J / g (Figure 23). TGA showed a weight loss of 12.9% at 140°C (Figure 24). According to KF test, it contained 0.75 equivalent (13% by weight) of DMF and 0.06 equivalent (0.4% by weight) of acetonitrile residue (Figure 22).

[0387] The XRPD pattern of crystalline Form F is shown in Figure 17, and the 2Θ values are shown in Table 5:

[0388] Table 5. XRPD characteristic peaks of crystalline Form F

[0389] Example 6: Preparation of crystalline Form G

[0390] Example 6: Preparation of crystalline Form G

[0391] Example 6: Preparation of crystalline Form G 1 HNMR characterization. Crystalline Form G is a DMF solvate with high crystallinity. The XRPD characteristic peak positions and intensities are shown in Table 6, and the XRPD pattern is shown in Figure 21. 1 H-NMR showed it contained 0.75 equivalent (13% by weight) of DMF and 0.06 equivalent (0.4% by weight) of acetonitrile residue (Figure 22). DSC showed it started to lose solvent at 103°C with an enthalpy of 116 J / g, and after losing solvent it melted at Tonset of 243.0°C with a melting enthalpy of 102 J / g (Figure 23). TGA showed a weight loss of 12.9% at 140°C (Figure 24).

[0392] The XRPD pattern of crystalline Form G is shown in Figure 21, and the 2Θ values are shown in Table 6:

[0393] Table 6. XRPD characteristic peaks of crystalline Form G

[0394] Example 7: Preparation of crystalline Form H

[0395] Take 100 mg of compound (I) and place it in a 40 mL glass bottle. Add 21 mL of mixed solvent (DMF / acetone = 1:4) and dissolve it thoroughly at 50°C. The resulting solution is filtered through a 0.45 μm nylon filter to obtain a clear solution. The resulting clear solution is stirred in an ice bath at 0°C for about 4 h. The resulting suspension is filtered by centrifugation using a 0.45 μm nylon filter tube at 14,000 rpm. A white powder of Form H (59 mg) is obtained.

[0396] Form H is characterized by XRPD, DSC, TGA, 1 HNMR, KF. Form H is a dihydrate and has high crystallinity. The XRPD characteristic peak position and intensity are shown in Table 7, and the XRPD pattern is shown in Figure 25. 1 H-NMR shows that it contains 0.12 equivalent (1.4% by weight) of acetone and 0.74 equivalent (9.9% by weight) of N,N-dimethylformamide (Figure 26). DSC shows that it starts to lose water at 104°C with an enthalpy of 108 J / g, and after losing water, it melts at Tonset of 243.0°C with a melting enthalpy of 96 J / g (Figure 27). TGA shows a weight loss of 12.9% at 140°C (Figure 28). According to the KF detection result, it contains 1.7 equivalents (5.9% by weight) of water.

[0397] The XRPD pattern of Form H is shown in the X-ray powder diffraction pattern in terms of 2θ angle, and the 2θ values are shown in Table 7:

[0398] Table 7 XRPD characteristic peaks of Form H

[0399] Example 8: Preparation of Form J

[0400] Take 91 mg of Form E and heat it to 217°C in a VT-XRPD, maintain for 10 min, and then cool it to 25°C to obtain a white powder of a mixture of Form J + a small amount of Form P (90 mg).

[0401] Form J + a small amount of Form P mixture is characterized by XRPD, DSC, TGA, 1 HNMR. Form J is an anhydrate and has medium crystallinity. The XRPD characteristic peak position and intensity are shown in Table 8, and the XRPD pattern is shown in Figure 29. 1 H-NMR shows that no solvent residue is detected (Figure 30). DSC shows that it melts at Tonset of 243.8°C with a melting enthalpy of about 103 J / g (Figure 31). TGA shows a weight loss of 0.9% at about 100°C (Figure 32).

[0402] The XRPD pattern of Form J is shown in Table 8 as 2Θ values in an X-ray powder diffraction pattern expressed in terms of 2Θ angle:

[0403] Table 8 XRPD characteristic peaks of Form J

[0404] Example 9: Preparation of Form K

[0405] About 50 mg of Compound (I) was weighed into 0.5 mL of methanol and stirred at 400 rpm at 25 °C for 2 weeks. The resulting suspension was filtered by centrifugation at 14,000 rpm using a 0.45 μm nylon filter. Form K white powder (41 mg) was obtained.

[0406] Form K was characterized by XRPD, DSC, TGA, 1 HNMR characterization. Form K is a methanol solvate. It has high crystallinity. The XRPD characteristic peak positions and intensities are shown in Table 9 and the XRPD pattern is shown in Figure 33. 1 H-NMR showed that it contains 2.4% (0.38 equivalent) of methanol by weight (Figure 34). DSC showed that it starts to desolvate at 72 °C with an enthalpy of 26 J / g; followed by an endothermic peak at Tonset 203.8 °C with an enthalpy of 6 J / g, and finally melts at Tonset 242.7 °C with a melting enthalpy of 106 J / g (Figure 35). TGA showed a weight loss of 3.1% at 120 °C (Figure 36).

[0407] The XRPD pattern of Form K is shown in Table 9 as 2Θ values in an X-ray powder diffraction pattern expressed in terms of 2Θ angle:

[0408] Table 9 XRPD characteristic peaks of Form K

[0409] Example 10: Preparation of Form L

[0410] About 100 mg of Compound (I) was weighed into a 2 mL glass vial. 1 mL of ethyl acetate was added and the temperature was cycled between 5 °C and 50 °C at a rate of 0.1 °C / min while stirring at 400 rpm on a magnetic stirrer for 5 min. After 3 cycles, the resulting suspension was filtered by centrifugation at 14,000 rpm using a 0.45 μm nylon filter at 5 °C. Form L off-white powder (93 mg) was obtained.

[0411] Form L was characterized by XRPD, DSC, TGA, 1HNMR, KF characterization. Form L is a monohydrate with high crystallinity. The XRPD characteristic peak position and intensity are shown in Table 10, and the XRPD pattern is shown in Figure 37. 1 H-NMR showed no solvent residue was detected (Figure 38). DSC showed it started to lose water at 54 °C with an enthalpy of 56 J / g, and after losing water, it melted at Tonset of 239.2 °C and 243.7 °C with melting enthalpy of 17 J / g and 87 J / g, respectively (Figure 39). TGA showed a weight loss of about 0.5% at 60 °C, and a weight loss of 2.1% between 60 °C and 220 °C (Figure 40). According to the KF test result, it contained 0.5 equivalent (1.9% by weight) of water.

[0412] The XRPD pattern of Form L is shown in the X-ray powder diffraction pattern with 2 theta angle, and the 2 theta values are shown in Table 10:

[0413] Table 10 XRPD characteristic peaks of Form L

[0414] Example 11: Preparation of Form M

[0415] About 50 mg of Compound (I) was weighed into 0.5 mL of isopropyl acetate, and temperature cycling was performed at a rate of 0.1 °C / min between 5 °C and 50 °C with stirring at 400 rpm on a magnetic stirrer. After 10 cycles, the resulting suspension was filtered by centrifugation at 14,000 rpm on a 0.45 pm nylon filter membrane centrifuge tube at 5 °C. Form M white powder-like (43 mg) was obtained.

[0416] Form M was characterized by XRPD, DSC, TGA, 1 HNMR, KF characterization. Form M is a monoisopropyl acetate-monohydrate solvate with high crystallinity. The XRPD characteristic peak position and intensity are shown in Table 11, and the XRPD pattern is shown in Figure 41. 1 H-NMR showed it contained 3.1% by weight (0.16 equivalent) of isopropyl acetate (Figure 42). DSC showed it started to lose water / solvent at 15 °C and 96 °C with an enthalpy of 30 J / g and 69 J / g, respectively, and after losing water / solvent, there was an exothermic peak with an enthalpy of 3 J / g at Tonset of 186.6 °C, followed by melting of the sample at Tonset of 238.8 °C and 242.2 °C with melting enthalpy of 93 J / g and 0.2 J / g, respectively (Figure 43). TGA showed a weight loss of 2.0% at 85 °C, and a weight loss of 5.1% between 85 °C and 220 °C (Figure 44). According to the KF test result, it contained 1.3 equivalent (4.6% by weight) of water.

[0417] The XRPD pattern of Form M is shown in Figure 44, and the X-ray powder diffraction peaks are shown in Table 11.

[0418] Table 11. XRPD characteristic peaks of Form M

[0419] Example 12: Preparation of Form N

[0420] About 50 mg of Compound (I) was weighed into a 2 mL glass vial. 0.5 mL of dioxane was added, and temperature cycling was performed at a rate of 0.1 °C / min from 5 °C to 50 °C while the resulting suspension was stirred at a speed of 400 rpm on a magnetic stirrer. After 10 cycles, the resulting suspension was centrifuged and filtered at a speed of 14,000 rpm on a 0.45 μm nylon filter at 5 °C. Form O white powder (42 mg) was obtained.

[0421] Form N was characterized by XRPD, DSC, TGA, 1 Form N is an anhydrate with high crystallinity. The XRPD characteristic peak positions and intensities are shown in Table 12, and the XRPD pattern is shown in Figure 45. 1 H-NMR showed no solvent residue was detected (Figure 46). DSC showed that it melted at Tonset of 240.5 °C with a melting enthalpy of 113 J / g (Figure 47). TGA showed a weight loss of 0.9% at 80 °C (Figure 48). According to the KF test result, it contained 0.4 equivalent (1.3% by weight) of water.

[0422] The XRPD pattern of Form N is shown in Figure 45, and the X-ray powder diffraction peaks are shown in Table 12.

[0423] Table 12. XRPD characteristic peaks of Form N

[0424] Example 13: Preparation of Form O

[0425] About 50 mg of Compound (I) was weighed into a 2 mL glass vial. 0.5 mL of dioxane was added, and temperature cycling was performed at a rate of 0.1 °C / min from 5 °C to 50 °C while the resulting suspension was stirred at a speed of 400 rpm on a magnetic stirrer. After 10 cycles, the resulting suspension was centrifuged and filtered at a speed of 14,000 rpm on a 0.45 μm nylon filter at 5 °C. Form O white powder (42 mg) was obtained.

[0426] Form O was characterized by XRPD, DSC, TGA, 1HNMR, KF characterization. Form O is a 1,4-dioxane-monohydrate with high crystallinity. The XRPD characteristic peak position and intensity are shown in Table 13, and the XRPD pattern is shown in Figure 49. 1 H-NMR showed that it contained 11.4% (0.72 equivalent) of 1,4-dioxane by weight (Figure 50). DSC showed that it started to lose water at 9°C with an enthalpy of 12 J / g, and then lost solvent at 75°C and 118°C with enthalpy of 31 J / g and 20 J / g, respectively, followed by melting of the sample at Tonset of 238.8°C and 241.9°C with melting enthalpy of 73 J / g and 19 J / g, respectively (Figure 51). TGA showed a weight loss of about 1.4% at about 75°C, and a weight loss of 8.9% between 75°C and 160°C (Figure 52). According to KF test result, it contained 0.5 equivalent (1.7% by weight) of water.

[0427] The XRPD pattern of Form O is shown in the X-ray powder diffraction pattern with 2Θ angle, and the 2Θ values are shown in Table 13:

[0428] Table 13 XRPD characteristic peaks of Form O

[0429] Example 14: Preparation of Form P

[0430] Take 100 mg of compound (I) and place it in a 2 mL glass bottle. Add 1 mL of acetonitrile and stir at 50°C for about 1 day. The resulting suspension is filtered by centrifuging with a 0.45 μm nylon filter tube at 14,000 rpm. Form P white powder (92 mg) is prepared.

[0431] Form P is characterized by XRPD, DSC, TGA, 1 HNMR, KF characterization. Form P is a monohydrate with high crystallinity. The XRPD characteristic peak position and intensity are shown in Table 14, and the XRPD pattern is shown in Figure 53. 1 H-NMR showed no solvent residue was detected (Figure 54). DSC showed that it started to lose water at 13°C with an enthalpy of 15 J / g, and then melted at Tonset of 240.4°C with a melting enthalpy of 107 J / g (Figure 55). TGA showed a weight loss of about 1.7% at 70°C (Figure 56). According to KF test result, it contained about 0.6 equivalent (2.3% by weight) of water.

[0432] The XRPD pattern of Form P is shown in the X-ray powder diffraction pattern with 2Θ angle, and the 2Θ values are shown in Table 14:

[0433] Table 14 XRPD characteristic peaks of Form P

[0434] Example 15: Preparation of Form Q

[0435] Take 50 mg of Compound (I), add 0.5 mL of tetrahydrofuran, and perform temperature cycling at a rate of 0.1 °C / min while stirring at a speed of 400 rpm on a magnetic stirrer at 5-50 °C. After 10 cycles, the resulting suspension is centrifuged and filtered at a speed of 14,000 rpm at 5 °C using a 0.45 μm nylon filter. Form Q white powder (39 mg) is obtained.

[0436] Form Q is characterized by XRPD, DSC, TGA, 1 HNMR characterization. Form Q is a tetrahydrofuran solvate with high crystallinity. The XRPD characteristic peak position and intensity are shown in Table 15, and the XRPD pattern is shown in Figure 57. 1 H-NMR shows that it contains 12.5% (0.99 equivalent) of tetrahydrofuran by weight (Figure 58). DSC shows that it starts to desolvate at 71 °C with an enthalpy of 74 J / g, and after desolvation, it melts at Tonset of 229.9 °C with a melting enthalpy of about 3 J / g, and there is a recrystallization peak at 231.4 °C with an enthalpy of 2 J / g, followed by melting at Tonset of 238.5 °C and 242.4 °C with melting enthalpies of 43 J / g and 38 J / g, respectively (Figure 59). TGA shows a weight loss of 1.5% at 70 °C and 4.7% between 70 °C and 150 °C (Figure 60).

[0437] The XRPD pattern of Form Q is shown in the X-ray powder diffraction pattern in terms of 2θ angle, and the 2θ values are shown in Table 15:

[0438] Table 15 XRPD characteristic peaks of Form Q

[0439] Example 16: Preparation of Form R

[0440] Take 100 mg of Compound (I), and place it in a 2 mL glass bottle. Add 1 mL of ethanol, and perform temperature cycling at a rate of 0.1 °C / min while stirring at a speed of 400 rpm on a magnetic stirrer at 5-50 °C. After 3 cycles, the resulting suspension is centrifuged and filtered at a speed of 14,000 rpm at 5 °C using a 0.45 μm nylon filter. Form R white powder (96 mg) is obtained.

[0441] Form R is characterized by XRPD, DSC, TGA, 1HNMR, KF characterization. Form R is dihydrate with high crystallinity. The XRPD characteristic peak position and intensity are shown in Table 16, and the XRPD pattern is shown in Figure 61. 1 H-NMR showed no solvent residue was detected (Figure 62). DSC showed it started to lose water at 14 °C and 89 °C with enthalpy of 42 J / g and 97 J / g, respectively, followed by the sample melting at Tonset of 240.5 °C and 243.8 °C with melting enthalpy of 96 J / g and 1 J / g, respectively (Figure 63). TGA showed 2.6% weight loss at 80 °C and 3.6% weight loss between 80 °C and 130 °C (Figure 64). According to KF test result, it contained 1.7 equivalent (6.0% by weight) of water.

[0442] The XRPD pattern of Form R is shown in Figure 61, which is the X-ray powder diffraction pattern in terms of 2 theta angle, and the 2 theta values are shown in Table 16:

[0443] Table 16 XRPD characteristic peaks of Form R

[0444] Example 17: Preparation of Form S

[0445] Take 100 mg of compound (I) and place it in a 2 mL glass bottle. Add 1 mL of acetone, and perform temperature cycling at a rate of 0.1 °C / min between 5 °C and 50 °C while suspending under magnetic stirring at a speed of 400 rpm. After 3 cycles, the obtained suspension is centrifuged and filtered through a 0.45 μm nylon filter tube at a speed of 14,000 rpm at 5 °C. Form S white powder (94 mg) is prepared.

[0446] Form S is characterized by XRPD, DSC, TGA, 1 HNMR, KF characterization. Form S is dihydrate with high crystallinity. The XRPD characteristic peak position and intensity are shown in Table 17, and the XRPD pattern is shown in Figure 65. 1 H-NMR showed it contained 0.1% (0.01 equivalent) of acetone solvent residue by weight (Figure 66). DSC showed it started to lose water at 6 °C and 89 °C with enthalpy of 49 J / g and 96 J / g, respectively, followed by the sample melting at Tonset of 239.2 °C and 242.6 °C with melting enthalpy of 92 J / g and 3 J / g, respectively (Figure 67). TGA showed 2.7% weight loss at 80 °C and 3.6% weight loss between 80 °C and 130 °C (Figure 68). According to KF test result, it contained 1.9 equivalent (6.4% by weight) of water.

[0447] The XRPD pattern of Form S is shown in Figure 65, which is the X-ray powder diffraction pattern in terms of 2 theta angle, and the 2 theta values are shown in Table 17:

[0448] Table 17 XRPD characteristic peaks of Form S

[0449] Example 18: Preparation of Form T

[0450] About 50 mg of Compound (I) was weighed into 0.5 mL of mixed solvent (dimethyl sulfoxide / isopropyl alcohol = 1:4), and temperature cycling was performed at a rate of 0.1 °C / min from 5 °C to 50 °C while being suspended in a magnetic stirrer at a speed of 400 rpm. After 10 cycles, the resulting suspension was centrifuged and filtered at 5 °C at a speed of 14,000 rpm using a 0.45 μm nylon filter tube. Form T-like white powder (36 mg) was prepared.

[0451] Form T was characterized by XRPD, DSC, TGA, 1 HNMR, KF. Form T is a dihydrate with high crystallinity. The XRPD characteristic peak position and intensity are shown in Table 18, and the XRPD pattern is shown in Figure 69. 1 H-NMR showed that it contained 0.5% (0.03 equivalent) of dimethyl sulfoxide solvent residue by weight (Figure 70). DSC showed that it began to lose water at 24 °C and 92 °C with enthalpy of 30 J / g and 90 J / g, respectively, and after losing water, it melted at Tonset of 239.1 °C with a melting enthalpy of 102 J / g (Figure 71). TGA showed a weight loss of 2.5% at 90 °C and a weight loss of 3.9% between 90 °C and 160 °C (Figure 72). According to the KF test results, it contained 1.7 equivalents (6.0% by weight) of water.

[0452] The XRPD pattern of Form T is shown in the X-ray powder diffraction pattern in terms of 2θ angle, and the 2θ values are shown in Table 18:

[0453] Table 18 XRPD characteristic peaks of Form T

[0454] Example 19: Water activity competition experiment

[0455] To study the critical water activity among the initial crystal form of Compound (I), Form C, Form D, Form E, Form F, Form H, Form J, Form L, Form N, Form P, Form R, Form S, and Form T, a water activity experiment was performed at 25 °C in an ethanol / water system.

[0456] Approximately 5 mg of each of the initial crystalline form of Compound (I), Form C, Form D, Form E, Form F, Form H, Form J + small amount of Form P, Form L, Form N, Form P, Form R, Form S and Form T was separately taken in 0.7 mL of the corresponding saturated solution of ethanol / water system and the resulting suspension was suspended at 25 °C. The resulting suspension was then centrifuged and the resulting solid was subjected to XRPD analysis.

[0457] Table 19 Water activity experiment

[0458] Note: "*" water activity was calculated from UNIFAC method.

[0459] " / / ": not performed

[0460] As can be seen from Figure 73, the XRPD pattern of sample AW1 after 2 days at 25 °C was identical to that of Form R, indicating that it had converted to Form R. The XRPD pattern of sample AW2 after 2 days at 25 °C had 2 additional peaks compared to that of Form E.

[0461] As can be seen from Figure 74, the XRPD pattern of sample AW3 after 2 days at 25 °C, the XRPD pattern of sample AW4 after 2 days at 25 °C, the XRPD pattern of sample AW5 after 2 days at 25 °C and the XRPD pattern of sample AW6 after 2 days at 25 °C were all identical to that of Form E.

[0462] As can be seen from Figure 75, the XRPD pattern of sample AW2 after 5 days at 25 °C was identical to that of Form E, indicating that it had completely converted to Form E.

[0463] The experimental results showed that both the anhydrous forms and the hydrates converted to the dihydrate Form E at 25 °C a.w. = 0.2-1 and to the hydrate Form R at 25 °C a.w. = 0.

[0464] Example 20: Variable temperature XRPD (VT-XRPD) experiment

[0465] The conversion relationship of Form E, Form F, Form I and Form J was investigated by variable temperature XRPD.

[0466] Form E was used as the starting material and one cycle of temperature increase and decrease was performed in this experiment. The XRPD of the sample at the starting state was collected under ambient conditions. The rest of the XRPD tests were collected at different temperature points under nitrogen purge. Cycle: 25 °C (starting) - 94 °C (5 min) - 152 °C (5 min) - 217 °C (10 min) - 25 °C (10 min).

[0467] Table 20 Temperature Modulated XRPD (VT-XRPD) Experiment

[0468] When the temperature was increased to 94 °C (5 min, N2), part of the hydrate form E was dehydrated and transformed into a crystalline form similar to form F. When the temperature was increased to 152 °C (5 min, N2), it was completely dehydrated and still in a crystalline form similar to form F. When the temperature was increased to 217 °C (10 min, N2), a solid-solid transformation occurred and it was further transformed into form I. When the temperature was decreased to 25 °C (10 min, N2), the XRPD of form I changed a little bit and the crystalline form was named form J. Form J did not change under ambient conditions at 25 °C. Form I and form J were very similar from the XRPD point of view and form I was measured at high temperature and should be just a peak shift caused by the high temperature. From the DSC cycle of form E, there was no thermal event when the temperature was decreased from 217 °C to -20 °C, which indicated that there was no crystalline form transformation. So, in fact, form I should be form J.

[0469] Example 21: Dehydration and desolvation experiment

[0470] The dehydration and desolvation behaviors of form E, form Q, form O, form G, form B and related crystalline form transformations were studied by TGA heating experiment.

[0471] Form E was used as the starting material and heated to 150 °C by TGA. After the heated solid was transferred to ambient conditions, the obtained solid was characterized by XRPD, DSC, TGA, 1H-NMR and KF.

[0472] Form Q, form O, form G were used as the starting materials and heated to 220 °C by TGA. After the heated solid was transferred to ambient conditions, the obtained solid was characterized by XRPD.

[0473] Form B was used as the starting material and heated to 230 °C by TGA. After the heated solid was transferred to ambient conditions, the obtained solid was further characterized by XRPD, DSC, TGA and 1H-NMR. 1

[0474] Table 21 Dehydration and desolvation experiment

[0475] Example 22: Solid stability of form E

[0476] ​Open containers containing Form E were placed in 25 °C / 93% RH, 25 °C / 60% RH and 40 °C / 75% RH for 1 week. Closed containers containing Form E were placed in 60 °C for 1 week. The samples were tested for XRPD, HPLC and observed for color change under these stress conditions.

[0477] Table 22 Solid state stability of Form E

[0478] The experimental results showed that Form E exhibited good physical and chemical stability under the above accelerated stability conditions.

[0479] Example 23: Solubility test of Form E

[0480] 21.4 mg of Form E was weighed into a 20 mL glass bottle. 10 mL of dissolution medium was added. The resulting suspension / clarified solution was stirred at 37 °C for 2 h and 24 h at a rotation speed of 400 rpm, and then the resulting suspension / clarified solution was centrifuged at 37 °C at a rotation speed of 14,000 rpm for 5 min. The solubility was tested by HPLC, the supernatant pH was determined by a pH meter, and the residual solid was tested by XRPD.

[0481] Table 23 Solubility of Form E

[0482] Note " / / ": no test was performed on the clarified solution

[0483] The experimental results showed that the solubility of Form E in pH 1.2 HC1 solution, pH 1.6 FaSSGF, 10% DMSO + 10% Solutol + 80% citrate buffer and 2% DMSO + 98% citrate buffer were all ≥ 2 mg / mL. The solubility in FeSSIF-vl, pH 5.0 was better, about 0.1 mg / mL. The solubility in pH 4.5, pH 6.8 buffer, water and FaSSIF-vl, pH 6.5 was smaller, < 0.07 mg / mL. After the solubility test, the crystal form of Form E remained unchanged.

[0484] Example 24: Hygroscopicity of Form E

[0485] The water absorption and dehydration behavior of Form E was studied by DVS. The humidity program: 25 °C, 40-0-95-0-40% RH, dm / dt 0.002, the shortest equilibrium time was 60 min, and the longest equilibrium time was 360 min. The sample after DVS test was tested by XRPD to determine whether a crystal form transition occurred.

[0486] Table 24 Hygroscopicity of Form E

[0487] Hygroscopicity

[0488] Note "N / A": not performed

[0489] The results show that Form E has slight hygroscopicity. It adsorbs about 0.6% moisture between 40% RH and 95% RH at 25°C. The sample obtained after DVS testing is still Form E. In addition, during the DVS testing, Form E only loses one molecule of water at 0% RH, and the water adsorption and loss are reversible.

[0490] Example 25: Mechanical property testing of Form E

[0491] Simulated tabletting experiment

[0492] About 10 mg of Form E sample of ARD-885 was weighed and compressed under 10 MPa pressure for 5 min. The changes in crystallinity and polymorphic transformation were investigated by XRPD characterization.

[0493] Table 25 Simulated tabletting experiment

[0494] Simulated dry milling experiment

[0495] About 10 mg of Form E sample was weighed and hand-milled for 1, 3 and 5 min, respectively. The changes in crystallinity and polymorphic transformation were investigated by XRPD characterization.

[0496] Table 26 Simulated dry milling experiment

[0497] Simulated wet granulation experiment

[0498] About 10 mg of Form E sample was weighed and added to water or ethanol to wet the sample thoroughly. The wetted sample was gently milled with a pestle and then the sample was left to dry under ambient conditions for 10 min. The changes in crystallinity and polymorphic transformation were investigated by XRPD characterization.

[0499] Table 27 Simulated wet granulation experiment

[0500] The results show that Form E exhibits good resistance to simulated tabletting, simulated dry milling and simulated wet granulation, with no polymorphic transformation and no significant decrease in crystallinity.

[0501] Based on the experimental results of Examples 19-25, solvates are not recommended as the crystal form for further development research. All amorphous and hydrated crystal forms were transformed into hydrate crystal form E at 25°C and aw = 0.2-1. Crystal form E is the dominant crystal form. At the same time, crystal form E has good solid stability, hygroscopicity, and mechanical properties, which can support subsequent drug development.

[0502] The applicant declares that this application illustrates the crystal form, preparation method, and application of the present application through the above embodiments, but this application is not limited to the above embodiments, that is, it does not mean that this application must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvements to this application, equivalent substitutions of the raw materials selected in this application, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of this application.

Claims

1. A crystalline form of Compound (I), wherein, The compound (I) is N-(1-(1-(acetylpiperidin-4-yl)azetidin-3-yl)-3- (difluoromethyl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-3-yl)picolinamide as shown in the following figure; the crystal form is Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form J, Form K, Form L, Form M, Form N, Form O, Form P, Form Q, Form R, Form S, or Form T; the crystal form B has characteristic peaks in X-ray diffraction spectrum expressed in 2θ angle at 13.49±0.20°, 19.10±0.20°, 20.74±0.20°, 23.32±0.20°, 26.18±0.20°, 29.58±0.20°; the crystal form C has characteristic peaks in X-ray diffraction spectrum expressed in 2θ angle at 4.66±0.20°, 15.57±0.20°, 17.84±0.20°, 18.68±0.20°, 20.53±0.20°, 23.21±0.20°; the crystal form D has characteristic peaks in X-ray diffraction spectrum expressed in 2θ angle at 12.50±0.20°, 13.34±0.20°, 18.12±0.20°, 21.05±0.20°, 24.62±0.20°, 24.86±0.20°; the crystal form E has characteristic peaks in X-ray diffraction spectrum expressed in 2θ angle at 9.10±0.20°, 12.52±0.20°, 13.35±0.20°, 18.15±0.20°, 21.06±0.20°, 24.88±0.20°; the crystal form F has characteristic peaks in X-ray diffraction spectrum expressed in 2θ angle at 5.68±0.20°, 15.42±0.20°, 16.46±0.20°, 20.79±0.20°, 25.95±0.20°, 26.21±0.20°; the crystal form G has characteristic peaks in X-ray diffraction spectrum expressed in 2θ angle at 12.48±0.20°, 17.56±0.20°, 19.87±0.20°, 20.66±0.20°, 25.88±0.20°, 29.01±0.20°; the crystal form H has characteristic peaks in X-ray diffraction spectrum expressed in 2θ angle at 12.44±0.20°, 17.47±0.20°, 19.85±0.20°, 20.65±0.20°, 25.84±0.20°, 28.99±0.20°; the crystal form J has characteristic peaks in X-ray diffraction spectrum expressed in 2θ angle at 7.80±0.20°, 14.85±0.20°, 19.95±0.20°, 21.56±0.20°, 21.75±0.20°, 24.50±0.20°; the crystal form K has characteristic peaks in X-ray diffraction spectrum expressed in 2θ angle at 13.49±0.20°, 19.66±0.20°, 19.94±0.20°, 20.49±0.20°, 26.21±0.20°, 29.60±0.20°; the crystal form L has characteristic peaks in X-ray diffraction spectrum expressed in 2θ angles at 5.68±0.20°, 11.15±0.20°, 15.43±0.20°, 20.55±0.20°, 22.34±0.20°, 23.26±0.20°; the crystal form M has characteristic peaks in X-ray diffraction spectrum expressed in 2θ angles at 4.68±0.20°, 10.66±0.20°, 18.69±0.20°, 19.81±0.20°, 21.90±0.20°, 24.24±0.20°; the crystal form N has characteristic peaks in X-ray diffraction spectrum expressed in 2θ angles at 11.21±0.20°, 15.59±0.20°, 17.84±0.20°, 20.38±0.20°, 20.54±0.20°, 23.24±0.20°; the crystal form O has characteristic peaks in X-ray diffraction spectrum expressed in 2θ angles at 4.65±0.20°, 15.64±0.20°, 18.62±0.20°, 21.53±0.20°, 23.17±0.20°, 24.02±0.20°; the crystal form P has characteristic peaks in X-ray diffraction spectrum expressed in 2θ angles at 16.62±0.20°, 19.95±0.20°, 20.36±0.20°, 20.86±0.20°, 21.22±0.20°, 25.54±0.20°; the crystal form Q has characteristic peaks in X-ray diffraction spectrum expressed in 2θ angles at 18.73±0.20°, 21.76±0.20°, 22.00±0.20°, 22.26±0.20°, 23.43±0.20°, 24.19±0.20°; the crystal form R has characteristic peaks in X-ray diffraction spectrum expressed in 2θ angles at 4.66±0.20°, 10.83±0.20°, 18.78±0.20°, 21.77±0.20°, 23.27±0.20°, 24.21±0.20°; the crystal form S has characteristic peaks in X-ray diffraction spectrum expressed in 2θ angles at 4.66±0.20°, 5.57±0.20°, 11.23±0.20°, 17.89±0.20°, 20.52±0.20°, 23.30±0.20°; the crystal form T has characteristic peaks in X-ray diffraction spectrum expressed in 2θ angles at 4.67±0.20°, 12.95±0.20°, 18.68±0.20°, 21.42±0.20°, 21.79±0.20°, 24.17±0.20°.

2. The crystalline form of Compound (I) according to claim 1, wherein, the crystal form B is a methanol solvate of compound (I); Preferably, the differential scanning calorimeter analysis of the crystal form B shows that it starts to desolvate at 63°C and melts at 242.3°C; Preferably, the thermal gravimetric analysis of the crystal form B shows a weight loss of 3.0% at 170°C.

3. The crystalline form of Compound (I) according to claim 1, wherein, The crystal form E is a dihydrate of compound (I); Preferably, the differential scanning calorimetry analysis of the crystal form E shows dehydration starting at 6°C and 90°C, followed by a solid-solid transition at 189.2°C, and then melting at 239.2°C; Preferably, the thermal gravimetric analysis of the crystal form E shows a weight loss of 2.8% at 90°C, and a weight loss of 3.6% between 90°C and 140°C; Preferably, the crystal form E is in irregular shape; Preferably, the particle size of the crystal form E is about 5 μm to 20 μm; Preferably, the crystal form E is stored at a relative humidity of less than 93% RH; Preferably, the storage temperature of the crystal form E is room temperature to 40°C.

4. The crystalline form of Compound (I) according to claim 1, wherein, The crystal form G is a DMF solvate of compound (I); Preferably, the differential scanning calorimetry analysis of the crystal form G shows desolvation starting at 103°C, followed by melting at 243.0°C; Preferably, the thermal gravimetric analysis of the crystal form G shows a weight loss of 12.9% at 140°C; Preferably, the crystal form M is an isopropyl acetate-monohydrate solvate of compound (I); Preferably, the differential scanning calorimetry analysis of the crystal form M shows dehydration / solvent starting at 15°C and 96°C, followed by an endothermic peak at 186.6°C after dehydration and desolvation, and then the sample melts at 238.8°C and 242.2°C; Preferably, the thermal gravimetric analysis of the crystal form M shows a weight loss of 2.0% at 85°C, and a weight loss of 5.1% between 85°C and 220°C.

5. The crystalline form of Compound (I) according to claim 1, wherein, The crystal form N is an anhydrate of compound (I); Preferably, the differential scanning calorimetry analysis of the crystal form N shows melting at 240.5°C; Preferably, the thermal gravimetric analysis of the crystal form N shows a weight loss of 0.9% at 80°C; Preferably, the crystal form O is a 1,4-dioxane-monohydrate solvate of compound (I); Preferably, the differential scanning calorimetry analysis of the crystal form O shows dehydration starting at 9°C, followed by desolvation at 75°C and 118°C after dehydration, and then the sample melts at 238.8°C and 241.9°C; Preferably, the thermal gravimetric analysis of the crystal form O shows a weight loss of 1.4% at 75°C, and a weight loss of 8.9% between 75°C and 160°C. Preferably, the crystal form Q is a tetrahydrofuran solvate of compound (I); Preferably, the differential scanning calorimetry analysis of the crystal form Q shows desolvation starting at 71°C, followed by melting at 229.9°C after desolvation, and a recrystallization peak at 231.4°C, and then the sample melts at 238.5°C and 242.4°C; Preferably, the thermal gravimetric analysis of the crystal form Q shows a weight loss of 1.5% at 70°C, and a weight loss of 4.7% between 70°C and 150°C.

6. A method for preparing the crystal form of compound (I) according to any one of claims 1-5, comprising the following steps: Preparation of crystal form B: mixing compound (I) with methanol, heating and stirring until clear, cooling, centrifugal filtration to obtain the crystal form B; Preparation of crystal form E: mixing compound (I) with water, heating and stirring, centrifugal filtration, vacuum drying to obtain the crystal form E; Preparation of crystal form G: mixing compound (I) with DMF, heating and stirring until clear, cooling, centrifugal filtration to obtain the crystal form G; Preparation of crystal form M: mixing compound (I) with isopropyl acetate, heating and stirring until clear, cooling, centrifugal filtration to obtain the crystal form M; Preparation of crystal form N: mixing compound (I) with water, heating and stirring, centrifugal filtration, vacuum drying to obtain the crystal form N; Preparation of crystal form O: mixing compound (I) with 1,4-dioxane, heating and stirring until clear, cooling, centrifugal filtration to obtain the crystal form O; Preparation of crystal form Q: mixing compound (I) with tetrahydrofuran, heating and stirring until clear, cooling, centrifugal filtration to obtain the crystal form Q. Preparation of the crystal form G: compound (I) is mixed with N,N-dimethylformamide, heated and stirred to dissolve completely, filtered, the mother liquor is cooled to precipitate solid, centrifuged and filtered to obtain the crystal form G; Preparation of the crystal form M: compound (I) is mixed with isopropyl acetate, suspended for multiple times in a temperature cycle of rising and falling, centrifuged and filtered to obtain the crystal form M; Preparation of the crystal form N: compound (I) is mixed with acetonitrile, suspended for multiple times in a temperature cycle of rising and falling, centrifuged and filtered to obtain the crystal form N; Preparation of the crystal form O: compound (I) is mixed with dioxane, suspended for multiple times in a temperature cycle of rising and falling, centrifuged and filtered to obtain the crystal form O; Preparation of the crystal form Q: compound (I) is mixed with tetrahydrofuran, suspended for multiple times in a temperature cycle of rising and falling, centrifuged and filtered to obtain the crystal form Q.

7. The production method according to claim 6, wherein In the preparation of the crystal form B, the mass-volume ratio of the compound (I) to methanol is 1 mg:(0.02-0.2) mL; Preferably, in the preparation of the crystal form B, the temperature of heating is 50-70℃; Preferably, in the preparation of the crystal form B, the cooling is cooling to 0-5℃ for 1-3 days, and then filtering; In the preparation of the crystal form E, the mass-volume ratio of the compound (I) to water is 1 g:(5-30) mL; Preferably, in the preparation of the crystal form E, the temperature of heating and stirring is 30-40℃, and the stirring time is 16-30 hours; Preferably, in the preparation of the crystal form E, the time of vacuum drying at room temperature is 20-30 min; In the preparation of the crystal form G, the mass-volume ratio of the compound (I) to N,N-dimethylformamide is 100 mg:(4-5) mL; Preferably, in the preparation of the crystal form G, the temperature of heating and stirring is 50-60℃; Preferably, in the preparation of the crystal form G, the cooling of the mother liquor is cooling to 2-8℃ for 1-3 days; In the preparation of the crystal form M, the mass-volume ratio of the compound (I) to isopropyl acetate is 100 mg:(0.5-2) mL; Preferably, in the preparation of the crystal form M, the temperature range of the temperature cycle of rising and falling is 0-60℃, and exemplarily is 5-50℃; Preferably, in the preparation of the crystal form M, the rate of the temperature cycle of rising and falling is 0.05-0.2℃ / min; Preferably, in the preparation of the crystal form M, the number of the temperature cycle of rising and falling is 8-12 times; In the preparation of the crystal form N, the mass-volume ratio of the compound (I) to acetonitrile is 100 mg:(0.5-2) mL; Preferably, in the preparation of the crystal form N, the temperature range of the temperature cycle of rising and falling is 0-60℃, and preferably the temperature range of the temperature cycle of rising and falling is 5-50℃; Preferably, in the preparation of the crystal form N, the rate of the temperature cycle of rising and falling is 0.05-0.2℃ / min; Preferably, in the preparation of the crystal form N, the number of the temperature cycle of rising and falling is 3-5 times; In the preparation of the crystal form O, the mass-volume ratio of the compound (I) to dioxane is 100 mg:(0.5-2) mL; Preferably, in the preparation of the crystal form O, the temperature range of the temperature cycle of rising and falling is 0-60℃, and preferably the temperature range of the temperature cycle of rising and falling is 5-50℃; Preferably, in the preparation of the crystal form O, the rate of the temperature cycle of rising and falling is 0.05-0.2℃ / min; Preferably, in the preparation of the crystalline form O, the number of temperature cycling is 8-12 times; In the preparation of the crystalline form Q, the mass / volume ratio of the compound (I) and tetrahydrofuran is 100 mg:(0.5-2) mL; Preferably, in the preparation of the crystalline form Q, the temperature range of the temperature cycling is 0-60°C, preferably the temperature range of the temperature cycling is 5-50°C; Preferably, in the preparation of the crystalline form Q, the rate of the temperature cycling is 0.05-0.2°C / min; Preferably, in the preparation of the crystalline form Q, the number of temperature cycling is 8-12 times.

8. A pharmaceutical composition comprising any one or a combination of at least two of the crystalline forms of any one of claims 1-5, and optionally present pharmaceutically acceptable pharmaceutical adjuvants.

9. A preparation comprising any one or a combination of at least two of the crystalline forms of any one of claims 1-5, and optionally present pharmaceutically acceptable pharmaceutical adjuvants.

10. Use of the crystalline form of any one of claims 1-5 or the pharmaceutical composition of claim 8 or the preparation of claim 9 in the preparation of a drug for preventing and / or treating IRAK-mediated diseases or disorders.

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